MANUAL NEPHROLOGY
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- MANUAL NEPHROLOGY
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Manuai of
Nephrology
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Diagnosis and Therapy
Second Edition
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Edited by
Robert W. Schrier, M.D.
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Professor and Chairman Department of
Medicine, University of Colorado School
of Medicine, Denver, Colorado
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Community Health Cell
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BANGALORE
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Little, Brown and Company
Boston/Toronto
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Preface
Copyright © 1985 by Robert W. Schrier, M.D.
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Second Edition
Second Printing December 1986
Previous edition copyright © 1981 by Little, Brown and Company (Inc.)
All rights reserved. No part of this book may be reproduced in any form or by
any electronic or mechanical means, including information storage and
retrieval systems, without permission in writing from the publisher, except by
a reviewer who may quote brief passages in a review.
Library of Congress catalog card No. 84-82131
ISBN 0-316-77478-2
Printed in the United States of America
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The first edition of Manual of Nephrology: Diagnosis and Therapy was written
explicitly for the primary care physician. This updated edition maintains that
A practical approach to diagnosis and therapy constitutes the focal point of the
Manual. Our companion text. Renal and Electrolyte Disorders (3rd ed.), due or
publication by Little, Brown in 1985, emphasizes the importance of an under
standing of the pathophysiology of disease. Although there is overlap in the areas
discussed in these two texts, the approaches differ considerably. Manualof Ne
phrology avoids the discussion of pathophysiology of disease and instead addresses
a number of important clinical problems from a diagnostic, therapeutic, and costeffective viewpoint.
For example, Dr. Fredric L. Coe presents a practical approach to the diagnostic
evaluation and treatment of the patient with renal stones, and Dr. L. Barth Keller
discusses urinary tract infections. Dr. Michael J. Dunn deals with the practical
and cost-effective diagnosis and treatment of the hypertensive patient. Drs. Robert
E. Cronin and Ronald B. Miller discuss the diagnosis and management of the
patient with acute or chronic elevation in blood urea nitrogen and/or serum cre
atinine. Dr. Miller also discusses many practical points that the primary caie
physician should know concerning modalities for treatment of end-stage renal
disease by dialysis or transplantation. This information will allow the physician
to participate in a more knowledgeable way with the patient, the family, and the
nephrologist in making important decisions about modes of treatment of end-stage
renal disease. Diagnostic and therapeutic approaches to various electrolyte and
* acid-base problem^ are presented in a systematic manner for (x) the edematous
patient (Dr. Mortimer Levy), (2) hypo- and hypernatremia (Dr. Robert W. bchner),
(3) hypo- and hyperkalemia (Dr. Richard L. Tannen), (4) elevation and depression
of serum bicarbonate (Dr. Jordan J. Cohen), and (5) hypo- and hypercalcemia and
hypo- and hyperphosphatemia (Drs. Zalman S. Agus, Stanley Gokfarb, and Alan
Wasserstein).
What constitutes a practical approach to the evaluation of the patient with hematuria and /or proteinuria is discussed by Drs. Antoine M. de Tom it6 and
J Anderson. For example, the question of which patients with her atuna should
have cystoscopy, renal biopsy, or renal angiogram is examined. How the physician
should alter drug therapy in the patient with renal dircase is discussed by Dr.
William M. Bennett. Drs. Marshall D. Lindheimer and Adnan I. Katz present a
practical approach to management of the pregnant patient who has hypertension
or renal disease, or both. They also discuss which patients the physician should
advise not to become pregnant because of either danger to the mother or the pros
pect of worsening of renal disease. Lastly, many sophisticated and expensive
radiologic procedures besides excretory urography (e.g., ultrasonography, com
puterized tomography, cyst puncture, renal scan, renal angiography) are available
now. Drs. Robert A. Older, Larry M. Crane, Daniel E. Wertman, and Hector hidalgo
present a practical and systematic approach for the use of these procedures in the
evaluation of the patient with a renal mass, renal failure, urinary tract obstruction,
hematuria, renal transplant, renal and perirenal infection, or renal hy tension.
The authors of these chapters were invited by the editor to contribute > the Manual
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Preface
Contents
not because of their sophistication in the science of medicine, although sophisticated
scientists they are, but because they are physicians who are able to use their
scientific knowledge in a practical way to allow for a cost -effective plan of therapy
and treatment that is in the best interests of their patients In this same spirit I
would like once again to dedicate this to Professor Hugh de Wardener, a humane
phvsican, a man of science, and above all, a practical man whose uncanny ability
to focus on important issues in many areas, including sodium and water metabolism, bone disease, chronic dialysis, and hypertension, has benefited medical sci-
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ence and his patients for over 35 years.
R.W.S.
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Contributing Authors
ix
1
The Edematous Patient
1
Robert W. Schrier
2
The Patient With Hyponatremia or
Hypernatremia
15
Richard L. Tannen
3
The Patient With Hypokalemia or
Hyperkalemia
31
Jordan J Cohen
4
The Patient With Abnormal Plasma
Bicarbonate, Arterial PCO2 or pH
49
5
The Patient With Disorders of the
Serum Calcium and Phosphate
63
6
The Patient With Renal Stones
83
7
The Patient With Urinary
Tract Infection
97
8
The Patient With Proteinuria or an
Abnormal Urinary Sediment s
113
9
The Patient With Acute Azotemia
135
3
Mortimer Levy
-3
3
3
3
Zalman S. Agus, Stanley Goldfarb,
and Alan Wasserstein
3
Fredric L. Coe
3
L. Barth Roller
5
Antoine M. de Torrent^
and Robert J. Anderson
Robert E. Cronin
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Ronald B. Miller
10
The Patient With Chronic Azotemia,
With Emphasis on Chronic Renal
149
Failure
William M. Bennett
11
Approach to Drug Use in the
Azotemic Patient
185
Marshall D. Lindheimer
and Adrian I. Katz
12
The Patient With Kidney Disease
and Hypertension in
Pregnancy
201
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Preface
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U^^dtents
Michael J. Dunn
13
The Patient With Hypertension
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221
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14
Robert A. Older, Daniel E.
Wertman, Jr., Larry M. Crane,
and Hector J. Hidalgo
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Contributing Authors
Use of Radiologic Techniques in
the Patient With Renal Problems
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247 fe
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Index
X
Zalman S. Agus, M.D.
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Robert J. Anderson, B&D.
^5
William M. Bennett, M.D.
Fredric L. Coe, M.D.
Jordan J. Cohen, M.D.
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Sne; Chief. Renal-Electrolyte
Section, Hospital of the University of
Pennsylvania, Philadelphia,
Pennsylvania
Chapter 5
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Associate Professor of
University of Colorado School of
Mpdicine- Renal Division, University
Hospital,’The University of Colorado
Health Sciences Center, Denver,
Colorado
Chapters
Professor of Medicine and Pharmacology,
Oregon Health Sciences University,
Head Division of Nephrology, Oregon
Health Sciences University Hospital and
Clinics, Portland, Oregon
Chapter 11
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Professor of Medicine and Physiology,
University of Chicago, The Pr‘uk^r
^School of Medicine; Director, Nephrology
Program, University of Chicago
Hospitals, Chicago, Illinois
Chapters
__ _____ x
___ ___
^ProfessoTand Associate Chairman^rf
Medicine, University of Chicago Pr
School of Medicine; Chairman of
Medicine, Michael Reese Hospital,
Chicago, Illinois
Chapter 4
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Larry M. Crane, M.D.
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Chapter 14
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Contributing Authors
Contributing Authors
Robert E. Cronin, M.D.
Associate Professor of Internal Medicine,
The University of Texas Southwestern
Medical School of Dallas; Chief, Renal/
Hypertension Clinic, Dallas Veterans
Administration Medical Center, Dallas
Texas
Chapter 9
Ronald B. Miller, M.D.
Clinical Professor of Medicine,
University of California, Irvine*,
California College of Medicine, Irvine;
Co-director, Dialysis and Transplant
Center, St. Joseph Hospital of Orange,
California
Chapter 10
Michael J. Dunn, M.D.
Professor of Medicine, Case Western
Reserve University School of MedicineDirector. Division of Nephrology.
Department of Medicine, University
Hospitals. Cleveland, Ohio
Chapter 13
Robert A. Older, M.D.
Clinical Associate Professor of Radiology
and Clinical Assistant Professor of
Urology, Duke University School of
Medicine, Durham and Clinical Associate
Professor of Radiology', University of
North Carolina at Chapel Hill School of
Medicine, Chapel Hill; Attending
Radiologist, Durham County General
Hospital, Durham, North Carolina
Chapter 14
L. Barth Reller, M.D.
Professor of Medicine, University of
Colorado School of Medicine; Attending
Physician and Director of Clinical
Microbiology, University Hospital,
University of Colorado Health Sciences
Center, Denver, Colorado
Chapter 7
Robert W. Schrier, M.D.
Professor and Chairman, Department of
Medicine. University of Colorado School
of Medicine; Attending Physician,
Department of Medicine. University
Hospital, University of Colorado Health
Sciences Center, Denver, Colorado
Chapter 2
Richard L. Tannen, M.D.
Professor of Medicine and Director,
Nephrology Division, The University of
Michigan Medical School, Ann Arbor,
Michigan
Chapter 3
Antoine M. de Torrente, M.D.
Privat-Docent, Faculte de M^decine,
Universite de Geneve, Geneva; Co-Head,
Service de Medecine, Hopital Communal,
La Chaux-de-Fonds, Switzerland
Chapter 8
Alan Wasserstein, M.D.
Assistant Professor of Medicine, The
University of Pennsylvania School of
Medicine; Director, Stone Evaluation
Center and Attending Physician
(Nephrology), Hospital of the University
of Pennsylvania, Philadelphia,
Pennsylvania
Chapter 5
Stanley Goldfarb, M.D.
Hector J. Hidalgo, M.D.
Adrian I. Katz, M.D.
Mortimer Lev7, M.D., F.R.C.P.(C)
Marshall D. Llndheimer, M.D.
Associate Professor of Medicine, The
University of Pennsylvania School of
Medicine; Attending Physician
(Nephrology), Hospital of the University
of Pennsylvania, Philadelphia,
Pennsylvania
Chapter 5
3
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6/
Clinical Assistant Professor of Radiology,
Duke University School of Medicine,
Durham, and University of North
Carolina at Chapel Hilf School of
Medicine. Chapel Hill; Attending
Radiologist. Department of Radiology,
Durham County General Hospital.
Durham. North Carolina
Chapter 14
1 -3
3
3
3
Professor of Medicine,’ University of
Chicago. The Pritzker School of
Medicine; Attending Physician.
University of Chicago Medical Center,
Chicago. Illinois
Chapter 12
Professor of Medicine and Physiology,
McGill University Faculty of Medicine;
Senior Physician and Director,
Nephrology Division, Department of
Medicine. Royal Victoria Hospital,
Montreal. Quebec, Canada
Chapter 1
Professor of Obstetrics and Gynecology
and Medicine, University of Chicago, The
Pritzker School of Medicine; Attending
Physician, Departments of Obstetrics and
Gynecology and Medicine, University of
Chicago Medical Center, Chicago, Illinois
Chapter 12
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Contributing Authors
Manual of Nephrology
Daniel E. Wertman, Jr., M.D.
Assistant Clinical Professor of Radiology,
University of North Carolina at Chapel
Hill School of Medicine, Chapel Hill;
Attending Radiologist, Durham County
General Hospital, Durham, North
Carolina
Chapter 14
I
Diagnosis and Therapy
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Notice
The indications and dosages of all drugs
in this book have been recommended in
the medical literature and conform to the
practices of the general medical
community. The medications described
do not necessarily have specific approval
by the Food and Drug Administration for
use in the diseases and dosages for which
they are recommended. The package
insert for each drug should be consulted
for use and dosage as approved by the
FDA. Because standards for usage
change, it is advisable to keep abreast of
revised recommendations, particularly
those concerning new drugs.
The Edematous Patient
-3
Mortimer Levy
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I. Types of edema. Edema refers to an excessive collection of fluid within the interstitial
space (i.e., within the nonvascular portion of the extracellular fluid volume). Edema
itself is not a disease but a symptom of many different disorders that share as a
common feature the propensity to induce fluid collection within the interstitial space.
Edema may be localized or generalized.
A. Localized edema. Localized edema occurs when alterations of the Starling forces
are restricted to a given organ or discrete vascular territory. Fluid collects locally
because of either an increment in capillary hydrostatic pressure (induced by ar
teriolar dilatation or, more commonly, venous obstruction) or some obstruction
to regional lymphatic flow. Less commonly, there may be some increase in capillary7
wall permeability, resulting from either trauma or histamine release. Alterna
tively, a generalized disturbance such as hypoalbuminemia may find clinical
expression only as localized ankle edema because of postural considerations. De
pending on the magnitude of the local disturbance, the edema may vary in volume
from barely detectable amounts to several hundred milliliters of fluid. Although
conceptually there may be a period of transient plasma volume contraction and
urinary sodium retention in these patients, by the time they are seen by their
physicians they are generally free of urinary sodium retention or any alteration
of systemic or renal hemodynamics.
Clinical causes of localized edema include:
1. Inflammation
2. Trauma (burns)
3. Venous obstruction (thrombophlebitis)
4. Lymphatic obstruction (postsurgical or metastatic)
5. Angioedema
B. Generalized edema. Generalized edema can occur when the potential for fluid
to leave the vascular space exists for all vascular beds within the body. Depending
on the nature of the underlying disease, postural influences, and magnitude of
the underlying disorder, however, fluid may be detected only in a single site,
such as the lungs (pulmonary edema) or lower extremities. Patients confined to
bed may preferentially collect edema in the presacral area, periorbital area, or
fingers.
1. Clinical causes. Important conditions associated with generalized edema are
as follows:
x
a. Low-output cardiac failure
b. High-output cardiac failure
c. Kidney disease
(1) Nephrotic syndrome
(2) Acute glomerulonephritis
(3) Acute renal failure
(4) Chronic renal failure
d. Cirrhosis of the liver
e. Idiopathic recurrent edema
f. Consumption of certain drugs (e.g., estrogens and antihypertensive va
sodilators)
g. Toxemia of pregnancy
1
1: The Edematous
1: The Edematous Patient
-- tPrecapillary
sphincter ___________
"
Postcapillary
sphincter
•2. Physiologic disturbances. Conditions associated with generalized edema may
be accompanied by a variety of physiologic disturbances:
Forces
moving
To
venule
a. Urinary sodium retention (i.e., urinary sodium excretion is less than sodium
Forces moving
Huid in
intake when sodium intake is normal.)
From
1
fluid out
b. Urinary composition (urinary sodium less than 20 mEq/L, urinary os
arteriole Br
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molality greater than 400 mOsm/kg HjO, urine-plasma creatinine ratio
greater than 35) confirms prerenal failure unless acute or chronic renal
Pressures:
&
failure or diuretic use is present.
. Plasma colloid
I. Capillary hydrostatic
Total
plasma
volume,
particularly
the
venous
portion,
is
usually
expanded;
oncotic pressure
c.
• 1SF oncotic
decreased plasma volume may, however, occur with nephrotic syndrome.
!• Negative-free ISF
d. Inappropriately elevated or normal plasma levels of renin, aldosterone,
and antidiuretic hormone are present in spite of sodium and water retention.
i
e. Hypokalemia and hyperuricemia may be present.
Excess fluid
f Hyponatremia may be present even without excess water intake.
.
Si
enters
q Increment in blood urea nitrogen (BUN) is generally greater than increment
lymphatics
in serum creatinine (i.e., ratio greater than 10:1)—evidence of prerenal
\ To venous
azotemia and renal hypoperfusion.
•]“ circulation
The volume of plasma transudate that may accumulate as. edema, particularly
within the peritoneal space as ascites, is often much larger than the circulating
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plasma volume. Generalized edema would be a self-limiting process were it
Lymphatic capillary_________
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not for continuing urinary sodium retention, which permits replenishment of
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the plasma volume. Two physiologic disturbances highlight the progressive
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fortes for.™™.
accumulation of edema: (a) urinary retention of salt and water, and (b) the
dislocation of retained fluid into the nterstitial fluid from the intravascular
compartment under the dictate of altered Starling forces.
occur Pitting reflects the opportunity
s^hmOTement andmay |
11. Starling forces as determinants of edema formation
A Starling forces. Extracellular fluid (ECF) represents in normal circumstances
1'1
about 20 percent of the total body weight. Of the approximately 14 liters found
in an average 70-kg man, about 25 _percent of the total, or 3.5 to 4.5 liters, circulates
within the vascular space as ptasma, while the remainder is confined to thenonvascular portion of the extracellular space as interstitial fluid (ISF) and lymph.
The volumes of fluid normally found within and without the vascular tree are
in equilibrium. Fluid leaves the arteriolar end of capillaries to enter the Ibr
because capillary hydrostatic pressure exceeds plasma colloid osmotic pressure;
fluid reenters the capillary at the venular end because plasma colloid osmotic
pressure exceeds capillary hydrostatic pressure at that site. This balance of hy
1. Weight gam.
•„<«,;» weight (heaviest in the evenings).
drostatic and colloid osmotic pressures regulating the transcapillary m®^me
i Very marked diurnal swings in weignv
of fluid is termed the Starling forces. Interstitial fluid that is not resorbedinto
3 Reduction in urinary output.
capillaries is returned to the vascular compartment by lymphatic drainage, in
45.
very, tight and uncotnfortabie during the day.” X
events are summarized in Figure 1-1.
B Edema formation. Edema occurs when more fluid leaves the vascular compart
i II1
than can be returned there by the lymphatics. Since fluid can leave the
6. “I feel bloated.”
7. “Urine looks darker m co or
tight»
only at the level of the capillary bed, it follows that edema can accumulate only
8. “Swollen eyes on ^"Ul^tion.
when those factors that normally determine the transcapillary partitioning
9 Cough or dyspnea in honzonta pu
V7
ECF become deranged. The more important of these factors are:
in individual edema states
10. Shortness of breath on exertion.
. .
1. Decreased plasma colloid osmotic pressure
The nature <"
2. Increased capillary hydrostatic pressure
3. Increased permeability of the capillary wall
will of course------4. Obstruction of regional lymphatic flow
process.
Although localized edema can occur with local disturbances of capillary hydros
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IV.
pressure, increased permeability, and obstruction to lymph flow, generalized edema
can occur only when there is a widespread increment in capillary hydrostatic
■ pressure and/or a marked decrement in plasma colloid osmotic pressure.
p- .
ill. Clinical signs and symptoms
.
.
is
A “Pittind” versus “nonpitting” edema. Because of postural influences, ed®}113
' usually first detected by the physician in the subcutaneous space of the_ lower
extremities (ankles), but fluid can collect in any organ or tissue
is leaving the vascular space. The edema is said to be pitting if digits P
,
causes transient indentation of the skin and “nonpitting” if such indentation does
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1: The Edematous Patient
1: The Edematous Patient
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arrhythmias, hyperthyroidism, pulmonary embolic episodes, or chronic obstructive
lung disease. Evidence for these underlying diseases is generally present.
B Nephrotic syndrome. Nephrotic syndrome refers to a constellation of clinical
findings, which includes heavy proteinuria, hypoalbuminemia, hypercholester
olemia, and edema. This syndrome may occur secondary to lipoid nephrosis or
nil disease, in which the light microscopy of the kidney is normal, or it may be
secondary to some form of glomerulopathy (membranous, focal glomerulosclerotic,
proliferative, or membranoproliferative). Renal lesions leading to nephrotic syn
drome may also appear with a variety of systemic diseases, such as diabetes mellitus, lupus erythematosus, malignancies, or infections, or with a variety of drugs.
The various causes of nephrotic syndrome are listed in Table 8-3. The diagnosis
is made by demonstrating marked proteinuria (usually in excess of 3.5 gm per
day); usually an abnormal sediment, which may contain red and white blood
cells’ various types of casts, and oval fat bodies; and marked hypoalbuminemia.
Edema may be localized to the lower extremities but is often quite diffuse. Ne
phrotic patients may present with generalized anasarca, which may include both
peritoneal and pleural effusions. Periorbital edema, especially on awakening in
the morning, and edema of the fingers may be quite common.
Edema accumulates because of the marked decrement in plasma colloid osmotic
pressure caused by albumin losses in the urine. If the formation of edema has
been particularly rapid, especially if salt intake has been low, patients may present
with oliguria, dizziness, and orthostatic hypotension. A renal biopsy may be re
quired to diagnose the cause of the heavy proteinuria, particularly if systemic
causes have been excluded.
C. Acute glomerulonephritis. Edema may accompany any renal lesion which produces
an acute glomerulopathy (i.e., acute glomerulonephritis). Acute glomerulonephritis
may occur with malignant hypertension, poststreptococcal renal involvement, an
acute collagen vascular disease such as lupus erythematosus, or hypersensitivity
vasculitis. The edema is usually mild and restricted to the lower extremities, unless
there is a marked reduction in the glomerular filtration rate (GFR). Hypertension
and mild-to-modest oliguria may be present. The urinary sediment is character
istically abnormal; proteinuria, many red and white cells, and a large number of
granular and red cell casts in their various forms are present.
Serum creatinine and BUN are invariably elevated to some extent, and there
may be mild hypoalbuminemia. Serum complement levels may be reduced if the
glomerulonephritis is due to the deposition of immune complexes within the kidney
(e.g., glomerulonephritis associated with streptococcal infection, lupus nephritis,
or bacterial endocarditis). Systemic symptoms such as pleuritis, arthralgias, and
cutaneous rashes may be present, depending on the underlying lesion (e.g., vas
culitis and collagen vascular diseases). A renal biopsy may be required for di
agnostic purposes.
D. Cirrhosis of the liver. In cirrhosis of the liver, edema is generally confined to the
peritoneal space as ascites because of the portal venous hypertension, and to the
lower extremities because of the combined effects of hypoalbuminemia and the
increased pressure on the abdominal vena cava exerted by tense ascites. Edema
in cirrhosis usually does not occur until the disease is well advanced, and diagnosis
is easily made by the history, physical examination, and results of liver function
tests.
E. Idiopathic recurrent edema. Idiopathic recurrent edema refers to a group of signs
and symptoms observed predominantly in obese premenopausal women, but it
may occur rarely in males. The syndrome is usually characterized by anxiety,
irritability, abdominal bloating, headaches, and recurrent edema, usually most
marked in the lower extremities. Renal, hepatic, and cardiac functions are normal.
Although the edema may be cyclic, it may also be persistent and may demonstrate
a marked diurnal variation (i.e., nonexistent in the morning and marked in the
evenings). The diagnosis of this syndrome is one of exclusion.
*
F. Drug ingestion. Edema caused by ingestion of drugs is generally a diagnosis o»
exclusion which is made by obtaining a history of drug intake. The drugs usually
involved are estrogens, oral contraceptives, and antihypertensive vasodilators,
especially minoxidil.
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V TreXn^Xema. Appropriate therapy for edema in clinical practice rests on
three basic principles: (a) identification, and when possible, treatment of the ur
derNing cause o/urinary sodium retention; (b) manipulation of dietary intake of
salt and water; and (c) modification, when possible, of the renal excretion of salt and
water Because manipulation of dietary sodium intake and modification of renal
sodium excretion are common modes of therapy for all the edematous states, let us
AOI1Vanipulation of dietary intake of sodium. Readjustment of salt intake in the diet
ororide ^ssible a smaller amount of sodium than is excreted in the urine
may be quite helpful in treating edema. This is particularly useful m rhe=
retention associated with chronic renal failure, because in this situation daily
urinary sodium excretion proceeds at a fairly fixed rate provided urinary omput
is maintained at a reasonable level. Ingestion of less dietary sodium than is ex
cret-d in the urine often leads, within several days, to complete mobilization of
the edema Even when daily urine and sodium excretion is quite modest restriction
Xal mtake may allow the patient to achieve “sodium balance without proF^^lonVfoXSg sodium Intake. Patients who “lively form edema
retain a fraction of the daily ingested sodium to replenish the effect,ve err
culating arterial volume. Measurement of the 24-hour urinary excretion of
X thus provides a measure of the renal ability to handle an oral sodium
load A proper “balance" study is not required, because by definition such
Xmatous patients are in positive sodium balance, and the daily unnary output
represents the best that the kidneys can do with the patient on a given diet.
In fact even a 24-hour urine collection is unnecessary to assess whether or
not the patient is retaining sodium; low sodium concentrations in an aliquot
of urine (e g less than 10 to 15 mEq/L), especially when coupled with an
elevated urin^-plasma creatinine ratio (greater than 35), suggest very strongly
that the patient is in positive sodium balance.
2 Guidelines for dietary planning
a In planning dietary restriction of salt, it is helpful to recall that a 1-gn
‘ salHNaCl) diet contains 17 mEq of Na+, whereas a 1-gm Na diet contains
about 43 mEq of Na*. Restricting sodium to less than 20 mEq per day is
probably not worthwhile, because such diets are quite unpalatable, and
patient compliance is low. The average sodium intake mi North America
is about 80 to 200 mEq per day. By restricting use of the saltsnaker at
mealtime, this level of intake can be reduced to /0 to 125 rfiEq per da>.
it can be additionally reduced to 50 to 70 mEq per day by the avoidance
of salt in the cooking and preparation of foods.
b. When a patient is on a diet of severe salt restriction, to avoid hyponatremia
free-fluid intake should be restricted to about 1200 to 1500 ml per day.
particularly if the patient is taking a diuretic agent as well.
c For those patients who cannot tolerate a low salt diet, a variety of sal
substitutes is available. These contain largely potassium chloride and
therefore should not be prescribed in the presence of marked renal failure. in which urine output is markedly reduced, or when captopril or a potas
sium-sparing diuretic is being administered (e.g., spironolactone, amilonde,
triamterene).
B. Modification of salt excretion: diuretics
1. Indications for using diuretics. Edematous patients who cannot be managed
successfully with dietary therapy alone should be placed on diuretic therapy.
So potent and effective are these drugs in producing renal salt wasting that
any patients may be treated with just these agents while dietary managemen
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___________ ________ ——----------
'
Comments
fnrro
Generic Name
Acetazolamide
Diamox
250 mg
250 mg q i d.
uHefu! as a^nct U> the -PJ m refir
eZX cause hypokalemia, ineffective
25-200 mg q.d.
Hydrochloro
thiazide
Chlorthalidone
Hydrodiuril
50 mg
XX S hXeff«t,ve with GFR <25 mhmin
50-100 mg q-d. (frequently used
Hygroton
50, 100 mg
on alternating-day regimen)
20-120 mg q d. or b.i.d.
Furosemide
Lasix
Ethacrynic acid
Edecrin
20, 40, 80
mg
Rapid onset 30
potent; shoul
60 100 mg q d25, 50 mg
GFR <25 ml/m.n
25-100 mg q i d.
Spironolactone
Aldactone
Semia when GFR <25 mVmin
25 mg
100-300 mg b.i.d.
Triamterene
Metolazone
Amiloride
Dyrenium
100 mg
Zaroxolyn
1 mg
Midamor
5 mg
^mm-
Grspanl;Zntramd.cated because of danger of hyperLong-acting; .^{^^Z^th
’GFR <25
i-sparing;
dth GFR <25
pauents wth d.abetes.^P stones and drug
'Xd Xstitial nephritis being reporud wth
1-10 mg q.d.
Xl*—• —- -
X"ng;^^"sad-
5-20 mg q.d.
Sattoted wth GFR <25 mVmtn
Commoniy used when ^paring .s demred o
Triamterenehydrochloro
thiazide mix
Dy azide
Triamterene
50 mg; thia
zide 25 mg
1 tablet b.i.d.
avoid prescribing; K p
u or with K sup“K'S SnceSfaWta increases
(12%) in patients over age 60________________ _______
ture
GFR = glomerular filtration rate.
•in*—--
..... -iiii. :=!-w=«bk.
■r
•.
.-.--.-sit—
iaassttaz.
atr.:
sa®^' ?
1
8
1: The Edematous Patient
1: The Edematous Patient
9
''S
be reserved for situations in which the patient is resistant to the thiazide
diuretic, or a more vigorous diuresis is required.
d. The diuretics acting on the more distal parts of t he nephron (e.g., spiron
olactone, amiloride, triamterene) are weak and also potassium-sparing, an
effect that may cause hyperkalemia in the presence of renal failure, acidosis
or a diet very high in potassium. These diuretics, therefore, should never
be used in the presence of renal failure or with potassium supplements.
¥
I
I
*
C. Treatment of the specific underlying disorder
1. Congestive heart failure (CHF)
a. Cardiac glycosides. Because CHF generally occurs when the heart fails
as a pump, the major thrust of therapy in this clinical circumstance is to
improve the efficiency of ventricular performance. This is usually accom
plished with a cardiac glycoside preparation, most commonly, digoxin.
(1) Action of digoxin. Although a thorough discussion of digoxin is beyond
the scope of this chapter, it should be emphasized that the drug is
extremely effective in reversing low-output cardiac failure as well as
in controlling the ventricular rate in atrial fibrillation and a variety
of supraventricular tachyarrhythmias. Its marked inotropic effect on
the ventricular myocardium is particularly efficacious in the heart
failure associated with coronary artery disease, hypertension, or val
vular disease. It is less effective in states of high-output heart failure
(e.g., thyrotoxicosis and severe anemia), in cor pulmonale, and in con
ditions in which there is a disturbance in renal functioniimiting the
ability of the kidneys to increase the fractional excretion of salt and
water in response to an improved cardiac output (e.g., uremia or an
acute glomerulopathy). Digoxin is also rather ineffective when there
is pericardial tamponade or constrictive pericarditis, and it is generally
contraindicated in hypertrophic obstructive cardiomyopathy because
of the danger of worsening the subaortic stenosis.
(2) Administration and dosage of digoxin. In prescribing digoxin, one
should recall that there must be either a reduction in dosage or an
increment in dosage interval when renal failure is present. Although
theoretically one can administer a standard loading dose, in practice
it is probably much safer to administer either a reduced loading dose
(e.g., 30 to 50 percent of the usual dose over a period of 24 to 36 hours)
or the maintenance dosage without a loading dose, when there is no
requirement for rapid digitalization. Additional drug therapy in the
azotemic patient is discussed in Chapter 11. In elderly patients, the
serum creatinine may not accurately reflect the GFR because of loss
of muscle tissue. A serum creatinine of 1.2 mg per deciliter may in
fact be associated with a GFR of less than 60 ml per minute. Such
considerations should be kept in mind when the potentially lethal car
diac glycosides are prescribed for geriatric patients with CHF, and if
there is any doubt, creatinine clearance should be measured and suit
able formulas employed for calculating the required dose (see Chap.
11). In practice, because of the serious potential problems associated
with glycosides, many physicians prefer to initiate therapy with dietary
salt restriction and a diuretic, and avoid using digoxin unless it is
absolutely necessary (e.g., for atrial fibrillation).
b. Control of predisposing factors. In addition to cardiac glycosides, control
of factors predisposing to CHF should be instituted. These conditions include
hypertension, thyrotoxicosis, anemia, hypoxia, and polycythemia. Dietary
restriction of salt, reduction in physical activity, avoidance of extremes of
heat, moderation in sexual activity, sedation, and use of diuretics usually
complete the therapeutic program, although all these maneuvers are not
required for every patient. Extreme salt restriction and/or abdSe of diuretics
may actually be harmful to the patient in CHF. The failing heart maintains
a reasonable cardiac output, in part because of plasma volume expansion
(caused by renal sodium retention) and increased venous return, which
5.0 -
Normal—
■
5
Cardiac output
(L/min>
i
2.5 -
B
-Q.
Heart failure
§
ei...»
11
T
..15
0
5-^
3
1
a
v
€
30
I
Left ventricular filling pressure imm Hg)
and left ventricular filling pressure
Fiq. 1-2. Relationship between cardiac ouitput
.
under normal circumstances (upper curve) and low-output con;igestive heart failure
or improved contractility
Diuretic-induced preload reduction
Hu
[2nd ed.J. Boston: Little, Brown, 1980.)
p
1 3
5
3e
□3
Congestive symptoms
1 *
==:=3=£E??S=
output even more and may aggravate existing prerenal failure (Fig. 1-2).
2
a'^Abstinence from alcohol and sodium restriction. Treating thp
cause of established alcoholic cirrhosis of the liver is extremely difficult
Nevertheless, abstinence from alcohol and consumption of a nutritious di.t
may improve hepatic function and retard the rate of cirrhotic progression.
Such improvement may allow the resolution of existent edema and asc^s
or at least permit other therapy tp become more efficacious. In patients
with decompensated cirrhosis who actively retain urinary sodium, dietary
restriction of sodium is indicated according to the guidelines discussed
b Useof diuretics. Most cirrhotic patients with ascites require diuretics at
’ some stage in their disease. Nonetheless, there is no urgency to trea.small
amounts of ascites in well-nourished patients abstaining from alcohol, and
even large amounts of ascites probably never should be removed by par
acentesis. There is rarely any urgency m removing ascrtes uniess it is
associated with marked pain and discomfort, malnutrition, orJ^culatory
or respiratory embarrassment. Conservative therapy always should be at
tempted first. Sodium restriction (20 to 50 mEq per day), with on y m e^
I
h
?
-
f ■
10
1: The Edematous Patient
EH
11
1: The Edematous Patient
water restriction and bed rest, results in a spontaneous diuresis and mo
bilization of ascites in approximately 10 to 20 percent of hospitalized pa
tients with ascites.
Diuretics should not be used until it is clear that abstinence from alcohol,
salt restriction, provision of a nutritious diet, and bed rest have failed.
The diuretic agent of choice in the cirrhotic patient is spironolactone. It
should be started in doses of 50 mg four times per day and increased at
weekly intervals to 75 mg q.i.d. and then 100 mg four times per day if no
response is observed. The daily dosage of this agent should not exceed 400
mg. The great advantage of spironolactone is that it is a weak diuretic,
inhibiting the transport of no more than 1 to 2 percent of the filtered sodium
load at the distal cationic exchange site of action of aldosterone; thus a
slow, gentle diuresis proceeds. In contrast, furosemide or a thiazide may
inhibit transport of as much as 10 to 15 percent of the filtered sodium load
and thus initiate a more vigorous diuresis, with attendant complications.
c. Rate of diuresis. It is of great importance that a diuresis proceed gently
in the cirrhotic patient with ascites, since diuretic losses tend to cause
underfilling of the arterial circulation, and vascular replenishment can
occur only from the peripheral edema and ascites depots. Ascites, however,
must be resorbed into a vascular compartment (splanchnic capillaries)
where hydrostatic and osmotic forces (portal hypertension and hypoalbuminemia) do not favor the resorption of fluid. Hence, mobilization of
fluid may not keep up with diuretic losses. It has been demonstrated in
cirrhotic patients that probably no more than 9£KLml of ascitic fluid can
be transferred across the peritoneum in a single day. It is probably wise,
therefore, to keep weight loss induced by diuretics at no more than 0.5 to
1.0 pound per day. Along with volume contraction and the subsequent
tendency to induce renal failure, hypokalemia and hyponatremia are fre
quent complications associated with the overenthusiastic use of diuretics.
Hypokalemia has been suggested as a cause of hepatic encephalopathy.
Spironolactone may cause hyperkalemia and worsen any tendency for hy
perchloremic renal tubular acidosis. Spironolactone may also be associated
with painful gynecomastia. -Thiazides or furosemide should not be added
to spironolactone unless it has been clearly demonstrated that spirono
lactone alone is not effective.
d. Plasma volume expansion. Such maneuvers as infusion of iso-oncotic or
hyperoncotic albumin, reinfusion of ascites, and infusion of saline solution
generally are not helpful and may actually induce variceal hemorrhage
by increasing plasma volume and portal venous pressure transiently.
Portacaval shunts. Side-to-side portacaval fistulas may be attempted to
alleviate marked portal venous hypertension. End-to-side fistulas are as
sociated with unacceptable mortality and should not be contemplated. The
former operation carries as much as 40 percent operative mortality and
should be reserved only for young patients with cirrhosis who have given
up alcohol and whose liver function is reasonably intact. Thus, patients
with cirrhosis who have had previous episodes of encephalopathy and who
have ascites, jaundice, hypoalbuminemia, and vitamin K-resistant pro
longed prothrombin times are not good candidates.
f. LeVeen shunt As many as 95 percent of patients treated with conservative
techniques (including diuretics) exhibit complete or partial discharge of
the ascites. For those who do not (i.e., “intractable” patients), one may
attempt insertion of a LeVeen shunt.
(1) Technique. A LeVeen shunt is a Silastic, pressure-sensitive valve that
is implanted beneath the abdominal muscles under local anesthesia.
One end of the tubing rides within the peritoneal space while the other
!
is tunneled subcutatieously and inserted into a jugular vein. The valve
permits flow of fluid from the peritoneum to the jugular vein only as
long as a 3- to 4-cm water-pressure difference exists across the valve.
The valve functions as an exogenous thoracic duct, conducting fluid
'It'
i4<
--y?
uX'1*
gP-
’M ■
may decline.
__
-. pWeen shunt LeVeen shunts are
spreads, more and more
(2) Indications and complications o
not trouble-free, h°*ever-.a^
^for placement of a LeVeen
problems are being observed c
asates for which con-
!
n : 1
11
F15
■=!>
,
C
' a-
(a) Disseminated intravascular coagulation
(b) Continuous leak of ascites
(c) Thrombosis of jugular vein
(d) Infection of shunt and peritonitis
(e) Fever
(f) Variceal hemorrhage
(9) Pulmonary edema
!-
i ■
£\»^d not be
S
following medical
is marked encephalopathy, or if
is in congestive ^ai^l’urfe’ ’‘“t variceal hemorrhage. A thorough
there have been eP'^
LeVeen shunts in cirrhotic patients
phrotic syndrome is very difficult
dnietic agents. Admin-
zrx.Xvxxs.’a-
and secondary
11
$
I4
■ |
gome, such as Hixlgkins
!
allergy, and
I with specific therapy, and on resosyphilis), may be successfully treatea wi
thy generally dis-
it is virtuaiiy im-
nephropathy, and collagen-vascular d^8;
possible to reverse the nepl
for exampL,
cannot be reversed by coni
cumstances, a favoral
alone or <
hosphamide. An example of the latter suua
or cyclophosphamide.
disease is a course of prednisone. The
;
g
ent of
j proteinuria
„ a„. .1 .-««■. rgyggKffiA.«. ■■
I
4
'
I
1: The Edematous Patient
13
1: The Edematous Patient
used in combination with a barbiturate. The decision to use this drug should
i^Tbe taken lightly, however, and the patient must be carefully monitored^
Recent evidence suggests that dopamine agonists may be quit? helpfu tn
nnjdu^ing a natriuretic effect in women with idiopathic recurrent edema,
bu* it is not yet clear whether this drug is suitable for long-term therapy^
The majority of these patients are treated with dietary salt restriction and
diuretii. Although in many cases this therapeutic regimen may keep th
patient edema-free, there are potential complications with the long-term
S of diuretics in this syndrome. The patient may come to exhibita marked
“denendence” on these drugs and use them as cure-alls for many differen
tvpK of complaints. Indeed, many women with recurrent edema are anxious
and often irritable. Abuse of thiazide diuretics or furosemide may lead to
chronic hypokalemia, which in itself may be a salt-retaining influence. It
has also been postulated that in sensitive people volume contraction induced
by diuretics may provoke persistent secondary hyperaldosteronism and
excess tubular retention of sodium such that edema may actually be pro-
obtained although the dosage may be progressively decreased when it is
cleTthat the patient is showing a beneficial respon^. A response is gen-
jf
i
el
but aecrea-’
-snonding to steroids or is exhibiting frequent relapses
-3
i
3
theofXotdste.g" hypertension, thromboembolic pheX™ inclased predisposition to infection, osteoporosis, aseptic necrosis,
and of alkylating agents (e.g., bone marrow suppression, in-
e
3
SSSSS2SSS JI
3
1 -S.
indications
vt
3
4
at least 50 percen^■ °f "u11
in31dl(JUS its course may be
North America. The onset,ot
sp(>ntaneous remission in as
indolent ant'
^./whether steroids are useful in the treatment
many as 20 percent of cas^ wne
of the poor progof this disease is s i
ronath- is permitted to continue unabated, many
nosis if membranous nephropatfi, I*
fanction
nephrologists advocate a tn al o^ nen py
F
undertaken, it should
is not severely
re per day or 125 mg on alternate
be vigorous tag. 60 to 80
f pred
d^ation of therap, (at reduced
days) for as long as 2
days) lasting for 6 to 12 months, betore
< ,
1
3
3
1
3
ei-
kherBa^ ;hs:
may be beneficial in patiente w ft Xctory edema. There tends to be a transfer of blood to the central
" wift bed test, resulting in an augmented cardiac output and -mproved
renal perfusion. Bed rest may also lead to a decrease in circulating levels of an
tidiutetic hormone and aldosterone. Bed rest often converts an edematous patient
who i« refractorv to diuretics to one who is more responsive to diuretics, whic
»■
5
c.
are not generally “‘“s ^ue Xllagen vascular disease (e g., lupus
^hematasms) the primary disease should be fully treated with prednisone
2.
usefuI in these
4. Acute glomerulonephritis. Edema may occm
ritis. Although diuretics an
*’*sodium retention will come only
5. Idiopathic edema. Women
dlSorder. Sinc7the cause
ci
s rxsst——.. ■«- tsloss,Sssss^—may;«*3**
’K£:Sse
prove quite helpful. Almost all women
. ^fiteCavXy: ofTe o^hostatic pos.tion, combined with the wearing
of elastic support hose.
f
<
!
obtained relief with the use of sym-
SSSKHKX“"S”
UsewmbaabOM of diuretics that act at diKereot sites within ths neP^
3. (e g acetazolamide, followed by large doses of furosemide, thiazides,
spironolactone). The combination of furosemide and metolazon? administered
together has been proposed as an effective alternative in furosemide-resistant
4. Attempt to improve renal perfusion by infusing preglomerular vasodilators
teasioSndanynon’lv marginal adrenal function is present, particularly in elderly
Sts who have been chronically >11 and who have recently suffered irom
Additional acute stresses. In these circumstances, intravenous injections of
given dosage of
soluble glucocorticoid may permit a
diuretic, perhaps by increasing gJome^U^^tfrteC^V
in specific edematous states, it may
dT^e^d procedures
D.
S recumbent
—
‘
----------1
with
toxemia
nw®
Thus, pregnant women
§th(?mQ(^Tiamics^s
aired
ly discussed,
position in bed. a posture that improve^^R
p________ .
■gffbj^d^p Le^&m fjli#iiang, whereas
patients with cirrhosis of the liver
ron^ir^TlaneojKs iqjvisions of hyp_.._
: ’
/
'■
;-J“;—
patients with
nephrotic
syndrome
&
peroncotic albumin and diuretics. I q ,
[IO *
5
C “ -A
"
1: The Edematous Patient
14
The Patient With
Hyponatremia or
Hypernatremia
approach may improve renal perfusion (despite a reduction in blood pressure),
and a more potent diuretic response may be obtained. Because penpheral reStance is in part angiotensin-dependent in CHF, captopril, a new, potent vasodilator that inhibits angiotensin generation, has been particularly helpful in
K v Xe patients with advanced CHF and refractory edema^ It produces marked
Bife Xload reduction and assists in the mobilization of fluid. Because of ita potency
liBC1 potentially hazardous complications, the physician should become thoroughly
I
Robert W. Schrier
A-,
'
■
I
I
1
v
' familiar with this agent before contemplating its use.
Hyponatremia
Suggested Reading
Hyponatremia, defined aa a piasma
liter, is a frequent occurrence in th
Boston: Little, Brown. In press.
Brenner, B. M. and Stein, J. H. (Eds.). Sodium and Water Howostas^ Contemporary
Issues in Nephrology, Vol. 1. New York: Churchill-Livingstone, 1978.
■ntration of less than 135 mEq per
-cen=that
’
)3 have a 1OW plasma sodium
A
11 i
Cannon, P. G, the kidney in heart failure. N. Engl. J. Med. 296:26, 1977.
Epstein, M. Thi> LeVeen shunt for ascites and hepatorenal syndrome. N. Engl. J.
Of a specific disease state. For example ^"sodium concentration also may
overt
A 1°* ???..
, disease hypopituitarism, or
Zresel^he patient with
symp.
hypothyroidism, or it may be a harbinger of exaL. tre^HTriw-also present as a
Med. 302:62^1^
Levy M tan.d SeW. J. F. Pathophysiology of Edema Formation. In B. M. Brenner
Xd F C.’ XtorXiEds.), The Kidney (2nd ed.). Philadelphia: Saunders, 1980.
MacGregor, ^arkandu N.
C" “d
0'
^LTnec^
H. E. Is “idio^afcg .edema “idiopathic ? Lancet 1.39/, 19/9.
Swales, J. D.,^ium Metabolism in Disease. London: Lloyd-Lube Medical Books,
1975. ’
i
•
1
s
'
yclophosphamide), or it may
It is cfeir, therefore, that even in
i- the
— asympto^ the speciric
natremia cannot be ignored^rather, a
causeTihe hyponatremia must be used.
C-____
I
«r «
>*4
ZS.jssa.---X2.
II. Signs and Symptoms
•
I ih
00LhvaHet^hthJrateofdeclinei.n
____
______’u thA affe'of the patient, m geueia.,
the plasma_a)dium concentrate
ific leveToTH^onatremia better than
H 4
oi dsvelopwont °f W-*
ZS.. bo."'
accompanies hyponatremia, requi
swelling is very effective with the
hand, this protective
Zs oZeefe, so that an elderly person
chronic development of hyponahemia over days^w
may present without signs or symptoms even wi
h
below 110 mEq per liter.
raatmintestinal symptoms, including
Gastrointestinal and CNS dysfunction. G^trXatremia; however,, the
the more
more
ji ’■
n
anorexia
and
nausea,
severe later
signs
and symptoms relate-to
that occurs with hyponatremia is
|i
F . .
“^Trigid encasement
may lead t0 brain edema and
8i
so..™S'
heXtX^hVsre& ’repid
XtremtaX Should be considered in the
15
r
W-“
‘
2: The Patient With Hyponatremia or Hypernatremia
17
2: The Patient With Hyponatremia or Hypernatremia
In summary, symptoms that may be associated with hyponatremia include:
■
i
1. Lethargy, apathy
2. Disorientation
3. Muscle cramps
4. Anorexia, nausea
5. Agitation
associated with hyponatremia include:
Signs that may be
1. '’Abnormal sensorium
2. Depressed deep tendon reflexes
z
3. Cheyne-Stokes respiration
4. Hypothermia
5. Pathologic reflexes
/
6. Pseudobulbar palsy - '
7. Seizures
e
4^
the Ptesma 0 ®
■' patient with Waldenstrom’s macroglobulmemia reveals a
from the PjasraapXtPtS ^ plasma water. Because ultracentrifugation may
e-l
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each 10(? mg
decjHter rise in blood
if the urinary sodium concentration is greater than 20 mEq per liter in zi .
nrvolemVc hyponatremic patient, the kidney is not responding appropriately to
?he ECF vorume depletion and renal losses of scxiium and water must be eons.dered
r SnteTtea.sodium less than 10 mEq
ax■*-ysxrssss-x tiJ a
mannitol administration or h^rg
ztl .ei.»
‘
conroTtraten in the total
plasma
iv;n2 hvnonatremia with near normal total uodj sodium.
n Siematous hyponatremic patient. This clarification of' the. hyponatremic: patent
D. Kenrarous
focus and diminishes the diagnostic possibilities.
The'hvnonatremic edematous patient must have either cardiac failure cirrhosis
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Q infused Pseudohyponatremia does not require a
in plasma water is normal.
a hypotonic solution
^prote^^Tntey have a large ^reentage of their
;
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' b^v 'Odium The volume-depleted patient with flat neck veins decreased skm
tmgor dX mucous membranes, and orthostatic hypotension and teehycardm is
XEfiedL having hyponatremia with a deficit of total body sodium. Lastly, the
p“without eiUier^dema or evidence of ECF volume deplefon is classified
€■
oer liter In a hypovolemic hyponatremic patient with unnary sodium con
centration less thmi 10 mEq per liter, a gastrointestinal;^fX^nX
water losses must be sough I. This may be readily apparent if the patient p e
sents with a history of vomiting and/or diarrhea. In the absence of an ob' ious
Msterv of gastrointestinal fluid losses, several other diagnostic possibilit.es
must be considered. Substantial ECF losses may occur into the abdominal
cavity with peritonitis or pancreatitis and into the bowel lumen with lieu o
membranous colitis. The surreptitious cathartic abuser may present with t.idence of ECF volume depletion and no history of gastrointestinal losses. A
due to this diagnosis may be the presence of hypokalemic metabolic acidosis
and phenolphthalein in the urine. Loss of haustra on barium enema and me
lanosis colHre other clues to cathartic abuse. Burns or muscle damage may
also lead to a state of hypovolemia and hyponatremia secondary to substantial
2 S^aTl'XXXlum grXtt^nVmEq'per liter. In a
- sF vissttfss
with inaulm and towerwg! of theuft‘^g
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the hvDonab’emic patient into one of the above catego. ies.
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ede~"nt is classified as having hyponatremia with an excess of total
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hyponatrSfic patent with a urinary sodium level greater than 20 mEq per
liter several different diagnostic possibilities must be considered.
a. Diuretic use. Foremost among these diagnoses is excessive use of diur
Tn fact a fall in plasma sodium concentration in a patient receiving diur t
mav be the Hrst clue to the need to readjust the dosage of the diuretic.
Xe are
patients with diuretic abuse in whom ECF volume depletion
ishnotreadib apparent from clinical examination. As
ever, to the diagnosis of diuretib-induced hyponatremia is that virtually
all of these patients have an associated hypokalemic alkalosis. Cessatio
of use of the diuretic is the. best means of confirming the diagnosis oi
diuretic-induced hvponatrernia. It must be remembered however, tha
restorl'tion of ECF volume and potassium balance are also necessary to
b ^ZeptWous diuretic abuse. Surreptitious diuretic abuse is becoming~yery
Common, particularly among premenopausal women who use diuretic^ for
weight loss or other cosmetic reasons (e.g., thick ankles or calves puffy
faceg swelling of ankles.) These patients may be difficult to distinguish
from patients with surreptitious vomiting, because both may present wit
evidence of ECF volume depletion and hypokalemic metabolic alkalos .
j
R
' 2: The Patient With Hyponatremia or
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the hyperkalemia. MoreoY"’^hus if adrenal insufficiency is suspected,
may fall within the normal range Th
lest should be performed. In
a 2-hour cosyntropm
yn ’ entration greater than 20 mEq per liter,
addition to a urinary sodmm■ ““centf
^an 20 mEq per liter may be
a urinary potassium
deflciency. If fluid intake has been reanother clue to mineralocorticoid^efic y
h
stricted, the patient with Addison s dis
£ ,f
ECF volume d
natremia, and hyperkalemia may not be iNecessary to make
pletion is not severe. Thus, a hig
Thege Patients may present with
is obligating urinary sodium
uncontrolled diabetic patient
(1) Glucose, urea, or mannitol diuresis.^
electrolyte losses
may have substantm! g!ucosuntgcg
relief of urinary
and thus ECF volume ^P’rtl0ny J™,“ osmotic diuresis that can
tract obstruction is anomer ^^^“Xnnitol infusion without
cause ECF volume deple
•
similar situation.
electrolyte ^‘“““^“^^cretion also can obligate renal water
(2) Bicarbonaturia.
“frequently encountered example of
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20 mEq/L) urinary chloride “n“"‘r® Xliary cystic disease, chronic inc. Salt-losing nephritis. Pat'®"^ *
analgesic nephropathy, partial unterstitial nephntis,
glomerulonephritis may present
nary tract obstruction, and, rare y,
gait-losing nephritis. These
with hypovolemic
renal impairment with serum
patients generally have moderately
deciliter. This diagnosis should
ip
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2: The Patient With Hyponatremia or Hypernsiremia
■
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2: The Patient With Hyponatremia or Hypernatremia
(3) Ketaouria. Ketoacids are other anions that can obligate renal electrolyte
losses in spite of ECF volume depletion: this may contribute to urinary
electrolyte losses in diabetic or alcc^ioiic ketoacidosis and starvation.
Euvolemic hyponatremic patient There sre a limited number of diagnostic
possibilities with hyponatremic patients who exhibit neither enema nor
-s
ECF volume depletion (i.e., euvolemic hyponatremic patients). Two en
docrine disorders must be considered -hypothyroidism and secondary ad
renal insufficiency associated with pituitary or hypothalamic disease.
(1) Hypothyroidism. The occurrence of hyponatremia with hypothyroidism
generally suggests severe disease, iociuding myxedema coma. In some *
patients' particularly the elderly, the diagnosis may not be readily
apparent. Thus, thyroid function must be assessed in the euvolemic
hyponatremic patient.
(2) Glucocorticoid deficiency. An intact rrnin-angiotensin-aldosterone
system avoids ECF volume depleh&n with secondary adrenal insuffi
ciency, but it is clear that glucocorticoid deficiency alone can impair
water excretion and cause hyponatremia. Altnough skull films and
computed axial tomography (CT scans should always be obtained in
th?'-euvolemic hyponatremic patient 'a'hen the cause of the hypona
tremia is not obvious, normal skull films or CT scans do not exclude
secondary adrenal insufficiency. A Isw plasma cortisol level associated
with a low adrenocorticotropic hormone (ACTH) level supports the di
agnosis of secondary adrenal insufficiency. In this setting, both sec
ondary adrenal insufficiency and sKendary hypothyroidism may con
tribute to the hyponatremia accompanying pituitary insufficiency.
(3) Emotional stress, pain, and drugs. In the absence of endocrine dis
orders, drug effects and emotional or physical stress must be considered
in the euvolemic hyponatremic patient before invoking the diagnosis
of the syndrome of inappropriate antidiuretic hormone (SIADH) se
cretion. Acute pain or severe emotional stress (e.g., decompensated
psychosis associated with continued water ingestion) may lead to acute
and severe hyponatremia. Drugs that either stimulate the release of
antidiuretic hormone (ADH) or enhance its action include:
(a) Nicotine
(b) Chlorpropamide
(c) Tolbutamide
(d) Clofibrate
(e) Cyclophosphamide
(f) Morphine
(g) Barbiturates
(h) Vincristine
(I) Carbamazepine (Tegretol)
(j) Acetaminophen
(k) Indomethacin
(l) Isoproterenol
Thus, determining whether the pattent is receiving such drugs is an
important diagnostic step with the euvolemic hyponatremic patient.
(4) SIADH. After exclusion of the diagnoses given above in the euvolemic
hyponatremic patient, the diagnosis of SIADH may be considered. In
general, the causes of SIADH include:
(a) Carcinomas
(!) Lung
(il) Duodenum
(111) Pancreas
(b) Pulmonary disorders
(!) Viral pneumonia
*
(11) Bacterial pneumonia
(Hi) Pulmonary abscess
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(Iv) Tuberculosis
(v) Aspergillosis
_____________
(c) Central
nervoussystem
systemdisorders
disorders
f
(I) Z_._
Encephalitis,
viral or bacterial
("
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(11) Meningitis, viral, bacterial, or tubercular
(ill) Acute psychosis
’
’
(iv) Stroke (cerebral thrombosis or hemorrhage)
(v) Acute intermittent porphyria
(vi) Brain tumor ,
(vii) Brain abscess
(vlil) Subdural or subarachnoid hematoma or hemorrhage
(ix) Guillain-Barte syndrome
/ * Head trauma
(x)
™
•
□
(5) Evaluation of urinary sodium concentration. The urinary sodium
centration in SLADH^as well as in other conditions leading to euvolemic
hyponatremia is generally greater than 20 mEq per liter However, if
the patient with SIADH is on a sodium-restricted diet or is volume
depleted, the urinary sodium concentration may be less than 10 mEq
per liter Refeeding with a normal salt intake or expansion oi isCr
volume with saline will increase urinary sodium concentration to
greater than 20 mEq per liter, but the hyponatremia will persist m
the patient with SIADH or another euvolemic cause of hyponatremia.
V Therapy. The therapy of hyponatremia depends on several factors, including (a) t e
’ cause of the hyponatremia, (b) the degree of the hyponatremia, and (c) the seventy
of signs and symptoms relating to the hyponatremia. Hyponatremia relating to mi
neralocorticoid, glucocorticoid, and/or thyroid hormone deficiency is of course best
TaS^cmcht^tmentPofCcauM of hyponatremia. Drug-induced hyponatremia or
3
5
3
3
F
hvponatremia related to physical or emotional stress is best managed by remova
of the drug or stress. Treatment of edematous disorders (e.g.. cardiac glycosides
with cardiac failure or corticosteroids with nephrotic syndrome secondary to nil
disease or lipoid nephrosis) may also suppress nonosmotic vasopressin release
and improve the renal capacity to excrete water, thus correcting the hyponatremia
Correction of ECF volume depletion, whether secondary to gastrointestinal o
•bird space losses, diuretic abuse, Addison’s disease, or salt-losing nephritis also
may correct the hvponatremia. In an occasional patient with diuretic-induced
hyponatremia, cessation of the drug and restoration of ECF volume is >"adeTua^
to correct the hyponatremia if total body potassium stores are not repleted. Treat
ment of the uncontrolled diabetic patient with profound hyperglycemia ketonuna,
and glucosuria will also diminish renal losses of fluid and electrolytes, thereby
alleviating the precipitating cause of the hyponatremia.
B Restriction of water intake. If none of these specific treatments is possible, adequate restriction of water intake will increase plasma sodium concentration in
dependent of the cause of the hyponatremia. Adequate fluid resmction is re
striction to an amount less than urine output and estimated
, s“
For example, if a hyponatremic patient nas a daily urine output of 500 ml and
estimated daily insensible losses of 500 ml, daily water restriction to 1000 ml
should be expected to prevent additional lowering of the plasma sodium conden
sation; moreZvere fluid restriction to less than 1000 ml per day is necessary
^smeclochto^t'racycllne administration. In a patient witti chronic SIADH who
c. will not voluntarily restrict waler intake to a degree sufficient to avoid sy mp
e
d
*
tomatic hyponatremia, the administration of demeclochlortetracychne <600> to U00
mg per day) may be used to create a state of drug-induced nephrogenic diabete,
insipidus thereby allowing more liberal fluid intake without associated hypo
natremia It must be remembered, however, that demeclochlortetracychne is me
tabolized largely by the liver, and patients with liver disease may develop amtemia
associated with high plasma drag concentrations and nephrotoxicity. This tetra
2: The Patient With Hyponatremia or Hypernatremia
22
23
2: The Patient With Hyponatremia or Hypernatremia
cycline may also cause a natriuresis, with subsequent ECF volume depletion.
Lithium has also been used to cause a vasopressin-resistant nephrogenic diabetes
insipidus in patients with chronic SIADH and symptomatic hyponatremia, but
this drug is less consistently effective and has more side effects than demeciochlortetracycline. Specific antagonists to arginine vasopressin have now been de
veloped and should be available for clinical use in the near future.
D. Treatment of acute symptomatic hyponatremia with furosemide and hypertonic
saline. For the asymptomatic patient who has no reversible cause of hyponatremia
and a plasma sodium concentration of not less than 130 mEq per liter, only careful
monitoring may be appropriate^On the other hand, if the plasma sodium con
centration decreases to 125 mEq per liter or less, cell swelling is no doubt occurring,
and appropriate water restriction to maintain plasma sodium concentration at a
level greater than 130 mEq per liter is indicated. As already emphasized, however,
the rate of decrease in plasma sodium concentration is an important determinant
of associated signs and symptoms.
1. Indications for treatment. In a patient with acute hyponatremia and CNS
symptoms, including stupor, coma, or seizures, rapid treatment to decrease
the brain swelling is indicated. The best approach is to increase ECF osmolality
by administering hypertonic (3%) saline at a rate equal to furosemide-induced
renal losses of sodium, potassium, and chloride. The difference in the hourly
rate of urine flow and hypertonic saline infusion will equal the net negative
fluid balance. For example, if a furosemide-induced (1 mg intravenously) di
uresis of 1 liter per hour occurs and the urinary electrolyte losses are replaced
by 150 ml of 3% saline, then 850 ml of net negative water balance has been
achieved. This approach avoids dangerous overexpansion of ECF and corrects
the primary cause of the hyponatremia—excessive total body water. When
available vasopressin antagonists will be very useful in the treatment of acute
symptomatic hyponatremia.
2. Calculation of desired negative water balance. The following example illus
trates the method of correcting the plasma sodium concentration from 115 to
130 mEq per liter in a stuporous, hyponatremic 70-kg man:
42L
Total body water (TBW) = body weight x 60%
or
70 x 0.6
osmolality, thus avoiding frank
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Therefore, 5.5 liters (42.0 L-36.5L) negative water balance will be needed to
raise plasma sodium concentration to 130 mEq per liter.
Therefore, an approximate net negative fluid balance of 900 ml per hour in
this patient should raise the plasma sodium concentration to 130 mEq per
liter in 6 hours. Nevertheless, careful monitoring of the patient during these
rapid changes in fluid balance is important.
J
Hypernatremia, defined’ asJ a plasma sodium concentration greater than 150 inEq
per liter, is less frequent than hyponatremia. This is probably not due to a~ more
frequent occurrence of disorders of renal dilution than of renal concentration. If there
is an inability to dilute the urine, however, water intake of 1 to 2 liters per day may
hyponatremia. This amount ot
of tluid
fluid intake may be
ingested as routine oenaviui
behavior
cause Hyponatremia.
oe ingestea
in spite of a hypo-osmolar stimulus to suppress thirst, thus perhaps explaining the
frequency of hyponatremia. On the other hand, renal concentrating defects that cause
renal Water losses generally do not cause hypernatremia unless a disturbance in
thirst is present or the patient cannot drink or obtain adequate fluid to drink. The
very young, the very old, and the very sick are, therefore, the populations that develop
hypernatremia most frequently. In the absence of an inability to drink (e.g., coma,
“
nt of lnstances of central diA. Central diabetes insipidus. APPr''x‘“
5° cause and thus are classified as
abetes insipidus have no detectable unde y
pituitary or hypo.
idiopathic. Trauma, surgica1 P10c® ■
or secondary te.g., metastatic breast
thalamus, and neoplasms, either p
r^naining cause3 of central diabetes in* radition'enrepKti, sarcoidosis, or eosinophilic granuloma may cause
1:
il
IP
115 mEq/L
x 42 L = 36.5 L
130 mEq/L
Hypernatremia
L vasopressin (nephrogenic diabetes lnslP^; .
central diabetes insipidus.
Hiabetes insipidus can be secondary
B Nephrogenic diabetes insip«dus. Nephrogenic diabetes insipiu
to a variety of conditions (Table 2-1).
Then,
Actual plasma concentration x rpgyy . or
x TBW - or
Desired plasma concentration
either secondary to inadequate
*
1
Table 2-1. Acquired Causes
of Nephrogenic Diabetes Insipidus
Chronic renal disease
Polvcystic disease
Medullary cystic disease
Pyelonephritis
Ureteral obstruction
Far-advanced renal failure
Analgesic nephropathy
Electrolyte disorders
Hypokalemia
Hypercalcemia
Drugs
Lithium
Demeclocycline
Acetohexamide
Tolazamide
Glyburide
Propoxyphene
Amphotericin
Methoxyflurane
VinblastineColchicine
Sickle cell disease
Dietary abnormalities
Excessive water intake
Decreased sodium chloride intake
Decreased protein intake
Miscellaneous
Multiple myeloma-'
Amyloidosis
Sjogren’s disease
Sarcoidosis—------------------------
tion, 1979.
I
24
SW’.
2: The Patient With Hyponatremia or Hypernatremia
Secondary to renal diseases. Medullary or interstitial renal diseases are particularly likely to be accompanied by vasopressin-resistant renal concentrating
defects- the most frequerit of these diseases are medullary cystic disease, chronic
interstitial nephritis (e.g., analgesic nephropathy), polycystic disease, and
partial bilateral urinarv tract obstruction Far-advanced renal disease of any
cause i« uniformly associated with a renal concentrating defect. However, because of the very low glomerular filtration rate, the renal water loss (i.e.,
polvuria) is modest (2 to 4 L per day).
.
,
2 Secondary to hypercalcemia and hypokalemia. Hypercalcemia secondary to
‘ any cause, including primary hyperparathyroidism, vitamin D intoxication,
milk alkali svndrome, hyperthyroidism, and tumor, may cause nephrogenic
diabetes insipidus. Similarly, hypokalemia secondary to any cause, including
primary aldosteronism, diarrhea, or chronic diuretic use, may cause nephro
genic diabetes insipidus.
3 Drugs, dietary abnormalities, and other causes \ anous drugs impair the
end-organ response to ADH and thus cause a renal concentrating defect (Table
2 1> Excess water intake as well as dietary sodium and/or protein restriction
also'has bevn shown to impair urinary concentration. Other unique causes of
nephrogenic
epinrogenic diabetes insipidus include multiple myeloma, amyloidosis, Sjogren’s disease, and sarcoidosis.
.. . ,lo^es without
. ,
. ad,
C .nsSe^ZoTm^resls.
Excessive insensible
2: The Patient With Hyponatremia or Hypernatremia
‘ gsssssgsssi
1
equate intake will cause hypernatremia since these losses are always hypotonic
in nature. Also, renal losses are generally
morally hypotonic
bpotomc• during
durmg an osmotic diuresis
such as occurs with glucose, urea, or mannitol
i-“ * "'and thus may lead -to- hypernatremia.
However, hypernatremia will occur
to hypotonic losses only if (a) the
occursecondary
----------- ...
,
" ’ ' or (c) the patient is unable
thirst mechanism is impaired, (b) fluid is not available,
to obtain and or drink fluid. Thus, since hypotonic fluid losses; are most frequently
fritect^hi^T'mechanism. availability of fluid, and ability to
associated with an i..---- -------drink,
nypernatremm is uut
drink, hypernatremia
not a
a frequent
frequent occurrence.
occurrence^
D Administration of hypertonic salts. A rare cause of hypernatremia is the adminU SZSt sub3tances"-_'nius, hypernatremia may occur during
cardiopulmonarv resuscitation and
amounte of sodium
.nd administration of large amounts
bmarbonate or
or during
during inadvertent
inadvertent intravascular infusions of hypertonic saline
bicarbonate
in therapeutic abortions. Sea water drowning or hemodialysis with a mistakenly
i
- use
high sodium concentration dialysate are other causes of hypernatremia. The
of sodium chloride tablets without adequate water intake m a hot, humid en
vironment may occasionally lead to profound hypernatremia in somedimple. The
modest elevation of plasma sodium concentration m patients with Cushing s syn
drome or primary hvperaldosteronism may provide a clue to the diagnosis but is
of no clinical consequence. When hypernatremia occurs m any of the above clinical
settings severe signs and symptoms may be associated.
II Signs and symptoms Polyuria and polydipsia may be prominent symptoms of the
' parient who subsequently develops hypernatremia in association with inadequate
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rCNSdylfunctlon. Neurologic abnormalities constitute the most P™minent
ifestations of hypernatremic states. These neurologic manifestationappe^ te
be due primarily to cellular dehydration and shrinkage of brain cells that is as
seriated with tearing of cerebral vessels. Capillary and venous congestion subcortical and subarachnoid bleeding, and venous sinus thrombosis all have been
B p)ogn^
hypernatremia. The signs and symptoms of
hypernatremia are more severe with acute than with chronic
i
I
/
25
n^nles some of which appear to be amino acids: these idiogemc osmmes are
osmotically active and restore brain water to near control levels m spite of per
sistent hypernatremia. The presence of these idiogemc anions with chronic hy
pernatremia, although protective against brain dehydration and snrinAage, may
predispose to brain edema if the hypernatremia is corrected too rapidiy.
CorrelSion of CNS dysfunction with degree of hyperosmolality. The earliest
D. manifestations of hypernatremia are restlessness, increased irritability, and
lethargv These symptoms may be followed by muscular twitching, hyperflexia,
tremulousness, and ataxia. The level of hyperosmolality at which these signs and
symptoms occur depends not only on the rapidity of the change in the plasma
sodium concentration but also on the age of the patient; the very young and the
very old exhibit the most severe manifestations. In general however these sign
and symptoms may occur progressively with plasma osmo ality in the range- i
325 to 375 mOsm per kilogram of water. At plasma osmolalities abo^e this level
tonic muscular spCticity, focal and grand mal seizures, and death may occur
The elderly patient with dementia or severe cerebrovascular disease may dem
onstrate these life-threatening signs and symptoms at a lower level of plasma
BecausTof the'potential severe consequences of hypernatremia, it is important
tn make a specific diagnosis of the cause and institute appropriate therapy.
Diagnosis Is with hyponatremia, a diagnostic approach (Fig. 2-2) that classify
111. patents on the basis of total body sodium or ECF volume status may be used. Such
an approach allows the clinician to focus on the most likely diagnosis m each category.
A. Hypovolemic hypernatremic patient. The hypernatremic patient may nave evi
dence of ECF volume depletion that has occurred secondary to eitner renal or
extrarenal losses.
. .
1 Extrarenal losses. If the losses have been from an extrarenax site (e.g., aiar‘ rhea) then sodium and water conservation by the kidney should be readily
apparent. In such patients the urine sodium concentration is less than 10 mEq
per liter and the urine is hypertonic.
.
2 Renal losses. In contrast, hypotonic electrolyte losses may occur in the urine
* during an osmotic diuresis. In these patients evidence of renal sodium and
water conservation is of course not present because the urine is the source of
the losses. Thus, the urine is not hypertonic, and unne sodiuni concentration
is generally greater than 20 mEq per liter. In the hyperglycemic diabetic patient
with good renal function and profound glucosuria, hypernatremia may be a
presenting feature because hypotonic renal losses may obscure any effect of
hyperglycemia to shift water osmotically from cells to ECI’.
Hypovolemic hypernatremic patient. Patients with hypernatremia ?lso may have
B.
evidence of ECF volume expansion. Generally, these are patients \vho have re
ceived excessive amounts’of hypertonic sodium chloride or sodium bicarbonate.
In such an acute setting the incidence of ECF volume expansion is most like y
to be associated with pulmonary congestion and/or elevated neck veins raJie
than peripheral edema. This variety oQiypervolemic hypernatremia is rather
eJvoSc hypernatremic patient. More frequent are hypernatremic patients who
c. exhibit evidence of neither ECF volume depletion nor expansion. These are pa
* |
Indeed, 75 percent mortality has been reported in association with acute , p
natremia in adults with acute elevations of plasma sodium concentration above
160 mEq per liter. These adults, however, frequently nave severe primary diseases
associated with their hypernatremia, and these primary diseases may largely
account for the high mortality. A 45 percent mortality has been reported in chil
dren with acute hypernatremia, and as many as two-thirds of the surviving children may have neurologic sequelae.
3
a.
A
tients who have suffered primarily from water losses without electrolyte losses.
Because of free permeability of membranes to water, waterMosses are on y onethird from the ECF conipartment and two-thirds from within cells. This is the
main reason that hypernatremia rather than ECF volume depletion primarily
occurs with water losses.
.
-.
1 Insensible water losses. Ill patients who do not receive replacement of msensible losses will become hypernatremic. The acchmatizea patient also has
primarily water loss without electrolyte loss with prolonged sweating and may
1
26
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27
2: The Patient With Hyponatremia or Hypernatremia
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become hypernatremic. This is rare, however, since stimulation of thirst and
water intake are generally adequate to avoid hypernatremia. With these extrarenaf water losses the urine becomes concentrated, and the urine sodium
concentration reflects sodium intake.
2. Partial central diabetes Insipidus. Patients with partial central diabetes in
sipidus, particularly with hypothalamic lesions associated with hypodipsia.
may present with hypernatremia and hypertonic urine.
3. Hypernatremia, hypodipsia, and hypertonic urine. Patients with virtual ab
sence of osmotic vasopressin release may maintain normal nonosmotic vaso
pressin release (e.g.. secondary to volume depletion) and present with hyper
natremia, hypodipsia. and maximally concentrated urine. These patients
generally have hypothalamic brain lesions. Their disorder has in the past been
termed essential hypernatremia or a reset osmostat.
4. Complete central diabetes insipidus. In patients with complete central diabetes
insipidus the urine is hypotonic in spite of plasma hyperosmolality, which
normally stimulates vasopressin release and concentrates the urine.
5. Responses to fluid deprivation and exogenous ADH. In Table 2-2 are shown
the responses to fluid deprivation (3 to 5 percent loss of body weight) followed
by exogenous vasopressin administration in patients with partial and complete
diabetes insipidus compared to normal subjects. Patients with compulsive water
drinking may present with polyuria and a blunted response to the fluid dep
rivation test; on cessation of fluid intake, hypernatremia does not develop in
these patients and their renal concentration defect is primarily due to a re
sistance of the kidney to vasopressin. However, since patients with central or
nephrogenic diabetes insipidus may present with polyuria and polydipsia in
the absence of hypernatremia, awareness of the diagnosis of compulsive (psy
chogenic) water drinking is quite important. Menopausal women with previous
psychiatric problems are particularly prone to compulsive water drinking.
Lastly, the patient with nephrogenic diabetes insipidus may occasionally have
vasopressin-resistant hypotonic urine (e.g., hypercalcemic or hypokalemic
nephropathy); thus, the temporary absence of fluid intake because of an in
tercurrent illness can be associated with hypernatremia. In all hypernatremic
patients who have primarily water losses, the urine sodium concentration
merely reflects sodium intake.
IV. Therapy. The treatment of hypernatremia depends on two important factors ECF
volume status and rate of development of the hypernatremia.
A. Correction of ECF volume depletion. If the hypernatremia is associated with
ECF volume depletion, the primary therapeutic goal is to administer isotonic
saline until restoration of ECF volume is achieved, as assessed by normal neck
veins and absence of orthostatic hypotension and tachycardia. Hypotonic (0.45%)
sodium chloride or 5% glucose can then be used to correct plasma osmolality.
B. Correction of ECF volume expansion. In contrast, if hypernatremia is associated
with ECF volume expansion, diuretics can be used to treat the hypernatremia.
The loop diuretic furosemide appears to be particularly useful in the generation
of hypotonic urine and thus is particularly effective in this setting. In the presence
of renal failure the patient with hypernatremia and fluid overload may need to
be dialyzed to treat the hypernatremia.
C. Water
—III^UIUU
method VI
of WMivr««wwiw»
calculation. Lastly,J the patient with
euvolemjc
VVCIld Ireplacement
upiawilivill ------ --------- -*
hypernatremia may be treated primarily with water replacement either orally
*■ *
. - .
mi
.i i /*
i
i . a?__ _pii_ * ncc
or parenterally with 5% glucose in water. The method of calculation of the
essary water replacement for a 75-kg man iwith
’ a plasma sodium of 154 mEq per
liter is as follows:
**
i'.v
.
....
»
. »
.>
.
".I
Total body water (TBW ) = body weight x 60% or TBW = 75 x 0.6
Then,
3 *-.
J
Actual plasma sodium
x TBW
Desired plasma sodium
or
154 mEq L
x 45 L
140 mEq L
49.5 L
I
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. 1 .
45 L
:
i
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1
| 28
2: The Patient With Hyponatremia
2: The Patient With Hyponatremia or Hypernatremia
or Hypernatremia
29
r-—
A
------------------- --------Normal subjects
F| Complete central
diabetes insipidus
Partial central
diabetes insipidus
Compulsive water
drinking
Uosm after
Vasopressin
% Change
(in Uosm)
18
1067 ± 68.7
168 ± 13
978 ± 79.4
445 ± 52
-8.9 ± 3.0
180 ± 41.4
12
437 ± 33.6
548 6 ± 28.2
28.5 ± 4.7
7
738.2 ± 52.9
779.8 ± 73.1
5 ± 2.2
Number
of Cases
Mean Uosm
with Dehydration
9
Data from M. Miller, T. Dalakos, A. M. Moses, et al.. Recognition of partial defects in
antidiuretic hormone secretion. Ann. Intern. Med. 73: <21, 1970.
VX H,
Fichman, M. P-, vo.neri, ,
ponatremia, Ann. Intern. x»
’
Therefore, 4.5 liters (49.5 L - 45.0 L) positive water balance would correct the
plasma sodium concentration.
rate of correction of the hypernatremia
D. Rate of correction. The recommended
recoi--- ------------lonment of the hypernatremia and the associated
depends on the rate of development
symptoms. More neurologic signs and symptoms are associated with acute hy
pernatremia; therefore, this biochemical abnormality should be corrected rapidly
Idiog^osmoks appear to accumulate in brain cells during periodsof chronic
hypernatremia, a mechanism that protects against brain shrinkage Thus, rapid
correction of chronic hypernatremia can create an osmotic gradient between the
ECF and intracellular compartments with osmotic water movement into cells
and brain edema. In general, therefore, chronic hypernatremia is best corrected
gradually at a rate not to exceed 2 mOsm per hour. Total correction time should
be 48 hours or longer.
Suggested Reading
Anderson, B. Regulation of water intake. Physiol. Rev. 58:582, 1978.
Arieff, A. I., and Guisado, R. Effects on the central nervous system of hypernatremic
and hyponatremic states. Kidney Int. 10:104, 1976.
Arieff, A. I., Llach, F., and Massry, S. G. Neurological manifestations and morbidity
of hyponatremia: Correlation with brain water and electrolytes. Medicine (Baltimore)
55:121, 1976.
Berl.
Berl. T.,
T., Anderson,
Anderson, R. J., McDonald, K. M., and Schrier. R. W. Clinical disorders of
water metabolism, Kidney Int. 10:117, 1976.
Berl T and Schrier, R. W. Water metabolism and the hypo-osmolar syndromes. In
B M Brenner and J. H. Stein (Eds.), Sodium and Waler Homeostasis. Contemporary
Issues in Nephrology, Vol. 1. New York: Churchill Livingstone, 1978.
Better, O. S., and Schrier, R. W. The disturbed volume homeostasis in patients with
cirrhosis of the liver. Kidney Int. 23:303, 1983.
Bichet, D. G„ Van Putten, V. J., and Schrier, R. W. Potential role of the increased
sympathetic activity in impaired sodium and water excretion m cirrhosis. N. Kngi.
J. Med. 307:1552, 1982.
Covey, C. M., and Arieff, A. I. Disorders of sodium and water metabolism and their
effects on the central nervous system. In B. M. Brenner and J. H. Stein (Eds.), Sodium
and Water, Homeostasis. Contemporary Issues in Nephrology, Vol. 1. New itorK.
Churchill Livingstone, 1978.
It
/ \
vasooressin antagonist on renal
X":s- "• —
3
e
C. K. .«■
„ 1971
’
Jhikawa, S, Kiro J.
3-
3
1983.
'-*■
j
Med. 294:507, 1976.
In R. W. Schrier (Ed.),
Schrier, R. W„ and Berl,
Boston: Little, Brown. In press, 1984.
^7' 7 W Berl T and Anderson, R. J- Osmotic and nonosmotic control of va“7^. Am.7. P^ol. 236:^1. 19,9^of
.
3
i
- <- ——
n,,. T.V.W., H.
! '
Tsbte 2-2. Responses to Fluid Deprivation and Exogenous V asopressm
Schrier, R. W„ and Blchet’ °0®7pXedCwater excretion in adrenal, thyroid and
release and the Pathogenesis oUmpairedg
W
3
-1
Kidney Mt. 10:82, 1976.
___nnd Solute Balance m Health
Preserving Fluid and Solute Bala)
Valtin, H. lienal Function: Mechanisms
(2nd ed.l. Boston. Little, Brown, 1983.
3
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I
1
The Patient With
Hypokalemia or
Hyperkalemia
Richard L. Tannen
i
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bar more impviumt, uuntiti,
______ 1—«««. r^lariTofinn IQ r-nt.irallv
,
——---------
-
dependent on the relation between extracellular and intracellular potassium. ™
major clinical manifestations of hypo- and hyperkalemia,
centrations (Ke/Ki).
.»■>,. The
-------------------caused by alterations of membrane phenomena in excitable tissues, are abnormalities
11
, sgsss:-«?“• •*
>dy potassium stores and factors affecting transcellular distribution. Total body
potassium
slum content,
content in a normal person averages 50 mEq per kilogram and ranges
31 to 57 mEq per kilogram (Fig. 3-1). Only 1.5 to 2.0 percent of potassium is
tlum (IGF),
(ivri, largely
largely in
m umscie.
xuv normal
J serum potassium concentration ranges
fluid
muscle. The
3.8 to 5.0 mEq..per -liter, and intracellular
1from
__________
< potassium concentration is estimated
to
be
150
mEq
per
liter.
In^iew^nhe mlrk^disparity between the potassium content of the intra- and
distribution of potass.um
3;2).
are’critical for maintaining normal serum levels (Fig. 3-2).
A Ljn.
pH. ZAUILIUOIO
Acidosis promotes
potassium -exit
from cells and increases the Ke. Ki
Ml VXAAV^iO
-----------------------alkalosis acts in the opposite fashion and tends to decrease serum potassium con
centration. Alterations in bicarbonate concentration without changes in plasma
pH can also modifv transcellular potassium movement. In addition, mineral and
nonmineral acids may affect potassium in somewhat different fashions. Ajou£h
A rough
guideline is that each 0.1 unit change in pH results in a reciprocal 0.6 mEq per
Ute7changV?rsZ^
^uZium with typerchlotemic
liter
change in serumMpotassium
hyperchloremic acidosis, but the same
change ini
in pH causes an average 0.4 mEq per liter or kc?
less ?.
change in 0potassium
with other acid-base disturbances.
B.
B. Insulin.
Insulin. Insulin promotes potassium entry into cells, which is, at least in pa ,
independent of its action on glucose uptake. Because potassium can stimulate
.
.• •
. ________ _ •./^/nil ntAvnr mnnnQTliQrni _
insulin release,
action
may Arepresent
JCj this
U111O CXK.LAV/1X
XiXXA^y
>^*,**““ ” a regulatory mechanism.
_
.
C Aldosterone. The major effect of aldosterone is modification of urinary potassium
excretion. Although it has been suggested that it may also promote cellular potassium uptake, this issue remains unresolved at present.
D. Beta-adrenergic agents. Beta-adrenergic agents, specifically those with B2-agonist
- - potassium
’ - -’by
--r a direct effect on the
properties, promote
cellular
properties,
uiuxxxuvc tcnuiai
v... uptake
----. sodiumpotassium pump. Whether potassium can, in turn, stimulate epinephrine release
1...^
has not knnn
been vocnlvrvrt
resolved rtofinitplv.
definitely.
Total
body
potassium.
It is apparent that alterations in one or several of the
E.
above factors can modify the serum potassium concentration independent ot any
change in total body potassium content. In the absence of changes in these factors,
serum potassium concentration parallels changes in cellular potassium stores;
depletion results in hypokalemia, and surfeit, in hyperkalemia.
Firm guidelines do not exist to estimate the magnitude of depletion from the
measured serum potassium level. A rough rule of thumb is that each 1 mEq per
liter decrement in serum potassium concentration corresponds to a loss ot ap
proximately 200 to 300 mEq per liter of body potassium stores. Reliable data
correlating hyperkalemia with the magnitude of potassium retention are not
available, but an increase in potassium of 1 mEq per liter above normal probably
1.11OV&XXAA
I
!
Potassium,' the major intracellular cation, influences several enzymatic processes,
V/***VW^*W
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iti
-----
31
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3: The Patient With Hypokalemia or Hyperkalemia
33
3: The Patient With Hypokalemiaor^Hyperkalemia
i
to the distal nephron and perhaps by increasing sodium reabsorption at distal
nephron sites. A decrease in sodium excretion diminishes potassium excretion.
Dietary intake
----- <70 mEq)
•-
3.8-5.0 mEq/L
150mEq/L
fill
56 mEq
3150 mEq
300 mEq
eyX
ECF
ICF
Other
' ~ Stool
(7 mEq'
Urine
(63 mEq)
Changes in serum K'
1. Acid-base
Altered total body stores
A. t Acidosis
B. I Alkalosis
1
(Q.4-0.6 mEqT. of K" \
] \
0.1 pH unit
/
2. Insulin
1 Depletion—1 mEq/L decrease
for each 200- 300 mEq deficit
2. Retention—1 mEq/L increase
reflects 200 mEq excess. No
data for larger increments
d 5
3. Aldosterone
4. Beta-adrenergic agents (fi? agonists)
Fig. 3-2. Changes in serum potassium concentration.
I
i
( )
3
or more of ingested
XtantiX impaired, stool losses may account for a
with sodium deprivation.
B Mineralocorticoids. Mineralocorticoids promote sodium retention and potassium
excretion, although the two effects may be the result of separate mechamsms.
Furthermore, a high potassium concentration stimulates aldosterone secretion,
whereas a low potassium concentration is inhibitory. This results from a dire*
effect of potassium on the adrenal glands rather than an indirect, renm-mediated
mechanism, because a high potassium level suppresses and a low potassium level
stimulates renin secretion. This interrelation between potassium and aldosterone
appears to present an important feedback control mechanism for the regulation
C
D;o
a 70-kg person, showing the.relationship
Fla 3-1. Normal potassium homeostasis for
^distribution
in body compartments.
between potassium intake, output, and _:e-’
!
Altered trunscellular distribution
iustments maintain potassium balance despite variations in sodium intake. In
fact an acute potassium load is excreted more readily on a low than on a high
sodium diet, in apparent contrast to the influence of acute changes in sodium
excret.on on potassium. This probably results from the higher aldosterone level
Excretion of poorly reabsorbable anions such as sulfate
kaliuresis. An increase in the negative transtubular voltage across the epithelium
of the distal nephron (by providing a more favorable electrochemical gradient for
potassium movement into the tubular lumen) and an increase in tubu ar flow
rate both may increase potassium secretion. In addition, recent studies indicate
timt a decreased chloride concentration in distal tubular fluid directly promotes
net potassium secretion by this segment -of the nephron.
D’ 1ACsXmic pH. Changes in systemic pH appear to alter the potassium content
of the renal tubular cell in a manner analogous to the effect on other tissues
(i e acidosis decreases and alkalosis increases intracellular potassium).
There is evidence indicating that acute acidosis decreases^potassium^etion
via this mechanism, whereas alkalosis acts in the opposite fashion. Howevei^
this effect is transitory and overridden by other factors when the acid-base
abnormality is sustained. Chronic metabolic acidosis is usually accompanied
bv mild potassium depletion; chronic respiratory acidosis and alkalosis, b>
little change in total body potassium; and chronic metabolic alkalosis, by severe
2 Armnonia metabolism. A relation between potassium and renal ammonia me
tabolism has been elucidated. Potassium depletion stimulates renal ammonia
production, whereas a high potassium intake is inhibitory. Enhanced ammonia
production and excretion in the urine decrease potassium cxeretion possib y
by favoring hydrogen ion and thereby diminishing potassium secretion. This
mav be an additional feedback mechanism for control of potassium excretion,
but its quantitative importance has not been clearly defined.
Dietary potassium. Finally, the renal capacity to excrete or retain potass.um is
E. influenced bv the daily potassium intake. The kidney possesses substantial flex
ibility in potassium handling, with the capacity to excrete up to 10
(700 mEq for a 70-kg man'day) or less than 10 mEq per day. Several days are
Ingestion of Ttagh potassi’^’di'et increases aldosterone and the enzyme Na-K-
ATPase which promotes potassium entry into renal tubular cells. This adapted
kidney has an enhanced capacity to excrete potassium, and the adapted person
has an increased ability to survive an otherwise lethal
ingestion of a low potassium diet, urinary potassium excretion diminishes to.less
than 10 mEq per day within a week. The early potassmm-conserving response
appears to depend, at least in part, on a decrease in plasma aldosterone concern
tration; alter several days, however, the mechanism is independent of the
and involves an intrinsic adaptive response by the kld«eys. The precise cell
mechanism responsible for low K‘ adaptation is undefine .
Considering the multitude of factors influencing renal potassium excretion, it k
3: The Patient With Hypokalemia
34
-I
3: The Patient With Hypokalemia or Hyperkalemia
not surprising that a variety of pathologic events can modify renal potassium
handling. Furthermore, when potassium homeostasis is altered by extrarenal
i phenomena, appropriate and effective modification of renal potassium excretion
transpires.
Hypokalemia
□
r
Hvperkalemia
Serum K'
(mEq/Ll
U — 5.0-6 5
T
Normal
P-R
Hypokalemia
T
>6.5
u
I. Clinical setting. Hypokalemia occurs as a result of (a) factors that influence the
transcellular distribution of potassium, (b) total body potassium depletion, or (c) a
combination of these phenomena. Th^most common cause of hypokalemia secondary
to altered transcellular distribution is alkalosis, either respiratory or metabolic, but
it also occurs with exogenous glucose or insulin administration. True potassium def
icits result from gastrointestinal or renal losses and, rarely, sweat losses. Hypokalemia
should be anticipated with loss of either upper or lower gastrointestinal tract se
cretions; tKe common renal causes are diuretic therapy or states of excess miner
alocorticoid secretion. Potassium depletion is frequently seen in association with
metabolic alkalosis, since common mechanisms underlie the development of both
disorders.
II. Signs and symptoms. The important manifestations of hypokalemia are given in
Table 3-1. The major symptoms result from aberrations in membrane polarization
that affect function of both neural and muscular tissue.
1
P-R
R
>8.0
s
-----------------
'
f
.i
I
T
_ _________ ]
■
<p wave is flattened and the
a
l i
Table 3-1. Clinical manifestations of hypokalemia
Cardiac
Predisposition to digitalis intoxication
Abnormal ECG
Atrial and ventricular ectopic beats
Cardiac necrosis (rare)
Hemodynamic
Decrease in blood pressure
Decreased pressor response to angiotensin II
Neuromuscular
GI: constipation, ileus
z
Striated muscle: weakness, paralysis
Life-threatening respiratory paralysis
Rhabdomyolysis
Kidney
Decrease in GFR and renal blood flow
Polyuria and polydipsia
Concentrating defect
Stimulates thirst
Increased renal NH3 production
Predisposition to hepatic coma
Sodium retention
v
Hyponatremia (with concomitant diuretic therapy)
Chloride wasting
Metabolic alkalosis
Endocrine
Decrease in aldosterone
Increase in renin
Increase in prostaglandins (possible)
Decrease infinsulin
Carbohydrate intolerance
cardiac arrest is imminent.
however, hypokalemia increases the ses I« g into^.ation. For this reason, po-
motensive and hypertensive animals and^may na^ a
“■ “““
^3
J®
^3
9
&
I
diminished vascular
"
,
n -
C.
"m is less than 3.0
with hypokalemia can be manifested in .
XrSties can vary from^Id
emng respiratory paralysis -The latter^
D.
ssstf
p
te
frank ileus. Striated muscle
n paralysis, with life-threatP* &
—m condepietion a so predisposes
,
36
3: The Patient With Hypokalemia or Hyperkalemia
yv -
the development of severe chronic renal failure. Myoglobinuria-induced acute
renal failure represents the other serious renal complication induced by potassium
depletion. The most commonly recognized defect of hypokalemia is an inability
to concentrate the urine maximally, but potassium depletion also directly stim <■>
ulates thirst. This combination results in polydipsia and polyuria, which can
sometimes provide a clue to underlying potassium depletion but seldom is of a
magnitude to require specific clinical attention.
I
Renal ammonia production is stimulated by potassium depletion. This may explain
why hypokalemia can provoke hepatic coma in patients with cirrhosis. Increased
ammonium excretion also accounts for a higher than normal urine pH. Potassium
depletion promotes sodium retention and may predispose toward edema formation
under certain circumstances. Although potassium depletion has been incriminated
as a cause of hyponatremia in association with diuretic use, the clinical importance
of this effect has not been clearly defined. Severe potassium depletion appears to
result in renal chloride wasting. This abnormality may account for the devel
opment of metabolic alkalosis with severe depletion (serum potassium less than
2.0 mEq/L).
E. Endocrine. Th^ levels of several hormones are modified by potassium depletion.
Aldosterone is depressed, but this is probably a physiologic control mechanism.
Hypokalemia also elevates plasma renin activity (PRA). Stimulation of the vas
cular receptor secondary to renal vasoconstriction and an effect on the macula
densa both may account for the increase in hypokalemia-induced PRA. When the
potassium deficit is severe, pancreatic insulin release is inhibited; this probably
accounts for the abnormal carbohydrate tolerance of potassium-depleted patients.
This phenomenon may complicate management of the diabetic patient and oc
casionally may contribute to a false diagnosis of diabetes mellitus.
III. Differential diagnosis. By employing a systematic approach to the patient in whom
hypokalemia is identified, it should be possible to identify the cause in the majority
of instances. The important clues are derived from the clinical setting and certain
key laboratory parameters, including plasma acid-base values and urinary potassium
and chloride measurements. In some instances an assessment of the renin-angiotensinaldosterone system is indicated. The presence or absence of hypertension may be
helpful in the differential diagnosis.
A. Pseudohypokalemia. Potassium concentration can be lowered spuriously if a blood
specimen with a high WBC count (> 105/ml) is stored at room temperature. The
fall in plasma or serum potassium, which is caused by uptake by the leukocytes,
can be prevented by prompt separation of plasma or serum.
B. Hypokalemia secondary to redistribution. The first question is whether a low
serum potassium concentration reflects an alteration in distribution or results
from a true potassium deficit. The causes of altered transcellular distribution are
as follows:
1. Alkalosis. Alkalosis is identified by measurement of plasma pH (either arterial
or venous) and determination of either total COa or PCO2. The rough guide
line—a o.l unit increase in pH results in a 0.4 mEq per liter or less decrease
in serum potassium—gives some indication of whether the hypokalemia results
solely from altered transcellular distribution. Chronic respiratory alkalosis
does not result in potassium depletion, but metabolic alkalosis is usually as
sociated with a substantial potassium deficit.
2. Insulin excess. Insulin administration can decrease serum potassium con
centration. More commonly, an acute glucose load promotes insulin release
and hypokalemia.
3. Beta-adrenergic agonists. Systemic administration of drugs with B2-agonist
properties (e.g., epinephrine, salbutamol, terbutaline) can decrease the serum
potassium concentration.
4. Hypokalemic periodic paralysis. Hypokalemic periodic paralysis is a rare he
reditary disorder with autosomal dominant transmission. It is characterized
by recurrent attacks of flaccid paralysis affecting the trunks and limbs, which
last for 6 to 24 hours. Attacks are accompanied by hypokalemia caused by
redistribution of potassium into cells.
».
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4;
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1
3
3
3
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---3: The Patient With Hypokalemia or Hyperkalemia
37
5. Barium poisoning. Barium poisoning, caused by ingestion of acid-soluble bar
ium salts, can produce flaccid paralysis and hypokalemia, which appear to
result from potassium redistribution into cells. Associated vomitihg and diar
rhea differentiate it from periodic paralysis.
6. Toluene intoxication. Toluene intoxication commonly causes severe hypoka
lemia, often associated with severe muscular manifestations. In part the hy
pokalemia may result from redistribution of potassium into cells, although
renal potassium wasting secondary to acquired renal tubular acidosis may
also nlay a role.
>
Altered transcellular distribution clearly can coexist with a change in total body
potassium. This should be anticipated in patients with metabolic alkalosis. Con
versely, with severe acidosis the serum potassium may be normal in the presence
of a potassium deficit. This can be confirmed by monitoring serum potassium as
the acidosis is corrected. Diabetic ketoacidosis is a classic example of this phe
nomenon.
•
ri .
C. Potassium depletion. Hypokalemia unaccounted for by redistribution reflects a
true potassium deficit. The cause should be defined not only to guide therapy,
but also because it may provide a diagnostic clue to some other clinically important
disorder.
.
.
A flow diagram for the diagnostic approach to hypokalemia is shown m r igure
3-4. The first step is to determine whether the potassium loss has a renal or
extrarenal cause.
...
1. Extrarenal potassium loss. If the primary source of potassium loss is extrarenal
and the deficit has persisted for several days, evidence of effective renal po
tassium conservation should be present. Urinary potassium excretion should
be less than 20 mEq per day. The potassium concentration of a spot urine can
be misleading because of the associated polyuria; however, a fractional po
tassium excretion (FEK) of less than 6 percent or a potassium (mEq/L)-creatinine (grams) ratio of less than 20 may be useful for a more rapid but less
precise assessment of urinary potassium handling.
The most common causes of extrarenal potassium depletion are losses from
the lower gastrointestinal tract, which also result in metabolic acidosis because
of bicarbonate loss. Overt diarrhea does not present a difficult diagnostic prob
lem, nor does copious drainage from a fistula or villous adenoma. Chronic
laxative abuse can pose problems of diagnosis because the patient may not
admit to use of these agents. Patients with villous adenoma and laxative abuse
may also present with a normal acid-base picture or with metabolic alkalosis.
Other extrarenal causes are less common. Inadequate potassium intake in the
absence of concomitant gastrointestinal problems is an unusual cause of hy
pokalemia, but it can be seen with anorexia nervosa or in the elderly patient
on a tea and toast diet. Potassium depletion from severe perspiration produces
an unusual clinical picture, with normal serum potassium levels and high
rates of urinary potassium excretion despite substantial cellular potassium
depletion. The explanation for these findings is unclear.
2. Renal causes of potassium depletion. In the hypokalemic patient a renal
cause of potassium wasting should be anticipated if the urinary potassium
exceeds 20 mEq per day. As shown^in Figure 3-4, the differential diagnosis
can be approached by initially segregating the causes according vo the acid
base status of the patient.
a. With metabolic acidosis. Renal potassium wasting with an accompanying
acidosis can be seen in diabetic ketoacidosis, with either the proximal or
distal forms of renal tubular acidosis (RTA), or as a result of therapy with
carbonic anhydrase inhibitors (e.g., acetazolamide), which produce a clinical
picture similar to RTA. Distal RTA is associated with a hyperchloremic
acidosis, inability to acidify the urine, and renal stones or nephrocalcinosis
distributed in a medullary pattern. Although uncommon, its initial pre
sentation may be severe potassium depletion with paralysis. Proximal RTA
has a similar electrolyte pattern, but the urine can be acidified and ne
phrocalcinosis does not occur. It is usually accompanied by other mam-
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39
festations of proximal tubular dysfunction (hypouricemia, hypophospha
C
i| i |
Ol Oil
|
3: The Patient With Hypokalemia or Hyperkalemia
as
. ^.i-
corticoid-induced cause for the hypokaienue alkalosis
(b) Mineralocorticoid excess. All the abnormalities m this category
S===F?==1=
-r»■ t&nsansxsls:K“ x
^msho^d be measured as a reflection.of sodiuir^Uk^^
on both a high and low sodium diet may be necessary. -«
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I
Renal K‘ loss
(urine K’ > 20 mEq/day)
Metabolic alkalosis
High urine Cl"
10 mEq/day)
(urine Cl~ > 1*
Low urine Cl(urine CP < 10 mEq/day)
Mineralocorticoid excess
1. Vomiting or
gastric drainage
2. Diuretics
3. Post-hypen apneic
4. Congenital Cl
losing dian hea
'
‘
BP1
__
Other
__________
1. Diuretics
2 Banter’s
syndrome
3. St; vere K
depletion
L*>u- or normal
aldosterone
High aldosterone
High renin
Lou renin
1
1. Renovascular
hypertension
2. Malignant
hypertension
3. Renin-secreting
tumor
Primary
hyperaldosteronism
A. Adenoma
B. Hyperplasia
Fig. 3-5. Differential diagnosis of hypokalemia secondary to renal causes.
1. Excess DOC or
corticosterone
2. Glycyrrhizic acid
(licorice)
3. Liddle's syndrome
4. Cushing’s syndrome
5. Ectopic ACTH
t BP: high (blood pressure.
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mA
3: The Patient With Hypokalemia.orjlyperkalenua
42
43
3: The Patient With Hypokalemia or Hyperkalemia
with magnesium depletion is undefined, but serum and urine
magnesium should be measured when the cause of hypoka
lemia is unclear.
iV. Therapy
A. Established potassium deficiency. Treatment of established potassium deficiency
requires a decision regarding (a) the type of potassium salt, (b) the route of re
placement, and (c) the quantity and speed of drug administration.
1. Type of potassium salt. The patient with metabolic alkalosis who is chloride
as well as potassium depleted requires potassium chloride for effective cor
rection of the potassium defidit. With the combination of metabolic acidosis
and a potassium deficit, potassium with bicarbonate or metabolic precursors
of bicarbonate (gluconate, acetate, citrate) is preferable. The diabetic in ke
toacidosis is usually phosphate depleted as well as potassium depleted, so
potassium phosphate is the most rational therapy. When the cause of the po
tassium depletion is unclear, potassium chloride is the best choice because it
effectively corrects all forms of potassium depletion.
With primary hyperaldosteronism, sodium restriction concomitant with po
tassium supplementation is needed to correct the potassium deficit. Alter
natively, the aldosterone antagonist, spironolactone, can be used to correct
the hypokalemia. As a general rule, the concomitant administration of po
tassium supplements and potassium-sparing diuretics should be avoided, be
cause of the risk of hyperkalemia.
2. Route of replacement. Oral replacement is generally desirable. The exceptions
are severe, symptomatic potassium depletion that requires more rapid cor
rection or the inability of the patient to tolerate oral medication.
3. Quantity and speed. The guidelines cited earlier (sec. I.E.) can provide an
estimate of the amount of potassium depletion; however, adequate replacement
is determined by monitoring the serum potassium value during therapy.
In the patient without paralysis, digitalis intoxication, or hepatic coma, it is
preferable to replace potassium at a slow rate. Oral potassium or, if necessary,
intravenous administration in dosages of 80 to 120 mEq per day is usually
satisfactory, and with very minimal depletion even 40 mEq per day may suffice.
When intravenous therapy is employed in a nonurgent setting, the potassium
concentration of intravenous fluids should not exceed 40 mEq per liter, and
the rate of administration should not exceed 10 mEq per hour.
If urgent treatment is required (digitalis intoxication, paralysis), potassium
can be administered more rapidly but should not exceed 40 mEq per hour. In
this circumstance ECG monitoring in an intensive care unit is advisable. Po
tassium concentrations greater than 40 mEq per liter should be administered
into a large vein to avoid phlebitis, but central (intracardiac) administration
should be avoided because of the danger of cardiac arrhythmias.
B. Potassium replacement with diuretic therapy. In the majority of patients receiving
thiazides or loop diuretics for antihypertensive therapy, severe potassium depletion
does not develop. Although, prophylaxis is therefore not warranted, the serum
potassium should be monitored. If the serum potassium decreases to less than
3.0 mEq per liter, or if the patient develops symptoms attributable to potassium
depletion, replacement therapy is advisable. Patients receiving cardiac glycosides
or with cardiovascular disease may require potassium supplements with a plasma
potassium between 3.0 and 3.5 mEq per liter.
Patients receiving diuretics for edema may be more prone to potassium depletion,
and potassium supplementation seems advisable. It is indicated for patients who
are susceptible to hepatic coma.
Liquid potassium chloride preparations are probably the therapy of choice, but
wax matrix potassium chloride (slow-K) is a suitable substitute if the liquid form
is not, tolerated. The salt substitutes that contain potassium chloride are the least
expensive option for potassium replacement. An alternative is the use of the po
tassium-sparing diuretics, spironolactone, triamterene, or amiloride. These di
uretics are the preferred therapy in the patient with fluid retention secondary
to hepatic disease.
i
8
C. Complications
i
a.
b.
rXial'rS^h'^ wax matrix preparations in the presence of
c. « ^^^tXS intravenous potassium mfusion.
2.
£ '4
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triamterene.
4
Hyperkalemia__
I. Clinical setting. Hyperkalemia shoukI be
af^Xn“es^!ly w'ithU^e
Sn^or^^XTo^s-m^oad; Other ^disposing factors are mineral-
ocorticoid deficiency, insulin de^cienc^®Il ^ical manifestation of hyperkalemia
The sequence of ECG
II.. Signs and symptoms. The most
>».
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c&
paralysis, but cardiotoxicity usually precedesand glucagon
C ..4
III.
C J
entiate between a spurious’ >a^^4e“™ur^ly ^i^iga3-6)- Because
"nic°al ^"Z^h^erkalenua relate to the Ke/Ki ratio, the latter two
j
3
molyzed specimen. With severe degr
Dlatelets during clotting or from
cytosis (> 105/ml), potassium released from the Plat^
potassium
the white blood cells during storage in e
ECG
normal The potassium
determination. Under these circumstances thethrombocytosis and if
will be normal if a heparinized specimen,1s
the plasma is promptly
serum potassium conce
B. Redistribution. Acidosis tend> to elevate the seru p
smaller rise
largest increase occurs
acId-indueed
r
Hara
If
Hyperkalemia
Potassium retention
Redistribution
Pseudohyperkalemia
1. Acidosis
2. 1 insulin
3. Beta-adrenergic blockade
4. Arginine infusion
5. Succinylcholine
6. Digitalis overdose
t massive)
7. Periodic paralysis
1. Hemolysis
2. Thrombocytosis
3. Leukocytosis
GFR > 20 ml/min
GFR < 5 mh'min
1
Oligoanuria
iany etiology)
2. Potassium loud
A Exogenous
B Endogenous
(1) Tissue necrosis
(2) Hemolysis
(3^ Hypercatabolism
Normal or hiah aldotltrant
1, Primary tubular disorders
A. Acquired
(1) Renal transplant
(2) Lupus erythematosus
(3) Amyloid
(4) Sickle cell
(5) Obstructive uropathy
B. Hereditary
2. Drugs
A. Spironolactone
B. Triamterene
C. Amiloride
Low aldosterone
1 Addiwin’s diuease
2 Hyporeninemic
hypoaldosteronism
3. Drugs
A. PG synthetase
inhibition
B. Captopril
C. Heparin
|____________________ _ _______________________ —--------- —---------------—----- T—----------- - —
Fig. 3-6. Differential diagnosis of hyperkalemia. PG: prostag an in.
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46
3: The Patient With Hypokalemia or Hyperkalemia
3: The Patient With Hypokalemia or Hyperkalemia
this condition may represent the converse of Bartter’s syndrome, with enhanced
sodium chloride reabsorption at some site proximal to the aldosterone exchange
site, and these cases have been called pseudohypoaldosteronism, type II.
T’
4. Drug-induced hyperkalemia
a. Spironolactone. Spironolactone causes hyperkalemia by antagonizing the
effects of aldosterone.
b. Triamterene and amiloride. Both of these drugs inhibit potassium secretion
by an aldosterone-independent mechanism.
IV. Therapy. Treatment of hyperkalemia is dictated by the level of serum potassium
and by the findings on ECG. Every hyperkalemic patient should have an immediate
ECG. If the ECG findings reflect an> changes attributable to hyperkalemia other
than peaked T waves, or if the serum potassium exceeds 6.5 mEq per liter, aggressive
and prompt therapy should be instituted.
A. Acute hyperkalemia. This condition includes acute measures to counteract the
effect of potassium on membranes and to shift it into cells, as well as definitive
procedures to remove potassium from the body. The uses of calcium gluconate,
sodium bicarbonate, and glucose plus insulin are detailed in Table 3-3. These
substances act quickly and provide time for definitive therapy (i.e., the removal
of excess potassium from the body). This removal of potassium can usually be
accomplished successfully with the use of the cation exchange resin, sodium pol
ystyrene sulfonate (Kayexalate). Kayexalate can be given either orally or as a
retention enema.
1. P.O. Forty grams of Kayexalate plus 20 ml (70%) sorbitol. Each gram removes
approximately 1 mEq of potassium. Repeat every 2 to 4 hours as required until
serum potassium is in the normal range.
2. Enema. Fifty to one hundred grams of Kayexalate in 200 ml water, by retention
enema. Insert via Foley catheter and inflate balloon to ensure retention for
30 to 45 minutes. Each gram removes approximately 0.5 mEq of potassium.
Repeat every 2 to 4 hours as required.
3. Dialysis. Dialysis'is rarely required to manage hyperkalemia, since cation
exchange resins work so effectively. On occasion, however, such as after colonic
surgery or when the rate of endogenous potassium release is massive (crush
injuries), dialysis may be required.
a. Hemodialysis. Hemodialysis can remove as much as 25 to 30 mEq of po
tassium per hour.
b. Peritoneal. This technique is significantly less efficient, with the capacity
to remove only 10 to 15 mEq of potassium per hour.
B. Chronic hyperkalemia. Chronic and more modest elevations of serum potassium
can be managed in several ways, depending on the underlying pathogenesis.
Table 3-3. Treatment of Acute Hyperkalemia
47
1. Kayexalate. Kayexalate is effective in any setting and need not be given with
sorbitol, which patients find unpleasant. An effective, less potent cathartic
such as bisacodyl (Dulcolax) tablets can also be used.
,
2 Mineralocorticoids. Mineralocorticoid deficiency can be treated with exogenous
mineralocorticoids. A high salt diet and Florinef are indicated m Addison s
disease. With hyporeninemic hypoaldosteronism, mineralocorticoids usually
decrease hyperkalemia, but sodium retention and hypertension may be un
desirable side effects.
,
3 Diuretics. Diuretics such as furosemide may reduce hyperkalemia in hypo
reninemic patients. There is a suggestion that thiazides may be effective in
certain patients with renal tubular disorders, but this observation is not firmly
4. Intake reduction. Reduction in dietary potassium intake is always appropriate.
Suggested Reading
Adrogue, H. J., and Madias, N. E. Changes in plasma potassium concentration during
acute acid-base disturbances. Am. J. Med. 71:456, 1981.
Cox, M., Stearns. R. H., and Singer, I. The defense against hyperkalemia: The roles
of insulin and aldosterone. N. Engl. J. Med. 299:525, 1978.
Issues Nephrol. 2:205, 1978.
Gabow, P. A., and Peterson, L. M. Disorders of Potassium Metabolism. In R. W.
Schrier (Ed.), Renal and Electrolyte Disorders (3rd ed.). Boston: Little, Brown. In
<9
press.
Gennari, F. J., and Cohen, J. J. Role of the kidney in potassium homeostasis: Lessons
from acid-base disturbances. Kidney 1 nt. 8:1, 1975.
Kassirer, J. P., and Harrington, J. T. Diuretics and potassium metabolism: A reas
sessment of the need, effectiveness, and safety of potassium therapy. Kidney in .
11:505, 1977.
Schambelan, M., Sebastian, A., and Hulter, H. N. Mineralocorticoid excess and deficiency syndromes. Contemp. Issues Nephrol. 2:232, 1978.
Schwartz, W. B„ van Ypersele de Strihou, C., and Kassirer, J. P. Role of anions in
metabolic alkalosis and potassium deficiency. N. Engl. J. Med. 279:630, 1968.
<3
C <
Antagonize membrane
effects
Redistribute
Calcium gluconate (10-30 ml of
10% solution)
NaHCO-, (44-132 mEq)
Glucose (50 gm) + regular insulin
(10 U)
Cation exchange resin: sodium
polystyrene suflonate (Kayexalate)
Enema (50-100 gm)
Oral (40 gm)_
Few minutes
New York: Wiley, 1983. Vol. 6, p. 151.
Tannen, R. L. Potassium and blood pressure control. Ann. Intern. Med. 98 (Part
15-30 minutes
15-30 minutes
2):773, 1983.
van Ypersele de Strihou, C. Potassium homeostasis in renal failure. Kidney Int. 11.491,
Dialysis
Hemodialysis
Peritoneal
1977.
Wright, F. S., and Giebisch, G. Renal potassium transport: Contributions of individual
nephron segments and populations. Am. J. Physiol. 235:F515, 1978.
60 minutes
120 minutes
Few minutes after start
Few minutes after start
I!
IH ...
Kidney I nt. 11:453, 1977.
Tannen, R. L. Potassium Metabolism. In H. C. Gonick (Ed.), Current Nephrology.
Onset of action
I
II
Tannen, R. L. Relationship of renal ammonia production and potassium homeostasis.
Treatment
I
! !
Stems, R. H., Cox, M., and Feig, P. U. Internal potassium balance and the control
of the plasma potassium concentration. Medicine. 60:339, 1981.
Mechanism
Remove
b
Cronin, R. E., and Knochel, J. P. The consequences of potassium deficiency. Contemp.
*3
/
I
I i
*
t
J i
?
The Patient With Abnormal
Plasma Bicarbonate,
Arterial PCO2, or pH
Jordan J. Cohen
ei a
‘ A
Disturbances of acid-base equilibrium are extremely common m clinical Practice,
especially among hospitalized patients. Their presence may be suspected on the basis
of bedside appraisal, but, in the final analysis, accurate diagnosis and appropriate
management require reliable laboratory data.
The carbonic acid-bicarbonate buffer system is the keystone to the understanding
and classification of acid-base disturbances. The following equations are used to de
scribe the equilibrium state of this buffer system in blood:
el
[H ] (nEq/L) = 24
’1
/
i
r
pH
«5 5
«; -3
C
3
C
!
I
I
- |i
I
i
?*
ci *
’
6.1 + log
PaCO2
[HCOa’l
[HCO3-]
0.3 x PaCO2
Henderson equation
Henderson-Hasselbalch equation
These are equivalent mathematical expressions differing only in the units chosen
to express blood acidity-nanoequivalents per liter of hydrogen ion in one and pH
in the other (Table 4-D. In each case, carbonic acid concentration is expressed as
ihe partial pressure of carbon d.oxide (PaCO2) in mm Hg, and plasma bicarbonate
conontration is expressed directly in mEq per liter In normal people, arterial carbon
dioxide tension and plasma bicarbonate concentration average approximately 40 mm
Hg and 24 mEq per liter, respectively. Consequently, normal arterial hydrogen ion
is approximately 40 nEq per liter, (pH 7.4). It is apparent from either equation that
aciditv is determined by the ratio of these two physiologic variables. Thus, analyss
of acid-base disturbances requires identification of the pathophysiologic events
i.
from the arterial blood are preferred. The most accessible sites for direct arterial
puncture are the brachial, radial, and femoral vessels. When frequent assessment
of acid-base equilibrium is required, it may be preferable to place an inlying artenal
catheter rather than risk multiple arterial punctures. Venous blood *awn without
stasis and free-flowing capillary blood obtained by finger stick (especially in infants
and voung children) may be used, if necessary.
Blood samples for PCO2 and pH measurements must be prevented from clotting
Heparin is far superior to any other anticoagulant for this purpose because the smm
quantity required has a negligible effect
acid-base composition. Care must be
taken to avoid even brief exposure of the blood sample to air to avoid loss of carbon
dioxide. Even when anaerobic conditions are maintained during blood sampling,
continued cellular metabolism in vitro tends to alter the acid-base status of the spec
imen. For this reason, measurements should be made immediately or the specimen
should be cooled (e.g., by immersing the syringe in crushed ice) before it is transported
to the laboratory. Even with this precaution, measurements should be made within
1 hour after sampling.
,
,
Both hydrogen ion concentration (pH) and carbon dioxide tension can be measured
directly bv standard electrochemical techniques. Bicarbonate concentration is gen
acidified
serum
erally estimated from the total carbon dioxide (tCO2) released from an aci_i
---- sen
’”’
49
50
4: The Patient With Abnormal Plasma Bicarbonate, Arterial PCO2, or pH
a?
4: The Patient With Abnormal Plasma Bicarbonate, Arterial PCO2, or pH
Table 4-1. Equivalent Values for pH and Hydrogen Ion Concentration
pH
[H]
nEq/L
7.70
7.65
7.60
7.55
7.50
7.45
7.40
7.35
7.30
7.25
7.20
7.15
7.10
7.05
7.00
6.95
6.90
6.85
6.80
20
22
25
28
32
35
40
45
50
56
63
71
79
89
100
112
126
141
158
sample; approximately 95 percent of the carbon dioxide released is derived from
bicarbonate ions under virtually all circumstances. Measurement in the same blood
sample of any two of the three acid-base variables is, of course, sufficient to permit
calculation of the third. Normal acid-base values are as follows:
Plasma [HCO3 ]
PaCO2
Plasma [H*]
pH
24-26 mEq/L
39—43 mm Hg
39-42 nEq/L
7.38-7.41
II. Definitions and terminology
.
r
,
A. Acidemia and alkalemia. Acidemia and alkalemia signify increase and decrease
in hydrogen ion concentration, respectively (or decrease and increase in pH). Ab
normalities of acid-base equilibrium can be initiated by changes m either PaCO2
or plasma bicarbonate concentration. When an increase or decrease in PaCU2
initiates the disturbance, it is referred to as respiratory acidosis or respiratory
alkalosis, respectively. When changes in bicarbonate concentration initiate the
disturbance, it is called metabolic acidosis or metabolic alkalosis. Each initiating
(primary) process, whether respiratory or metabolic, sets in motion secondary
physiologic responses that alter the level of the opposing variable. The metabolic
disturbances produce a ventilatory response that rapidly alters PaCO2 and min
imizes the impact on acidity. The respiratory disturbances result in an immediate
titration of tissue buffers that acutely alters the level of bicarbonate. It the res
piratory disturbance-js prolonged (a few days or more), changes in renal acid
excretion and bicarbonate reabsorption occur that result in additional adjustments
in acid-base equilibrium. The respiratory disturbances are, therefore classified
as either acute or chronic. In the absence of confounding factors, each of these
secondary physiologic responses (ventilatory, buffer, and renal) is roughly pro-
€
*
e tv
e -
51
portional to the magnitude of the initiating, primary disorder. Thus, a range of
anticipated physiologic responses can be anticipated for each class of acid-base
disturbance.
B. Simple and mixed acid-base disturbances. A simple acid-base disturbance de
notes the presence of one primary process, coupled with its appropriate physiologic
response. A mixed acid-base disturbance refers to the coexistence of two or more
primary processes. Since these processes may have either additive or nullifying
effects on plasma acidity, mixed acid-base disturbances may produce extreme
deviations in hydrogen ion concentration on the one hand, or minor or undetectable
deviations on the other hand.
111. Recognition of ecid-base disturbances
A. Clinical settings. The presence of an acid-base disturbance can never be definitely
established without appropriate laboratory confirmation. Nevertheless, there are
certain clinical settings in which acid-base disturbances occur so frequently that
the index of suspicion should be quite high (Table 4-2).
B. Clinical signs. Occasionally, an acid-base disturbance is first suspected on the
basis of clinical signs. Thus, acidemia may present as hypotension, hypercapnia
as obtundation, and alkalemia as paresthesias, tetany, or convulsions. Hyper
ventilation may be the first clue to the presence of metabolic acidosis or primary
respiratory alkalosis. It is much more frequently the case, however, that acid
base disturbances are discovered serendipitously because of abnormalities in bi
carbonate concentration detected by routine serum electrolyte determinations.
e
I
■
i
h
Table 4-2. Clinical Settings Commoniy Associated with Acid-base Disturbances
Respiratory
Metabolic
3
Clinical Setting
Acidosis
Sepsis
X
£
:1
is
Acidosis
Alkalosis
X
Renal failure
Cardiopulmonary arrest
C .4
Alkalosis
Gastric-suction.'vo'miting
Diarrhea
Small-bowel or biliary drainage
Diabetes mellitus with ketonuna
Airway obstruction
X
X
X
X
X
X
x'
X
Chronic obstructive pulmonary
disease
Hepatic insufficiency
Recent alcoholic binge
Drugs
Diuretics (overt, surreptitious)
Carbonic anhydrase inhibitors
(glaucoma)
Amphotericin B
Ammonium chloride
Salicylates (overdose)
Sedatives (overdose)
Poisons
Methanol
Ethylene glycol
Paraldehyde
X
X
X
X
X
X
X
X
X
X
X
X
X
X
/
I
tn
M
«
I
\
Average Relation*~
’
Primary Change
Secondary Response
APaCO- = 12 A[HCO:» 1
Disorder
Metabolic acidosis
UHCQ, 1
Metabolic alkalosis
1(HC0i 1
Respiratory acidosis
JPaCOz
tlHCO:, 1
lPaCO2
llHCO:t )
Respiratory alkalosis
RH-HlpH)
!PaCO>
HH' I (IpH)
APaCO. = 0.7 AlHCOu 1
Acute: A| HM ' 0-75 APaCO,
Chronic: AlHCO. J = 0.35 APaCO,
UITKtpH)
Acute: A|H+1 = 0.75 APaCO,
Chronic: A[HCO,1 = 0.50 APaCO,
IlH'litpH)
| PaCO.
med that arid-base vahto. are given in the following units of measure: PaCO. mm
*In these relations it is assu:
7
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_t___ a- -
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54
4: The Patient With Abnormal Plasma Bicarbonate, Arterial PCO2, or pH
4: The Patient With Abnormal Plasma Bicarbonate^ Arterial PC02, or pH
55
1
(1) Distal renal tubular acidosis. In distal renal tubular acidosis, the terminal segments of the nephron are unable to sustain a large transepithelial hydrogen ion concentration gradient. As a consequence,
urinary hydrogen ion concentration remains relatively low (pH greater
than 5.5) even after acid loading. Both the acidosis and the frequently
associated hypokalemia generally are corrected by daily alkali therapy.
Growth retardation in youngsters can also be corrected by adequate
alkali administration. Distal renal tubular acidosis may be primary
(idiopathic) or secondary. Among the disorders frequently associated
with secondary’ distal^renal tubular acidosis are hyperglobulinemic
states, Sjogren’s syndrome, sickle cell disease, hypercalcemia, ampho
tericin toxicity, toluene toxicity (glue or paint sniffing), and lithium
toxicity.
(2) Proximal renal tubular acidosis. In proximal renal tubular acidosis,
the proximal tubule is unable to to sustain a normal rate of bicarbonate
reabsorption. The urinary acidification process in the distal nephron
is normal but may be obscured by the increased delivery of bicarbonate
from the proximal tubule. Even large doses of administered bicarbonate
may be ineffective in fully correcting the acidosis because the admin
istered alkali is not conserved by the kidney and escapes rapidly into
the urine. Proximal renal tubular acidosis is frequently associated with
other proximal tubular transport defects (e.g., Fanconi’s syndrome) and
may be seen either in association with certain errors of metabolism
(cystinosis, Wilson’s disease* or as a consequence of heavy metal toxicity,
outdated tetracycline, multiple myeloma, dysproteinemia, nephrotic
syndrome, or transplant rejection. A mild form of proximal renal tubular
acidosis may be seen in primary or secondary hyperparathyroidism.
c. Tubulo-interstitial renal diseases. Tubulo-interstitial renal diseases (pye
lonephritis, analgesic abuse nephropathy, acute or chronic transplant re
jection) are often accompanied by hyperchloremic metabolic acidosis because
of the presence of tubular dysfunction out of proportion to glomerular in
sufficiency. A mild degree of hyperchloremic acidosis often accompanies
hyporeninemic hypoaldosteronism associated with mild diabetic or inter
stitial renal disease.
d. Administration of ammonium chloride. Administration of ammonium
chloride or of the cationic amino acids,, lysine and arginine (e.g., some forms
of parenteral nutrition), can cause hyperchloremic acidosis because these
substances yield hydrochloric acid when metabolized.
2. Increased anion gap
a. Lactic acidosis. Lactic acidosis is a very frequent cause of life-threatening
metabolic acidosis. The overproduction of lactic acid results most often
from an interference with oxidative metabolism. Because hepatic use of
lactate produced by peripheral tissues can regenerate the bicarbonate ion
dissipated by this acid, the presence of hepatic dysfunction, which is fre
quent in patients with lactic acidosis, may contribute importantly to the
severity of the acid-base disturbance. Lactic acidosis may occur in asso
ciation with severe tissue hypoxia (shock, low cardiac output states, very
severe anemia) bowel infarction, alcoholism, diabetes mellitus (with or
without ketoacidosis), and certain types of leukemia. Lactic acidosis may
develop without a recognized cause (“spontaneous”), especially in chron
ically ill, debilitated patients. A firm diagnosis can be made only if the
serum lactate level is found to be elevated. Even in the absence of a lactate
determination, however, a strong presumptive diagnosis can be advanced
if the undetermined anion concentration is clearly elevated and all of the
other recognized causes of anion gap acidosis have been excluded.
The only satisfactory treatment for lactic acidosis is removal of the un
derlying cause. The efficacy of oxidizing agents (methylene blue) or potent
vasodilators (sodium nitroprusside) as a means of improving the redox state
of cells remains to be confirmed. Large quantities of sodium bicarbonate
are frequently required to offset the acid load and may lead to marked
hvperosmolality and serious vascular congestion; lfdiur^g^i^1 £
promote adequate sodium and water losses, dialysis may be required to
prevent volume overload during alkali administration.
Diabetic ketoacidosis. Diabetic ketoacidosis is a major cause of anion gap
metabolic acidosis. The fatty acid metabolitesjcetoacettc acid and tetahydroxybutyric acid, are the major acids produced m uncontrolled diabetes.
The diagnosis of diabetic ketoacidosis is most reliably confirmed by a pos
itive nitroprusside reaction (Acetest) in the serum. This test provides a
semiquantitative assay for acetoacetate but does not detect beta-hydroxi
ybutyrate. Low-dose insulin therapy has proved to be as reliable as highK dose therapy in correcting the acid-base disturbance of uncontrolled dia-
3
-
"C/z
- Patients with diabetic ketoacidosis are occasionally found to have a co. - existing element of lactic acidosis. When this occurs, a marked discrepancy
> may be noted between the increment in unmeasured anions (and decrement
in bicarbonate, and the degree of positivity in serum nitroprusside reaction.
i;'4
This discrepancy can arise not only from the presence oHactate but also
: - from a preponderance of beta-hydroxybutyrate, because of the diminished
X
.
oxidative potential of the tissues.
,
"Example: A patient with insulin-dependent diabetes enters the hospital
in shock following a myocardial infarction. The blood sugar is 500 mg per
deciliter; the serum sodium is 140, potassium 4.8, chloride 10o,.and bi
carbonate 8 mEq per liter. The serum nitroprusside reaction is oftlyl +
in a 1 • 2 dilution. These data strongly suggest that diabetic ketoacidosis
is not the only form of acidosis present; the anion gap is markedly elevated
at 27 mEq per liter (140 - 1105 + 8] mEq/L), but the nitroprusside reaction
is only weakly positive. The clinical setting is in keeping with the presence
of lactic acidosis from hypotension. Indeed, a measured lactate level was
12 mEq per liter (normal is less than 2 mEq per liter).
c Starvation. Starvation is also characteristically associated with an increased
‘ breakdown of fattv acids, and a mild ketoacidosis is frequently seen.
d. Alcoholic ketoacidosis. Alcoholic ketoacidosis can occur after a period ot
heavy alcohol abuse. A history of protracted vomiting is often ^teineft A
preponderance of bete-hydroxybutyric acid typically seen. Because d rect
measurement of this acid is not readily available, the diagnosis is usually
I
*
V
r
4z
J
1
• t
ir
I I
e. Overdosage! Overdosage with several potential poisons may result. m a
severe metabolic acidosis, caused by the overproduction of various largely
f RenaHnsufficiency. Renal insufficiency results in metabolic acidosis not
because of an overproduction of endogenous acids
because of a dimin
ished capacity of the few remaining tubules to reabsorb fillered bicarbonate
and to generate sufficient urinary ammonium. The elevated
anion concentration characteristically seen is the consequence of a ^ction
in glomerular function, which leads to a retention of a large variety of
filterable anions te.g., sulfates and phosphates).
3. Simple metabolic acidosis versus mixed acid-base disturbances. Because
metabolic acidosis often occurs in complex
circu.T^^^^
common for it to be present in the company of other acid-base abnonnalities
Such mixed acid-base disturbances can usually be detected by a careful analysis
of the acid-base values and of the pattern of serum electroiytes. The Pre^e
of an independent primary respiratory disturbance tends to dlstort^h®
between PaCO2 and plasma IHOV1 ordinarily observed in simp e meUo c
acidosis. The degree of secondary hypocapnia accompanying stabie
acidosis is roughly proportional to the magmtu^of the steady-state bicarbonate
decrement; on the average, each mEq per liW reduction in plasijia^kar na
I
■
i
.’2
I \
56
Howconcentration is associated with a 1.0 to 1.3 mm Hg reduction in
m PaCO2. _However during the rapid onset of severe metabolic acidosis, the abrupt fall m
plasma bicarbonate may outstrip the secondary decrement m PaCO2, giving _
rise to extreme elevations in plasma hydrogen ion concentration. Similarly
during the rapid repair of severe metabolic acidosis a normal or near normal
level ofplasma bicarbonate may be restored before hyperventilation subsides, A j ,
resulting in a marked reduction in plasma hydrogen ion concentration i.i.e.,
3j
alkalemia'. Excluding such transient circum^s if respiratory adjustments
fall short of the anticipated level ti e., if PaCO, is higher than expected for a
.
given decrement in plasma bicarbonate), an element of respiratory acidosis
Ln be diagnosed; conversely, if respiratory adjustments appear excessive (i.e., £.
if PaCO, is lower than expected), an independent element of primary respiratory
alkalosis can be diagnosed.
A
a. Metabolic acidosis and respiratory alkalosis
Example: A patient with gram-negative septicemia is found to be m shock
and to have rapid, deep respirations. Arterial blood studies rev eala j
of 15 mm Hg. a pH of 7.35 ([H 1,45 nEq per liter), and a plasma bicarbonate
w
concentration of 8 mEq per liter. Plasma bicarbonate is 16 mEq per liter
<
below normal (24 - 8 mEq/L) as a result of metabolic acidos.s presumably
on the basis of lactic acid overproduction. Thus, one might expect a reduction
in PaCO, of approximately 19 mm Hgjust as the resu t of the physiologic
response to this degree of metabolic acidosis <16 mEq/L x 1.2 mm Hgper
mE^'L = 19 mm Hg). The actual reduction in PaCO2 is about 25 mm Hg
(40 q 15 mm Hg). This discrepancy between the observed and expected C
degrees of hyperventilation signifies an independent process stimulating
•
ventilation and thus evidences a mixed disturbance in which metabolic
acidosis and respiratory alkalosis coexist. This particular mixed disturbance
s,
R
is encountered with some frequency in patients with gram-negative sepsis.
b Metabolic acidosis and metabolic alkalosis. The coexistence of metabolic
aefoosto and metabolic alkalosis can be diagnosed by the pattern o serum
electrolytes if the component of acidosis is due to the overproduction of
endogenous acid (see Table 4-3>. Under these circumstances the increment
in unmeasured anioniconrentration
the normaWalue
icentration above me
normal vaiue of
ui 8
u to 12
x*- mEq
|
the decrement in plasma HCO3 below its normal
• ^Tf^TX^ hteLSs-repancy
signifies
that
plasma
__ it;ciemifips that nlasma
3
1
4: The Patient With Abnormal Plasma B.cmt-onat^ArterialPCO^pH
F »>•
4- The Patient With Abnormal Plasma Bicarbonate, Arterial PCO2, or pH
e'
■
chronic renal failure), long-term a>kah
?nate (e „ citrate) may be
XimXTed S"
”a dose adjusted emptncally to maihUin
^reqlSn ‘f ^underlymg
i
ss ssssasssx-
Uhrium; When^hls precaution is oLrved, tetany, ahered mental status, and
convulsions rarely occur.
3
3
!
3
3
i
F
desired increment
bt
i
and must be adjusted to suit indiv
, .
true when increased acid production or
period of therapy
Stion of
X 2. L -
asjo^hpndelines
,
te losses continue during the
Xre“ reduced (plasma
^nmis-
amounts of bicarbonate (with sodium), it may be necessary
». gssssst - -™
e3
cl 3
•sBsssss
enous alkali; and persistent hyperventilation due to lingering
within the
Although a reduction in plasma
B. Respiratory alkaiosis (low [HCO3J, low40^
of respiratorybicarbonate concentration may be the
manifestation of the secondary
j
3
e .1
$
physiologic1!response to resgra^ta
Zm°a bXZnate and hydrogen ion Concentration) to assess the seventy of
i^^Xsphatoiy aiha.osjs. Any process
X
SSSS mueiUXpiee ~ oTthis condition can be classified as follows:
.1
%
Example: Body weight 70 kg, aPPar®“’ p
to institute peritoneal dialysis or hemodialysis
3
i
ronnired to produce a desired incre-
sSimates of bmarbonate
higher than normal (i.e., a metabolic alkalosis must have been Present
at the onset of the metabolic acidosis. The patient s history suggests that
this ■'hidden” alkalosis resulted from vomiting. Specifically, the serum br C" ,
carbonate must have started at 42 mEq per liter andI then <
“sed to 12
mEq per liter as the hydrogen ions accompanying the 30 mEq per liter
4 Therapmific'princFples] Treatment of metabolic acidosis centers around removal
of thfuXlymc “ause when possible and provision of adequate amounts of
bicarbonate when necessary. If plasma bicartxmate is only moderately depressed
(plasma IHCO, 1 greater than 15 mEq/L), and if the cause of the acidosis can
te
:So^S-^^=the^=f —
t-
bicarbonate has been titrated to Us ojisereed value irom a level higher
than normal and. thus, that a metabolic alkalosis is ako present.
Example A patient with chronic alcoholism is evaluated after several days
of proftise vomiting. Laboratory studies reveal serum sodium 13o. potassium
3 0P chloride 80. and bicarbonate 12 mEq per liter. Arterial blood pH is
7 27 i!H-] 54 nEq per liter), and PaCO2 is 27 mm Hg. It is evident that
a moderately severe metabolic acidosis is present and that its cause is in
thT mcreased anion gap category. Indeed,
alcoholic ketoacidosis~ —
largely
lueeu, aivuiivuv
o--.
due to beta-hydroxybutyric acid was documented.
c__
. _ Careful analysis,
. _ however, demonstrates that the anion gap is 43 mEq per liter 13o
I
12] mEq'L), which is at least 30 mEq per liter higher than normal,. This
is an elevation much greater than would be ^quiredta accouta for• a re
normal level of 24 mEq per liter to its
57
i
I
3
a. Central nervous system disease
(1) Anxiety, hysteria
(2) Cerebrovascular accident
(3) Trauma
(4) Infection
(5) Brain tumor
58
4: The Patient With Abnormal Plasma Bicarbonate, Arterial PCO-,, or pH
■o
4: The Patient With Abnonnal Plasma Biearbonate^rterial PCO2. orpH
59
* *
b. Pulmonary diseases
(1) Pulmonary emboli
(2) Mild pulmonary edema
(3) Pneumonia
(4) Ventilation-perfusion imbalance with hypoxia
c. Metabolic disorders
(1) Fever
(2) Salicylate intoxication
(3) Hepatic insufficiency
(4) Gram-negative septjeemia
(5) Pregnancy
2. Acute versus chronic respiratory alkalosis. Many causes of respiratory alkalosis are short-hved. In these instances the acid-base disturbance is man
ifested by the primary decrement in PaCO2 and a small, secondary decrement
in bicarbonate concentration that results from the titration of nonbicarbonate
tissue buffers. A decrement in bicarbonate of 3 to 4 mEq per liter may be
expected to occur within several minutes after PaCO, is lowered to 20 to 25
mm Hg. The resulting change in plasma hydrogen ion concentration is roughly
proportional to the change in PCO2; on the average, each mm Hg reduction
in PaCO2 in acute respiratory alkalosis results in a fall in plasma hvdrogen
ion concentration of approximately 0.75 nEq per liter.
Less commonly, respiratory alkalosis lingers long enough (a few days or more)
for secondary renal adjustments in bicarbonate concentration to occur. Such
chronic forms of respiratory alkalosis are especially likely to occur in patients
with hepatic insufficiency, chrcnic salicylate intoxication, chronic hypoxic
states, and central nervous system neoplasms. When secondarv renal adjust
ments are fully expressed and a new steady state is maintained, the average
reduction in plasma bicarbonate concentration is approximatelv 0.5 mEq per
liter for each mm Hg reduction in PaCO2.
3. Treatment of respiratory alkalosis. The only satisfactory treatment of this
acid-base disturbanceTs removal of the underlying cause.
V. Elevated plasma bicarbonate concentration. An elevated plasma bicarbonate con
centration is a characteristic feature of both metabolic alkalosis and respiratory aci
dosis (see Table 4-2). The clinical setting in which an ('
elevated' plasma bicarbonate
is found often suffices to distinguish between these two possibilities. Patients with
respiratory acidosis usually
covAcxiij have
nave evident
eviuent pulmonary disease by history, physical
examination, or chest x-ray. rThe
r,L
•2
i
1
> •
magnitude
of<•.the
bicarbonate
increment may also
be helpful. Values greate^a^O
Htel'llmolt'never occur in response to
hypercapnia alone, even when renal adapUtion is complete; such high levels, there
fore, signify the presence of metabolic alkalosis. Any doubt about which class of acid
base disturbance is responsible for an elevated bicarbonate can be resolved by measuJ?nF pH ,an<!/or PaCO2. A high bicarbonate in association with some decree of
alkalemia is diagnostic of metabolic alkalosis; a high bicarbonate and acidemia signify
respiratory acidosis.
'
A. Metabolic alkalosis (high [HCO3’J, low [H+])
1. Causes of•i metabolic
’’ ’
ineiaooiic alkalosis.
aiKaiosis. The
1 he causes of metabolic alkalosis can’ be ”
divided
into two 1major subgroups^
’
22
sodiiun
chloride responsive and sodium chloride
resistant, on the basis of the pathogenetic mechanisms involved (Table 4-5).
a. Sodium chloride responsive. The me
'
lost frequently
encountered mechanism
O I Lz O 1 AO1
iis
r* ♦
I-,
. J~
responsible for sustained metabolic* alkalosis
the
loss of£* L.body
chloride
«?.POrtLOn3O}l}j 10SS °f so<*ium- When this occurs, heightened renal
sodium
conservation (due to
a reduction in the effective CALI
extracellular
fluid
.
-- — - ^*-w*-*.A^*.* AAA.
dLCHUJcH 11U1U
volume) accelerates the rate of renal sodium bicarbonate reabsorption, be•j
so<llum 1S no Wenger accompanied by a normal complement
I o- chloride. This discrepancy between the renal avidity for sodium and the
I availability of chloride explains the sustained alkalosis seen with gastric
losses, with use of potent diuretics (furosemide, ethacrynic acid, thiazides,
organic mercurials), and after abrupt relief of chronic hypercapnia. In each
of these conditions, a diagnostic hallmark is the virtual absence of urinary
Table 4-5. Causes of Metabolic Alkalosis
Sodium Chloride Resistant
Sodium Chloride Responsive
,.
Vomiting
Gastric suction
Use of certain diuretics
Abrupt relief of chronic hypercapnia
J
’
V
Hyperaldosteronism
Bartter’s syndrome
Cushing’s syndrome
Severe potassium depletion
Licorice ingestion
■
>
chloride (unless, of course, diureHc actionds still present). A=^iU
R
1
£4
*
“ "X-th potassmm and, if needed, so-
b. sodi’um chloride resistant The
(S
1
sustained metabolic alkal°®1® .
between sodium chloride and sodium
reabsorption. Whenever the ba
of bicarbonate, the kidney susbicarbonate reabsorption is shifted m1
, a decrease in plasma
tains an increase in biwrbon^eti7en^eXily electrolyte intake. This
chloride concentration, nresp«tive of the d^y
al
-9f
e
mechanism plajb an imPO.r
Hronocorticism- these states include pntypically found in sta^^ ddrome. and Cushing’s syndrome (espemary aldosteromsm Bartter s y
etion) Occasionally, very severe
cially that produced b} ectopic A
I
or legs) may produce
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o
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i?
II
*"
2.
S'
5
3
a change in PaCO2 that is roug y p
metabolic alkalosis, each
bicarbonate concentration. Specifica y,
P
average, to evoke a
mEq per liter increment of bica^naU
^boi^lkalosis who
0.5 to 0.8 mm Hg increment inPaCO2. Fatten
. for . this reiation
manifest levels ot PaCO2 higher .han
Conversely, patients with
are likely to have independent-sinrW
manlfest
metabolic alkalosis whose Pa 2
indeoendent respiratory alkalosis.
some stimulus to ventilation and suffer
"^hoX h^been treated with
a j.
-.f
Example: A patient
and edema.
ft V
-I?
'
—
However, the 14 mEq per liter mere
increment in PaCQ? if
-540 mm Hgt This I^repX
f
superimposed on the underlying metabolic alkalosis.
U
/ \
60
s
■
4: The Patient With Abnormal Plasma Bicarbonate, Arterial PCO2, or pH
3. Therapeutic principles. The key to the correction of sodium chloride-responsive
forms of metabolic alkalosis is the provision of adequate dietary or parenteral
chloride. Because potassium deficits are almost universally present, potassium
supplements administered as the chloride salt are generally advisable in ad
dition to sodium chloride to correct any volume depletion. Sodium chlorideresistant forms of metabolic alkalosis respond to treatment of the underlying
centration, however, is 12 mEq above normal (37 - 25 mEq'L). This discrep
ancy between the observed and anticipated levels of bicarbonate signifies an
independent process augmenting plasma bicarbonate and, thus, supports mixed
acid-base disturbance in which an element of metabolic alkalosis is present.
3. Treatment of respiratory acidosis. Optima) treatment of respiratory acidosis
is directed at removing the underlying cause. Tracheal intubation and me
chanical ventilation may be required to reverse life-threatening hypercapnia
(and hypoxia). Pharmacologic stimulants have not proved to be especially
helpful in assisting patients with either acute or chronic carbon dioxide re
B. Respiratory acidosis (high [HCO,"], high [H+I). Although an increase in plasma
bicarbonate concentration may be the first clue to the presence of respiratory
acidosis, the diagnosis is more often suggested by the clinical setting (see Table
4-2) Because the increment in plasma bicarbonate in this condition reflects the
secondary physiologic responses to the underlying primary hypercapnia, it does
not provide an index of the severity of the acid-base disturbance. A value for
PaCO2 should be obtained by direct measurement or by calculation (from plasma
bicarbonate and hydrogen ion concentration) to confirm the diagnosis and to
characterize the acid-base disturbance fully.
1 Causes of respiratory acidosis. Any process other than alkalemia that pro’ duces alveolar hypoventilation results in respiratory acidosis. The causes can
be divided into three categories, as follows:
a. Central nervous system disease
(1) Sedative overdose
(2) Respiratory arrest
(3) Primary alveolar hypoventilation
i
I
(4) Brain tumor
b. Pulmonary disease
(1) Acute airway obstruction
(2) Chronic obstructive pulmonary disease
(3) Severe pneumonia
(4) Severe pulmonary edema
(5) Pneumothorax
(6) Respiratory muscle disease
(7) Restrictive disease of the thorax
c. Metabolic disease: myxedema, hypophosphatemia
2 Acute versus chronic respiratory acidosis. Many of the common causes ot
respiratory acidosis result in abrupt, short-lived hypercapnia. The acid-base
disturbance under these circumstances is characterized by the initiating in
crement in PaCO2 coupled with a small, secondary increment in bicarbonate
concentration due to the titration of nonbicarbonate tissue buffers. This buffer
response is generally of small magnitude, accounting for only a 2 to 3 mEq
per liter increase in plasma bicarbonate even when PaCO2 is increased by 30
mm Hg or more. As a consequence, there is a striking increase m plaMna
hvdrogen ion concentration. On the average, each mm Hg increment in PaCO2
in acute respiratory acidosis results in a 0.75 nEq per liter increment in plasma
hydrogen ion concentration.
In chronic respiratory acidosis (most often the consequence of chronic obstruc
tive lung disease), secondary renal responses result in a more marked increase
in plasma bicarbonate concentration. The mean increment in bicarbonate con
centration in patients fully adapted to chronic hypercapnia is approximately
0.3 to 0.4 mEq per liter for each mm Hg increment in PaCO2. The coexistence
of metabolic acid-base disturbances in patients with primary respiratory aci
dosis can be assessed by determining whether the level of plasma bicarbonate
concentration corresponds to the level anticipated for the observed degree and
duration of hypercapnia.
Example: A patient with long-standing lung disease has a PaCO2 of 55 mm
Hg and a plasma bicarbonate concentration oi 3/ mEq per liter. The increment
above the normal PaCO2 is approximately 15 mm Hg (55 - 40 mm Hg). Thus
one might anticipate an increment in plasma bicarbonate concentration of
approximately 6 mEq per liter just on the basis of chronic hypercapnia (15
mm Hg x 0.4 mEq/L/mm Hg). The observed increment in bicarbonate con
3
e
'■3
tention.
Suggested Reading
3
I
T*
s
A
e‘ a
Arbus G S., Hebert, L. A., Levesque, P. R., Etsten, B. E., and Schwartz, W. B.
Characterization and clinical application of the “significance band” for acute res
piratory alkalosis. N. Engl. J. Med. 280:117, 1969.
Brackett, N. C., Jr., Cohen, J. J., and Schwartz, W. B. Carbon dioxide titration curve
of normal man: Effect of increasing degrees of acute hypercapnia on acid-base equiequi
librium. N. Engl. J. Med. 272:6, 1965.
Cohen J J. Disorders of Hydrogen Ion Metabolism. In L. Earley and C. Gottschalk
(Eds.),'Diseases of the Kidney (3rd ed.). Boston: Little, Brown, 1979.
Cohen. J. J., and Kassirer, J. P. (Eds.). Acid-Base. Boston: Little, Brown, 1983.
Cohen, J. J., and Schwartz, W. B. Evaluation of acid-base equilibrium in pulmonary
insufficiency: An approach to a diagnostic dilemma. Am. J. Med. 41:162, 1966.
Emmett, M., and Narins, R. G. Clinical use of the anion gap. Medicine (Baltimore)
56:38, 1977.
Gennari, F. J., Goldstein, M. B., and Schwartz, W. B. The nature of the renal ad
aptation to chronic hypocapnia. J. Clin. Invest. 51:1722, 1972.
3
e.
e ■
3
Kaehny W. D., and Gabow. P. Pathogenesis and Management of Metabolic Acidosis
and Alkalosis. In R. W. Schrier (Ed.), Renal and Electrolyte Disorders (3rd ed.). Boston:
Little, Brown. In press.
Kaehnv W D Gadow, P. Pathogenesis and Management of Respiratory and Mixed
Acid-Base Disorders. In R. W. Schrier (Ed.), Renal and Electrolyte Disorders (3rd
ed.). Boston: Little, Brown. In press.
Kassirer, J. P. Serious acid-base disorders. N. Engl. J. Med. 291:773, 1974.
Lennon, E. J., and Lemann, J.. Jr. Defense of hydrogen ion concentration in chronic
metabolic acidosis: A new evaluation of an old approach. Ann. Intern. Med. 65:^65,
I
€: >
r^.
I V
61
4: The Patient With Abnormal Plasma Bicarbonate, Arterial PCO2, or pH
1966.
"
Narins, R. G., and Emmett, M. Simple and mixed acid-base disorders: A practical
approach. Medicine 59:161, 1980.
van Ypersele de Strihou, C„ and Frans, A. The respiratory response to chronic metabolic alkalosis and acidosis in disease. Cltn. Sci. Mol. Med. 45:439, 1973.
1
V
Th® Patient With Disorders
of the Serum Calcium and
Phosphate
< /
•5 J
Zalman S. Agus, Stanley Goldfarb,
and Alan Wasserstein
t
A
Disorders of the Serum Calcium
'I
kt
i
I.
c ?
instead measure the total calcium. This fact is important in assessing disorders of
the serum calcium level, because the serum ionized calcium may vary independently
of the total calcium. Thus, hvpoalbuminemia is associated with a reduction in the
total calcium because of a reduced protein-bound component but the ionized calcium
level is normal, and the patient exhibits no symptoms referable to hypocalcemia.
Conversely, alkalosis increases binding of ionic calcium to protein, thereby increasing
the fraction of the total calcium that is protein bound and reducing the ionized calcium
concentration; the patient, therefore, exhibits signs and symptoms of hypocalcemia,
but the total calcium as determined in the laboratory is normal.
II. Regulation of ionized serum calcium. Regulation of the ionized serum ca cium eve
is accomplished at three levels. Calcium is absorbed from the gastrointestinal tract
principally under the influence of vitamin D and its metabolites; deposited in bone
released from bone; and excreted by the kidneys. Bone deposition and release> of
calcium are for the most part regulated by vitamin D, parathyroid honnone (FTHk
'and the serum phosphate. The renal excretion of calciufn is in um determined by
the serum calcium level and the level of PTH. Increased levels of PTH result in
increased reabsorption of filtered calcium in distal portions of the nephron (Fig. 51). Virtually all of the clinical disorders of serum calcium resuIt from disturbances
in either gastrointestinal absorption or bone resorption, with the^kidney p aying a
secondary role.
III. Hypercalcemia
->
I
*s
<k4'-
■
Plasma forms of calcium. Calcium exists in plasma in several different forms. Much
■'
.
-
A Causes. With the advent of the autoanalyzer and routine determi nationot serum
calcium levels, recognition of hypercalcemia has become more common. The causes
of hypercalcemia can be subdivided into two basic categones-increased gut ab
sorption and increased bone resorption. The most common causes of hypercalcemia
are malignancy and hyperparathyroidism, and granulomatous disorders such as
sarcoidosis, tuberculosis, and berylliosis run a distant third ^Table 5- ).
1. Primary hyperparathyroidism. In the majority of instances (80 to 85 percent),
hyperparathyroidism is associated with a single adenoma. In a smaller number
of patients there is hyperplasia of two or more glands. Hyperplasia is frequently
observed in familial hyperparathyroidism and in the multiple endocrine neo2. Malignancies. Malignancy can be associated with hypercalcemia through sev
eral pathogenetic mechanisms. Metastases to bone can cause local dissolution
and release of calcium. In myeloma and lymphoma and perhaps other tumors
as well, the recently discovered osteoclast-activating factor may mediate such
bone dissolution. Although ectopic secretion of PTH in malignancy has been
suspected for many years, recent evidence suggests that this mechanism occurs
S3
I i
I
I
r
5: The Patient With Disorders of the Serum Calcium and Phosphate
Vitamin D
Liver
25 OHD
A
PTH
| Bone resorption
| Serum calcium
e
calcium reabsorption
e
| Gut
rarelv if ever. Rather, a substance that is immunologically distinct from PTH
but shares certain physiologic actions (hyTercalcemia, decreased renal tuouiar
phosphate absorption) may account for so-called humoral hyper^cemia of
malignancy. Finally, hypercalcemia has been associated with
production in several types of solid tumors, Put the relative incidence of th..
3 h^rease^^^
ca|cium- increased gastrointestinal
’ absorption of calcium plays the predominant role m the genesis.of the hypo
calcemia of vitamin D intoxication and the granuiomatous disorders. The
is evidence that the mechanism of increased absorption in smxoidosis (and
possibly other granulomatous disorders) may be increased production of 1 25
dihydroxycholecalciferol, 1,25 (OH)2D, the active metabohte of vitamin D The
incidence of hypercalcemia in sarcoidosis is approximately 10 percent, but hy
| Renal tubular
calcium reabsorption
i
* ■ -s
4 Sher causes, plmili^ hypocalciuric hypercalcemia (FHH) is^characterized
by hypercalcemia (usually asymptomatic), hypocalciuna (factional^alcmm
excretion less than 1 percent), and hypercalcemia m family membera Mthpug
serum PTH levels may be mildly elevated, parathyroidectomy is of no value,
thiT^dition should be exchl^d before parathyroid exploration, particularly
Wrotrhl?^
3
Fig. 5-1. Regulation of the serum calcium.
I
3
Table 5-1. Causes of Hypercalcemia
Hyperparathyroidism
Adenoma
Hyperplasia
Multiple endocrine neoplasia syndrome
Familial
Malignancy associated
Metastatic, resorption of bone
Secretion of PTH-like substance
Osteoclast activation factor
Prostaglandins
Hormonal therapy of breast cancer
Granulomatous disorders
Sarcoidosis
Berylliosis
Tuberculosis
Histoplasmosis
Coccidioidomycosis
Familial hypocalciuric hypercalcemia
i
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Ij
c
<
Postrenal transplant
e
e
SI
______
p
Ji
*
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on bone to increase resorption. It
causes hypercalciuria and, less often, hypercalcemia. At least two mechanism*
mav be important in the hypercalcemia of milk-alkali syndrome. There is
viously an increase in calcium intake and subsequent gut
_
tionally alkalosis stimulates the renal tubular reabsorption of filtered calcium,
and this mechanism probably potentiates the de^opment of hypercalcemia
in this syndrome. The mechanism of the hypercalcemia that is occasionally
seen in Addison’s disease is unknown, but volume depletion with mcreased
concentration of protein-bound calcium is one likely factor. Deficiency of g, cocorticoid hormone may also enhance bowel calcium absorption a* mediate
Other causes'of increased bone resorption that may cause hypercalciuria and,
less frequently, hypercalcemia include Paget s disease and immobilization.
Administration of thiazides can be associated with the development o ypercalcemia. In normal persons there is only a slight, transient e^e^loa
serum calcium, which is due to concentration of serum prote n from fluid oss
and a decrease in urinary calcium excretion associated with volume contraction,
as well as a possible direct effect of thiazides on renal tubular calcium reab
sorption In patients with accelerated bone resorption due to hvper^rathyroidism, immobilization, Paget’s disease, or vitamin D
^nrto potehtmtethe underlying bone dissolution and may be associated with
B Si^%dners7mmpX.s itself a manifestationofan
defying disease process, several signs and symptoms that may be^as^ociated
hypocalcemia are manifestations of the primary process, whereas others relate
to the hypercalcemia per se.
. . . ,
1. Signs and symptoms associated with hypercalcemia include.
Paget’s disease
Addison’s disease
Thyrotoxicosis
Vitamin D intoxication
Milk-alkali syndrome
Immobilization
Thiazides
.
Recovery from acute renal failure (e.g., T rhabdomyolysis I
65
l,25diOHD
Kidney
a. Anorexia
b. Nausea and vomiting
x
c. Constipation
d. Polyuria, nocturia, and polydipsia
e. Hypertension
f. Confusion, stupor, and coma
g. Acute and chronic renal insufficiency
h. Nephrolithiasis
i. Metastatic calcification
j. Peptic ulcer disease, pancreatitis
k. Electrocardiographic changes
66
5: The Patient With Disorders of the Serum Calciuir.mid.Phosphate
5: The Patient With Disorders of the Serum Calcium and Phosphate
67
••
> -'4
Jz
>7
2. Signs and symptoms associated with underlying disease processes include:
Hyperparathyroidism: anemia,
myopathy,
hy
a. 1
'
- hyperchloremic acidosis,
........................................................
pophosphatemia, bone disease, pseudogout
b. Sarcoidosis: disturbances on chest x-rays, rash, lymphadenopathy
c. Systemic manifestation of malignancy
d. Thyrotoxicosis
Hypercalcemia in and of itself may produce a symptom complex characterized
by anorexia, nausea and vomiting, constipation, polyuria, nocturia, polydipsia,
and central nervous system (CNS) disturbances, including confusion, psychosis,
lethargy, stupor, and coma. A^serum calcium above 15 mg per deciliter in
association with stupor or coma and renal insufficiency (hypercalcemic crisis)
is most commonly seen in malignancies but also occurs in hyperparathyroidism.
It requires urgent treatment. Hypercalcemia is often associated with hyper
tension. If the process is prolonged, metastatic calcification and resultant renal
insufficiency may ensue. This is most commonly seen in hyperparathyroidism,
sarcoidosis, and the milk-alkali syndrome. Other associations with hypercal
/
cemia include peptic ulcer disease and pancreatitis as well as a proximal my
opathy that is more commonly associated with hyperparathyroidism. Neph
rolithiasis may be associated with any cause of prolonged hypercalcemia and'
or hypercalciuria but is more commonly seen in patients with hyperparathy
roidism. Laboratory findings are nonspecific, with the exception of ECG and
urinalysis. Electrocardiographic manifestations of hypercalcemia include
shortening of the Q-T interval and, rarely, serious arrhythmias. The polyuria,
nocturia, and polydipsia reflect an inability to concentrate the urine maximally
*
and possibly a primary stimulation of thirst also. Acid-base disturbances that
may be seen include a metabolic alkalosis associated with bone dissolution
and release of alkali salts, and an increase in bicarbonate reabsorption produced
by hypercalcemia/When hyperparathyroidism is present, however, the alkalosis
is usually overshadowed by the effect of PTH on the renal tubule to decreas^
bicarbonate reabsorption, resulting in a hyperchloremic acidosis. HyperparV
athyroidism also produces the classic radiologic findings of osteitis fibrosa—j
subperiosteal resorption of phalanges, “ground-glass” appearance of the skulU
and resorption of the distal clavicles.
C_. Diagnosis
1. Indirect demonstration. In the past, the diagnostic approach to hypercalcemia
was oriented toward an indirect demonstration of increased parathyroid hor
mone activity, including abnormally increased phosphate excretion and evi%
dence of subperiosteal reabsorption. The frequent association of hyoerpara- A
thyroidism with a hyperchloremic acidosis has also been considered a diagnostic _J
feature. Changes in serum phosphate and chloride have even been combined
into a single diagnostic test. A ratio of serum chloride to phosphate exceeding
33 is said to favor hyperparathyroidism; a ratio less than 30, hypercalcemia
of other causes. All of these tests are indirect, however, and often there are
other factors present that may alter renal phosphate and/or bicarbonate han
>
dling independently, thereby adversely affecting the diagnostic accuracy and
specificity of these determinations. At present, with the ready availability of
the PTH assay, there seems to be less need for these classic tests.
2. Measurement of plasma immunoreactive PTH. The diagnostic workup, there
fore, should begin with determination of the PTH level. PTH determinations
that relate serum PTH to concurrent serum calcium level and provide prob
abilities for PTH-dependent versus PTH-independent hypercalcemia are com
mercially available. Assay of the C-terminal fragment of the hormone is most
• useful in the diagnosis of hyperparathyroidism. Measurement of immuno
reactive PTH should be done regardless of the presence of other potential causes
of Hypercalcemia, because there are clear examples of the coexistence of hy
perparathyroidism with a variety of conditions, including sarcoidosis, tuber
r
culosis, thyrotoxicosis,and malignancies.
The diagnosis of hypercalcemia is almost always evident from the clinical sethowever, and the role of the PTH determination is usually to confirm
r
£
1
r
rather than to make the
hypercalcemia discovered incidental y
g
majority of patients
have primary hyperparathyroidi^idiagnosed before the hywith hypercalcemia of malignly ha^ve ma ng
y
hyperparathypercalcemia is detected. In the paben
diagnosis and parathyroid exroidism. a frankly elevated PTH
eatinine ratio should
ploration may be undertaken. Ho~ a
particularly lf
be obtained to exclude fam hal
tHr;rormal range (“inapthe patientisasymBtoniatic. U the P .
diagnosis of primary hyperpropriate-ToFtKTlevel of hyperoJ™5 'j’^f may be desired before
parathyroidism is still
surgery. In
; sequential PTH determinations
Datient with malignancy,
Pfl t
RrH production,
hyperparathyroidism solely on the Prese^
PTH, which is in fact in the normal range^
i
ticularly common with certain
.
of k.nown malignancy. A
exploration may be rewarding even in theJ)
lcemia and malignancy
PTH level in the normal range in a
thTnonspecificity of the PTH
is frequently observed, and iss pre.a
of hypercalcemia, the diagnosis
immunoassay. In patients i
vitamin D intoxication, which is usup° cture8,; dominated by the underlying disease
-v™: six
xi sKsfissss
calciuric hypercalcemia. Hyoercalcemia^XXortiillOO mg daily for
malignancy should be detecte
y c
Although weight loss and anemia
protein electrophoresis^and^iton as well as in malignancy, the
may occur in.primary
reneated failure to document hyperpara-
and perhaps investigation of^heigastr
posited
-tr-ascular siu
c
d in the management
‘"ru^r kS0HamWy weight (ap-
immediate. This treatment is 0I\e
of caldum and phosphate can occur
Unfortunately the extravascular•depo
f
use of intraanywhere m the body, —ng ‘he he a^rtand kid ney,
.
I
vqnous phosphate has been a
recommended.
arrest, and sudden death, f or ese> rea
with a reduced serum phosOral phosphate therapy, parti<=“
y ,^d
effective by reducing both
iiumgu^bsor^tmnand bone --p"
Kfh"V 5WZX or Neutra-Phos 250 mg phosphorus per cap-
/ \
63
5: The Patient With Disorders of the Serum Calcium and Phosphate
sale) Serum calcium usually begins to fall within 24 to 48 hours after admin
istration. Oral phosphate therapy should never be used m pat.ente with an
increased serum phosphate, because the risk of extravascmar calcification is
2 GBteS and mtthramycin. Several agents that
to reduce bone resorption
as a primary action are available. Calcitonin, given as 4 units per kilogram
of body weight intravenously followed by subsequent doses of 4 units per kil
ogram subcutaneously at 12 to 24 hours, often lowers serum calcium to or
toward normal within several hours after administration. Approximately 20
to 25 percent of patients do not respond, however In those who do respond,
continued use may be limited by the rapid development of resistance; this
resistance may be avoidable, however, with concomitant steroid administration
Despite these limitations, calcitonin is an attractive agent because of its rapid
initial effect and remarkable freedom from side effects. Mithramycin is an
Diphosphonates also inhibit bone resorption and have the following twoi ad
vantages over calcitonin and mithramycin-they can be given orally, and they
mav ameliorate bone pain in patients with bone metastases. Currently, only
etidronate is available in the United States, and this agent7^,°flS^‘asCildae
Other diphosphonates, which are being used m Europe, do not have this side
effect and mav soon be available in this country. Indomethacim by inhibiting
prostaglandin synthesis, may eventually prove useful in selected patients with
hypercalcemia and malignancy, but at the present time there are not sufficient
data to justify its widespread use. In fact, prostaglandin inhibition in the hyGlucocorticoidTcta^
intest:na( absorption either directly
L
3. or via inhibition of vitamin D metabolism: therefore, they are effective in hy
percalcemia due to vitamin D intoxication or sarcoidosis. They are also effective
m some malignancies (notably, multiple myeloma and breast earcmomat either
bv tumoricidal effects or inhibition of bone resorption. Usual dosages are 3 to
5 mg/kg/day of hydrocortisone-equivalent initially, followed by smaller main
tenance dosages.’ln those patients who respond, serum calcium usually begins
4
-I
< \
Saline andrfurosemide. Finally, urinary calcium excretion can be increased
by inhibition of tubular sodium reabsorption at those sites at which sodium
and calcium transport appear to be linked. Thus, saline and/or sodium sulfate
infusion produces expansion of the extracellular fluid volume and subsequent
5: The Patient With Disorders of the Serum Calcium and Phosphate
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inhibition of proximal tubular sodium and calcium reabsorption.
j
rapid expansion of the ECF volume may produce volume overload,C i
in elderly patients or m those with underlying cardiovascular disease. A useful
adjunct to this type of therapy is the simultaneous use of a diuretic: that.acta
J.
in the loop of Henle. This serves to potentiate calciuna markedly by >nh>biting
>t
calcium and sodium transport at a site downstream from the proximal tubule.
In addition, natriuresis prevents overload of the cardl0vasc^a”yd Tatpn
of the diuretic before the induction of volume expansion may be self-defeating,
because resultant natriuresis will produce contraction of the ECF volume in
creased proximal tubular reabsorption of sodium and calcium, and consequent
P
rrn----- anTherefore,
init lai priming saline infusion of
aggravation
of ihypercalcemia.
fhour should be given. The approach is as follows:
1 to 2 liters over
a priming dose of 1 to 2 liters saline IV ovef 1 hour.
a. Begin with .
'' mg IV, and repeat every 2 to 3 hours.
b. Give furosemide 40 to 80
Measure urine volume every hour and unne sodium-potassium concen
c.
tration every 4 to 6 hours.
G9
d. Replace urine volume with saline and added potassium chloride.
e. If hypercalcemia is prolonged, add magnesium (15 mg per hour).
Once diuretics are given, urinary losses of sodium and potassium must he
measured and replaced. Sodium sulfate is theoretically more calciuric than
saline because of the formation of calcium sulfate complexes that are not
reabsorbed by the tubule. Sodium sulfate has not proved to be more effecSve
than saline, however, and its use is often complicated by hypernatria,
because it is most often prepared as an isotonic hypernatremic solution.
5. EDTA administration. EDTA’ also increases urinary calcium excretion. Its
principal virtue, however, is that by complexing with calcium in the blood
before excretion, it reduces the ionized calcium level immediately. EDTA, 15
to 50 mg per kilogram oyer 4 hours, is probably the most effective immediate
therapy for hypercalcemia. Unfortunately, there has been a significant inci
dence of nephrotoxicity associated with EDTA administration in high doses.
For this reason, its use should be restricted to life-threatening situations in
which immediate reduction of the ionized calcium level is critical.
E. Therapeutic approach
A. Acute hypercalcemia. Therapy of acute symptomatic hypercalcemia of any
f
grade of severity begins with volume expansion, which alone may be adequate
in mild-to-moderate hypercalcemia. After ECF volume expansion is achieved,
the addition of furosemide at intervals commensurate with the severity of
hypercalcemia additionally enhances calciuria. Additional therapy depends
on the severity and urgency of the clinical picture. Severe hypercalcemia
(greater than 15 mg per deciliter) with acute neurologic, cardiovascular, or
renal dysfunction constitutes hypercalcemic crisis and is a medical emergency.
In most instances, the addition of mithramycin or calcitonin to saline-furo
semide infusion provides adequate acute therapy. Neither agent requires renal
function to be effective. Calcitonin has a faster onset of action, although it is
less uniformly effective than mithramycin. If after several hours of saline
furosemide diuresis and calcitonin infusion, hypercalcemia greater than 15
mg per deciliter persists and the clinical condition remains unstable, additional
therapy is required. In these rare instances, immediate reduction of the serum
ionized calcium by infusion of sodium EDTA may be required. Rapid effects
can also be obtained with hemodialysis; this is preferred in the patient with
/ oliguric renal failure.
Chronic hypercalcemia. Management of subacute or chronic mild hypercal
cemia is dependent to a certain extent on the cause of the hypercalcemia:
at Steroids
(1) Sarcoidosis
(2) Multiple myeloma
(3) Breast cancer (50 percent)*
(4) Vitamin D intoxication
(5) Immobilization
zb. Oral phosphate
v (1) Hyperparathyroidism (nonsurgical candidates)
(2) Most malignancies
/ C. Mithramycin: If oral phosphate isinef_____
______ te is elevated.
fective or serum .phospha
luus, steroids are most effective in syndromes characterized by increased intestinal
calcium absorption and in some malignancies,. In other malignancies and in nonsurgical candidates with hyperparathyroidism, oral phosphate therapy is a relatively safe and effective treatment. If the serum phosphate is elevated, however,
the use of phosphate is contraindicated, and chronic administraiionTormithramyrin
at 5- to 7-day interval's is a reasonable alternative. The use of indomethacirTHas
not been carefully evaluated yet, but it is a potentially useful drug in the man
agement of hypercalcemia because it inhibits prostaglandin production in seme
malignancies.
Finally, it should be pointed out that parathyroid surgery is the treatment of
choice for hyperparathyroidism; chronic medical therapy is indicated only in pa-
~ Tjiar * « ■
1-^
70
-
5; The Patient With Disorders of the Serum Calcium and Phosphate
5: The Patient With Disorders of the Serum Calcium and Phosphate
tients in whom surgery has been repeatedly unsuccessful or is contraindicated.
The management of the patient with asymptomatic mild hypercalcemia detected
on routine screening remains controversial. Unless adequate follow-up can be
ensured, surgery is usually indicated to avoid the potential complications of bone
disease, kidney stones, and renal damage.
IV. Hypocalcemia
A. Causes. The causes of a reduced serum calcium level are listed in Table 5-2.
1. Hypoalbuminemia. Hypoalbuminemia lowers the total serum calcium level
by reduction of the fraction that is bound to protein. The ionized fraction is
unaffected by this reduction, a'hd the patient is, therefore, asymptomatic. A
useful rule of thumb to estimate the contribution of hypoalbuminemia to hy
pocalcemia is that total serum calcium will fall by 0.8 mg per deciliter for
every decrement in serum albumin of 1 gm per liter.
A reduction in the ionized calcium level usually reflects a disturbance in the
production, metabolism, or response to parathyroid hormone or vitamin D, the
two principal factors that regulate the ionized calcium level. Additionally,
removal of calcium from the serum and deposition in extravascular sites can
produce hypocalcemia.
2. Primary disturbances in the parathyroid system. Disturbances in the para
thyroid hormone system that can produce symptomatic hypocalcemia include
decreased production (hypoparathyroidism) or inadequate response to normal
circulating levels of parathyroid hormone (pseudohypoparathyroidism). Hy-
71
poparathyroidism is most “m™^^'Sue^rf
t
I
I
disease is known as P-udopseud^ypopara^
rts^Tpl*
4a
I
J"
Table 5-2. Causes of Hypocalcemia
Hypoalbuminemia
.
Disturbance in parathyroid systera
Hypoparathyroidism
Surgical
Infiltrative
Idiopathic
_
Pseudohypoparathyroidism
Hypomagnesemia
Disturbances in vitamin D system
Decreased intake—nutritional
Decreased absorption—malabsorption
Decreased production of 25(OH)D—liver disease
Increased metabolism of 25(OH)D
Phenobarbital
Phenytoin
Alcohol
I
Glutethimide
Accelerated loss of 25(OH)D
Nephrotic syndrome
Disturbances of enterohepatic circulation
Decreased production of l^StOH^D
Hereditary
Renal disease
Removal of calcium from serum
Hyperphosphatemia
Laxatives
I Phosphate enemas
'
‘ Cytotoxic treatment of leukemias and lymphomas
Rhabdomyolysis * ~
Osteoblastic metastases
Acute pancreatitis
f I
11
d^X^The^rdTnalVatures
of this
disorder are --------------a serum magnesmm
level
;uresoi
un»
,
...
1 mg per deciliter and a resistance to therapy until
rrn
k«rr\nmaAftATTI 1 JI 1T1"
Ikohoi
’ism'^d --nephrotoxicity
seconds^ to
ClltUllVllQ***)
— f---------------------•*
platin. The latter two agents apparently
urinary magnesium wasting.
r
.i
if
4.
^5
ssgsses *
sequent ypoca ce
Sute^
gastrointestinal disease is now the most
'4 I
3r
in .
4
‘1.
:iy
Emulation and with loss into the urine in the nephroUe syndrome. Defectrve
i
72
5: The Patient With Disorders of the Serum Calcium and Phosphate
5: The Patient With Disorders of the Serum Calcium and Phosphate
enzvme activity in the kidney, either as a result renal disease and a reduction
in functioning parenchyma or as a hereditary defect (vitamin D-depcndent
rickets) produces low levels of 1,25(OH)2D and hypocalcemia. Deficiency of
PTH mav also be associated with diminished l-SSfOHliD. Recently, several
___ ___________________
cases
have been described with the features of vitamin D deficiency but elevated
1XX of 1,25(OH)D; these patients apparently have target organ resistance
to vitamin D metabolites. ,
Rnmmtal nf
5 HyM^hosphatemla, osteoblastic metastases, and pancreatitis Removal of
' calcium from the serum by deposition elsewhere can be produced by hyper
phosphatemia and osteoblastic metastases Acute hyperphosphatemia can occur
with phosphate ingestion (cow’s milk in infante laxatives or enemas containing
phosphates, and potassium phosphate tablets! as well as following lysis of cells,
as in treatment of acute leukemia or lymphoma or with rhabdomyolysis. Os
teoblastic metastases rarely cause hypocalcemia by enhanced bone formation
in carcinoma of the breast, prostate, and lung, fhe hypocalcemia of pancreat.Us
urobably also fits into this category; precipitation of calcium soaps m the ab
dominal cavity is the major mechanism, and inadequate parathyroid response
B
carpopedal spasm. Latent tetany may be detected by tapping over the facial nene
to pnXce a facial twitch (Chvostek’s sign), orby inflation of a b!ood
cufT over systolic pressure for 3 minutes to produce carpal spasm (Trousseau s
sign). Other manifestations include seizures associated with severe hypocalcemia,
mfntal retardation in children, and dementia or psychosis m adults. Extrapy
ramidal movement disorders may occur with or without evidence of basal ganglia
calcification. Myopathy is due to secondary hyperparathyroidism, phosphate
pletion. or vitamin D deficiency, rather than to hypocalcemia per se. In^hypo
parathyroidism. dermatitis, eczema, and psoriasis may occur associated w th
coarse, brittle hair and patchy alopecia. Cataracts occur with prolonged hypo
calcenna; progression can be prevented with treatment. Characteristic denti l abnormalities occur when hypocalcemia is present during early d^elopment and
include hypoplasia, failure of eruption, defective enamel and root formation, and
Hypoten^may complicate acute hypocalcemia and hypocalcemia may occa
sionally contribute to the development of frank congestive heart failure due to
decreased myocardial contractility. Electrocardiographic mamfestations include
a characteristic lengthening of the Q-T interva,. Hypocalcemia
insensitivity to digitalis. Rarely, disordered ventricular condudtion with hypo-
C. Dteg^sii’The' dte^osUc^prol^to hypocalcemia is
the laboratory indicates a reduction in ionized calcium levels. In the absence of
< >
Measure serum albumin level
7_
Hypoalbuminemia does not account
for hypocalcemia
Hypoalbuminemia
accounts for hypocalcemia
»
1
Measure magnesium level
■
Magnesium level normal
Hypomagnesemia
<0.8 mEq/L
Evaluate serum phosphate and
draw PTH level
Signs wd^mptoms. A^with hypercalcemia, the manifestations of hypocalcemia
range from the acute, dramatic, and life-threatening to the subtle and misleading
that go undiagnosed for many years. The major maniiestations of hypocalcemia
involve disturbances of the following areas:
1. Psychiatric
2. Neuromuscular
a. Tetany
b. Seizures
c. Intellectual impairment
d. Extrapyramidal disorders
Myopathy
3. Ectodermal
4. Ocular cataracts
5. Dental
6. Cardiovascular
1_ ■ irritability, is the hallmark of
Tetany, with markedly enhanced neuromuscular
icral paresthesias. Motor manifesUttoSde ^iffn^ch^sine^muscle spasms, tramps, and the
73
Low PTH and high PO,
Elevated PTH
| ~~
Low serum PO<
Vitamin D deficiency
— ——
|
Normal or high PO,
v
Pseudohypoparathyroidism
I
Hypoparathyroidism
Confirm with clinical picture,
measurement of vitamin D metabolites,
a rd/or response to PTH infusion
Fig. 5-2. Diagnostic evaluation of the patient with hypophosphatemia.
-
$
a
1
I
t.
3
3
direct measurements of this fraction, measurement of the serum albumin level
provides a reasonable guide. If the fall in calcium is greater than can be accounted
for by a reduction of 0.8 mg per deciliter for each 1 gm per deciliter reduction in
serum albumin level, physiologic hypocalcemia can be presumed. The next step
is to measure the serum magnesium level. If the magnesium concentration is
less than 0.8 mEq per liter or 1 mg per deciliter, hypomagnesmia is likely to be
a major factor in the genesis of hypocalcemia. If the magnesium level is not low,
the plasma phosphate concentration is helpful. A high serum phosphate suggests
hypoparathyroidism; a low value is compatible with secondary hyperparathy
roidism due to vitamin D deficiency. Renal failure causes both high serum phos
phate and 1,2o(OH)2 vitamin D deficiency but is readily excluded by the usual
measures of renal function. The discrimination between hypoparathyroidism and
vitamin D deficiency can be confirmed by measurement of parathyroid hormone
levels. A low PTH level is expected in hypoparathyroidism; an elevated level is
consistent with either pseudohypoparathyroidism or vitamin D deficiency. The
clinical picture should distinguish the latter two syndromes. The presence of the
classic osteodystrophy confirms the diagnosis of pseudohypoparathyroidism. Gas
trointestinal disease, liver disease, anticonvulsant medication, and or nephrotic
syndrome all point to vitamin D deficiency. In the absence of clinical clues, this
differentiation can be made by measuring the circulating levels of 25(OH)D and
1,25(OH)2D and/or by evaluating the urinary cyclic AMP response to PTH infusion.
Most instances of viUmin D deficiency are due to malabsorption of vitamin D;
few are due to disturbances in the metabolism of 25(OH)D. As assays for the
various vitamin D metabolites become more widely available, it will be possible
to examine the components of this system more closely. For the present, however,
it is sufficient to make the diagnosis of vitamin D deficiency and to institute
therapy on that basis.
F
74
5: The Patient With Disorders of the Serum Calcium and Phosphate
D. Therapeutic approach
. ,
,
..
1 Acute hypocalcemia. Acute symptomatic hypocalcemia should be considered
a medical emergency because of the possibility of laryngeal spasm and'or sei
zures. Intravenous therapy to provide 200 to. 300 mg calcium should be in
stituted at the first sign of incipient tetany. This can be accomplished with
20 to 30 ml of a 10% calcium gluconate preparation (one 10-ml ampule contains
90 mg of elemental calcium) or 10 ml of 10% calcium chloride (360 mg per 10ml ampule) The advantages of reduced volume with the chloride preparation
are probably outweighed by the greater irritation produced by extravasation
of calcium chloride than of c^cium gluconate. Calcium should not be mixed
with any solution containing bicarbonate because of the possibility of precip
itation of calcium salts. If the cause of hypocalcemia is unknown, the serum
magnesium level should be checked immediately. If the level is-below 0.8 mEq
per liter or 1 mg per deciliter, 1 to 2 gm (8 to 16 mEq) of 10% magnesium
sulfate solution should be given intravenously over a period of 15 to 20 minutes.
In the first few days following surgery on the parathyroid glands or adjacent
structures, subacute transient hypocalcemia may appear. If the patient has
symptoms suggestive of tetany, therapy should be instituted as above. Following
acute therapy, calcium can be continued intravenously and oral calcium sup
plementation begun when regular oral intake is started. It is helpful to restrict
phosphorus (i.e., milk and meat) intake during this transition period If hy
pocalcemia and/or hyperphosphatemia persist for longer than 10 to 14 days,
it is unlikely that normal parathyroid function will return, and long-term
therapy should be considered.
2 Chronic hypocalcemia. Chronic hypocalcemia, whether due to hypoparathy
roidism or vitamin D deficiency, is treated by increasing intestinal absorption
of calcium. This is done with vitamin D therapy and increased calcium intake.
In hypoparathyroidism, the initial step is to provide calcium in the range of
2 to 4 gm per day, either as calcium lactate (60 mg elemental calcium per 300mg tablet), calcium gluconate (90 mg per 1-gm tablet), or calcium carbonate
(260 mg per 650-mg tablet). If response to this therapy is inadequate and a
near normal serum calcium is not achieved, a vitamin D preparation should
be added. This can be given either as vitamin D2, ergocalciferol, 50,000 to
150,000 units or 1.25 to 3.75 mg per day, or dihydrotachysterol (DHT), 0.25
to
0.75
dosages are
many timeshigher
than-------the equivalent
to U.
io mg
mg per
per day.
uay. These
i ireae uusagca
<xic tuauj
—a----- -------physiologic dosage of 100 to 400 units of vitamin D2 per day required to treat
ti de vitamin D deficiency. In part, the resistance may be due to inadequate
true
production of 1,25(OH)D2 from 25(OH)D, due to PTH deficiency and hyper
phosphatemia. DHT has the advantage of more rapid offset of action if hyhy
As ex
Ipercalcemia supervenes. It also bypasses the need for 1-hydroxylation.
-----perience is
is gained
gained with
with the
the use
perience
-------of--1,25(OH)
-------- 2D, therapy
. - may be additionally
improved. The aim of therapy is to provide a near normal serum calcium, but
in the absence of the renal effects of PTH this produces hypercalciuna. Thiazides
hav7be<m
have been shown to beT
be effective in patients with hypoparathyroidism; the
careful use of hydrochlorothiazide may reduce both urinary calcium and the
need for vitamin D in this situation.
In hypocalcemia associated with disorders of vitamin D metabolism, therapy
can be individualized. In the usual.patient with malabsorption, calcium sup
plementation and vitamin D therapy, as given above, are appropriate. Dosage
of vitamin D ranges from 4000 to 12,000 units per day to high dosages com
parable to those required in hypoparathyroidism. In patients with very large
requirements, magnesium depletion should be considered. Measurement of
25(OH)D levels mav be useful in assessing adequacy of therapy, and 1,25(OH)2D
and 25(OH)D (calcifediol) may be particularly useful in conditions in which
hepatic 25-hvdroxvlase activity is compromised and in conditions of excessive
external losses of 25rOH)D, such as defects of the enterohepatic circulation or
the nephrotic syndrome. Patients taking anticonvulsant medication usually
respond to supplementation with 5000 to 10.000 units of vitamin D per day.
In the very rare patient with vitamin D-dependent rickets, therapy wit
y-
5: The Patient With Disorders of the Serum Calcium and Phosphate
fs
therapeutic approach is designed to prevent or treat bone
step in therapy is reduction of hyperphosphatemia with phosphate-binding
antacids. If this is unsuccessful, therapy with oral calcium and then w ith vi
tamin D is often required. Dihydrotachysterol or L,25(OH)JD compounds that
bypass the requirement for renal 1-hydroxylation have special merit. m th s
situation. Also, the complication of hypercalcemia is more rapidly reversib
with these compounds than with vitamin D.
Not infrequently, the diagnosis of hypocalcemia is based on al
termination in asymptomatic patients who often present with eit
disease or liver impairment and chronic alcoholism. In these patients the
cision whether or not to institute therapy should be based on
sessment. Mild hypocalcemia usually remains asymptomatic m these
stances, and the ‘principal complication is the potential development of
metabolic bone disease because of the associated vitamin D
primary disease responsible for malabsorption can be treated, therei s no need
for prolonged therapy with vitamin D. In a patient w‘tb‘‘rreve71^^3!
with expectation of a prolonged course or in a patient with symptomatic bone
disease treatment with vitamin D (approximately 1500 unite) is clearly in
dicated. In the absence of obvious gastrointestinal disease a workup is indicated
to evaluate the presence of occult steatorrhea or liver disease.
S
3.
R
75
,1
I
.
5
f
Disorders of the Serum
Phosphate
4.5 mg per deciliter, whereas total
Normal levels for serum phosphate are 3.5 to
r— ----- , qnn
intracellular phosphate concentration (inorganic and organic or®s 1.
•
-jiy
inuai-cuum. H
A |
V .
£
1'.
I w>
X,
*
r
.
sassi
_ _
nhnsnhatP is nrimanlV
extracellular phosphate, and since the cellular inorganic pool provides ph°sPhate tor
adenosine triphosphate (ATP) and phospholipid synthesis, the regulation of
it .
is critical to
cellular function.and
^_7™^/
“balance. That 13
is to
I. phosphate
Erternal^phosphate
bahnce.^dults
are in external
phosphate
say, intake, of phosphate (averaging 1200 mg per day) equals output <800 mg pe^
H| I
!
GlVact are not normalb^m^anTinnuences 0" PhosPhate^1^i^e^
|
t
^1“^^
meager is absorbed. The kidney, however, exerts a major influence on PhobP
homeostasis About 9000 mg per day is filtered and available for excretion. Normally,
approximately 90 percent is reabsorbed, leaving 800 mg to be excreted
a rise in parathyroid hormone levels can easily reduce the rate of Ph°^ate
sorption by 10 percent of the filtered load, which in turn produces a twofold ‘ucrea
in^xcretion A fall in PTH levels can lead to a 10 percent rise in phosphate reabsorption by the kidney and acutely reduce output to less than 100img
the total extracellular fluid phosphate content is only 56 mg,
nhosohate
changes in renal phosphate transport may lead to major changes!^ ™
level. Although these changes are primarily the result clmngi g■
, imnortant
independent defects in renal phosphate transport exist and lead to clinically important
disturbances in the serum phosphate level.
nhn^nhate Nor
Il Internal phosphate balance. There is also an internal balance for phosphate. N
‘ mally, inorganic phosphate exists in intracellular fluids at a ™ncent™t10" °^3
mg per deciliter, but total phosphate (organic
Th^shitein
decider. Extracellular fluid levels are 4 percent
phosphate across cell membranes can profoundly alter the serum P^P^eJe
Various hormones as well as changes in hydrogen ion content of the body fluids may
■■ j
j;
influence this transcellular distribution.
1
i
fli
*
...... ..
76
5: The Patient With Disorders of the Serum Calcium and Phosphate
HL Hypophosphatemia
A. Causes. Ten to fifteen percent of hospitalized patients may develop a lower serum
phosphate level (less than 2.5 mg per deciliter), and a smaller number may be
found with profound hypophosphatemia (less than 1.0 mg per deciliter). Hypo
or redistribution
phosphate
to intracellular
fluids
5phosphatemia
canofresult
from from
eitherextracellular
excess external
Josses (GI tract
or (Table
kidneys)
3). Inadequate phosphate intake alone is rarely responsible for severe phosphate
depletion, because compensatory’ mechanisms reduce both renal excretion and
GF secretion. The renal response is quite rapid, but the GI response may take
several weeks. Inadequate diet may cause mild-to-moderate depletion but does
not produce marked hypophosphatemia.
1. Gastrointestinal disturbances. Gastrointestinal losses of phosphate sufficient
to induce hypophosphatemia can be produced with protracted diarrhea or
ingestion of large amounts of aluminum-containing antacids. Aluminum binds
to phosphate (either dietary or secreted) in the GI tract and produces net losses
of phosphate from the body.
Hypophosphatemia in gastrointestinal disease is primarily the result of mal
absorption. Malabsorption of vitamin D and calcium leads to secondary hy
perparathyroidism, which in turn enhances urinary phosphate excretion. Al
though reduced GI phosphate absorption may also play a role, increased renal
excretion is more important in the genesis of hypophosphatemia.
2. Renal phosphate wasting—intrarenal factors. Renal phosphate wasting is due
to either intrinsic tubular transport abnormalities or inhibition of phosphate
reabsorption by extrarenal factors such as hormones, drugs, or acute expansion
of the extracellular fluid volume. The two must important iorms of intrinsic
tubular abnormalities that lead to phosphate wasting are vitamin D-resistant
rickets (VDRR), both adult sporadic and familial forms, and variants of Fan
coni’s syndrome. VDRR in the familial form represents a dominant sex-linked
disorder in which phosphate transport across the GI tract and kidney is de
fective. Hypophosphatemia occurs in early life. The primary clinical mani
festations are severe rickets and osteomalacia that do not respond to physiologic
doses of vitamin D A form of this condition occurs sporadically in adults. This
latter disorder is quite rare. It is usually associated with tumors of mesenchymal
I
5: The Patient With Disorders of the Serum Calcium and Phosphate
e.; 3
£& ]
-
I 33
eI 3
el 3
<i
3
ei
Table 5-3. Causes of Hypophosphatemia
I
r
I
Gastrointestinal disturbances
Inadequate intake
Aluminum-containing antacids
Chronic diarrhea
Secondary hyperparathyroidism
Malabsorptive states
Vitamin D deficiency
Primary renal losses
Primary hyperparathyroidism
Vitamin D-resistant rickets
Fanconi’s syndrome
Glycosuria
Diuretics
Extracellular fluid volume expansion
Redistribution
Insulin administration
Acute respiratory alkalosis
Catecholamine administration
%
c. 3
£
77
origin, usually sclerosing hemangioma. This tumor may elaborate a substance
that, although not structurally similar to parathyroid hormone, may have
similar phosphaturic activity.
1.
Fanconi’s syndrome refers to a primary injury to the renal proximal tubule
with reduced reabsorption of a number oi solutes normally reabsorbed in this
segment of the nephron, including bicarbonate, glucose, and amino acids, as
well as phosphate. The causes of this lesion include metabolic diseases (cystinosis, Wilson’s disease, hereditary fructose intolerance), neoplastic disorders
(multiple myeloma), inflammatory diseases (systemic lupus erythematosus),
and intoxication (heavy metal poisoning).
\
3. Renal phosphate wasting—extrarenal factors. Renal phosphate wasting due
to extrarenal factors primarily represents forms of hyperparathyroidism. In
both primary and secondary hyperparathyroidism (due to GI disturbances or
dietary vitamin D deficiency), elevated circulating levels of PTH chronically
depress renal tubular phosphate reabsorption and lead to hypophosphatemia.
The level of serum phosphate seen in these conditions is usually between 2.0
and 2.5 mg per deciliter. Severe hypophosphatemia is uncommon.
Certain other extrarenal factors may lead to phosphate wasting. Perhaps the
most important of these is glycosuria. Glucose and phosphate compete for
reabsorption in the proximal tubule. During hyperglycemia, renal phosphate
reabsorption may be reduced. This may contribute to the prominent hypo
phosphatemia seen during the therapy of unstably diabetes mellitus. Certain
diuretics, such as acetazolamide and metolazone, may reduce proximal tubular
phosphate reabsorption in a manner similar to the inhibition of phosphate
reabsorption that occurs during acute expansion of the extracellular fluid vol
ume with saline-or bicarbonate-containing solutions.
4. Redistribution of phosphate. Hypophosphatemia may be produced by redis
tribution of phosphate from the extracellular to the intracellular fluid. This
occurs with stimulation of glycolysis and formation of large quantities of phos
phorylated compounds. Glucose infusion, insulin administration, or respiratory
alkalosis has this effect. Hypophosphatemia is an inevitable consequence of
parenteral hyperalimentation unless phosphate supplementation is provided.
Marked hypophosphatemia is commonly seen in the treatment of diabetic ke
toacidosis. Catecholamine administration also stimulates cellular phosphate
uptake. The mechanism is unknown.
5. Hypophosphatemia of alcoholism. Perhaps the most common setting of marked
hypophosphatemia is the hospitalized alcoholic patient. Multiple factors con
tribute to the pathogenesis of this syndrome. Before hospitalization, inadequate
phosphate intake, chronic diarrhea, and secondary hyperparathyroidism (due
to calcium and vitamin D deficiency and'or malabsorption) combine to produce
a baseline state of phosphate depletion. On admission, the alcoholic is usually
treated with glucose-containing intravenous solutions that stimulate cellular
phosphate uptake'. Respiratory alkalosis develops as withdrawal from alcohol
and delirium tremens begin. The consequence of this sequence of events is
severe hypophosphatemia, often most marked 12 to 24 hours after admission.
B. Signs and symptoms. Since inorganic cellular phosphate depends on extracellular
fluid phosphate as its source, the consequences of hypophosphatemia may be the
same whether phosphate is actually lost from the body fluids (urine or stool) or
enters cells in an organic form. The primary disturbance is cellular ATP deficiency,
due to both disordered adenine metabolism and reduced high-energy phosphate
bond formation. In general, severe hypophosphatemia dess than 1.0 to 1.5 mg
per deciliter) is required to produce acute clinical symptoms.
The organ systems most profoundly affected by hypophosphatemia are. muscle
'(skeletal and cardiac), hematopoietic, central nervous system (CNS), and bone.
1. Muscle. A skeletal myopathy may occur in hypophosphatemia with elevated
creatine phosphokinase (CPK) levels and profound weakness. This disturbance
has led to alveolar hypoventilation and respiratory failure according to at least
one report.
78
5: The Patient With Disorders of the Serum Calcium and Phosphate
5: The Patient With Disorders of the Serum Calcium and Phosphate
79
<2.
Serum PO, <1.5 mg'dl
*
Measure urine PO,
■ 100 mglday
•100 m.
Determine presence of glucose infusions,
respiratory alkalosis, or epinephrine
Determine presence of glycosuria,
aminoaciduria, or bicarbonaturia
Present
t
Fanconi’s syndrome
(cysti nosis)
(Wilson's disease'
• Multiple myeloma'
(Systemic lupus
erythematosus)
(Heavy metal toxicity)
•
Absent
A bsent
Determine serum calcium
Present
Redistribution
of PO,
Elevated
J hyperparathyroidism
or
Ectopic hyperparathy
roidism
Normal or lbw
2' hyperparathyroidism
VDRR
Familial
—Spontaneous
I
GI PO, losses
(Malabsorption)
(AIOH, gel usage)
ft
Fig. 5-3. Diagnostic evaluation of the patient with hypophosphatemia.
2. Hematopoietic. Reduced red blood cell survival, reduced white cell function
(phagocytosis), and reduced platelet adhesiveness have all been reported in
hypophosphatemia but are almost always of a minor degree and subclinical
in nature.
3. CNS. Neurologic dysfunction manifested by obtundation, coma, and, rarely,
seizures has also been noted in severe hypophosphatemia, particularly in pa
tients with multisystem disease or severe trauma.
4. Bone. Osteomalacia has been shown to occur with severe, prolonged hypo
phosphatemia. The deficiency of ATP induced by phosphate depletion may be
a relative one. For example, resting muscle may not undergo rhabdomyolysis
with phosphate deficiency, but vigorous activity may quickly stress cells beyond
their ATP reserves and lead to tissue damage. Also, patients who have a modest
degree of phosphate deficiency may become severely symptomatic when cellular
glucose uptake is stimulated by glucose or insulin administration.
C. Diagnosis. The differential diagnosis begins with assessment of urinary phosphate
excretion (Fig. 5-3). The kidney removes phosphate from the urine rapidly when
the filtered load of phosphate begins to fall. In normal people, phosphate is virtually
eliminated from the urine below a phosphate level of 2.0 mg per deciliter. In a
patient with marked hypophosphatemia, urinary excretion of greater than 100
mg per day (corresponding to a urinary phosphate concentration of 5 to 10 mg
per deciliter) is inappropriate and indicates renal phosphate wasting, which is
due to either a tubular defect or increased levels of parathyroid hormone. Hy
perparathyroidism (primary or secondary) is distinguished by measurement of
the PTH level. The various tubular syndromes can then be identified by the pres
ence or absence of other components of proximal tubular dysfunction, such as
glycosuria, bicarbonaturia, and aminoaciduria.
If urinary phosphate excretion is appropriately low. the differential diagnosis
includes GI losses and redistribution of phosphate associated with respiratory
alkalosis and glucose infusion. The former is corroborated by a history of gas
trointestinal disease or the use of aluminum hydroxide gels.
i
3
'5
7
■3
e
D. Therapeutic approach. All patients with marked hypophosphatemia should be
treated. The route and rate of therapy, however, are a source of controversy. I he
first principle of therapy is to correct the underlying disturbance. In more than
60 percent of hospitalized patients, glucose infusions are the cause of hypophos
phatemia. In the majority of the remaining patients, respiratory alkalosis due
to sepsis, pulmonary disease, anxiety, alcohol withdrawal, or fever will be present
In these circumstances, correction of the primary disorder may preclude the need
for specific phosphate supplements. In some patients, however, obtundation, coma
seizure, respiratory failure, and congestive heart failure may coexist with and
be attributable to hypophosphatemia. In this case, therapy with phosphate sup
plements is indicated. Unfortunately, because of a highly variable patient response,
no regimen for intravenous phosphate therapy is completely safe. If hyperphos
phatemia occurs, deposition of calcium phosphate complexes in soft tissues blood
vessels, and other viscera, as well as severe hypocalcemia, may result. This un
toward reaction may occur whenever the solubility product of [Ca] x [Id
J
exceeds 60.
1. Oral phosphate. The preferred route of therapy is oral administration of phos
phate, since it is less likely to cause acute, severe hyperphosphatemia. The
dosage for the treatment of severe hypophosphatemia should not exceed 2000
mg per 24 hours in four divided doses. Serum phosphate should be monitored
once every 24 hours and phosphate repletion halted when serum phosphate
rises above 2.5 mg per deciliter. (Phospho-soda contains 650 mg phosphate
per 5 ml).
.
2. Intravenous phosphate. If oral therapy cannot be employed, then intravenous
phosphate may be used. The dosage should never exceed 2 mg per kilogram
of body weight over 6 hours, with monitoring of serum phosphate level every
6 hours until the level rises to 2.5 mg per deciliter. The prophylactic use of
intravenous phosphate is justified only in the setting of total parenteral nu
trition, for which studies have shown the need for 450 mg of phosphate for
each 1000 kcal infused. In other conditions in acutely ill, unstable patients,
intravenous phosphate supplementation is indicated only in the emergency
therapy of severe, symptomatic hypophosphatemia.
Prophylactic intravenous phosphate therapy has been suggested as a useful
adjunct to the management of diabetic ketoacidosis. The acute reversal of aci
dosis reduces oxygen delivery (Bohr effect), and superimposition of reduced
2,3 diphosphoglycerate (DPG) levels due to hypophosphatemia may additionally
impair tissue oxygenation. However, prospective studies now show no clinical
benefit to routine, prophylactic phosphate infusions in patients being treated
for diabetic ketoacidosis. Therefore, oral phosphate administration is the pre
ferred regimen when normal dietary intake of phosphates cannot be otherwise
achieved.
—
IV. Hyperphosphatemia
A. Causes. In the steady state, the level of urinary excretion is the major determinant
of the serum phosphate. In normal people, because of efficient renal excretion,
serum phosphate does not increase during periods of increased phosphate intake
even with an increase in intake to 4000 mg per day. Above that level, only small
rises occur, provided that phosphate intake is distributed over a 24-hour period.
If the increased intake is concentrated within a 2- to 3-hour period, hyperphos
phatemia will transiently result. There are three circumstances in which renal
excretion is insufficient to prevent hyperphosphatemia (Table 5-4).
1. Massive phosphate Infusion. Acute elevation of serum phosphate by massive
infusion into the extracellular fluid from either exogenous or endogenous
sources may exceed the ability of the kidney to excrete phosphate. Exogenous
souces include oral phosphate supplementation^ enemas, or laxatives. Severe
hyperphosphatemia (greater than 15 mg per deciliter) has been reported in
children receiving hypertonic phosphate enemas. Recent studies have shown
that the use of recommended quantities of phosphate-containing laxatives in
adults may acutely and transiently raise serum phosphate to 7 to 8 mg per
deciliter. Endogenous causes of increased phosphate include acute rhabd--
i
I
4
I
I
I j
J
80
el
Table 5-4. Causes of Hyperphosphatemia
Massive phosphate infusion
Endogenous
Cytotoxic therapy
Rhabdomyolysis
Exogenous
Phosphate enemas
Laxative abuse
Decreased glomerular filtration rate
Increased tubular reabsorption
Hypoparathyroid disorders
Acromegaly
Thyrotoxicosis
—
EHDP
Sickle cell anemia
Tumoral calcinosis
ethane-I-hydroxy-l, l-diphosphonate.
F
5: The Patient With Disorders of the Serum Calcium and Phosphate
Vs-'1
5- The Patient With Disorders of the Serum Calcium and Phosphate
Serum PO,
81
5.0 mg/dl
I
Evaluate renal function
GFR > 30 ml/min/nr
n
-e
Exogenous
—PTH deficiency
—Growth hormone excess
—Hyperthyroidism
—Use of di phospho nates
—Severe contraction of
extracellular fluid volume
—Tumoral calcinosis
------------------ e J
_ W
EHDP =
mvolvsis secondary to a wide variety of disorders, including trauma, hyper- Cj
Sermte aTd narcotic overdosage. In this setting, acute renal failure may also
|
occur as a result of myoglobinuria, so that underexcretion of phosphate may
be present as well. Several recent reports have shown that severe hyperphosphatemia may occur following cytotoxic therapy of a vaneW-euke^as (
and lymphomas. It has been suggested that pretreatment of these Patients
-.
with a low phosphate diet and aluminum hydroxide therapy woul re u
|
ehosnhate Lad imposed by the acute cell breakdown with cytotoxic therapy.
Unfortunately, phosphate depletion induces an adaptive increase m the rena
phosphate reabsorptive capacity. This increase in reabsorption 1s >nd^e"t
of the serum phosphate and would, therefore, markedly impair the ability of
?he kidney to excrete an acute phosphate load. Thus, although the intracellular
I
phosphate content may be reduced with a depleting regimen, marked hypernhosphatemia may still occur. This approach, therefore, is not recommended.
[
Decressed glomerular filtration rate. Reduction of glomerular filtration rate
2.
(CFR) is the second circumstance associated with inability of renal excretion
to maintain a normal serum phosphate. A decrease in GFR below 25 mbmin
I
m2 in either acute or chronic renal failure is associated with h^D?h^hatemia
3
if dietary intake is in the normal range (800 to 1200 mg per day). The degree
of hyXphosphatemia achieved in this setting is modest, 5 to 6 mg per
!
£
More^rere degrees of renal insufficiency or the combination of mild renal
insufficiency and increased phosphate intake are associated with more
J
liy^rphosphatemia. Even in severe oligoanuric failure, a serum phosphate of
greater than 10 mg per deciliter implies the presence of tissue breakdown or
|
1
y
Increased renal tubular
phosphate reabsorption
•3
1
1
Phosphate loading
Renal insufficiency
with PO4 retention
(if serum PO >10 mg/dl
seek alternative
explanations)
w-,
|i
EndogerMits
—Tissue breakdown
—Rhabdomyolysis
—Cytotoxic therapy of
leukemias or
lymphomas
L------- ------------------------------ —------------------------ ------ - ---Fig. 5-4. Diagnostic evaluation of the patient with hyperphosphatemia.
d
I
I
I
I
3 L“^PtuXa relbXuon. Hyperphosphatemia can also be produced by
n
in the tubular reabsorptive capacity for phosphate. Even though
i
the filtered load is normal, the kidney excretes less phosphate as the tubules
C ■ 'S'
tionally
anl^ate'Zr^miayG^h hormone and thyroid horrfimnlnte tubular phosphate reabsorption; thus, both acromegaly
diphostemia. Disodium ethane- 1-hydrozy-l, 1-diphosphonai>e (EHDP), a d.
V
1
I
«
B
t'frect°r'' ^™tion °fphosphalo is
the formation of insoluble calcium phosphate complexes. The symptoms that are
observed relate to the resultant hypocalcemia and metastatic soft tissue calci
fications. An acute rise in serum phosphate may. therefore, be associated with
tetany hypotension, and acute organ dysfunction, including acute renal failure
and cardiac arrest due to calcium phosphate deposition. Chrome hyperphospha
temia as seen in renal failure, also depresses bone resorption and intestinal cal
cium ’absorption and additionally aggravates hypocalcemia Secondary hyper
parathyroidism ensues, and the resulting osteitis fibrosa and myopathy may be
die presenting features. In the absence of parathyroid hormone, as in hypopar
athyroidism, hypocalcemia predominates in the symptomatology of chronic hy-
C. Snosi^Hrperphosphatemia is due to either defective excretion or massive
overload (Fig. 5-4). The latter, whether from endogenous or exogenous sources,
should be immediately obvious from the history and physical examination. Even
in the absence of an appropriate history land even in the presence of renal failure)
increased serum phosphate of greater than 10 mg per deciliter implies the presence
of increased phosophate load. Surreptitious laxative and enema abuse are often
associated with hypocalcemia or volume contraction. Measurements of serum
levels of CPK will reveal rhabdomyolysis.
Chronic mild-to-moderate hyperphosphatemia m the absence of an obvious so u
of phosphate implies a defect in renal excretion of phosphate due to either renal
failure or increased tubular reabsorption. In the absence of renal failure the
differential diagnosis includes the various forms of hypoparathyroidism, thyro
toxicosis, acromegaly, and tumoral calcinosis. Most forms of hypoparathyroidism
|
I
82
5: The Patient With Disorders of the Serum Calcium and Phosphate
are associated with hypocalcemia, whereas the clinical picture combined with
growth hormone and thyroid hormone assays should differentiate growth hormone
excess and hyperthyroidism. The diagnosis of tumoral calcinosis rests on the
demonstration of hyperphosphatemia in the absence of a markedly increased
phosphate load associated with normal levels of PTH and normal responsiveness
to PTH.
D. Therapeutic approach
1. Acute hyperphosphatemia. Acute, severe hyperphosphatemia with symptom
atic hypocalcemia can be a life-threatening disorder. If renal function is intact,
the hyperphosphatemia will usually resolve within 6 to 12 hours. The use of
saline infusions may increase renal phosphate excretion but will dilute the
already depressed serum calcium. Aoetazolamide in doses of 15 mg per kilogram
every 3 to 4 hours will increase phosphate excretion. If symptomatic hypo
calcemia is present, however, and particularly if renal function is compromised,
herpodialysis is the only effective therapy available.
2. Chronic hyperphosphatemia. Chronic hyperphosphatemia due to defective
renal excretion, as in renal failure or tumoral calcinosis, is treated primarily
with a low phosphate diet and aluminum binding gels. In dosages of 5 to 6
gm per day, these drugs produce a negative phosphate balance and prevent
hyperphosphatemia. Hypophosphatemia should be avoided. In dialysis patients,
predialysis values of 4 to 5 mg per deciliter are acceptable.
The Patient With Renal
Stones
Fredric L. Coe
>
I fi
whJ
In carrying out their regulatorj- fu“«ons, the Wneys
not only calcium but substances s
calcium forms highly msolub e aalta. Atthe
uric acid, which is a metabolic end product in
t
the ki(JneyS must
js also very insolub^
j materials are limited by
i i-
1
fee
the extent to which supersaturation m *
ion of caicium or uric acid, pecuSome people, because of a tendency to overexc
tend to eliminate excessive
ferities of diet, or fundamental metnboUidera g,
crystalluria is much
Suggested Reading
Agus, Z. S., Goldfarb, S.. and Wasserstein. A. Disorders of Calcium and Phosphate.
In B. M. Brenner and F. C. Rector, Jr. «Eds.), The Kidney (2nd ed.). Philadelphia:
Saunders, 1981.
DeLuca, H. F. Vitamin D metabolism and function. Arch. Intern. Med. 138:836, 1978.
Frame, B., and Parfitt, A. M. Osteomalacia: Current concepts. Ann. Intern. Med.
89:966, 1978.
Knochel, J. P. The pathophysiology and clinical characteristics of severe hypophos
phatemia. Arch. Intern. Med. 137:203, 1977.
Lentz, R. D., Brown, D. M., and Kjellstrand, C. M. Treatment of severe hypophos
phatemia. Ann. Intern. Med. 89:941, 1978.
Nusynowitz, M. L., Frame, B., and Kolb, F. O. The spectrum of the hypoparathyroid
states. Medicine 55:105, 1976.
Purnell, D. C., Scholz, D. A., Smith, L. H.. Sizemore, G. W., Black, B. M., Goldsmith,
R. S., and Arnaud, C. D. Treatment of primary hyperparathyroidism. Am. J. Med.
56:800, 1974.
Sitrin, M., Meredith, S., and Rosenberg, I. H. Vitamin D deficiency and bone disease
in gastrointestinal disorders. Arch. Intern. Med. 138:886, 1978.
Slatopolsky, E., Rutherford, W. E., Rosenbaum, R., Martin, K., and Hruska, K. Hy
perphosphatemia. Clin. Nephrol. 7:138, 1977.
Stewart, A. F. Therapy of malignancy associated hypercalcemia—1983. Am. J. Med.
74:475, 1983.
Suki, W. N., Yium, J. J., Von Minden, M.. Saller-Hebert, C., Eknoyan, G., and Mar
tinez-Maldonado, M. Acute treatment of hypercalcemia with furosemide. N. Engl.
J. Med. 283:836. 1970.
Wisneski, L. A., Croom, W. P., Silva. O. L., and Becker, K. L. Salmon calcitonin in
hypercalcemia. Clin. Pharmacol. Ther. 2-fc219, 1978.
si
V
£n
thorough metatsL.c ^est^oi^d^
g,r?rpxcretion of qivBlent. mine
»
t
t
cystinuria, for these^oneLngar^^^;;? ’ hich thejmnitrv tracUecomes
There iF^so a spga catego^of stone
to
infected withjirEjmsmU^^
-
;
!and
” “development
is of struvite stones^ • >* “ience in the American population
I. Clinical setting. Renal stone disease, has p
princlpally from
of approximately 5 cases per WOO people, in
8
lence
only a frac
hospital discharges. It probably Weretat^tti
Jithough calcium stones occur
tion of renal stone attacks require tospita^
approaches 2 : 1 or 3 : 1in men more frequently than in womei th°
than
men Cvstine
infection stones of stru\lt*
f
t.nbi''l^r*^'rrtpr- nn~”r W'ttl
stones, which are caused t?Y,
ccere very uncommon in children.
frequencfmTKtiwo^x^Calcium stones are_«y-------- ----83
Ii
.J
-
( >
&
S4
■■
6: The Patient With Renal Stones
Although the prevalence and attack rates vary geographically, stones are virtually
ubiquitous in the Western world. In the United States, as well as in the rest of the
Westem Hemisphere, there are “stone belts,” in which stone disease is particularly
prevalent. These geographic clusterings, however, have been of less clinical and investigative interest than was initially hoped, and the reasons for them have never
been elucidated. Abnormal levels of calcium or other minerals in the water supplies/
although long suspected, have never been documented. Differences in trace element
concentrations in foods, variations in soil chemistry, and other hypotheses also have
failed to gain support. About the only clear geographic risk factor is that of climate,
stone disease tends to occur more frequently in the hot and dry areas of the world.
This increase affects not only calcium stones but aiso uric acid stones. The presumed
reason is chronic dehvdration, which forces the kidney to eliminate normal or, in
some instances, abnormal amounts of insoluble material in lower than average vol
umes of urine.
II Signs and symptoms. As long as the stones remain attached to the renaljjapillae,
where they usually tend to form, thev^Foduce no symptomsexcept hematuria. Renal
stones^are oneoTThe commonest causes of hematuria, along with urinary tract and
renal neoplasia^ renal cysts, and urinary tract and renal infections. Once free to
move in the urinary stream, however, a stone can produce pain from acute obstruction
of the renal col I ectrng system anywhere from the ureteropelvic junction tothe ureterovesicarjun£n5m~The pain? which arises^ecg^Sfi^tllKi^aringju^ss^ con
sequent dilatation of the kidney and urinary collecting system, is usually known as
rpnnl coli'r~ It tendsln begin suddenly. Over a period of approximately 30minutes
ifreacHes a plateau of intensity andthen remains constant and often of unbearable
severity. In general, a pain that begins in the flank area and does not change its
locETwn reflects an obstruction anywhereUopg tlw.binary systenu but a pain that
hoginTm theTlank area and then moves downward, along the radiation path of the
ureter, ^Kich'is egentiaTly along the lateral and anterior aMomen^lmosLilways
indicates aTtone that has*moved down the ureter. Stones that lodge at the ureterovesical junction frequently present without renal colic, but rather with symptoms
suggestrngurmar^jnl^tdQnJi.e., dysuria, frequency7and urgency). The reason for
these symptomsTsrirrttanoh of theblacmer trigone. Stones at this location may also
cause pain that radiates into the testicle or vulva on th^t_gld£.Frequently, stones are"asymptomatic and are discovered on routine radiographic
assessment for another condition. Apart from uric acid^tones.j^^stones^re ra
diopaque—cystine stones because of the sulfur they
ofSefrcalcium content;- and~struvite~stones_b£cause. of their magnesium content.
In generalTcSIcium stones tend to present as small, densely radiopaque objects; cystine
stones are slightly less radiopaque and have “soft” edges; struvite stones frequently
form laminated, branching “staghorn” calculi.
Physical examination rarely reveals important findings except for those of urinary
obstruction or infection. The obstructed kidney tends to be tender and may be enlarged
enough to palpate. If urinary infection has supervened m an obstructed kidney, there
may well be signs of perinephric inflammation, including muscle spasm and costovertebral angle tenderness. Tenderness along the path of the ureters is an infrequent
sign even if the ureter is dilated by a distal stone. In patients who have a stone at
the ureterovesical junction and who present with symptoms of lower urinary tract
infection, the absence of bladder tenderness is often a striking negative finding.
III. Types of stone disease. Four main types of stones are encountered in clinical practice
(Table 6-1); calcium stones predomiriate. and a majority of these are composed of or
contain vaivium
calciunT'oxalale.
composition,
stones are
organized masses
coniain
uAaiavc. Whatever -their
-------------,------------ - ------■
of crystalsTKaFgF^Ton the surfaces of the renal papillae ^heneve^^^eQX^^
burdenof poorly soluble materials is excessive for the volume of urine that is available
to dissolve them. In the cases of calcium and cystine stones, the mam causes are
overexcretion of calcium, uric acid, or oxalate, or of cystine, respectively. Uric acid
stones can be caused by overexcretion of uric acid, but an abnormally low urine pH
is usually more important in pathogenesis. Struvite stones are produced only by
bacteria that possess the enzyme urease and, therefore, are a result of urinary in
fection.
6: The Patient With Renal Stones
85
Table 6-1. Types of Renal Stones
Major Constituent
Crystal Type
75
Calcium
Uric acid
Cystine
Struvite- !arbonate
Approximate
Percent of
Ail Stones
Calcium oxalate
Hydroxyapatite (CaPO4)
Brushite
Uric acid
Cystine (amino acid)
MgNH^PO^ and CaCO3
5
1
20
e
e
ei *
,
j
|
1-
3
I
(
'v-
e
l
W
?
t
I
C
I
„
^1*
AC Calcium stones? Hypercalciuric states, hyperuricosuria, and hyperoxaluria are
the main remediable causes of calcium stones.
1. Hypercalciuria. Hypercalciuric states that cause calcium stones include:
a
1
-i —* Idiopathic ------------hypercalciuri
a • ab. Primary hyperparathyroidism
2^
c. Renal tubular acidosis (including acetazolamide use)
d. Sarcoidosis
—
e. Cushing’s syndrome
f. Immobilization
g- Calcium-alkali excess (calcium phosphate stones)
h. Vitamin D excess
I. Hyperthyroidism
----------------- —----------j- Paget’s disease
The moSTCOmmbn cause is idiopathic hypercalciuria, which appears to be in
herited as a mendelian dominant trait and is present in nearly one-half of
patients with calcium stones. Primary hyperparathyroidism, in which hypercalciuna~is due to hypercalcemia from parathyroid hormone excess, is present
in about 5 percent of patients with renal stones. All other hypercalciurlcsSates
are uncommon causes of stone disease.
2. Hyperuricosuria. Hyperuricosuria,"usually due to excessive purine intake in
the form of meat, fish, and poultry, causes calcium stones frequently, in about
20 percent of patients probably by producing crystals of uric acid or its sodium
salt that act as seed nuclei upon which calcium oxalate can deposit.
3. Hyperoxaluria. Hyperoxaluric states that cause calcium stones include:
-------a. Intestinal disease (CrolTn’s disease, malabsorption)
I XMf
b. Ileal resection
c. J ej uno^TTearbypass
d. Vitamin C excess
e. Dietary oxalate excess
eroxaluria
f. Pi imar>' hyp
.__
Diseases of the :ileum or ileal resectiorspr bypass produces severe hyperoxaluria.
Although this cause of calcium stone disease is becoming better recognized
and perhaps even more common because of the increase in the number of pa
tients with jejuno-ileal bypass during the past decade, intestinal oxaluric states
are present in only a small percentage of all patients with renal stones. Fre^
quently, mild hyperoxaluria from~diet (rhubarb, tea) or excessive vitamin C
intake may contribute to stone disease in patients with other disorders. Primary
hyperoxaluria is very rare. In this condition stones begin in childhood, followed
by a gradual rise of stone disease. Elevated urine pH can also contribute to
calcium stones, because apatite or calcium phosphate (but not oxalate) crys
tallizes readily in alkaline urind; this is especially important in hereditary
distal renal tubular acidosis.
A
86
BL
6: The Patient With Renal Stones
6: The Patient With Renal Stones
4 '
B. Uric acid stones. Uric acid is weakly acidic, with a dissociation constant (pKa)
of 5.35. In a urine of that pH, 50 percent of the uric acid is dissociated into urate
and^jiotons. The undissociated acid is very insoluble con)pared .1 urate~ahd forms
H stones, whereas urate forms stones very rarely. Therefore, low urine pH is a critical
factor uTproducing uric acid stonesTand such stones rarely form and persist in
an alkaline urine. Patients with gout and members of families that are afflicted
with an inherited tendency toward uric acid stones elaborate a very acid urine
(Table 6-2), whose average pH is below 5.5 or even below 5.0 in extreme circum
stances, for reasons that are not fully understood. Urine pH is also low in patients
with an ileostQmy_or colostomy, whose drainage is alkaline. Loss of colon function
raises urine uric acid excretion, because about^oneThird of the daily production
of uric acid normally is degraded by colonic bacteria. Low urine volume, secondary
to hot climate, intestinal disease, orliabitual low fluid intake, also lowers urine
pH, as protonated urine buffers are rendered more concentrated. Perhaps the
only situation in which uric acid^stones form despite a normal urine pH is in the
Lggch-Nyhan syndrome, in which uric acid overproductionTs so extreme, and
hyperuncosuna is so massive, that the concentration of undissociated uric acid
exceeds the solubility limit at even a normal pH.
C. Cystine stones. Cystine, an amino acid, also has a solubility that depends on
pH, but its dissociation constant is so_high that its solubility does not increase
until urine pH rises above 7.4. In cystinuria, throughout the physiologic pH range,
urine is so saturated with cystine that stone formation is~freq_U£Ht. The basis for
cystinuria is a hereditary defecUof amino acid transport by the brush border
JL . membranes of the renal proximal tubules involving cystine, arginine, ornithine,
j rvk^Uand citrulline. Intestinal transport of these amino acids is also defective, but the
^^^^t^-Antestihai defect is clinically trivial. There is no cause for cystine stones except
cystinuria.
D. Struvite stones. Abnormal urine^pH is critical to the formation of these stones,
because struvite (MgNH4PQ4) contains PO/~ , which is present only at a high
pH, above 8,0; another requirement islbarurine [NH4 "1 be high. The kidney
itself cannot produce so alkaline a urine that also contains appreciable concen
trations of NH4 ’; this combination occurs only when bacteria that possess urease
colonizejthe'"urinary tract and generate ammonia from urea; the urea hydrolyzes
tq NH4' and raises the pH to above 8.0. At that pH not only does struvite crystallize
spontaneously, but calcium carbonate crystals also form and intermingle with
the struvite; thus these stones always contain both minerals.
IV. Evaluation of the patient
*
....
'
A. Clinical assessment. The main goals of clinical assessment are to characterize
the seriousness of stone disease and to search for clues to causes. The history and
physical examination are critical because treatment must be chronic if it is to
be effective, and it must be based on a complete understanding of the patient’s
health status. Most of the time, however, little of direct therapeutic relevance
<8
>
*
Ti a
•J 2
I
Table 6-2. Causes of Uric Acid Stones
Causes
Gout v
Familial *
Climate »
Ileostomy •
Colostomy »
*
Lesch-Nyhan 'syndrome
Low fluid intake (habitual) •
Hyper
uricemia
Hyperuricosuria
yes
no
no
no
no
no
yes
no
yes
no
Low Urine
pH
Low Urine
Volume
yes
yes
no
no
yes
yes
yes
yes
yes
mo)
noj
yes
± = trait occurs only some of the time.
7'
J
87
will be found in the examining room. Most stone formers, especially those with
calcium stone disease, are otherwise well, and the cause of their stones is detectable
only in the laboratory. The clinical assessment of the patient with nephrolithiasis
includes:
1. Stone disease characteristics
a. Numbers of stones passed, removed, or visualized
b. Current stone burden: radiograph of the kidneys, ureters, bladder
c. Stone morbidity: hospitalization, cystoscopy, surgery, urinary infection >
d. Damage from stones: loss of kidney substance, permanent unnaryirainage
abnormality, azotemia
e.
e. Family history of stones, especially stone type
f. Types of stones formed by the patient: crystallographic analyses
2. Symptomatic causes of stones
.
a. Hyperparathyroidism: peptic ulcer, bone disease, pancreatitis
b. Renal tubular acidosis: bone pain, waddling gait
c. Sarcoidosis: hilar lymphadenopathy, hepatosplenomegaly, erythema no-
d. Other: immobilization, Paget’s disease, Cushing’s syndrome, vitamin D
excess, vitamin C excess, hyperthyroidism, excess purine intake, alkali
excess, bowel disease, urinary tract infection (always obtain past culture
results), episodes of dehydration, history of low fluid intake.
B. Urinalysis
,
1. Hematuria. Ilematuna is common in nephrolithiasis and may reflect the presence of stones even when stones cannot be visualized radiographically. Red
cell casts, however, indicate glomerular disease as the cause of the hematuria.
2. Leukocyturia. Leukocyturia usually reflects the presence of urinary tract or
renal infection. Severe proteinuria is not produced by renal calculi per se, ut
it can be produced by some causes of stones. For example, tubulo-interstitial
renal disease from hvpercalcemia, as in primary hyperparathyroidism, or from
severe hyperoxaluria can cause excessive excretion of low-molecular-weight
proteins, such as p2 microglobulin or lysozyme, and very modest albuminuriano more than 500 mg per 24 hours. Renal calculi and more severe albuminuria
may be associated with renal disease secondary to hypertension, hypercalcemia,
or some underlying chronic renal disorder. Stone disease itself does not cause
I
Pi •
i i'
I
CHSt/S
3. Crystalluria. Crystalluria (Figs. 6-1 and 6-2 (color insert)) is diapiostically
important only in certain specific situations. Cystine crystals, which are flat
hexagonal plates, occur only in heterozygous or homozygous cystinuria. Struvite
crystals, rectangular prisms that resemble coffin lids, occur only when the
urine is infected with urea-splitting bacteria. The other crystals can occur in
normal urine. Calcium oxalate monohydrate forms round discs that resemble
red cells and may be connected in pairs, like dumbbells. Calcium oxalate dihydrate forms in the shape of pyramids, (they look as though a pyramid is
standing on a mirror). Calcium phosphate crystals, either apatite or octocalcium
phosphate, usually look like nondescript fine dust, because the crystals are
too small to be resolved by the light microscope. Brushite (CaHPO4), however
produces flat rectangular crystals that look like thin boards or laths. Uric acid
usually forms a fine dust that maybered if it adsorhadi.ricinex_ajed-pi^nent
normally present in nnffFH4ritr5cIddihydrate is uncommon in unnejRfcgnis
rhomboid crystals that are large and easily recognizable. Although the finding
of calcium “Oxalate? calcTum plwsplutg, or urtT acid crystals should arouse sus
picions about the probable cause of stones in a patient, any of these crystals
can be found in the urine of normal people.
C. Metabolic evaluation (Table 6-3)
1. Timing of outpatient workup. Hypercalcemia^ hypercalciuna, hyperoxaluria,
hyperuricosuria, and abnormal urine pH are all detected by measurements
made on serum and 24-hour urine collections. Three collections are recom
mended, despite the cost and time involved, because treatment of chronic dis
ease usually results from a positive diagnosis. The urine collections are a mirror
HU
I
i
6: The Patient With Renal Stones
8S
ef *
all
eIJ
I z.
■i
B
.*
SA
i
i
Fig. 6-2. Uric acid crystals in urine sediment (polarized light). (Courtesy of Jerome t.
.^^kassirer, M.D.)
$
I
*-1
»
■
6-3. Metabolic Assessment of the Patient With Nephrolithiasis
^3 I!
C
E
Fig. 6-1. Crystals in urine sediment.
B.
(40x). E. Struvite (40x). (Figs. A-E courtesy of Jacob Lemann, Jr., M.D.) F. Uric
acid f40’x). (Courtesy of Jerome P. Kassirer, M.D.)
I
>
i
of life-style and should, therefore, be collecteu while the patent is leading his
or her life as was usual when stones were being produced. There are endless
problems in obtaining useful collections of urine. New diets that have been
suggested bv friends and relatives or by a physician and unbraced as treatment
ofILnes must be discarded in favor of the old one. The high fluid intake that
most patients begin after recovery from a stone land gradually give up as time
goes on) must allo be willfully
for the collections,
collections. There
is no
nllfully set aside tor
mere w
nu sense
after surgery or even hospitalization, because patients
in collecting urine soon i
tites only after a few months have elapsed. It isoften
difficuTto wait6, beacmte plt ients are anxious for treatment
stave
a re.Linen* to
w Du**
• ** off a
misleading study, done
™^o^t regrettable error is to
Test
*
Serum3
24-Hour Urine Fresh Urine Aliquot
Calcium
gj^ric acid
Creatinine
..^K-xalate
r’hosphate
3
3
1
3
3
3
3
1
3
1
’ ^Sodium
- Jj^otassium
’• v Chloride
f
1
1
1
1'
content
1
t " Cystine screening1’
* ^Urinalysis
1
|
- -------;iSera drawn at the conclusion of each 24-hour collection; numbers represent number of
,.
parate samples suggested.
t "Nitroprusside reaction; detects above 75 mg/L of cystine.
90
6: The Patient With Renal Stones
6: The Patient With Renal Stones
91
4
do the workup in the hospital, for convenience, insurance purposes, or any,MM...
Table 6-5. Differential Diagnosis of Hypercalciuria
other reason. No one can eat, drink, and get about normally in a hospital, so
urine data are as artificial and divorced from real life as possible.
.
Serum
Usual Stone Type
Other Serum Values
2. Collection techniques. There is some art in the actual techniques of collecting
Calcium
Cause
samples. First of all, the physician must be in charge and everything done
Calcium oxalate and/or
Normal
through his or her office. Four-liter plastic containers, with a molded handle,:. A|
Normal
Idiopathic hypercalcalcium phosphate
as wide a mouth as possible, and a metal or plastic screw cap that does not
ciuria*
Calcium
oxalate and/or
leak, are most suitable. There should be a label for the collection times and
Hypophosphatemia,
High
Primary hyper
calcium phosphate
name of the patient. A teaspoon of thymol crystals is used as a preservative;
occasionally hyper
parathyroidism
it is worthwhile to have a brief list of written instructions for the collection.
chloremic acidosis
Calcium phosphate
Patients find it difficult to>inderstand that the collection is begun by voiding
Hyperchloremic
Normal
into the toilet, not into the container; the intuitive action is to void into the V. Renal tubular acidosis
acidosis
container, thus producing an erroneous overcollection. It is human nature to
be chagrined when the container is still nearly empty at the end of the day^J
—s^s^alk^^
*Sarcoiuu»i»,
----------and to drink extra water to fill it up. Patients should be warned that the bottle
thyroidism.
Paget’s disease, rapidly progressive -ist be excluded on clinical grounds.
Is large enough to accommodate almost anyone and that few will fill it even
(which cause hypercalciuria though not stones) mm
halfway. The office staff must also understand this. Finally, there is the “impossible” problem of collecting at least two of the urine samples during regular
I
weekdays at work and at least one on Sunday. Every executive and professional
is sure such an indignity is not intended for him or her; people who work in
j
a factory or on a construction site think the physician must not be serious—
after all, there just is not unlimited bathroom time, teachers assure the phy-^* .
sician that the classroom is not the place for urine-collecting jugs; and so forth.
However, everyone does manage to collect and. judging from the constancy of
sequential urines, collect well or at least consistently.
. .
r
;
a.
D. Interpretation of metabolic data. Overexcretion is defined using upper limits of a]
formation whatever other caus
whether it is due to dietary
normal (Table 6-4). Criteria are given both in terms of absolute amounts and
differential diagnosis of
usually need not be
normalized for body weight and for urine creatinine excretion, which tends to
|
intake or to endogenous ^erp^u'Uo^is d
rttonu jf pUrine intake
parallel muscle mass. Although the 3 serum calcium concentration measurements
must be interpreted using the
normal
for the laboratory that performed . them,
______
__________
values above 10.3 mg per deciliter should be viewed with suspicion, especially
|
all three are high. It is useful to summarize metabolic data in clear diagnostic
categories, such as hvpercalcemia, hypercalciuria, hyperuricosuria. or hyperox-^1
in diet is not indicated.
from history and physical exaluria. using Table 6-4 as a guide, and then go on to the finer details. The inter3. Hyperoxaluria, intestinal causes a
ileal resection, jejuno-ileal
pretation and analysis of hypercalcemic states, of which primary hyperparathyI
roidism is the most important when one is concerned with renal stone disease,
are discussed elsewhere (see Chap. 5, set. III).
.
i
1. Hypercalciuria. The differential diagnosis of hypercalciuria is presented
Table 6-5. Primary hyperparathyroidism, always a hypercalcemia state.
.
by enhancing the formation of ca cium
p
>ate w^ch usually combines
discussed in Chapter 5, section III. Renal tubular acidosis is detected because
I
f
leaving an abnormally
absorption? In addition, some
of hyperchloremia (serum chloride above 108 mEq L> and low carbon dioxide^^l__
with calcium to form insoluble Mdte W* io
Pmucosa
oxalate. Bile
content (serum carbon dioxide below 24 mM); urine pH values will all be above
fatty acids can enhance the pert
?
h the coion> where they
5
3
•J
SZX'S zjs?. S—1. -4-
Material
Male
Female
mg/kg/24 hr
mg/gm creatinine/
24 hr
Calcium
Uric acid
Oxalate
Cystine j
300
800
. 50
250
750
50
4
150
0.73
e
e
and low urine pH is summarized in
60*____________ ;
Heterozygous cystinurics, who rarely produce cystine stones, excrete between 60 and
mg gm creatinine/24 hr; homozygous cystinurics excrete above 300 mg/gm creatinine/^
I
•“
!
I I
salt malabsorption allows ex^1^e R t important to question patients about
may increase mucosal permeabdi
Ms impirtan
q
dietary oxalate excess (Table 6-6), as we i as
childhoodi
hances oxalate production in some
1
u primary hyperoxaluria.
followed by severe stone disease and ^otenua
Xh^sto^s are pure
4. Uric acid stones. The most importantcase> in which either mixed
uric acid or admixed with calciu™are present, the patient must be
stones or both calcium and un
diseases were present, because treattreated as though two indepe1^tn6r^lt in continued formation of the other.
, hyperuncosuria, low daily urine volume,
Table 6-4. Upper Limits of Normal for Excreted Materials
mg^24 hr
Ih
a e
.
cvstine stones are a
5’
sSF
A
F
92
0
6: The Patient With Renal Stones
6: The Patient With Renal Stones
Table 6-6. Common High Oxalate Foods
0.1% Oxalate by Weigh*
0.02*« Oxalate by Weight
Beets
Beet tops
Dried figs
Lime peel
Nuts
Parsley
Rhubarb
Spinach
Swiss chard
Black tea
Chocolate
Cocoa
Blackberries
Blueberries
Concord grapes
Red currants
Gooseberries
Oranges (and peel)
Rasberries
Strawberries
Beans (green and wax)
Carrots
Celery
Roasted coffee
Endive
Okra
Green onions
Green peppers
I
Sweet potatoes
Renal calculus __
with increased urine calcium excretion
e; I
Urine calcium
excretion still
increased
e
e
3
3
$
1
J
a
ii
Idlooathlc hypercalciuria (Fig. 6-3)
a Thiazide therapy. Tlie best available treatment for idiopathic hypercalciuria
and recurrent stones is a thiazide diuretic agent. When used chronically,
drugs of this class decrease urine calcium excretion and prevent stone re
currence. A convenient drug is trichlormethiazide, 2 mg twice daily. At
this dosage, which is one-third of the full dose, potassium rep^cement is
rarely necessary. A high salt intake lessens the hypocalciunc effectiveness
of thiazide and is a common cause of treatment failure, so sodium excretion
must be measured along with calcium and creatinine m follow-up, 24-hour
urinp collections. It is best to reassess calcium excretion after 8 weeks o
initial treatment and 8 weeks after any change in thiazide dosage or salt
intake. Thereafter, a yearly follow-up is desirable,
P-ssiu™ -h each purine eoUee^
Occasional patients develop a maculopapular or urticarial skin rash from
thiazide derivatives and must then discontinue the medication^
Low calcium diet A low calcium diet is an alternative to a thiazide diuretic
b.
for those patients who have formed only a single stone. The best way to
determine if diet will work in a given patient is to place the patient on a
conventional low calcium diet of about 500 mg per day which is essentially
a diet free of dairy products. If urine calcium excretion falls into the normal
range the treatment has been successful. Persistent hypercalciuria could
reflect extremely efficient intestinal calcium absorption or a renal tubule
leak of calcium; in either event, diet alone is not a realistic therapy.
Restrict dairy
products and
recheck urinary
calcium excretion
in 8 weeks
Urine calcium
excretion
normal
Urine sodium
>100 mEq/24 hr
Urine sodium
<100 mEq/24 hr
Restrict dietary
sodium and
recheck in 8
weeks
Increase thiazide
dose by 50% and
recheck' in 8
weeks
/
Urine calcium
excretion
normal
Urine calcium
excretion still
increased
Leave on
current diet
and recheck
urine calcium
in 1 year
Begin thiazide
treatment, recheck
calcium and sodium
excretion in 8
weeks
. I
I
Fig. 6-3. Treatment of idiopathic hypercalciuria.
state.
V' recSn stones. The treatment of primary hyperparathyroidism and of renal
tubular acidosis is discussed elsewhere (see Chap. 4, sec. IV, and Chap. 5, sec. Ill
I
I
/
€
i
I
One stone
Begin thiazide
treatment and
recheck calcium and
sodium excretion in
8 weeks
/
excretion but is not in itself a basis for diagnosis or treatment. Similarly the
1
At least
two stones
93
e
>'4
*
Je. ”#
A.
stool This drug can cause chronic calcium depletion m patients with de
fective renal calcium conservation because it restricts calcium absorption
severely Under ideal research conditions, renal hypercalciuria can be dis
tinguished from absorptive hypercalciuria, but the tests are complicated
and open to dispute. Furthermore, cellulose phosphate is not yet available
as a standard drug and is still mainly of research interest.
2 Hyperuricosuria. Since diet is the main problem in most patient with hy* ppruricosuria, a reduction of purine intake from meat fish, and PO^ry-an
ideal treatment. Usually it is difficult for patients to change their habits, and
many fail to do so, at least right away. For this reason>
has severe recurrent stone disease, allopurinol may be instituted, 100 mg twice
dailv, to provide protection during period of dietary
last'l to 2 years Some of these patients are unwilling or unable to do without
the drug; others evemually can be treated by diet alone. Given a patient who
has formed onlv one stone, however, diet is a proper first treatment. Navura y,
diet will not work when there is endogenous overproduction of uric acid, and
hyperuricosuria will persist despite ingestion of a diet that is not excessive m
3.
HyperVxaluda.' Dietary sources of excess oxalate should be reduced or ehnu-
94
6: The Patient With Renal Stones
6: The Patient With Renal Stones
cium mainly precipitates oxalate in the bowel lumen and is eliminated in the
feces. A reasonable starting dosage is 3 gm per day of calcium, as calcium
carbonate, taken in two divided doses, one after each meal. A low fat diet is
also helpful, because unabsorbed fatty acids form complexes with calcium in
the bowel lumen, thereby offsetting the benefits of oral calcium supplements.
Certain fatty acids may also increase the permeability of the colonic mucosa
to oxalate and thereby foster its absorption. If calcium supplementation and
low fat diet both fail, cholestyramine is indicated. This ion-exchange resin
adsorbs both oxalate and bile acids, and it can reduce oxalate excretion in
almost all instances of absorptive hyperoxaluria.
Intestinal bypass for obesity tends to produce severe hyperoxaluria that is
difficult to reverse except with cholestyramine. Azotemia and acquired tubular
defects are common. Hyperoxaluria causes intratubular obstruction through
the formation of masses of calcium oxalate crystals, and interstitial deposits
of cajcium oxalate lead to tubulo-interstitial renal disease. As a rule, the bypass
should be removed if there is any evidence of renal functional impairment or
if hyperoxaluria is refractory to treatment.
4. Idiopathic calcium lithiasis. When no metabolic cause of stones is found, the
best available treatment is oral phosphate supplementation, at a daily dosage
of 2 gm of phosphorus in four divided doses. In addition, as in every form of
stone disease, adequate hydration is recommended. The effectiveness of this
treatment is not as well documented as when hypercal ci uri a, hyperoxaluria,
• and hyperuricosuria are reversed. The course of stone disease during phosphate
treatment has not been published in detail for a large group of patients except
in two instances. In both, phosphate was given in a dosage of only 1 gm daily,
and it was without effect. The higher dosage has been described as effective
in a large group of patients, but the clinical details about the patients have
never been published. Other treatments, including methylene blue, magnesium,
or pyridoxine supplementation, are untested and cannot be recommended.
B. Uric acid stones
1. Alkali administration. Whatever their cause, uric acid stones are first treated
by raising the urine pH into the normal range through oral alkali supple
mentation. The pH of the 24-_hour urine should be between 6.0 and 6.5; in
dividual voidings should all have a pH of above 5.5 and below 7.0. Sodium
bicarbonate tablets (10-grain tablets each contain 7.2 mEq of base) are given
at a dosage of 0.5 mEq base per kilogram of body weight in four divided doses,
one on arising, one at bedtime, and the other two between meals. The patient
should be given pH test paper, so that the pH of individual voidings can be
recorded; the dosage of alkali may then be raised or the timing of doses altered
until control throughout the day is achieved.
2. Allopurinol administration. Hyperuricosuria above 1000 mg per 24 hours re
quires treatment with allopurinol; 100 mg twice daily usually is sufficient. If
purine intake is very high, a reduction to, but not below, normal is also prudent.
Modest hyperuricosuria, between 800 and 1000 mg per day, should be treated
with allopurinol only if alkali treatment fails to control stone disease, or if
alkali cannot be used properly because of heart failure or intestinal disease.
Otherwise, a reduction of dietary purine intake is sufficient.
Intestinal disease may pose special problems. Adequate urine volume can be
difficult to achieve when diarrhea is severe or when a colostomy or an ileostomy
is present, because intestinal fluid losses are high. Furthermore, a large fluid
. intake may be poorly tolerated by patients with bowel disease because the
volume of diarrhea or the drainage from an ileostomy or colostomy may rise,
and abdominal pain may ensue. Alkali also may be poorly tolerated, because
of abdominal distention and bloating, yet urine pH tends to be very low because
of ihtestinal bicarbonate loss. When these problems are present, allopurinol
should be used even if the urine uric acid excretion rate is normal. Naturally,
fluids and alkali should be used up to the limit of tolerance.
3. Acetazolamide. Acetazolamide (Diamox) has a useful role in special cases. If
given in two to four doses of 250 mg daily it causes sustained bicarbonaturia;
thus sodium bicarbonate can be given despite heart failure or hypertension.
5>
□
:i
3
1
e. >
e
e
95
Given as 250 mg at bedtime, the drug will raise the overnight urine pH. In
patients whose first morning urine is very acid despite alkali treatment, this
measure'can be of critical value.
C Cystine stones. The primary treatment is sufficient water to produce a urine
volume that will dissolve the amount of cystine excreted daily. Since cystine dis
solves to the extent of almost 300 mg per liter in urine, the required urine, volume
can be calculated if cystine excretion is quantified. As a rule, at least 3 liters ot
urine are needed daily, and urine flow must be as high at night as during me
dav. Alkali treatment of limited value because cystine solubility begins to increase
only above pH 7.4, and so elevated a pH can be attained only by administering
very large doses of base, above 2 to 4 mEq/kg/day. D-penicillamme, which produces
soluble complexes with cvsteine and thereby aids greatly in preventing cystine
precipitation, is an ideal agent except for an extraordinary frequency (above 40
percent) of hypersensitivity reactions, ranging from skin rash to nephrotic syn
drome. Because it is a potent antigen, the drug is best reserved for patients whose
stone disease cannot be controlled with high fluid intake and aklali.
,
D. Struvite stones
1 Surgical considerations. Struvite stones must be removed if tney produce
persistent obstruction of the ureter or ureteropelvic junction, intractable pain,
serious
serious renal
renal infection,
infection. or clinically important bleeding. Otherwise, surgery
should be delayed, because recurrence is very frequent and subsequent surgeryto remove recurrent stones is technically difficult and carries a high ns o
nephrectomy. Renacidin infusion into the pelvis at the time of surgery may
prevent recurrence.
2. Medical treatment. Because the stones are infected foreign bodies, it is un
realistic to expect to eradicate urinary infections. The best course is to suppress
infection by the chrome administration of methenamine mandelate (Mandelamine) or the combination of sulfamethoxazole and trimethoprim (Bactrim or
Septra). Acute exacerbations of infection are best treated with a 3-week course
of an antibiotic to which the organism is sensitive at that time; a new urine
culture must be obtair^ed with each such episode to assess antibiotic sensitivity.
Patients with struvite stones frequently have had metabolic stone disease m
the past and harbor specific causes of such stones. These should be treated to
forestall the formation of new stones.
I
u
t
I J
Suggested Reading
Brenner B. M., Stein, J. H.. and Coe, F. L. (Eds.). Nephrolithiasis. Contemporary
Issues in Nephrology, Vol. 5. New York: Churchill Livingstone, ,1979.
Coe, F. L. Nephrolithiasis: Pathogenesis and Treatment. Chicago: Year Book, 1978.
Coe, F. L. (Ed.). Hypercalciuric States. Orlando, Fla.: Grune & Stratton, 1984.
;I
Coe F. L., and Favus, M. Disorders of Renal Stone Formation In B. M. Brenner and
F. C. Rector, Jr. (Eds.), The Kidney (2nd ed.). Philadelphia: Saunders, 19/9.
Coe, F. L„ and Favus, M. J. Nephrolithiasis. In R. G. Petersdorfet al (Eds.) Harrisons
Principles of Internal Medicine (10th ed.). New York: McGraw-Hill, 1983.
David, D. S. (Ed.). Calcium Metabolism in Renal Failure and Nephrolithiasis. New
’'a
York: Wiley, 1977.
Fleisch, H., Robertson, W. G., Smith, L. H., and Vahlensieck, W. (Eds.). Urolithiasis
V
p
Research. New York: Plenum Press, 1976.
Nordin, B. E. C. Metabolic Bone and Stone Disease. Baltimore: Williams & Wilkins,
1973.
/
Pak, C. Y. C. (Ed.). Symposium on nephrolithiasis. Kidney Int. 13:341, 1978.
.I
W-"
The Patient With Urinary
Tract Infection
^4
L. Barth Reller
1
■
a
eJ
eU
i
t
*?
\
e
e
e; ,
e
1?
e
r
*
^4^
( >
Urinary tract infections are exceeded in frequency among ambulatory patients only
by respiratory and gastrointestinal tract infections. Bacterial infections of the urinarj’
tract are the commonest cause of both community-acquired and nosocomial infections
in patients admitted to hospitals in the United States. The prognosis and management
of urinary tract infections, however, depend on the site of infection and any predis
posing factors.
.
I Definitions. Some definitions are necessary, since infection of the urinary tract may
’ result from microbial invasion of any of the tissues extending from the urethral
orifice to the renal cortex. The first useful distinction is betweeen upper (kidney)
and lower (bladder, prostate, and urethra) urinary tract infections. Although the
infection and resultant symptoms may be localized at one site, the presence of bactena
in the urine (bacteriuria) places the entire urinary system at risk of invasion by
bacteria. Significant bacteriuria is definedas the presence of 100,000 or more colony
forming units (cfu) of bacteria per milliliter of urine. Although lesser colony counts
can be of diagnostic importance, bacteriuria commonly implies a colony count of
greater than or equal to 105 bacteria per milliliter of urine.
The basic clinical entities included in the category of urinary tract infections are
the following. Pyelonephritis is nonspecific inflammation of the renal parenchyma.
Acute bacteria! pyelonephritis is a clinical syndrome characterized by chills and
fever, flank pain, and constitutional symptoms caused by bacterial invasion of the
kidney. Chronic bacterial pyelonephritis is long-standing renal infection with healed
residua or smoldering foci and persistent bacteriuria; symptoms often are absent.
Infections confined to the bladder (cysttfs), the urethra (uretlyftis), and the^prostate
(prostatitis) commonly cause dysuria, frequency, and urgency. Recurrence of urinary
tract infection is the result of either relapse or reinfection. It is clinically important
to make this distinction. Relapse is the recurrence of bacteriuria, with or without
symptoms, with the same infecting microorganism, which has persisted despite
treatment. In contrast, reinfection is recurrence of infection with a different, usually
drug-susceptible, microorganism. Relapse occurs more commonly after treatment of
bacterial pyelonephritis or prostatitis than after treatment of cystitis. Most episodes
of cystitis and urethritis are due to reinfection. Asymptomatic bacteriuria is an im
portant clue to the presence of infection somewhere in the urinary tract, however,
the importance of the infection and the need for treatment depend on the age, sex,
and underlying condition of the patient.
II. Clinical setting. To foster both prompt recognition and possible prevention, and un
derstanding of the epidemiology of urinary^tract infections > who gets them and why)
is particularly important for primary care physicians. In Figure 7-1 are shown the
major risk periods during life for symptomatic urinary tract infections and the in
creasing prevalence of asymptomatic bacteriuria that accompanies aging.
A. Asymptomatic bacteriuria. In the absence of instrumentation, asymptomatic
bacteriuria in men is rare until after the age of 60 years. In noncatheterized.
institutionalized elderly men the prevalence of bacteriuria exceeds 20 percent.
The cumulative prevalence of asymptomatic bacteriuria in women increases about
1 percent per decade throughout life. All pregnant women should be examined
for bacteriuria, since proper treatment lowers the subsequent incidence of acute
pyelonephritis in the third trimester from about 30 percent to 3 percent. In the
97
7: The Patient With Urinary Tract Infection
98
7: The Patient With Urinary Tract Infection
Symptomatic
infection
d> 9
Infancy
t
;«b
Prostatism
Preschool
"Pyelitis”
of
pregnancy
i?r\
"Honeymoon”
cystitis
I
2
A
-8
F
Asymptomatic
bacteriuria
St?
-6
-2
0
d < 1% —
5
10
15
20
25
Age in years
;
route.
.
in over 90 percent of ambulatory p
Catheter risk
r- 10%^
4. Instrumentation of urinary tract
a. Indwelling urinary catheter
b. Catheterization
c Urethral dilatation
30
60
70
* J
P*9- 7-1. Frequency distribution of symptomatic urinary tract infections and
prevalence of asymptomatic bacteriuria by age and sex. (Modified from the original
concept of Jawetz. From C. M. Kunin. Detection, Prevention and Management of
Urinary Tract Infections [3rd ed.]. Philadelphia: Lea & Febiger, 1979.)
absence of any symptoms, a systematic search for covert bacteriuria in other
population groups has not proved to be worth the cost. Why more women acquire
bacteriuria with increasing age is not known. Prostatic hypertrophy and an in
creased likelihood of instrumentation is thought to account for the bacteriuria
of older men. Differences between men and women in the rates of bacteriuria
have been attributed to the shorter female urethra and its proximity to the vaginal
and rectal mucosae and their abundant microbial flora.
B. Symptomatic urinary tract infections. Symptomatic urinary tract infections occur
in all age groups. Among newborns and infants, boys are affected more often than
girls. When the urinary tract is the source of neonatal sepsis, serious underlying
congenital anomalies are frequently present. During childhood persistent bacteriuria, with or without repeated symptomatic episodes, occurs in a small group
(less than 2 percent) of school girls. Such girls, and also school boys with bac
teriuria, should have a urologic evaluation to detect correctable structural ab
normalities when urinary tract infections are documented.
Sexually active women have a markedly increased risk for episodes of cystitis.
In the absence of prostatitis, bacteriuria and symptomatic urinary tract infections
are unusual in men. At any age, however, both sexes may develop symptomatic
infections in the presence of the following risk factors:
1. Obstruction to urine flow
a. Congenital anomalies
b. Renal calculi
c. l/reteral occlusion (partial or total)
2. Vesicoureteral reflux
3. Residual urine in bladder
a. Neurogenic bladder
b. Urethral stricture
C. Prostatic hypertrophy
gyasaasKs
f
and dysuria, however, do not
which can mimic both bladder
causes of the ^ute urethral syndrome,
infections, and prostatitis are commo
differentiate these clinical entities
Certain additional signs and
diagnosed with certainty only by
from urinary tract infections, which can De uiag
quantitative cultures of urine.
United States have an episode
1. Vaginitis. About 20 percent of,w°Pof tte^seek medical care. The presence
.
of dysuria each year, and one-ha
vaginjtis the likely cause of dysof vaginal discharge and irritation mak
can be confirmed by culture,
uria, unless a concomitant urinary trart
of vaginitis, can be demCandida albicans, the commonest SP«
t ceUs in a Gram-Stained
onstrated readily by culture or by fintogj preparation with potassmm
smear Of vaginal secretions <or in a sa
with a
prep.
hydroxide added. Trichomoniasis c* {vaginalis. Nonspecific
aration that shows the motile
A clue to the
vaginitis most often » associated witaG
ative bacilli that adhere
diagnosis is the presence of many sman g
to vaginal epithelial cells.
f
r than 3 days faVor a diagnosis
2. Urethritis. Acute frequency and dysuna for
vaginltl3. Chlamydia traof urethritis or urinary tract lnfec‘'“n
“ the Xte urethral syndrome
c/iomatis is now recognized as a commo
Unavailability of
V ‘J
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1
11
;M
1
1 ul
■ ■ i
I
3. transmitted agent that can cause severe y
h ges progenitalis can be
proximity to the urethral onfice-Tn^a£J “ansfomed cells in epidermal
4^
£
causes dysuria and frequency in middle g
t
d chronic
bacterial and nonbacterial Acute “^~"VUrgency, dysuria, perXtalTxanunaUon
sudden onset of chills and fever, un ary_
y
nation
ineal and low back pain, and ““““^^aLollen prostate
gland. Enteric
Enteric
irostate gland.
usually discloses an exquisitely tender, hot,
uaual pathogens
gram-negative bacilli, staphylococci, an
A hallmark of chronic proscultured from prostatic secretions or ™“etcv ‘^suria, nocturia, and
tatitis is relapsing urinary tract
Jn^toms. Nonbacterial prostatitis
low back and perineal pain are the tou ^yn>P
unknown cause> it minucs
is the most common 1----- —
.kn,„Ovpr
chronic bacterial prostatitis clinically, ho
and prostatic secretions are sterile.
‘• 11
i|
*
r
. ill
7: The Patient With Urinary Tract infection
101
7: The Patient With Urinary Tract Infection
100
Table 7-1. Microbial Pathogens of Kidney and Bladder __________
Urinary tract Infections. Fortunately, despite the mimicking syndromes, infections
' of the urinary tract can be established objectively and economically with quanf
titative cultures of urine obtained from patients with characteristic, albeit nonsoecific signs and symptoms. Acute uncomplicated urinary tract infections occur
(
r^ainly in women of childbearing age. The presenting features are only suggestive
of the site of infection. Although patients may present with classic symptoms of
• cystitis (dysuria, frequency, and suprapubic discomfort) or acute bacteria! pyelon-phntis (flank pain and tenderness, chills and fever, and nausea and vomiting),
acetate localization requires laboratory studies tee sec. IV). Patients with acute
a.
infection of the upper urinary tract commonly have lower tract symptoms; however,
the reverse is much less common.
Flank pains, chills and fever, and nausea and vomiting herald the onset or flare*1
up of kidney infections in patients with the risk factors outlined above (see sec.
II B) Moreover, those patients with obstruction to unne flow vesicoureteral reflux,
« !
large residual urines in the bladder, or instrumentation of the urinary- tract are
prune to bacteremia as a complication of their symptomatic bacteriuna. The unnarv tract is the most common source of gram-negative bacteremia m hospitals
in the United States. Classic hallmarks of bactenal sepsis are shaking chilis and
fever, often accompanied by circulatory collapse Contusion ■s an early manifes
tation of septic shock. Initially there may be hyperventilation and associated
respiratory alkalosis, but metabolic acidosis often ensues. Decreased arterial blood
pressure, venous pooling, renal ischemia, and diminished urinary output addi
tionally complicate the clinical picture. Prompt diagnosis and therapy may be
1
:|
B
f
i
€
lifesaving.
IV. Laboratory diagnosis
A‘ lUTnd^onrib7<h“X'is of urinary tract infection, from simple cystitis to
' complicated pyelonephritis with sepsis, can be established with certainty only
bv quantitative cultures of urine. The major indications for urine cultures are.
a. Patients with symptoms or signs of urinary infections
b. Follow-up of recently treated urinary infection
c. Removal of indwelling urinary catheter
d Screening for asymptomatic bacteriuria during pregnancy
e Patients with obstructive uropathy and stasis, before instrumentation
2 Methods Urine specimens must be cultured promptly, within 2 hours, or be
preyed by reflation or a suitable chemical addtoe (e.g. bone and-
sodium formate preservative). Acceptable methods of collection are.
a. Midstream urine voided into a sterile container after careful washing ater
or saline) of external genitalia (any soap must be rinsed away)
b. Urine obtained by single catheterization or suprapubic needle aspiration
c SterHe needle aspiration of urine from the tube of a closed catheter drainage
i
II
i >
i
urine without adequate preparation of the patient, fhe clean-vciided 'p'^trea^
technique of collection is preferred whenever possible to avoid the risk of in
ducing^nfection at the time of catheterization, a hazard that is greater iri elde y
natients confined to bed and in men with condom catheters. Occasionally, su
prapubic aspiration of the bladder is necessary to verify infection. This ^hmque
has been most helpfill in obtaining specimens from possibly septic infants and
from adults in whom repeated clean-voided specimens have y.elded equivocal
B Micrnobta“prttog^s.,1^e usual microbial pathogens isolated from patients with
urin“ tract infections are listed in Table 7-1. Results of cultures are highly
dependent however, on the clinical setting m which bacteriuna occurs. For ex_
ample E^herichn col: is found in the urine of 80 to 90 percent of patients with
acute cystitis or asymptomatic bacteriuria and no underiymg
malities of the urinary tract. Many patients with staghorn calculi of the k
---- ——--------- — Percentage of
Urine Cultures j
(with ^lO7’cfu/mi)
Microorganism
_
Escherichia coli
Klebsiella or Enterobacter
Proteus. Morganella, or Providencia
Pseudomonas aeruginosa
Staphylococcus epidermidis (saprophytidus)
■■
Enterococci
Candida albicans
Staphylococcus aureus
1 s
cfu
T4*
1
•
e
_______
50-90%
10-40
5-10
2-10
£-10 .
2-10
1-2
1-2
colony-forming units.
Candida aZfeicons are rarely encountoed ^
antibiotic therapy The
eters or relapsing infections afte
P ne most often is a clue to concomitant
frt
dilution method.
ea
known volume of urine to the
0 ^erXd accurately. A satisfactory alachieve isolated colonies that can be en
infections 1S the dipternative for the diagnosis of
for quantitative urine cultures in
slide method, which is particularljnitration and colorimetry, biolummessmaller clinics. Rapid methods based on fiItration a
widely tQ
cence, growth kinetics, or^oioc em^ ofbacteria. Their sensitivities are m the
screen urine specimens .or
P
simnlest is the paper strip test for detection
range of 10‘ to 10= cfu Per,™“ tot morning urine specimens. These methods
s
e ’
e
e
e; »
c
Because quantitation of bacteriuna is so im-
in properly collected and 7"
,r (.fiJ per milliliter from untreated patients
n 9) Cnlonv counts of W or lewei c*u
*•
are uncommon with true urinary trhct infections,
women with pyuria and ure“”r™-•“' “i or delayed traij^pcrc^^^^L
flora, usually imply poor collection otherwisejM^
diuresis may reduce transientlyAny
an growth f^^ni^cMdmed^vsujtoubi
ititatlvV'icpp fo
2. Suprapubic needle aspiration. A-y :
needle aspiration may be important
’
100 5&Pej mT
1K€I
culturing aspirated unne Pe™1^
ircrooT
Two or more colonies (equal to or les/
fe
star
such
ganism ensures the purity of gr"^®|7
- specWns and
je use
ig. SiimiW
dardized antimicrobial suseeptibil
^Is^Ythe nmtuOuy ‘ 'e. Excel
for patients who are receiving antm^o^plsV
' u/^>^-^uantitaXv^1teJT
*
fl
7: The Patient With Urinary Tract Infection
02
7: The Patient With Urinary Tract Infection
able 7-2. Interpretation of Urine Cultures
EPS
£10,000
.0,000 to 100,000
>100,000
Clean-Voided
Specimen
J
Catheterized
Specimen
.
(%)
(%)
2
5
811
2
50
95
750 -
I
A
I
Q.
JE
500 -
5
Z
1 I.:
3
Probable infections
but require confirmation
Q
250 -
infected
10'
w-
IO*
107
100,000
Number of bacteria/ml urine
:ig. 7-2. Results of quantitative bacterial counts from cultures of urine specimens.
From W. Brumfitt and A. Percival. Pathogenesis and laboratory diagnosis of nonuberculous urinary tract infection: A review. J. Clin. Pathol. 17:482, 1964.)
in unusual circumstances, the isolation of diphtheroids, alpha-hemolytic
streptococci, and lactobacilli indicates contamination of the urine specimen
with vaginal or periurethral flora.
3. Prostatic secretions. In men the distinction between a urinary source and
prostatic focus of infection must be njade. Figure 7-3 diagrams the procedure
for obtaining voided urine and expressed prostatic secretions in partitioned
segments that enable proper interpretation. VB! is the first 10 ml of voided
urine, and VB2 is the midstream specimen of urine obtained before prostatic
massage. Subsequently, the expressed prostatic secretions (EPS) arc collected
. before the final voided urine specimen tVBJ. When the bacterial colony counts
in the urethral culture (VBj) exceed by tenfold or more those of the midstream
(VE^) and prostatic cultures (EPS and VB3), the urethra is the source of the
infection. The diagnosis is bacterial prostatitis if the quantitative counts of
the prostatic specimens (EPS and VB3) exceed those of the urethral (VfiJ and
midstream (VB2) samples. A urinary tract infection with a prostatic origin,
Void
1
Not delivered promptly
or badly contaminated
c
'o
Prostatic
massage
200 ml
later
:fu = colony-forming units.
source: L. B. Reller, S. A. Sahn, and R. W. Schrier (Eds.), Clinical Internal Medicine. Boston: Little,
Irown, 1979.
1000 n
VB.
VB,
Probability of True Infection
Quantitation
cfu/ml urine)
103
e!
Midstream specimen
• 1st voided 10 ml
Urethral -
►
Bladder
Prostatic secretions
1st voided 10 ml
after massage
Prostate
Fiq. 7-3. Localization of infection with segmented cultures of the lower urinary tract
in men. (From E. M. Meares and T. A. Stamey. Bacteriologic
bacterial prostatitis and urethritis. Invest. Urol. 5:492, 1968. Copyright ©
Williams & Wilkins Co., Baltimore.)
or vice versa, is indicated by colony counts of 105 or more cfu per milliliter of
the same microorganism in all four specimens.
Microscopic examination of urine. Procedures for the microscopic examination
of urine are not yet standaniired; nonetheless, visualization of bactena, leukocytes,
and epithelial cells in urine can provide some useful information. The advantages
of microscopic analysis are immediate availability and low cost The disadvantages,
depending on the method, are lack of sensitivity or specificity or both. Only prop
erly collected and processed specimens for quantitative unne riiltures can provide
The microscopic examination can be done on either unspun urine or the centrifuged
sediment. A critical comparison of these two techniques is not available. The
presence of squamous epithelial cells and mixed bacterial flora indicates contam
ination and the need for a repeat specimen.
.
Unspun urine. When fresh, unspun urine from patients with significant oiu
cfu/ml) bacteriuria is examined microscopically (x 1000), 90 percent of spec
imens show one or more bacteria and 75 percent of specimens show one or
more white blood cells (WBCs) per oil-immersion field.
Centrifuged sediment When 10 ml of urine is centrifuged m a standard 1&ml conical tube for 5 minutes at 2500 revolutions per mmute m a clinical
centrifuge, three or four drops of the sediment are examined under a coverslip
at high ^wer (x 40CA in diminished light. Patients with significant baetertma
almost always show bacilli in the urinary sediment, whereas only about 1U
percent of patienU with less than 105 cfu pe^nulhUter show bactena. A^ut i
60 to 85 percent of patients with significant bacteriuria have 10 or more W BC&
per high-powered field (HPF) in the sediment of midstream-voided urine; how- |
ever, about 25 percent of patients with negative urine cultures also have pyuna
(10 or more WBCs cer HPF). Since only about 40 percent of patients with
y
iI
Hi
Hl
3
IJ
-I
I
;
•) \
7: The Patient With Urinary Tract Infection
7: The Patient With Urinary Tract Infection
pyuria have 105 or more bacteria per milliliter of urine by quantitative culture,
the presence of pyuria in a midstream specimen has low predictive value for
significant bacteriuria. In addition to urinary tract infection, any of the causes
of acute urethral syndrome (see sec. III.A) can result in pyuria. Genitourinary
tuberculosis is another cause of pyuria with negative routine urine cultures,
although mycobacterial cultures are positive in 90 percent of instances. An
algesic nephropathy, perinephric abscess, renal cortical abscess, disseminated
fungal infection, and appendicitis may also result in pyuria.
E Biochemical tests for bacteriufia. Two metabolic capabilities shared by most
’ bacterial pathogens of the urinary tract are utilization of glucose and reduction
of nitrate to nitrite; these are properties of all Enterobactenaceae. Since small
amounts of the glucose and nitrate are normally present in urine, the presence
of significant numbers of bacteria in urine results m absence of glucose and pres
ence of nitrite. Dipstick devices are commercially available for both types of testing.
Studies with nitrite indicator strips show that 85 percent of both women and
children with culture-confirmed significant bacteriuria show positive results if
three consecutive morning urine specimens are tested. The sensitivity of the glu
cose utilization test is about 90 to 95 percent in patients without diabetes melhtus.
Both biochemical tests have fewer than 5 percent false-positive results. Therefore,
these biochemical tests can be used by patients or parents after proper instruction
to determine when quantitative cultures are needed in the management of re
current episodes of urinary tract infection.
,
F. Localization of the site of Infection. The site of infection in the urinary trace has
great therapeutic and prognostic importance. Upper urinary tract infection (pye
lonephritis) indicates a much greater likelihood of underlying uropathy (e.g.,
congenital anomalies, renal stones, ureteral occlusion, vesicoureteral reflux,
neurogenic bladder, or prostatic hypertrophy) or previous instrumentation (see
sec II.B.4). Relapses with the same, often multiple-antibiotic-resistant bacteria
are common with pyelonephritis or chronic bacterial prostatitis. Treatment is
long (10 to 14 days minimum) and may be arduous. On the other hand, cystitis
rarely is complicated and treatment can be short tsingle-dose) and usually is
j
■
i
Unfortunately there is no ready way to distinguish between upper and lower
urinarv tract infections by simple laboratory’ tests. The difficulty in maKing this
distinction reliably on clinical grounds alone has been discussed (see sec. Ill-B).
Older indirect methods (e.g., serum antibodies, urine concentration test and uri
nary beta-glucuronidase activity) are neither sensitive nor specific. The newer
antibody-coated bacteria test has been useful in research studies. It has not
become established in routine practice, however, because of Idck of standardized
methods, expense, and difficulties in interpretation in children, catheterized pa
tients and men with prostatitis. Direct methods for localization (e.g., ureteral
catheterization, renal biopsy, and the bladder washout technique) are hazardous
or expensive or both. Fortunately, eradication of bacteriuria with single-dose
therany in symptomatic patients with uncomplicated disease is a practical method
for presumptive localization of infection to the bladder or urethra.
G. Radiography and other diagnostic procedures. The principal role of radiographic
and urologic studies in patients with urinary tract infections is to detect vesi
coureteral reflux, renal calculi, and potentially correctable lesions that obstruct
urine flow and cause stasis. Uncomplicated reinfections (cystitis and urethritis)
in females that respond to single-dose antimicrobial therapy are not an indication
for radiographic and endoscopic investigation of the urinary tract. Infants, boys,
and men with first episodes and girls and women with relapsing urinary tract
infections should have an intravenous pyelogram (IVP) with postvoiding radi
ographs. For a detailed evaluation of the ureterovesical junction, bladder, and
urethra, a voiding cystourethrogram and measurement of the residual urme after
voiding may be necessary. If vesicoureteral reflux is present after hcute infection
has been treated, a urologist should be consulted. Cystoscopy may be warranted.
Renal calculi can usually be detected on a plain radiograph of the abdomen. In-
105
!. s
!
of <
are common wjth_acute^yelon^nrirf
1 r^^S^verico^t^r^ux, diminished pyelogram, loss of renal outline.
-3
gical emergency.
complications,
tomography,
per^
,
*•
detecte<i initially by ultrasound and by computed
o;j radiocontrast-induced acute renal failure, ex
radiocontrast studies should be avoided whenever
1‘5
3
mg per deciliter, diabetes mellitus, or dehydration.
v.
c
e,
i
WKSX.
“J**
10s per milliliter on at least two occasions before treatment is considered.
2. tX svmpX are present, no attempt should be made to eradmate bacteriuria until catheters, stones, or obstructions are removed.
Selected patients with chronic bacteriuria may benefit from suppressive ther3-
4. A patient who develops bacteriuria as a result of catheterization should have
S Antimkrobi’aL6
e
treatment should be the safest and least expensive
*
6.
'1 5
struction to ur ne ^“^Xr^history of most uncomplicated urinary tract
*
fto 2 weeks liter completion’of antimicrobial therapy to insure eradication of
«■ I- ®
c
I
Stmenl kbis™. .nd lh.
1«-1 ,n T.W.
nr-.. .<SSSd^ Uud
.<
e.
S‘-th"omX bacteriuria or, if necessary, done under the cover of
itimicrobial therapy.
prophylactic antimicrobial
i
•i
■
ft
&
106
7: The Patient With Urinary Tract Infection
7? The Patient With Urinary Tract Infection
Table 7-3. Most useful antimicrobials for treatment of urinary tract infections
5
Infections
Approximate Cost
(10-day course)*
Antimicrobial
Adult Oral Dosage
Sulfisoxazole
Trimethoprim
Trimethoprim
sulfamethoxazole
Ampicillin
Amoxicillin
Nitrofurantoin
Tetracycline
Cephalexin or
cephradine
Carbenicillin
0.5-1 gm every 6 hours
100 mg every 12 hours
2 tablets ^80 mg/400 mg
each) every 12 hours
500 mg every 6 hours
250 mg every 8 hours
50-100 mg every 6 hours
250-500 mg every 6 hours
250-500 mg every 6 hours
$ 3-7
$ 7-8
$ 6-14
382-764 mg every 6 hours
$29-58
$ 8-19
$ 7-11
$ 2-14
$ 4-14
$25-55
*The cost of antimicrobials varies greatly between generic and trade-name products as well as from
pharmacy to pharmacy. The approximate costs noted were derived from The Medical Letter on Drugs
and Therapeutics: Handbook of Antimicrobial Therapy (rev. ed.), 1984, pp. 63-64.
C. Treatment of cystitis—single-dose therapy. Acute cystitis and low-colony-count
coliform urethritis are almost exclusively diseases of females, mostly sexually
active women between the ages of 15 and 45 years. Although reinfection is com
mon, complications are rare. There is now appreciable evidence that infections
truly confined to the bladder or urethra respond as well to single-dose therapy
as to conventional therapy for 10 days. Indeed, response to single-dose therapy
implies a lower urinary tract infection. All of the following oral regimens for
adult, nonpregnant women have been shown to give over 90 percent success:
amoxicillin, 3 gm; sulfisoxazole, 2 gm; or trimethroprim-sulfamethoxazole, four
tablets (80 mg of trimethoprim and 400 mg of sulfamethoxazole per tablet). This
is an important breakthrough in the management of uncomplicated cystitis and
coliform urethritis, because all patients were treated formerly with the standard
10 to 14 days of therapy. A logical approach would be to treat all patients with
acute lower urinary tract symptoms with single-dose therapy and to repeat the
urine culture in 48 to 72 hours. Patients with persistent bacteriuria would then
get an additional 10 to 14 days of therapy. All patients should get a subsequent
follow-up urine culture 1 to 2 weeks after cessation of treatment to document
successful treatment. Since 80 to 90 percent of episodes of acute cystitis are caused
by sensitive strains of E. coli, any of the less expensive antimicrobials listed in
Table 7-3 should prove effective, unless susceptibility testing discloses a resistant
microorganism. Symptomatic pyuria without bacteriuria in an otherwise healthy
young person suggests chlamydial urethritis.
D. Management of recurrent cystitis (reinfections). Some women, especially those
whose periurethral and vaginal epithelial cells support attachment of coliform
bacteria more avidly, suffer from recurrent episodes of cystitis in the absence of
recognized structural abnormalities of the urinary tract. In these women a single
dose of an antimicrobial after sexual intercourse or nightly at bedtime has been
shown to reduce significantly the frequency of episodes of cystitis from an average
of 3 per patient-year to 0.1 per patient-year. Effective single-dose regimens include
nitrofurantoin, 50 or 100 mg; penicillin G potassium, 250 mg; trimethoprim-sulf^methoxazole, 40 and 200 mg; and cephalexin, 250 mg. Although antimicrobial
prophylaxis is effective and usually safely tolerated for months to years, single
dose therapy for acute cystitis makes prophylaxis more expensive and possibly
moreliazardous for most patients because of alterations in fecal and vaginal bac
terial flora. Lastly, a behavioral regimen that stresses regular, complete emptying
of the bladder has been shown to be effective in preventing reinfection and re
current cystitis.
a
e
e- 3
3:
*1
g
y
F
e
'O
107
E. Treatment of acute bacterial pyelonephritis. The occurrence of flank pain, chills
and fever, and nausea and vomiting with or without dysuna suggests acute bac
terial pyelonephritis. In this clinical setting, blood cultures as well as quantitative
cultures of urine should be obtained. Whether or not ambulatory patients should
be admitted to the hospital for treatment depends in part on a subjective as
sessment of toxicity, likely compliance with therapy, and the home situation.
When the assessment is doubtful, the patient should be treated in the hospital,
at least until there has been a clear response to therapy. This policy also applies
to patients with known underlying uropathies, since complications are more com
mon in these patients.
1. Outpatient therapy. Ampicillin, amoxicillin, and trimethoprim-sulfamethoxazole are the drugs of choice for initial therapy of pyelonephritis in outpatients.
After culture results and susceptibility tests are available, a full 10- to 14day course of antimicrobial therapy may be completed with the least expensive
drug to which the patient’s microorganism is susceptible.
2. Inpatient therapy. Patients who require admission to the hospital should be
treated initially with parenteral (intramuscular or intravenous^ gentamicin
or tobramycin (1.5 to 2 mg/kg every 8 hours, with appropriate alteration of
the dose interval if the serum creatinine exceeds 1 mg/dl) if the urine shows
gram-negatiVe bacilli on microscopic examination. If gram-positive cocci are
seen in the urine, intravenous ampicillin (1 gm every 4 hours) should be given
in addition to the aminoglycoside to cover the possibility of enterococcal in
fection while awaiting the results of unne and blood cultures and antimicrobial
susceptibility tests. If no complications ensue and the patient becomes afebrile,
the remaining days of a 10- to 14-day course can be completed with oral therapy.
The urinary tract is a common source of sepsis and bacteremic shock in patients
with underlying uropathies. As with other patients in septic shock, intravenous
fluids must be given to maintain adequate arterial perfusion, which usually
results in a urinary output in excess of 50 ml per hour. Mortality may be
reduced by massive pharmacologic doses of corticosteroids (3 mg/kg of dexa
methasone or 30 mg kg of methylprednisolone given as a single bolus infusion
through a central venous catheter over 10 to 20 minutes and repeated once
only after 4 hours if needed). Failure to respond to seemingly appropriate
therapy suggests the possibility of undrained pus. Examination by ultrasound
or computed tomography may disclose an obstructed ureter or perinephric ab
scess, both of which require surgical drainage.
F. Management of recurrent renal Infections (relapses). Chronic bacterial pyelo
nephritis is one of the most refractory problems in clinical medicine; relapse rates
are as high as 90 percent. The entity is a heterogeneous one with multiple un
derlying factors.
1. Risk factors. To improve the success rate, it is of utmost importance that any
correctable lesion be repaired, that obstructions to urine flow be relieved, and
that foreign bodies (e.g., indwelling urinary catheters or renal staghorn calculi)
be removed if possible. If the risk factors cannot be corrected, long-term erad
ication of bacteriuria is almost impossible. To attempt eradication in such
instances leads only to emergence of more resistant strains of bacteria or fungi;
consequently, one must be resigned to treatment of symptomatic episodes of
infection and to suppression of bacteriuria in selected patients.
2. Acute symptomatic infection. The treatment of acute symptoms and signs of
urinary tract infection in a patient with chronic renal bacteriuria is the same
as for patients with acute bacterial pyelonephritis. Urine cultures are important
to detect a possible change in antimicrobial susceptibility of the infecting mi
croorganism. Toxic patients should also have blood cultures.
3. Prolonged treatment Some patients with relapsing bacteriuria after 2 weeks
of therapy will respond to 6 weeks of antimicrobial therapy; this is especially
true of patients with no underlying structural abnormalities and of men with
normal prostatic examinations. Patients who fail the longer therapy, who have
repeated episodes of symptomatic infection, or who have progressive renal dis
ease despite corrective measures are candidates for suppressive chemotherapy.
I
I
i
I
108
7: The Patient With Urinary Tract Infection
7: The Patient With Urinary Tract Infection
4 Suppressive therapy. Patients selected for suppressive therapy should have
2 to 3 days of specific high-dose antimicrobial therapy to which their infecting
bacteria are susceptible .io reduce the colony counts in their urine. The preferred
agent, for long-term suppression is methenamine mandelate 1 gm four times
daily in adults. To be most effective the pH of the urine should be maintained
below 5 5; this can be accomplished with ascorbic acid, 500 mg two to four
times daily. Alternatively, the dosage of methenamine mande ate alone can
be increased to 8 gm or even 12 gm per day. The dosage should be adjusted
,
to the minimal amount required to keep the unne free of bacteria. To avoid
metabolic acidosis the dosage of methenamine mandelate must be reduced in
patients with renal insufficiency, in whom 2 gm per day may suffice; it should
not be used at all unless the creatinine clearance exceeds 10 ml per minute
5 Prognosis. Although a common cause of appreciable morbidity, urinary tract
’ infections do not play a major role in the pathogenesis of end-stage renal di sease. <
Patients who come to renal dialysis or transplantation because of chronic bactenal pyelonephritis almost always have an underlying stnictural defect. Most
often the lesion is chronic atrophic pyelonephritis associated with vesicouretera
reflux that started in infancy. The role of surgical correction of vesicoure^ra
reflux is not clear despite years of debate; what is certain, however, is the
importance of meticulous control of infection in children to prevent progressive
renal scarring and renal failure by early adulthood.
G’ ?TcXnb°X°a|{prostatitis. Acute bacterial prostatitis is commonly accomnamed by acute cystitis, which enables recovery of its causative pathogen by
culture of voided urine. Massage of an acutely inflamed prostate gland often
results in bacteremia; therefore, this procedure should be avoided unless the
patient is already receiving effective antibiotic therapy, lhe drug of choice is
the combination of trimethoprim-sulfamethoxazole (co-tnmoxazole> m the
dosage given in Table 7-3; treatment should be given for 30 days to prevent
chronic bacterial prostatitis. If co-trimoxazole cannot be given parenteral
gentamicin or tobramycin (see sec. V.E.) plus ampicillin should be used as
outlined for acute bacterial pyelonephritis until results of cultures and susUipiMUIB SUM31V4V,
--------------------------------ceptibility testing are known. After acute symptoms
subside, ci
a --suitable
oral
antibiotic can be given in full dosage for at least
L - - 30 days. Urethral cathetchnnld
erization should be avoided. If acute urinary retenUon develops, drainage should
I
!1
h
1
100
I
I
80
.£
■g
8
£
ft-
1
40 “
Closed drainage
20
|
|
s
g
|
0
2
I
4
6
8
10
Duration of indwelling catheter (days)
.A
Fio. 7-4. Prevalence of bacteriuria in catheterized patients according to duration of
catheterization and type of drainage system. (From R. J. Pass, A. S. Klamer an
R. L. Perkins. Urinary tract infection: Practical aspects of diagnosis and treatment.
J.A.M.A. 225:1509, 1973. Copyright 1973. American Medical Association.)
,<
Urinal rathetera 17e“Vh°eC slngle^mmonest cause of nosocomial infections and
1 >
A
£
i:
are given below.
Open drainage
60 -
.
bv a suprapubic cystostomy tube placed- under local anesthesia
-2 Chronic bacterial'
The hallmark^£
of “
chronic0 bacterial
P™statltis is
bacterial prostatitis.
prostatitis.. The^hallmark
tactena^
_ ■
" ’
It —
is ---most refractory
relapsing urinary tract infection.
1.
. to treatment. Althougn
.
—
errthromycin with alkalinization nf
of tho
the urine
urine has
has been
been effective against suscentible gram-positive pathogens, most instances of chrome bacterial prostatitis
are caused by gram-negative enteric bacilli. Co-tnmoxazole is the drug of choice. W
. About 75 percent of patients improve and 33 percent are cured with 12 weeks
of co-trimoxazole therapy (two tablets twice daily). Bor patients who cannot ::
tolerate co-trimoxazole, nitrofurantoin, 50 or 100 mg once or twice daily, can
be used for long-term (6 to 12 months) suppressive therapy.
H Recommendations for the care of urinary catheters. Urinary catheters are vah
■ uable devices for enabling drainage of the bladder, but their use is associated
with an appreciable risk of infection in the urinary tract. For a single (in and
out! catheterization the risk is small (1 to 2 percent; however, bactenuna occurs
in virtually all patients with indwelling urinary catheters with n 3 to 4 days
unless placement is done under sterile conditions and a stenle, closed dram g
system is maintained (Fig. 7-4). The use of a neomycm-polymyxin irrigant does
are responsible for more than 5000 deaths from gram-negative sepsis each year
in the United States. Explicit recommendations for the prevention of ratheterassociated urinary tract infections, formulated by the Center for Disease control,
109
hr
1. Indwelling urinary catheters should be used only when absolutely necessary,
they should never be used solely for nurse or physician convenience, and they
should be removed as soon as possible.
2 Catheters should be inserted only by adequately trained personnel; if practical,
a team of individuals should be given responsibility for catheter insertion
3. Urinary catheters should be aseptically inserted utilizing proper sterile tech
nique and the following sterile equipment: gloves, a fenestrated drape, stenle
sponges and an iodophor solution for periurethral cleansing, a lubricant jelly,
and an appropriate-sized urinary catheter. Following insertion, catheters
should be properly secured to prevent movement and urethral traction
4 Once- or twice-daily perineal care for catheterized patients should include
’ cleansing of the meatal-catheter junction with an antiseptic soap; subse
quently, an antimicrobial ointment may be applied.
A sterile closed drainage system should always be used^The unn^ry cathetfJ
5.
and the proximal portion of the drainage tube should not be disconnected
(thus opening the closed system) unless required for irrigation of an obstructed
catheter. Sterile technique must be observed whenever the collecting system
is opened and catheter irrigation is done; a large-volume stenle syringe and
sterile irrigant fluid should be used and then discarded. If frequent irrigations
are necessary to ensure catheter patency, a triple-lumen catheter permitting
continuous irrigation within a closed system is preferable.
6. Small volumes of urine for culture can be aspirated from the distal end m
the catheter with a sterile syringe and 21-gauge needle; the catheter must
7: The Patient With Urinary Tract Infection
110
111
7: The Patient With Urinary Tract Infection
first be prepared with tincture of iodine or alcohol. Urine for chemical analyses
can be sterilely obtained from the drainage bag.
7. Nonobstructed gravity flow must be maintained at all times; this requires
emptying the collecting bag regularly, replacing poorly functioning or ob
structed catheters, and ensuring that collecting bags aluays remain below
the level of the bladder.
8. All closed collecting systems contaminated by inappropriate technique, ac
cidental disconnection, leaks, or other means should be immediately replaced.
9. In patients with urinary catheterization of less than 2 weeks duration, routine
catheter change is not necessary except when obstruction, contamination, or
other malfunction occurs. Inpatients with chronic indwelling catheters, re
placement is necessary when concretions can be palpated in the catheter or
when malfunction or obstruction occurs.
10. Catheterized patients should be separated from each other whenever possible
and should not share the same room or adjacent beds if other arrangements
an/ available. Separation of bacteriuric and nonbacteriuric patients is par
ticularly important.
........................
' ’
’ and’ thej use of indwelling
These guidelines should
be adhered to meticulously,
urinary catheters should be kept to a responsible minimum.
Another hazard of indwelling urinary catheters is hospital-acquired urinary tract
infection caused by Candida albicans, which rarely occurs in the absence of pre
vious catheterization or multiple antibiotics or both. Recommendations for treating
candiduria include removal of the urinary catheter, discontinuation of antibiotics,
and continuous bladder irrigation with amphotericin B (50 mg TOGO ml of sterile
water via a three-way catheter for 24 hours for 5 days). Occasionally, systemic
therapy with oral 5-fluorocytosine or intravenous amphotericin B or both is re
quired.
Souney, P., and Polk, B. F. Single-dose antimicrobial therapy for urinary tract mfections in women. Rev. Infect. Dis. 4:29, 1982.
Stamm, W. E. Guidelines for prevention of catheter-associated urinary tract infections.
Ann. Intern. Med. 82:386, 1975.
Stamm W E Wagner, K. F., Amsel, R-. Alexander, E. R-. Turck,
/
E and Holmes, K.^. Causes of the acute urethral syndrome in women. N. Engl.
2-
J. Med. 303:409, 1980.
Thorley, J. D., Jones, S. R., and Sanford, J. P. Perinephric abscess. Med^ne (Bal
timore) 53:441, 1974.
Warren, J. W., Platt, R., Thomas, R. J., Rosner B and Kass E. H. Antibmtuir
rigation and catheter-associated urinary-tract infections. N. Engl. J. Med. 2.. .
.
1978.
i
u
2
2 4
>
-3
r &
i
/
4
it?
/ «!•/
*j
■r
i !i
Suggested Reading
Adatlo, K., Doebele, K. G., Galland, L., and Granowetter, L. Behavioral factors and
urinary tract infection. J_A.Af_A. 241:2525, 1979.
Fowler, J. E„ Jr., and Pulaski, E. T. Excretory urography, cystography, and cystoscopy
in the evaluation of women with urinary tract infection: A prospective study. N.
Engl. J. Med. 204:462, 1981.
Harding, G. K. M., and Ronald, A. R. A controlled study of antimicrobial prophylaxis
of recurrent urinary infection in women. N. Engl. J. Med. 291:597, 1974.
Kincaid-Smith, P., and Becker, G. Reflux nephropathy and chronic atrophic pyelo
nephritis: A review. J. Infect. Dis. 138:774, 1978.
Komaroff, A. L., Pass, T. M., McCue, J. D., Cohen, A. B., Hendricks, T. M., and
Friedland, G. Management strategies for urinary and vaginal infections. Arch. Intern.
Med. 138:1069, 1978.
Kunin, C. M. Detection, Prevention, and Management of Urinary Tract Infections (3rd
ed.). Philadelphia: Lea & Febiger, 1979.
S'
Nicolle, L. E., Bjornson, J., Harding, G. K. M., and MacDonnell, J. A. Bacteriuria
in elderly institutionalized men. N. Engl. J. Med. 309:1420, 1983.
I
■
2;
Z\*
t
Meares, E. M., Jr Prostatitis: Diagnosis and treatment. Drugs 15:472, 1978.
Nicolle, L. E., Harding, G. K. M.. Pierksaltis, J., and Ronald, A. R. The association
of urinary tract infection with sexual intercourse. J. Infect. Dis. 146:579, 1982.
'•it
e'
i
1
I
Savard-Fenton, M.» Fenton, B. W., Reller, L. B., Lauer, B. A., and Byyny, R. L. Single
dose amoxicillin therapy with follow-up urine culture: Effective initial management
for acute uncomplicated urinary tract infections. Am. J. Med. 73:808, 1982.
Silverman, D. E., and Stamey, T. A. Management of infection stones: The Stanford
experience. Medicine (Baltimore) 62:44, 1983.
•B
•*4K
The Patient With
Proteinuria or an
Abnorma! Urinary
Sediment
;
'
Antoine M. de Torrente
and Robert J. Anderson
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?eaSUrrdoa"tdaned1sea“s oTtheurin^' act may be accompanied by either pro
SE “i=s=i^=±=?—
rfmvSgaUon including lustory, physical examination, and laboratory and rad>o
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Ar0M1aI|e oatients To avoid unnecessary contamination of the urine specimen the
foreskm ' houid be retracted in uncircumcised men, the meatus cleaned witha
“pad moistened with water, and a “clean catch" midstream spec.men vo.ded
Female pat"en“women the labia should be spread apart the meatus cleaned
B.
and debris that may obscure meaningful findings. In 8®?®^■ > "insertion
^“^m^dSr " ^l^^owever, cannot be explained
by contamination with menses.
x
"• raurinae colon Urine is normally clear or amber. A Itsting of causes of abnormal
8 Urin^dimen" Th^urine specimen is shaken gently to mix its components.
Observ^n may reveal unusual color or abnormal foaming (protemuna). Ten
i
113
8: The Patient With Proteinuria or an Abnormal Urinary Sediment
8: The Patient With Proteinuria or an Abnormal Urinary Sediment
e
Table 8-1. Causes of Abnormal Urine Color
Red
Benzidine ( + ): RBC, hemoglobin, myoglobin
Benzidine < —beeturia (a harmless inborn error of metabolism), medications
(paraaminosalicylic acid [PAS], Congo red, phenolsulfonphthalein [PSP], senna,
phenolphthalein)
Porphyria
Orange
Medications (phenazopyridine [Pyridiqm], ethoxazene [Serenium], rifampin)
Porphyria
Brown/black
Hemoglobin or myoglobin with alkaline pH (should always be benzidine [ + ])
Bilirubin (yellow foam)
Medications5(L-dopa, methyldopa [Aldomet], phenol, phenacetin)
Melanin (tumor)
Homogentisic acid (alkaptonuria)
Porphyria
Blue/green
Medications (indigo-carmine dyes, methylene blue)
Pseudomonas infection
particularly helpful when a paucity of casts is present. One or two drops of the
sediment are then deposited on a microscope slide and examined first at a low
magnification ( x 100) and then at high power ( x400). The sediment should be
examined immediately, before drying. Staining is usually necessary only with
the Gram stain, often best in the area just outside the coverslip. Formed elements
and casts are more abundant at the edges of the coverslip. Usually 10 to 15 high
power fields (HPF) should be examined and the casts and formed elements ex
pressed as number per HPF. An exact quantitation in a counting chamber is not
recommended, since the conditions of collection are so variable. One red blood
cell cast per HPF is as important as 20 or 40. The various cells and casts are
shown in Figures 8-1 through 8-16.
C. Urine protein. The urine should be checked for protein with the dipstick method.
This method employs the alteration of an indicator dye by protein and is sensitive
to about 30 mg of albumin per deciliter. The method, however, does not detect
light-chain proteins and some other globulins. Other low-molecular-weight pro
teins excreted in tubular diseases also may not be detected by the dipstick method.
If light-chain or low-molecular-weight proteins are suspected, the sulfosalicylic
acid test should be performed on the urine as follows: Eight drops of 20% sul
fosalicylic acid are added to 2 ml of urine. A white cloud of precipitate indicates
a positive test. The sulfosalicyclic acid test is more sensitive than the dipstick
method but is less specific (Table 8-2). A highly concentrated (specific gravity
greater than 1.030) early morning normal urine may contain trace to 1 + protein
by the dipstick method. The findings in a normal early morning urine are:
1. Protein: 0 to 14<
2. Epithelial cells: occasional per HPF (may be numerous in females)
3. Crystals: occasional per HPF
4. Red blood cells: 0 to 5 per HPF
5. White blood cells: 0 to 3 per HPF
5. Casts: hyaline, occasional per HPF
__ L
Proteinuria
I. General patient evaluation. Detection of an abnormal quantity of protein in urine
is one of the most reliable signs of renal parenchymal disease. Urine from normal
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115
persons contains less than 150 mg of protein per day. Any quantity above this amount
should be investigated. (Thee proteinuria has been discovered by the dipstick or sulfosalicyclic acid method on a urine sample, the minimal workup should be undertaken
as follows:
k/A. Complete physical examination and history. A physical examination and history,
especially in search of acquired or familial renal diseases and hypertension, are
essential.
y B. Twenty-four-hour urine collection for quantitative protoIn excretion. This de
termination is absolutely mandatory to assess the degree of proteinuria, a quan
titation that may convey prognostic and diagnostic information.
C. Repeat 24-hour protein measurement. A repeat 24-hour protein measurement
on three or four samples is necessary to ascertain the persistent or intermittent
nature of the proteinuria. Intermittent proteinuria is usually associated with a
benign course.
y' D. Exclusion of orthostatic proteinuria. This simple test is done in the following
manner. The patient voids in the evening (sample 1). The patient then retires
immediately. Urine is collected the next morning while the patient is still supine
(sample 2). The patient is then allowed to rise and ambulate. The next voiding
is again collected (sample 3). All three samples are checked for protein. With
orthostatic proteinuria the specimen should be negative or trace on sample 2 and
positive on samples 1 and 3. If the proteinuria is orthostatic and less than 1 gm
per day, without sediment abnormalities, serious renal disease is unlikely and
the prognosis is benign.
.
/
E. Information on renal function. Information on renal function is obtained by
measuring plasma creatinine and blood urea nitrogen (BUN). Creatinine clearance
can be calculated if the sample for 24-hour protein is also used to determine 24hour creatinine excretion.
F. Careful examination of the urinary sediment and urine culture
G. Routine hematologic and blood chemistry studies. These include complete blood
count, electrolytes, and blood sugar tests.
These steps allow the proteinuria to be classified and at the same time provide a
framework for a differential diagnosis.
II. Degrees of proteinuria: ciinical characteristics and course
A. Low-grade proteinuria (less than 1 gm per day). This is a very common problem
in medical practice. Low-grade proteinuria can be caused by a number of different
renal afflictions (Table 8-3).
1. Idiopathic low-grade proteinuria. Idiopathic low-grade proteinuria is the di
agnosis if the history and physical examination are normal, the renal function
is normal, and no cells or casts are seen in the sediment. This proteinuria is
usually due to minor abnormalities of the glomeruli ok kidney vasculature.
Long-term studies have demonstrated that the prognosis is benign. The proper
approach, therefore, is to follow these patients carefully every 3 to 6 months
with regular blood pressure measurements and determinations of plasma cre
atinine. Renal biopsy is not indicated if the renal function is stable and normal.
The association of low-grade proteinuria and hematuria is a more serious matter
and may indicate a progressive glomerular disease.
2. Functional proteinuria. Functional proteinuria is induced for unknown reasons
by congestive heart failure, fever, or heavy exercise. The urine sediment is
usually normal. Plasma creatinine can be somewhat elevated, secondary to a
low renal perfusion with heart failure or dehydration in a febrile illness. The
proteinuria should resolve with the treatment of the primary disease.
3. Nephrosclerosis. Nephrosclerosis is observed in patients with long-standing
essential hypertension. Renal function is usually moderately decreased and
the urine sediment is normal. Control of the blood pressure may decrease the
proteinuria and ameliorate or stabilize the renal function.
4. Polycystic kidney disease. Polycystic kidney disease in its adult form may
come to the attention of the physician initially because of low-grade proteinuria.
A family history of death in the fourth and fifth decades due to renal failure,
palpable kidneys, episodes of hematuria, and flank pain are characteristic.
The excretory urogram and ultrasonogram usually confirm the diagnosis.
•J
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•1
116
8: The Patient With Proteinuria or an Abnormal Urinary Sediment
8 The Patient With Proteinuria or an Abnormal Urinary Sediment
;!
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"nd bv their context, e.g., obvious urinary infection n:.n pyuria as well as bncj Wia
OHvine of the red cells has obvious hemoglobin pipMoi but several other cells with
cytoplasm aro the same size and are. indeed, red cells. Bacilli are easily
recognized ip unstained preparations, as in this sedsmen,. but cocci ar.
Singuishable from urinary granules without the use of Gram stem. (Provided
courtesy of Ronald B. Miller, M.D.>
Flc 8-2 Many polymorphonuclear leukocytes, approximately ten renal tubule cells,
aS ! number rfgranutes(which are not red blood ceils). Cytoplasmic granules have
teen c" by the addition of a few drops of dilute acetic acid to the sediment
which allows the nuclei of the cells to be seen. In contrast to the poly morphonuclear
reukocvds, the renal tubule cells are larger vary in size and have.single nuc ei that
Severally
round, sometimes
sometimes eccentric. (Provided courtesy of Ronald B. Miller,
generally round,
M-D.)
ss szts
through t
p
r
sar ss < s:ss
tive than the surrounding urinary w^ter. With
SSXiXfSKSSf&• Fi9- 1
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Jerome P. Kassirer, M.D.)
tail of the hyaline cast. (Provided courtesy of Ronald B. .filler, .a. j.)
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Fig. 8-6. Another broad cast, somewhat more coarsely granular grounded by a
number of squamous epithelial cells. (Provided courtesy of Ronald B. Miller, M.D.)
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Fin P-7 A finely granular cast with a number of imbedded renal tubule cells (a so-
8-6
8-5
p.,OT„;these casts arc nonspecific. (Provided courtesy of Jerome P. Kassirer, M.D.)
« a' i
eoH r«Rt with a few cell outlines evident and considerable
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117
8: The Patient With Proteinuria or an Abnormal Urinary Sediment
18
119
8: The Patient With Proteinuria or an Abnormal Urinary Sediment
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3-13
Fig. 8-10. Another red cell cast in which individual cell outlines are less evident. This
cast is on its way to becoming a hemoglobin or blood cast (by breakdown of red cell
walls). As is usually the case in acute nephritis, there are innumerable red cells free
in the urine. (Provided courtesy of Ronald B. Miller, M.D.)
Fig. 8-11. A cast that at one end has discernible red cell outlines, at the other end a
homogenous or slightly granular morphology with an unequivocal hemoglobin-tint.
Thus, this cast is both a red cell cast and a hemoglobin or blood cast. The hemoglobin
pigment is indistinguishable from myoglobin, but one would not expect red cell casts
in a patient with myoglobinuria. (Provided courtesy of Ronald B. Miller, M.D. I
8-10
B-11
Fig. 8-9. A typical red cell cast with the hemoglobin pigment of the red cells
clearly evident and cell outlines well preserved. Such a cast usually indicates
glomerulonephritis, though red cell casts can also occur rarely with strenuous
exercise or trauma to the kidney. (Provided courtesy of Ronald B. Miller, M.D.)
!
!
Fig. 8-12. A barely discernible hyaline matrix with many fat globules, as might be
seen in a patient with the nephrotic syndrome. This is a hyalofatty cast. Were there
more fat globules, it would be called a fatty cast. Note the variable size of the fat
globules and their refractiveness with reduced illumination, characteristics that
distinguish them from red blood cells. ;(Provided courtesy of Ronald B. Miller, M.D.)
Fig. 8-13. A fatty cast with sufficiently reduced illumination so that the fat globules
are quite refractive. (Provided courtesy of Jerome P. Kassirer, M.D.)
Fig. 8-14. The same cast as in Figure 8-13 viewed with polarized light, which
demonstrates the anisotropic nature of the fat (usually thought to be cholesterol
ester). Although many are out of focus, several fat droplets can be seen to exhibit the
maltese-cross phenomenon. (Provided courtesy of Jerome P. Kassirer, M.D.)
Fig. 8-15. A cast that is broad and waxy at one end and has red cells incor
porated in its matrix at the other end. This unusual cast is from a patient with
glomerulonephritis. The innumerable red cells free in the urine suggest the nephritis
is acute or subacute. (Provided courtesy of Jerome P. Kassirer, M.D.)
Fig. 8-16. A busy or active sediment from a patient with acute tubular necrosis with
many broad waxy casts, one of which is convoluted, and with a.number of broad,
brown, granular casts that are somewhat more typical of acute tubular necrosis than
are the waxy casts. The pigment is not hemoglobin, but rather an unidentified brown
pigment, particularly common in the casts of patients with acute tubular necrosis, but
also occurring in casts of patients with chronic renal parenchymal disease. (Provided
courtesy of Jerome P. Kassirer, M.D.p
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120
I
8: The Patient With Proteinuria or an Abnormal Urinary Sediment.
Table 8-2. False-positive ( + ) and False-negative ( ) Reactions
With Dipstick or Sulfosalicylic Acid Test for Proteinuria
Clinical Setting
?
X-ray contrast media
Tolbutamide
Penicillins
.Sulfisoxazole (Gantrisin)
p-Amiposalicylic acid
Low molecular weight
proteins, light chains
Dilute urine
Alkaline urine
I
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lipstick
(+)
(+)
(+)
(+)
(+)
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5 Medullary cystic disease. Medullary cystic disease may be a cause of renal
failure in adolescence. The disease is characterized by polyuria, nocturia, a
severe anemia, and failure to thrive. A renal salt-wasting tendency is common
The sediment is unremarkable. The diagnosis is made mainly on clinical
grounds and by a careful family history. The kidneys are small on excretory
urogram and ultrasonogram, but these findings are nonspecific.
6. Obstructive uropathy. Chronic obstructive uropathy may present as nocturia,
polyuria, or polydipsia. Pyuria and proteinuria may or may not be present.
7. Chronic Interstitial nephritis. A nephropathy secondary to analgesic abuse,
lead, cadmium, oxalate, uric acid, hypercalcemia, and hypokalemia may also
present with mild proteinuria.
B Moderate proteinuria (1.0 to 3.5 gm per day). With severe, advanced disease
many of the disorders discussed above in association with low-grade proteinuria
(sec. II.A.) can lead to moderate proteinuria. By far the most common causes of
moderate proteinuria are glomerular diseases, however, interstitial diseases may
also cause moderate proteinuria.
C Heavy proteinuria (greater than 3 to 5 gm per day): the nephrotic syndrome.
The nephrotic syndrome is not a disease itself; it may be caused by a variety of
causative and pathogenetic mechanisms that result in a spectrum of pathologic
lesions with vastly different prognoses.
\
.
1 Clinical characteristics. Proteinuria above o gm per day is usually ciassmeu
as in the nephrotic range, but the symptom complex may vary widely from
one patient to another. In addition to heavy proteinuria and hpiduna (oval
fat bodies), the nephrotic syndrome is characterized by edema, varying from
minimal degrees to frank anasarca, hypoalbuminemiakbypercholesterolemia,
and hypertriglyceridemia) Even if all features of the syndrome are not present,
proteinuria above 3 gm per day usually indicates a disease state that may
lead with time to the complete nephrotic syndrome complex.
2 Patient evaluation. The nephrotic syndrome may be indicative of generalized
disorders and should be approached as such. A narrow focusing on the kidney
disease alone mav be misleading. In addition to the steps listed previously
(s^e A.I.), the evaluation of a nephrotic patient includes the following:
g. Renal biopsy. Except with typical clinical pictures such as steroid
responsive nil disease (minimal change nephrotic syndrome), far-advanced
diabetes mellitus. or constrictive pericarditis, a renal biopsy is usually
indicated for the proper differential diagnosis of the cause of nephrotic
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Ifil HlHlH'
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. KOI H -=e)3sT”3
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%
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F
History of diabetes, high blood pres
sure, retinopathy
Mediterranean origin, multiple myelo.no
Amyloidosis
Neoplasia
Ionic)
High blood pressure, third trimester
Pregnancy with protKilampsia
High blood pressure, target organ dise ase
(cardiac, ophthalmologic)
*- ——»
-. .............
tt W
li -Ji.
ft --4 .
rn
w tFv v
V
- Critical Laboratory Findings
No hematuria, normal renal biopsy on light
microscopy
Usually, decreased renal function, normal
or large kidney size
Usually decreased renal function, large
kidneys, renal biopsy specific on electron microscopy
Usually minimal change disease but mem
branous nephropathy may also be
present on biopsy
Increased serum uric acid, glomerular en
dothelial cell swelling on renal biopsy
Hematuria, decreased renal function
Abnormal hemoglobin SS or SC
Black race
Captopril, nonsteroidal antiinflammatory
agents
Allergens: poison ivy, insect bites
I
B ifl g-I
| g
w
,• _L_z,fiz> Syndrome
Qvndrome
;nosis ofn the
Nephrotic
Table 8-4. Differential Diagi——Clinical Clues__________
Diagnosis____________
—------------------------- Young age, no manifestation of systemic
disease, no hypertension
Minimal change disease
Poisons, drugs, and allergens
Mercury, bismuth, gold
Penicillamine, trimethadione
li
--
U, U uP
’
Constrictive pericarditis
i
I 9 § 8 E-S^3? a.
I®
ip &
Sickle cell disease
Mechanical factors
Severe congestive heart failure
a
3 ; l SrS--3 2, ^s$-g.^
“
Malignant or accelerated hypertension
CD
Q P c1 p- o- 5
BS.g2^2.
? ? B: g P 2 2- S’
Metabolic or systemic diseases
Diabetes mellitus
c ?? p »’ 2“■ £■§
p -w S 3 o’op
2.
2 c.
I
Evidence of heart failure on physical exami nation
Distended neck veins that distend more
on inspiration (Kussmaul s sign)
History of exposure
History of treatment of rheumatoid ar
thritis, seizures
History of exposure
Skin rash, arthralgias, arthrit.s.pholoafn-
I
Pulmonary congestion on chest x-ray
Evidence of pericardial effusion on echocardiogram and catdiac cathetenzal.on,
cardiac calcification on chest x-ray
Urinary determination of the metal
Membranous nephropathy on renal biopsy
Hematuria, positive serologic results
according to cause
! !<»
W
sitivity, hair loss
collagen vascular disease)_______
K-atrt
€
8: The Patient With Proteinuria or an Abnormal Urinary Sediment
124
8: The Patient With Proteinuria or an Abnormal Urinary Sediment
respond, but many (up to 50 percent) relapse and thus need another course of
steroid therapy. After complete remission (proteinuria less than 200 mg per day),
the patient should have 24-hour urine protein determinations and plasma cre
atinine determinations every 3 months. If the patient develops side effects from
steroids (moon facies, hypertension, weight gain) because of frequent attempts
at treating relapses, immunosuppressive agents, such as cyclophosphamide, should ^y
be considered after consultation with a nepnrologist.
Other farms of the nephrotic syndrome may remit if the cause of the disease is
reversible (e.g.. discontinuation of the offending drug, control of accelerated bypertension, or termination of pregnancy in the toxemic patient).
When the nephrotic syndrome is caused by a form of glomerulonephritis, the
prognosis is variable. The patient with systemic lupus erythematosus may have
nephrotic syndrome in association with membranous nephropathy, diffuse pro
liferative glomerulonephritis, and, rarely, focal proliferative glomerulonephritis.
Steroid therapy may produce a remission of the nephrotic syndrome in some of
these patients withlupus nephritis. One study suggests that patients with idi
opathic membranous nephropathy may respond to steroids. Except for some de
crease in proteinuria, no beneficial effect of steroids was found in these patients
compared to nontreated patients, until 2 years of follow-up. At that time, a sig
nificant deterioration in renal function was observed in the non treated group
compared to patients treated with steroids. 'Die results of this study should, how
ever, be considered preliminary. The recommended therapy is 2 mg per kilogram
of prednisone every other day for 2 months followed by tapering of the dosage
over a 2-month period.
C. Diet. If the renal function is normal, a high-quahty protein diet is encouraged to
offset the loss of large amounts of protein in the urine. Salt intake should be
minimized to decrease the accumulation of edema.
D. Additional comments. Patients with the nephrotic syndrome seem to be more
prone to infections than are normal persons. Thus, any complaint such as cough,
abdominal pain, or fever should be carefully evaluated. Any rapid decrease in
renal function in nephrotic patients should raise the suspicion of acute renal vein
thrombosis. This complication may be asymptomatic or it may be accompanied
by hematuria and costovertebral angle tenderness. The diagnosis should be pur
sued by renal venography. If venography documents the presence of renal vein
thrombosis, the patient should be anticoagulated because pulmonary embolus is
a feared complication. Chronic, asymptomatic renal vein thrombosis may also
accompany proliferative or membraboproliterative glomerulonephritis. Acute
deterioration in renal function in the nephrotic patient coultf also be due to volume
depletion, treatment with nonsteroidal antiinflammatory agents, or drug-induced
interstitial nephritis.
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Hematuria
?
Aside from proteinuria, hematuria is the most important clue to the presence of
kidney diseases or diseases of the urinary tract. A positive reaction with the Hemastix
indicates the presence of hemoglobin in urine due to the presence of either red blood
cells or free hemoglobin. More than three RBCs per HPF are required for a positive
test. Myoglobin will also give a positive reaction. To document the presence of red
blood cells, examination of the urine sediment is mandatory. Once true hematuria
has been confirmed by sediment examination, its origin should be determined and
the responsible lesion diagnosed. For practical purposes it is convenient to divide
hematuria into two basic categories: group 1—hematuria due to glomerular inflam
mation (i.e.5 ail the glomerulonephritides) and group II—hematuria due to other
j
CH U SOS.
I
*
Hematuria due to glomerular inflammation—group L The distinction between groups
I and II can be difficult. In group I diseases, hematuria is frequently accompanied
by severe proieHiuiia,
proteinuria, although
some ^•w***'-*
glomerular
diseases may
dv
tumuugn oomc
- ----------------------jipresent
--------- with hematuria
and minimal proteinuria. The presence of red blood cell casts provides absolute proof
f la
f
125
of the glomerular origin of the hematuria. Proteinuria, however, is a much more
common indicator of the glomerular origin of the hematuria than is the presence of
red blood cell casts. The combination of red blood-Cells, red blood cell .casts, and
proteinuria is commonly called a nephritic sediment. Recent studies suggest that
abnormal red blood cell morphology”on urinalysis also points to a glomerular site of
origin.
II. Hematuria due to nonglomerular causes—group H. Since glomerular inflammation
is absent in group II diseases, proteinuria is absent and red blood cell casts are not
seen. However, a rare patient with red blood cell casts after trauma to the kidney
has been described. Also, depending on the severity of the bleeding, actual blood
clots may be seen with nonglomerular diseases; this never occurs with the glo
merulonephritides.
HI. Approach to the patient with nephritic sediment—group I. Since there is a total
lack of specificity of a nephritic urinary sediment, a thorough clinical evaluation
and additional laboratory tests are needed to make the diagnosis.
A. Patient evaluation. The minimum workup of a patient presenting with a nephritic
urinary sediment includes the following:
1. History and physical examination. A complete history and physical exam
ination should be made, with special emphasis on family history of renal dis
eases and antecedent streptococcal infections. Skin rashes, heart murmur, ar
thralgias, and other manifestations of systemic disease should be carefully
sought.
2. Serologic tests. Serologic tests should include those for streptozyme, anti
nuclear antibody (ANA), total complement (CHsq), hepatitis B—associated an
tigen (HBAg), and VDRL.
3. Evaluation of renal function. This evaluation should include 24-hour protein
excretion and 24-hour creatinine clearance.
4. Routine laboratory tests. Other routine tests include complete blood count
with platelets and serum electrolytes.
B. Clinical and laboratory characteristics. Diseases that may present with a nephritic
sediment and their associated clinical findings are given in Table 8-5. This clas
sification is not based on pathogenic mechanisms but rather on clinical and lab
oratory characteristics that may lead to the correct diagnosis.
C. Nephrologic consultation and renal biopsy. It mav not be possible for the complete
evaluation of a patient presenting with a nephritic sediment to be completed by
a primary care physician alone. He or she may need the assistance and expertise
of a trained nephrologist and some sophisticated laboratory determinations.
Nevertheless, with a careful clinical evaluation the primary physician will be
able to focus on the most likely diagnosis. One specialized diagnostic test that
may be necessary is the percutaneous renal biopsy. This diagnostic procedure is
not without risk’ The morbidity is 5 to 10 percent for benign complications and
0.5 to 1.0 percent for serious complications. Mortality is rare. Indications for renal
biopsy vary widely among nephrologists. If the combination of a thofough history,
physical examination, and appropriate laboratory tests does not allow a diagnosis
with a reasonable degree of confidence, renal biopsy may be indicated. Never
theless, few histologic or immunofluorescence studies of renal tissue can lead to
diagnosis of one disease entity. Much more frequently, the findings are only com
patible with a specific diagnosis. Thus, the synthesis of clinical, laboratory, and
pathologic information may be necessary to establish the most likely diagnosis.
The renal biopsy may also provide some indication of the prognosis of the renal
disease. For instance, in a patient with glomerulonephritis, the finding of epithelial
crescents in more than 80 percent of the glomeruli indicates a poor prognosis
with respect to the potential reversibility and natural history of the renal disease.
This is particularly true when there is no evidence of associated systemic disease,
which indicates the diagnosis of idiopathic, rapidly progressive glomerulonephritis.
D. Therapy. Only a few therapeutic interventions are of proven benefit in the various
forms of glomerulonephritis. In general terms, control of blood pressure and elec
trolyte balance is of utmost importance in all forms of glomerulonephritis, in
dependent of any specific treatment.
•‘I
a
Table 8-5. Causes of Nephritic Sediment
Confirmatory Laboratory Tests and Findings
Clinical Clues
Glomerulonephritides
PostinfectiOUs
Poststreptococcal
PositiviTstreptozyme, low serum comple
ment
Positive VDRL, low complement
History of sore throat, impetigo, or skin
infection
History of syphilis with other physical
findings
History of exposure, fever, chills
Syphilis
Malaria
Bacterial endocarditis
Visceral abscesses
Viral hepatitis
Some other viral diseases (e.g., GuillainBarre, infectious mononucleosis)
Associated with multisystem diseases
Systemic lupus erythematosus (SLE)
Progressive systemic sclerosis (PSS)
Wegener’s granulomatosis
Mixed connective tissue disease
Sjogren’s syndrome
Leucocytoclastic vasculitis (hypersen
sitivity angiitis)
Thrombotic thrombocytopenic purpura
Adult hemolytic uremic syndrome
Heart murmur, fever, skin manifestations,
splenomegaly \
Fever, abdominal findings, postabdominal
surgery \
Anorexia jaundice, liver tenderness
Ascending neuropathy, sore throat,
splenomegaly
Positive antimalarial antibodies, charac
teristic blood smear
Positive blood cultures, low serum comple
ment
Low complement in one-third of patients
Positive HBAg, membranous nephropathy
on renal biopsy
Albuminocytologic dissociation on spinal
tap, positive “mono spot” test
s
Arthralgias, skin rash, serositis, hair loss,
photosensitivity
Skin changes, dysphagia, malabsorption
Associated sinusitis, abnormal chest x-ray
Features of SLE and PSS
"Sicca” picture, rheumatoid arthritis (RA)
associated
Palpable purpura, asthma
Systemic manifestetions with predominant
neurologic symptoms
Abdominal pain, diarrhea, arthralgias
Positive ANA and DNA antibody, low
serum complement
Positive Scl-1“
Nasal mucosa biopsy, lung and/or renal bi
opsy may be indicated
Positive nuclear RNPh
Positive SS-A or SS-BC in 60% of "sicca”
cases, negative with associated RA
Skin biopsy, eosinophilia
Microangiopathic hemolytic anemia, low
platelet count, gingival biopsy
Microangiopathic hemolytic anemia
A -A
•'
-____________________
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Polyarteritis nodosa
Systemic manifestations (lung, liver)
Essential cryoglobulinemia
Purpura, arthralgia, hepatosplenomegaly
Goodpasture’s syndrome
Hemoptysis, abnormal chest x-ray
Familial nephropathy (Alport’s syndrome)
Deafness, cataract (anterior or posterior),
lenticonus, family history
Idiopathic
! None
“Scleroderma-1 (Scl-1): a soluble antigen present in rabbit thymus nuclei.
'’Antiribonucleoprotein (RNP): complex of RNA and protein.
cSjdgren’s syndrome A and B (SS-A, SS-B): extractable antigen from lymphoid cells.
'iy
& & & & «£ &
Muscle and/or testicular biopsy, arterial an
giogram for splanchnic or renal mi
croaneurysms
Presence of cryoglobulins, low serum com
plement
Renal biopsy (linear immunofluorescence
staining), circulating antiglomerular
basement membrane (anti-GBM) anti
body
Renal biopsy indicated (duplication of glo
merular basement membrane by elec
tron microscopy)
None characteristic, renal biopsy indicated
i3&
8: The Patient With Proteinuria oran
123
t—
8: The Patient With Proteinuria or an Abnormal Urinary Sediment
Abnormal Urinary Sediment
ses*:■Ksr* TIs
bacterial endocarditis, ma
, yP
nephritis are best controlled
As
immunosuppressive agents to treat
with steroids. The combination
shown to be better than steroids
diffuse proliferative lupusA
alone. In rapidly progressive g~..
P
success. Steroidal and im- “
matosus. plasmapheresis has "ned
lasmapheresis to prevent immumunosuppressive
S^°U
ulomPat0'sis responds particularly well to
nologic rebound. Wegener s gr
pfis mav respOnd to drug withdrawal
cyclophosphamide.
^ion- a favorable response to steroid therapy A
1
.
pasture’s syndrome. With massive ®
, iifdivided doses) has been used, with
ylprednisolone (1 gm per
pheresis accompanied by steroids and cysuccess in some isolated case. ,
effective, but prospective controlled studies
Utoxicagentsh^beenrepo^
in to be performed.
controlpulmo^a^^temorrhage;
however, there have been well-documented cases
<
C.
of relapse after nePhr®ct“^m
C i
involve dangerous medications (steroids, im-
|
.
3’
““S;.”'SS2z&tsssssssr”“.SS »' « 3
their complications and sho
without proteinuria and red blood cell
IV.
■h““
e1 3
portant. Total hematuria througboiclearing of the urine suggests a
' i
with “actaaTcountmg of the red bloody>InSates
‘
.about 20 ml), continues voiding into
tHird Findings are shown in Table
j
the same differentiation. With
the urine stream into the firs
-
fill
^cannot he overemphasized that-“b^
■
of a curable disease, including a
diagnosis The urologist and radiologist
everyeftort should be made toestabh^sha^diagnosis.fTh^h
mmirnal
prostate enlargement or nodules, and of external genitalia (e.g., a right var
icocele may accompany a renal tumor on the right) should be made.
2. Assessment of the hematuria. This assessment should be made by the threeglass maneuver, as described above.
3 Routine laboratory tests. Routine tests should include those *or plateiets, pro
thrombin time, partial thromboplastin time (PTD, sickle cell preparation, and
skin test for tuberculosis (PPD).
.
4. Straining of urine. Straining of urine should be done for stone or tissue debris.
5. Flat plate. Flat plate of the abdomen and excretory urogram with nephroto
mograms should be done in search of radiopaque stones and renal masses.
g Cvstoscopy. If a bladder origin of the hematuria cannot be excluded, cystoscopy
should be performed.
7. Urine culture
.
.
B. Clinical characteristics. Causes of hematuria without proteinuria or red blood
cell casts, along with some clinical clues and recommended diagnostic tests, are
shown in Table 8-7. In 40 percent of patients with hematuria, a structural defect
can be found, such as a bladder abnormality, a calculus, or a renal tumor. Another
40 percent have a renal parenchymal disease, and in 10 to 15 percent a cause
cannot be determined.
.
A particularly important and frequent problem is the diagnosis of the patient
with hematuria in whom a solitary renal mass is discovered on excretory urog
raphy. The patient presenting with hematuria, flank pain, and a palpable mass,
although uncommon, is classic for the diagnosis of renal cell carcinoma, especially
if the patient has associated signs of weight loss, fever or night sweats, and anemia
or polycythemia. The main differential, diagnosis is with a benign renal mass
(e.g., solitary cyst, hematoma). Modem indirect techniques can make this dif
ferential diagnosis with near certainty and with less morbidity and mortality
than a direct surgical approach. A recommended investigative sequence of events
is shown in Figure 8-17. This diagnostic approach, if performed at an experienced
institution, is 100 percent as sensitive and 97 percent as specific as direct surgical
exploration. The mortality is also ten times less and the cost 50 percent less than
exploratory surgery. More recently, many radiologists are recommending only
CT scanning (with and without contrast) of renal masses. Such scans provide
information on the nature of the mass (solid versus cystic), the extent of the mass,
and the presence of nodal, renal venous, and hepatic involvement. Overall, this
approach may prove more cost-effective and sensitive then that shown in Figure
8-17 (see Chap. 14).
C. Therapy. In most diseases in this category (neoplasms, impacted stones) the
treatment is surgical. If acute interstitial nephritis is due to a drug hypersen
sitivity, withdrawal of the drag is essential. A short course of prednisone (1 mg
kg for 10 to 14 days) may hasten the recovery of renal function as well as the
completeness of recovery with acute interstitial nephritis.
»
Sa^Hc "ton of a patient presenting with hematuria without proteinuria
or red blood cell casta should indu
^t'h emphasis on factors such as a
1. History. A thorough history is n«“ant
and histOry of exposure
SS“ ATareXhy-al examination for renal masses, for abnormal
Table 8-6. The Three-glass Maneuver
____
Initial Hematuria
Total Hematuri^
Glass
4- + +
1
2
0/+________________
________
3
+ indicates the relative number of red blood cells.
Terminal Hematuria
0/+
0/+
+ ++
—
129
J*
,
A H-.
Pyuria
Pyuria may occur alone or associated with some degree of hematuria. Any acute or
chronic inflammatory disease of the kidneys or urinary tract can result m pyuria.
I. Patient evaluation, the pyuria can be in the form of isolated pus cells, clumps, or
rarely, true white blood cell casts, which indicate the renal parenchymal origin of
3
the disease process.
. .
,
The minimal workup of a patient who presents predominantly with pyuria includes
the following:
.
A. History and physical examination. A careful history includes episodes of fever,
recent sexual contacts, drug ingestion (analgesics, antibiotics), and previous uri
nary tract infection or symptoms (dysuria, frequency, urgency).
B. Determination of plasma uric acid, calcium, electrolytes, and lead, if history
indicates (e.g., drinking moonshine).
I
-*
o
ii
Table 8-7.C^uses of Hematuria Without Proteinuria or Red Blood Cell Casts
Hematuria
Hematuria of renal origin ,
Neoplastic diseases
Renal cell carcinoma
Critical Tests and Findings
Renal mass, flank or abdominal pain, fever,
weight loss, anemia
Excretory urogram < XU), ultrasound, an
giogram (tortuous "tumor” vessels, ar
teriovenous fistulae), CT
XU, retrograde pyelography, CT
XU, ultrasound, angiogram, CT
History of analgesic abuse
Renal mass
Carcinoma of renal pelvis
Other tumors of the renal parenchyma
Papillary necrosis
Diabetes mellitus
Flank or abdominal pain, history of SS
crisis
History, usually male (prostate)
Sickle cell (SS) anemia
Acute urinary tract obstruction
Cystic diseases
Polycystic kidney disease
Medullary sponge kidney
Solitary cyst
Medullary cystic disease
Vascular disorders
Renal embolus (including
atheromatous emboli)
Family history, hypertension, renal masses
History of previous stones, renal tubular
acidosis, nephrocalcinosis
Generally no hematuria
Rarely hematuria, salt losing nephritis,
azotemia
XU, ultrasound, CT
XU
Other embolic manifestations (e.g., abdomi
nal pain, hemiparesis), cold, no pulse,
painful extremity
Renal scan, angiogram, stool guaiac,
ultrasound for mural thrombus
Hematuria of ureteral origin
Neoplasm
Stone
Trauma
Hematuria of bladder origin
Cystitis (viral or bacterial)
Neoplasm
Stone and foreign body
Runner's hematuria
Trauma
Cyclophosphamide
Hematuria related to the urethra or pros
tate
Benign prostatic hypertrophy
Acute urethritis
Trauma and foreign body
-X-1
U’
Previous history of renal calculi
History of trauma, blood clots in urine
History of drug intake (penicillins, al
lopurinol, cimetidine, furosemide, sul
fonamides)
Stones
Trauma
Acute interstitial nephritis
H
I
I
■
ii
i
XU, ultrasound, angiogram, CT
ULAJIAJUL
<L
A
I
Straining of urine fof papillary debris in
urine
XU, positive Phenistix or ferric chloride
reaction in urine (salicylates), papillary
debris in urine
XU, papillary debris in urine, SS hemo
globin on hemoglobin electrophoresis
XU, papillary debris in urine
History, fever, bacteremia, flank or abdomi
nal pain
Middle-aged female, chronic pain, and
several-kilogram analgesic ingestion
Analgesic abuse
A
Clinical Clues
XU, straining of urine
XU, angiogram
Peripheral eosinophilia, fever, rash,
eosinophils in urine (possible pro
teinuria)
XU, regrograde pyelogram, CT
XU
XU, retrograde, pyelogram, CT
Pain
History of trauma
Dysuria, frequency, urgency
/
History
Severe physical exerciwe, generally ii(;cc>nv
panied by proteinuria
History of trauma, fractured pelvis
History of drug treatment, dysuria
History of nocturia, frequency, urgency, and
dysuria
Dysuria
History
*
Associated pyuria, positive culture
XU, cystoscopy, CT
XU, cystoscopy
I
XU, cystoscopy
Cystoscopy
XU, cystoscopy
Cystoscopy
Cystoscopy
I
JUrcroia
a
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a
132
8: The Patient With Proteinuria or an Abnormal Urinary Sediment
Renal mass on excretory urography
1
__ Ultrasonography____ _
Solid Mass
Cystic mass
Solid and cystic
Jr
Renal angiography
Malignant
Cyst puncture with
cytology and radio
contrast media
evaluation of cyst
Renal angiography
Suspicious
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R. V. Clayman, R. D. Williams, and E. E. Fraley, Current concepts in cancer: The
pursuit of the renal mass. N. Engl. J. Med. 300:72, 1979 »
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c. Urine culture, Gram stain of unspun urine for bacteria, dipstick for protein,
examination of urine sediment.
D. Evaluation of renal function. The evaluation should be made with plasma cre
atinine, early morning urine specific gravity, or osmolality.
E. Skin test. This test should be made with intermediate-strength PPD.
F. Excretory urography. If pyuria is chronic or intermittently acute, excretory
urography should be performed.
,
.
...
Frequent causes of pyuria, with some clinical clues and additional laboratory tests,
are presented in Table 8-8.
. .
.
II Clinical characteristics. Pyuria related to bacterial imection is discussed in Chapter
’ 7 The group of chronic interstitial nephritides is usually characterized by alterations
in tubular function before any important decrease in glomerqlar function occurs.
Polyuria and nocturia mav be prominent clinical features, especially in nephropathy
associated with nephrocal'cinosis or potassium depletion. Hyperchloremic metabolic
acidosis with a decrease in plasma bicarbonate and a concomitant increase m plasma
chloride, is common. Proteinuria is usually below 2 gm per day. Special mention
should be made of the frequency of analgesic nephropathy, which is a frequently
overlooked cause of unexplained chronic renal failure. The disease is especially com
mon in middle-aged women with neurotic habits. Papillary necrosis is the predominant
feature with either an acute presentation of pain, fever, and superimposed infection
or a more chronic form discovered only on excretory urogram. The excretory urogram
may be normal, however. Infection is present in approximately 40 percent of patients.
Very often the diagnosis can be made only by finding on two or three occasions
salicylate in urine (positive Phenistix) or acetaminophen in urine (measurement
done by a drug assay laboratory). The history is often exceedingly difficult to obtain
because the patient is reluctant to admit chronic drug abuse.
III. Therapy. The therapy of the various diseases manifested by pyuria is directed toward
the cause. Renal infectious processes are discussed in Chapter 7. Renal stone disease
is discussed in Chapter 6. In chronic interstitial nephritides special attention should „
be devoted to maintenance of an adequate extracellular fluid volume, since in some
■ patients renal water and salt losses are an important part of the clinical picture. In
the interstitial nephritides accompanied by hypertension (e.g., chronic urate ne
phropathy and nephrosclerosis), control of the blood pressure is essential.
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134
8: The Patient With Proteinuria or an Abnormal Urinary Sediment
The Patient With Acute
Azotemia
Suggested Reading
Baskin, A. M., Freedman, L. R., Davie, J. S., and Hathaway, J. S. Proteinemia in
Yale students and 30-year mortality experience. J. Urol. (Baltimore) 108:617, 1972.
Carson, C. C., Segura, J. W., and Greene, L. F. Clinical importance of microhematuria.
JA.MA. 241:149, 1979.
Chen, B. T. M., Ooi, B. S., Tan, K. R., and Lim, C. H. Comparative studies of asymp
tomatic proteinemia and hematuria. Arch. Intern. Med. 134.901, 19/4.
Glassock, R. J. Clinical Features of Immunologic Glomerular Disease. In B. M. Bren
ner and J. H. Stein (Eds.), Contemporary Issues in Nephrology, Vol. 3. New York:
Churchill/Livingstone, 1979. P. 255.
Glassock, R. J., and McIntosh, R. M. Clinical Aspects of Glomerulopathies. In R. W.
Schrier (fd.), Renal and Electrolyte Disorders (3rd edj. Boston: Little, Brown. In
press.
Kassirer, J. P., and Gennari, F. J. Laboratory Evaluation of Renal Function In L.
E. Earley and C. W. Gottschalk (Eds.), Strauss and Welt’s Diseases of the Kidney
(3rd ed.). Boston: Little, Brown, 1979.
Koehler, P. R. Hematuria. Med. Clin. North Am. 59:201, 1975.
Lanas, M. D., Wagoner, R. D„ Levy, F. J. Unilateral essential hematuria. Mayo Clin.
Proc. 54:88, 1979.
Northway, J. Hematuria in children. J. Pediatr. 78:381, 1971.
West, C. D. Asymptomatic hematuria and proteinemia in children: Causes and ap
propriate diagnostic studies. J. Pediatr. 89:1/3, 1976.
Robert E. Cronin
e
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I
e
A variety of disorders in both hospitalized and nonhospitalized patients may lead to |
acute azotemia. The term azotemia implies a retention in body fluids of nitrogenous
wastes normally excreted by the kidney. However, the presence of azotemia does not <
necessarily imply a malfunctioning kidney. A healthy kidney in a person depleted
of salt and water may quite appropriately reduce excretion of all solutes and fluids
to maintain an adequate blood volume. Conversely, an obstructed or otherwise acutely
injured kidney may result in acute azotemia in the absence of volume depletion. The
following exaihple may serve to illustrate the often complex circumstances that sur
round acute azotemia.
•
Example (Figure 9-1): A 41-year-old white man was admitted to the hospital on July
16, 1977, with leg pain. He had a history of severe bilateral atherosclerotic disease
of the peripheral vasculature and 2 years earlier had undergone a left above-theknee amputation. On this admission an arteriogram demonstrated complete occlusion •
of the aorta below the renal arteries. An unsuccessful revascularization procedure
under general anesthesia was followed in 3 days by a right below'-the-knee ampu
tation. Several revisions of the stump were required over the next 2 months. Because ■
of a persistent purulent drainage from the stump following the initial operation,
parenteral and oral antibiotics were begun. Despite a combination of cephalothin
and gentamicin, a fever of 100° to 103° F persisted. Seven weeks after admission a
wound culture grew Acinetobacter resistant to gentamicin, ampicillin, and cephal- •
othin, but sensitive to colistin and carbenicillin. The patient was begun on a 14-day ■
course of colistin. On the ninth day of colistin therapy, nonoliguric acute renal failure J
was noted for the first time. Five weeks following discontinuation of all antibiotics,
the patient’s renal function returned to baseline values.
This patient, like many hospitalized patients, was exposed to a variety of insults
capable of causing acute amtemia, including high-dose intravenous x-ray contrast,
surgery, general anesthesia, gram-negative infection, and'three potentially neph
rotoxic antibiotics.
I. Clinical setting and characteristic features. An elevated blood urea nitrogen (BUN)
and serum creatinine and a reduced unne volume are compatible with a variety of
disturbances that may be of renal or nonrenal origin. The mere documentation of
azotemia offers little guidance to the physician in choosing the proper diagnosis or
therapy. Acute azotemia ran usually be attributed to one of the causes described
below.
A. Prerenal azotemia. Prerenal azotemia represents a decrease in glomerular fil-
i
i
i, such as ocurs with:.
a. Excessive diuresis
b. Hemorrhage
c. Gastrointestinal losses
d. Third space losses
(1) Burns
(2) Traumatized tissue
(3) Peritonitis
(4) Pancreatitis
/-
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135
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136
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9: The Patient With Acute Azotemia
9; The Patient With Acute Azotemia
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'i 1 Flq 9-1. A 41-year-old male developed acute azotemia following exposure to multipleJ
July
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operations, infections, and potentially nephrotoxic drugs.
11
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a. Congestive heart failure
b. Acute myocardial infarction
C. Pericardial effusion with tamponaue
d. Acute pulmonary embolism
e. Renal artery emboli, thrombosis, or stenosis
3. Peripheral vasodilatation
a. Gram-negative sepsis
b. Antihypertensive medications
4. Increased renal vascular resistance
a. Surgery
,
b. Anesthesia
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137
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Prerenal a20temia aCCOUntS
always be excluded as a cause oi p
^.emia and it must be considered
for the vast^onty■ o P^^Xsis
is in doubt. Moreover
m every patient in t h
gj*
development of acute renal failure and
A
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reverses the azotemia, then prerenal azotemia Mas present).
B. Postrenal azotemia. The common causes ot postrenal azotemia include.
1. Urethral obstruction
a. Urethral valves
b. Urethral strictures
2. Bladder neck obstruction
Prostatic hypertrophy
b. Prostatic and bladder carcinoma
c. Autonomic neuropathy or ganglionic blocking agents
-1
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(1) Prostatic, bladder, or cervical cancer
(2) Retroperitoneal fibrosis
(3) Accidental ureteral ligation or trauma during pelvic surgery
The common denominator of acute azotemia in this set of disorders is obstruction
to the flow of urine. The patient most at risk for acute postrenal azotemia is the
elderly man in whom prostatic hypertrophy may lead to complete or partial ob
struction to urine flow. Young boys with congenital urethral valves may also
have acute obstruction. In women, complete urinary tract obstruction is relatively
uncommon in the absence of pelvic surgery or pelvic malignancy. However, tran
sient, unilateral, partial ureteral obstruction is not uncommon in the course of
acute bacterial pyelonephritis (pyogenic debris) or fungal (fungal ball) urinary
tract infection.
,
C. Acute renal failure. In contrast to the two preceding categories, the disorders
listed here and in the next two sections represent primary renal disturbances.
The course of acute azotemia in these situations cannot be changed by manip
ulating factors outside the kidney (e.g., volume repletion, improving cardiac
function, correcting hypotension, removing obstruction). The term acute tubular
necrosis (ATN) is often used interchangeably with the term acute renal failure.
However, proximal tubular necrosis, although present in many of these cases,
does not always occur in a patient who otherwise fits the description of acute
renal failure.
1. Ischemic disorders. Ischemic disorders predisposing to the development oi
acute renal failure include:
a. Complications of surgery
b. Hemorrhage
c. Trauma
d. Rhabdomyolysis with myoglobinuria
e. Gram-negative sepsis
f. Postpartum hemorrhage
g. Pancreatitis
With the ischemic disorders, reduced blood flow to the kidneys results from either
a decreased total blood volume or a redistribution of blood away from the kidney.
It is seen most commonly following surgery and trauma. Rhabdomyolysis with
myoglobinuria is being recognized with greater frequency and may account for
many of the cases of acute renal failure previously classified as “etiology unknown.”
2. Nephrotoxic disorders. Nephrotoxic disorders include those caused by:
a. Antibiotics
(1) Aminoglycosides
(2) Cephalosporins
(3) Colistin
—• b. lodine-containing x-ray contrast
Heavymetals
metals(arsenic,lead,
(arsenicjead?cadmium
mercury,bismuth,
bismuth,uranium)
uranium)
_ c. Heavy
cadmium, , mercury,
^d. Organic solvents (carbon tetrachloride)
' e. Ethylene glycol (antifreeze)
— f. Anesthetics (methoxyflurane, enflurane)
g. Cyclosporin
In hospitalized patients nephrotoxins have become a major cause of acute renal
failure. Antibiotics, particularly those of the aminoglycoside class, are the most
important contributors. Even with careful dosing and measurement of blood levels,
nephrotoxicity occurs in 15--25 percent of all patients treated with aminoglycosides.
Intravenous x-ray contrast administration is also a major cause of acute renal
failure, especially in patients with multiple myeloma and diabetes mellitus. The
increased susceptibility of diabetic patients has been appreciated only during the
A
138
9: The Patient With Acute Azotemia
past 10 years. The factors that put these patients at risk appear to be preexisting
renal insufficiency, volume depletion, hypertension, vascular disease, and pro
teinuria. It is also likely that administration of unrelated nephrotoxins may have
an additive nephrotoxic effect on the kidney. For example, in experimental an
imals, aminoglycoside antibiotics are more nephrotoxic if given after the fluoridecontaining anesthetic methoxyflurane. X-ray contrast media and aminoglycoside
antibiotics may also have additive nephrotoxicities, since both agents are normally
concentrated in proximal tubular cells.
D. Acute interstitial nephritis. The following therapeutic agents represent the primary
causes of acute interstitial nephritis:
1. Antibiotics
a. Penicillins
b. Cephalosporins
c. Rifampin
d. ^Sulfonamides
2. Miscellaneous drugs
a. Diuretics (furosemide, thiazides, chlorthalidone)
b. Allopurinol
c. Phenytoin
d. Phenindione
e. Phenylbutazone
f. Nonsteroidal antiinflammatory drugs
Although any member of the penicillin group of drugs may cause such a reaction,
methicillin is the agent most frequently described. In contrast to the proximal
■ tubular necrosis seen commonly with acute renal failure, the primary histologic
lesion of acute interstitial nephritis is marked edema of the interstitial space
and a focal or diffuse infiltration of the renal interstitium with lymphocytes,
macrophages, plasma cells, and polymorphonuclear leukocytes. Loss of renal
function from drug hypersensitivity tends to be less abrupt and severe than with
classic acute renal failure; nevertheless, dialysis therapy may be required. Re
covery of renal function following withdrawal of the drug may be slow and in
complete.
E. Primary renal, systemic, and vascular diseases. Diseases in these categories
associated with acute azotemia include:
1. Acute poststreptococcal glomerulonephritis
2. Rapidly progressive glomerulonephritis
3. Goodpasture’s syndrome
4. Systemic lupus erythematosus
5. Subacute bacterial endocarditis
6. Necrotizing vasculitis
7. Malignant hypertension
8. Postpartum renal failure
When acute azotemia develops in association with these disorders, it often rep
resents only one of many serious complications of an underlying disease. Moreover,
histologically, the primary site of injury is the glomerulus or the vascular supply
of the glomerulus, with the proximal tubule and the interstitial areas relatively
uninvolved. Azotemia during the course of acute glomerulonephritis is rare, but
the glomerular filtration rate is nearly always reduced. Anuric or severe oliguric
acute renal failure complicating acute' glomerulonephritis appears to be more
frequent in adults. Characteristically, acute azotemia developing in the course
of systemic vasculitis is an ominous sign, and recovery of renal function, if any,
is often delayed and usually incomplete.
IL Differentia! diagnosis
A. Evaluation of the acutely azotemic patient. Whether the patient is seen for the
first time in the office, in the emergency room, or in the hospital, careful tabulation
and recording of data is the first step in diagnosis and treatment. Vital signs,
daily weights, records of intake and output, past and current laboratory data,
and the fluid and medication list should be recorded on a flow sheet and included
in the patient’s chart. In situations in which the patient has been hospitalized
for several days or weeks with a complicated course before developing acute azo-
9: The Patient With Acute Azotemia
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139
temia, a carefully prepared flow sheet may often be the only way to comprehend
the problem and guide the way to proper therapy.
B. History.Tn evaluating a hospitalized patient with acute azotemia it is helpful to
determine whether the azotemia developed outside or inside the hospital.
1. Azotemia developed outside the hospital
a. Chronic systemic illness. Azotemia first discovered in the office or emer
gency room may be chronic or acute in origin. A previous systemic disease
(e.g., diabetes mellitus, hypertension, systemic lupus erythematosus) or a
history of kidney disease (e.g., kidney infection, abnormal urinalysis on a
previous physical examination) suggests that the azotemia may be chronic.
b. Acute systemic illness. Alternatively, an acute systemic illness (e.g., viral
influenza, gastroenteritis) may lead to acute azotemia through a-variety
of mechanisms (e.g.. volume depletion, rhabdomyolysis with myoglobi
nuria). Acute poststreptococcal glomerulonephritis is usually preceded by
streptococcal pharyngitis or pyoderma. Pyoderma may occur in children
and adults of any age and is characterized by vesicular lesions, usually
on the extremities, which become pustular and then crust.
c. Trauma. Trauma as the cause of acute azotemia is usually apparent at the
time of admission to the hospital, but the unconscious or comatose patient
may harbor internal injuries, extensive muscle damage, or acute urinary
retention that are not discovered initially.
d. Obstructive uropathy. Male patients with acute azotemia should be
screened carefully for symptoms of prostatism.
Adverse drug reaction. Antiinflammatory compounds that work by in
hibiting prostaglandin synthesis (e.g., aspirin, indomethacin, ibuprofen)
cause prerenal azotemia by removing important intrarenal vasodilating
prostaglandins. Steroids and tetracycline compounds cause an elevation
of blood urea nitrogen, presumably through enhanced protein breakdown
and urea production, but there is usually no effect on glomerular tiltration
rate, and thus in a strict sense this does not represent a renal disorder.
Demeclocycline. however, may be nephrotoxic in the patient with liver
disease. Diuretic agents with a structural similarity to sulfa compounds
(thiazides, furosemide, chlorthalidone), antibiotics (penicillins, cephalo
sporins, rifampin), and a variety of miscellaneous drugs may cause a hy
persensitivity reaction in the renal interstitium, leading to acute azotemia.
f. Intoxication. Accidental or intentional intoxication with heavy metal com
pounds, solvents, ethylene glycol, salicylates, or sedatives, especially in a
patient presenting with disordered mentation, may explain an otherwise
unexpected episode of acute azotemia.
2. Azotemia developed Inside the hospital. When azotemia develops in the hos
pital setting, the list of possible causes narrows.
a. Fluid and electrolyte depletion. Fluid and electrolyte depletion usually
results from a failure to appreciate and replace fluid losses (e.g., excessive
diuresis, nasogastric suction, surgical drains, diarrhea) in patients who
are too ill to control their own solute and water intake.
b. Surgery and anesthesia. Both surgery and anesthesia cause a vasocon
striction of the renal artery and release of antidiuretic hormone, both of
these effects may persist for 12 to 24 hours into the postoperative period.
As a result, reduced volumes of concentrated urine in the early postop
erative period tend to be the rule rather than the exception. If postoperative
infection or unexpectedly large wound or drain losses occur, negative fluid
balance may supervene, leading to prerenal azotemia.
c. Nephrotoxic drugs and diagnostic agents. Although there seems to be
little justification for continued use of methoxyflurane (Penthrane), an oc
casional case of acute renal failure frorp its use still occurs. Enflurane, a
related agent, may also cause acute renal failure, but the risk seems to
be much less. Prolonged administration of methoxyflurane (greater than
4 to 5 hours) or repeated administration appears to predispose to neph
rotoxicity.
Nephrotoxic drugs and diagnostic agents represent a major and serious
I
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140
9: The Patient With Acute Azotemia
9: The Patient With Acute Azotemia jUI
■ SS-
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5. Systemic diseases. The physic^xamm^mnmpnman'^
cause of acute azotemia. Since the kidney is the primary organ of excretion
for manv antibiotics and x-ray contrast agents, the renal tubular epithelium
is exposed to very high concentrations and not infrequently sustains camage. Nonoliguric acute renal failure (greater than 500 ml of urine per day
despite a rising BUN and serum creatinine> is characteristic of azotemia
that develops following aminoglycoside nephrotoxicity. Frank azotemia
secondary to aminoglycosides may develop for the first time after the drug
has been discontinued; conversely, recovery of renal function following
discontinuation of the nephrotoxic aminoglycoside is often delayed and
may require weeks to months to be complete; In contrast, acute renal failure
following intravenous or intraarterial administration of x-ray contrast
rts’is
agents
is characteristicaily
characteristically abrupt
abrupt in
in onset
onset and
and usually
usually oliguri§
oliguric) Recovery
Recovery
tends toj begin within 2 to 3 days. However, patients with
with^dyanced
advanced renal
failure, particularly
pen ni-uiai ij diabetic patients,
----- , may never recover function following
,
i *
onufo
x-ray contrast-induced
acuterensil
renal failure
failureand
andmav
may reauire
requirechronic
chronichehe
modialysis therapy.
. . .
A
n
,
C Physical examination. Since prerenal azotemia is the most common cause oi
* acute azotemia, the adequacy of extracellular fluid volume must be carefully
Ja
of
X^urina^t fiXgs, but the mucous membranes, eyes, joints, and skm
v
.
often demonstrate abnormalities.
D-i
of the first voided unne is often
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failure is ordinarily 10 • !•
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: 1 The first specimen of unne
U Adequacy of effective blood volume. Physical findings useful in assessing
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the status of the extracellular fluid compartment include:
a. Body weight
b. Postural blood pressure and pulse changes
c. Skin turgor
’
d. Mucous membrane moisture
e. Inti aocular pressure
Reduced body weight, a fall in systolic blood pre^ure of greater than 10 mm
He or a rise in pulse of greater than 10 bpm when assuming the upright posture,
“tenting” of upper thorax skin when pinched with the fingers, dry mucous
membranes, and reduced fullnes of the eyeballs on light palpatmn, all suggest
a reduction in extracellular fluid volume. Prerenal azotemia may also develop
in states in which extracellular fluid is expanded (e.g„ cardiac failure arehosis.
nephrotic syndrome). Although the ECF may be expanded as judged by bedside
criteria (e.g., elevated jugular venous pressure, pulmonary rales, ventricular
gallop rhythm, ascites, peripheral edema), the effective blood volume, or that
portion within the arterial circulation, may be decreased, thus leading to pre2 Urinary tract obstruction. The physical examination is. also important in di’ agnosing postrenal azotemia, especially in the unconscious patient or m the
confused patient in whom otherwise unexplainable agitation may be the only
clue to acute urinary retention. Careful abdominal examination may uncover
a distended, tender bladder or bilaterally hydronephrotic kidneys. A digital
examination of the prostate should be performed routinely m any azotemic
male patient, and pelvic masses should be sought in female patients through
a bimanual pelvic examination. In any patient m whom lower tract obstruction
is suspected as the cause of acute azotemia, a sterile “in-and-out diagnostic
postvoid bladder catheterization should be performed as a routine part of the
physical examination. The urine volume should be recorded and the specimen
saved for the studies described in section ll.D.1.a.
3 Hypersensitivity reaction. Physical findings with acute drug-induced inter‘ stitial nephritis may be lacking, although fever and a maculopapular or pe
techial skin eruption may occur with any of the agents, particularly the pen
icillin derivatives and allopurinol. Ordinarily, however, laboratory findings
are more helpful in making this diagnosis.
4 Toxins or muscle damage. The physical abnormaaties m these forms of acu
‘ renal failure may vary from none to many, depending on the circumstances.
When the cause is unclear, particular attention should be directed toward
uncovering evidence of intoxication (e.g., altered mental status, odors on the
breath or clothing) and muscle tenderness or edema.
i
|
.
. .
.
...
;
Table 9-1- Urinary Diagnostic Indices
-Ci*
’
_____ ____
Index
Urine sodium (U sab mEq/L
Urine osmolality, mOsm/kg H.0
Urine to plasma urea nitrogen
Urine (UCr) to Plasma (Per) creatinine
Prerenal
Azotemia
----7
<20
>500
>8
>40
Oliguric
ARF
>40
<350
<3
<20
Renal failure index
>1
Usa
RFI * Uer/Per
>.7
Fractional excretion of filtered sodium
__
FEn»
UNa ■ Per » WO
Psa '
ARF = acute renal failure.
<1
5y
- jd 9: The Patient With Acute Azotemia
I
acteristic of acute renal failure. Red cells and red cell casts suggest acute
glomerulonephritis or vasculitis. Heavy oxalate (envelope-shaped) or hip
purate (needle-shaped) crystalluria may be seen with ethyleqe glycol
ingestion. Trace to 1 + proteinuria on dipstick of the urine may be compatible with prerenal azotemia or acute renal failure, but higher grades
^of proteinuria suggest acute interstitial nephritis or glomerulonephritis.
^Rhabdomyolysis should be suspected when acute azotemia is associated
with frank muscle injury, a prolonged period of unconsciousness, alcohol
or drug abuse, seizures, Parkinson’s disease, hypokalemia, hypophospha
temia, or heat stress^Since the urinary dipstick does not distinguish be
tween hemoglobin and mybglobin, a strong presumptive diagnosis of rhab
domyolysis with myoglobinuria can be made by demonstrating heme
positive urine in the absence of red cells or on the supernatant of the urine,
an elevated creatinine phosphokinase (CPK) and aldolase in the serum,
and a normal color to the serum (i.e., absence of hemolysis).
In instances of acute drug-induced interstitial nephritis (e.g., after meth
icillin), fever_maculopapular skip rash, 10 to 60 percent eosinophilia in
peripheral blood, proteinuria, and urinary sediment abnormalities (gross
or microscopic hematuria, pyuria, ecsinophiluria, and casts) are common.
A Wright’s stain preparation on a freshly voided and sedimented urine
specimen may demonstrate that eosinophils account for 33 percent of the
urinary white cells. The urinary sediment is air-dried on a slide and
Wright’s stain is applied for 1 minute, followed by Wright’s buffer for 2
minutes. The specimen is then observed under the microscope using an
oil immersion objective lens. Eosinophils in the urine appear as granulated
binucleated cells. Because of varying urinary pH, the granules may or
may not take up the eosin.
If with these laboratory tests the cause of acute azotemia is still in doubt,
a blood screen for toxic chemicals and drugs may be warranted.
2. Radiographic studies
a. Plain film of abdomen. Several radiographic procedures to assess acute
azotemia are available, the simplest of which is the plain film of the ab
domen. Often this procedure can document the size of the kidneys, thus
giving information regarding the duration of the azotemia (e.g., small kid
neys suggest chronic renal disease, and normal or large kidneys suggest
an acute process).
b. Excretory urography. Excretory urography may give additional information
regarding renal anatomy, chronicity of the disease, and presence of urinary
tract obstruction. However, a combination of the noninvasive procedures
described below often give equally valid information without the risk in
herent in contrast administration.
C. Renal angiography and renal scan. Patients with a history of hypertension,
type IV hyperlipidemia, or atherosclerotic disease of the large vessels and/
or renal artery, because of cholesterol emboli, may experience chronic
prerenal azotemia or acute oliguria and azotemia may develop, sometimes
associated with flank pain and hematuria. Also, renal embolization of a
mural thrombus following a myocardial infarction may lead to acute azo
temia; however, such an event may be overshadowed in importance by a
concomitant, devastating central nervous system embolic stroke. When
acute oliguria develops as a consequence of acute renal embolization, renal
angiography is usually warranted, since acute surgical intervention in se
lected cases may restore renal function. In less critical situations a renal
scan is often useful in determining whether renal blood flow to one or both
kidneys is impaired.
3. Renal ultrasonography. This procedure may be useful in assessing kidney and
blatjder size. Also, a normal renal pelvis and calyceal system on ultrasonog
raphy virtually excludes important urinary tract obstruction. Thus, a com
bination of flat abdominal film, renal scanning, and renal ultrasonography in
9: The Patient With Acute Azotemia
2eL;-
most instances of acute azotemia can supply as much pertinent information as
excretory urography at virtually no risk to the patient.
Urologic studies. In instances of acute azotemia with a high suspicion of uri
nary tract obstruction (e.g., calculi, pyogenic debris, blood clots), cystoscopy
and retrograde pyelography should be performed, even if ultrasonography is
negative for obstruction. Ureteral calculi extraction or placement of ureteral
catheters or stints may relieve the obstruction and allow unnary drainage. It
is particularly important to consider this diagnostic course in patients with
superimposition of acute azotemia on a background of chronic stable azotemia.
Renal biopsy. In patients in whom the cause of acute azotemia is unknown
and a systemic disease (e.g., vasculitis) or acute interstitial nephritis is sus
pected but not proved, percutaneous or open renal biopsy may be warranted.
A renal biopsy in such circumstances may form the basis and justification for
aggressive therapy (e.g., high-dose steroids, cytotoxic agents, plasmapheresis^
In patients in whom the oliguric phase of acute renal failure extends beyond
4 to 5 weeks, a renal biopsy may be warranted to determine whether another,
less favorable diagnosis, such as cortical necrosis, should be entertained.
III. Treatment
A. Prerenal azotemia
1. Correction of underlying disorder
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a. Pure volume depletion. When prerenal azotemia is due to deficits in ex
tracellular fluid volume, therapy is geared to restoring fluids to the body
similar to those lost. In gastrointestinal and other types of acute hemor
rhage packed red cells in saline are indicated. When blood has not been
lost from the body, but plasma moves out of the intravascular compartment
to a third space (e.g., crush injury with extensive edema formation in de
vitalized muscle, bums), isotonic saline approximates extracellular fluid
tonicity and will restore blood volume and blood pressure. Gastrointestinal
fluid losses vary widely in electrolyte content and tonicity, and laboratory
analysis for sodium, potassium, and chloride concentrations is the most
precise way to determine the type of replacement fluid. Ordinarily, gastric
juices will require replacement liter for liter with one-quarter to one-half
normal saline containing 10 to 20 mEq per liter of potassium chloride.
Pancreatic, biliary, and small bowel losses will require replacement with
iaotonic saline. Diarrheal losses can be restored with 5% dextrose and water
to which has been added one ampule of 7.5% sodium bicarbonate (45 mEq
sodium bicarbonate) plus 20 to 30 mEq of potassium chloride.
b. Ineffective arterial blood volume with edema. Prerenal azotemia occurring
in this setting usually represents a secondary problem overshadowed by
a primary cardiac, hepatic, or renal disease.
\
41) Cardiac failure. In cardiac failure, diuretic agents in combination with
digitalis therapy may increase the cardiac output and improve renal
perfusion, and thus lessen the azotemia. Vasodilator drugs, such as
hydralazine, may also improve cardiac function. However, with ad
vanced heart failure refractory or only partially responsive to these
agents, the physician may be forced to accept mild-to-moderate prerenal
azotemia as a trade-off. Such azotemia rarely leads to acute renal failure
/
or symptomatic uremia.
. , ,
..
(2) Hepatic disease. Prerenal azotemia associated with advanced hepatic
cirrhosis, with or without the hepatorenal syndrome, is ofteri refractory
to attempts to improve intravascular volume. However, despite the
presence of peripheral edema and ascites, some of these patients may
' improve renal function and renal excretion in response to a saline
challenge. Ordinarily, however, such patients are best treated with
sodium-restricted diet (1 to 2 gm salt), modest water restriction (1500
to 2000 ml per day), and an aldostefone antagonist
mg four times daily ), while the usually mild prerenal state is ignored.
(40 *to“ on
80 mg
A potent diuretic agent such as furosemide
f------ —t-?
2 twice daily)
I1
i
:i
;
3
J’
\]
SJ!
144
■
4-
;t:
J
9: The Patient With Acute Azotemia
9: The Patient With Acute Azotemia
is sometimes successful in causing a diuresis and improving renal
function, but this therapy carries the risk of precipitating severe hypokalemia, increased ECF volume contraction, hepatic coma, or the
hepatorenal syndrome. Paracentesis and reinfusion of the ascitic fluid
into a peripheral vein may temporarily increase intravascular volume
and improve urine flow, but these benefits are of such short duration
that this cumbersome therapy is of little long-term practical value.
Moreover, infection and disseminated intravascular coagulation are
definite risks. For selected, compliant patients with intractable symptomatic ascites who have relatively good liver function, a peritoneovenous shunt (LeVeen shunt) may reduce ascites and improve renal
function (see Chap. 1). Major complications of the peritoneovenous shunt
are infections, disseminated intravascular coagulation, pulmonary
edema, and variceal bleeding.
(3) Nephrotic syndrome. Prerenal azotemia often occurs with nephrotic
syndrome from any cause, particularly when it is accompanied by severe
hypoalbuminemia (serum albumin less than 2.5 gm/L) and heavy pro
teinuria (10 to 20 gm/day). As in the other states of prerenal azotemia
associated with an expanded ECF but reduced effective arterial blood
volume, success in reversing the prerenal state depends on correcting
the primary disease state. Idiopathic nephrotic syndrome, especially
in children, usually responds to short-term, high-dose prednisone (1 to
2 mg/kg/day), but steroid resistance or frequent relapse may require
the addition of cyclophosphamide (1 to 3 mg/kg/day). When nephrotic
syndrome occurs as a complication of a primary renal disease (e.g.,
membranous nephropathy) or as a complication of a systemic disease
(e.g., diabetic nephropathy), the level of proteinuria and thus the level
of prerenal azotemia may wax and wane spontaneously, and no drug
therapy has been found to be especially useful in altering this pattern.
However, a recent multicenter cooperative study shows that patients
with membranous nephropathy treated with an 8-week course of pred
nisone (100 to 150 mg every other day) with subsequent tapering of
the dosage over 2 months appear to have better long-term renal function
than untreated controls.
2. Monitoring therapy. In most instances of prerenal azotemia secondary to volume
depletion, the volume of fluid required to replace the deficit can be estimated
from actual quantitation of fluid or blood losses or from changes in body weight.
A useful rule is to replace no more than one-half to two-thirds of the total
calculated deficit in the first 24 hours, especially in elderly patients or in pa
tients with a compromised cardiovascular system. The simplest way to follow
the patient’s response to replacement therapy is by bedside evaluation, with
frequent monitoring of orthostatic changes in blood pressure and pulse. The
jugular venous pulsation is a gross indicator of pressure in the central venous
area of the right heart. In a normovolemic patient, jugular venous pulsations
are visible when the patient is supine, but disappear when the patient assumes
the sitting position. Jugular venous pulsations are not visible in the volume■ depleted patient; thus, their reappearance following fluid administration sug
gests that the central venous pressure has returned to normal. The heart and
lungs should also be monitored regularly. The presence of basilar rales or a
third heart sound implies too vigorous fluid replacement, with resultant car
diopulmonary congestion.
In patients in whom vigorous resuscitation efforts are required and there is
doubt regarding cardiovascular tolerance to sudden fluid challenges, some form
of indwelling monitoring system is desirable.
a. Central venous catheter. In most instances in which rapid fiuid admin
istration is required and severe heart and or lung disease is absent, a cath
eter positioned in the central venous area of the right heart is a satisfactory
guide to the speed of fluid administration. Long polyethylene catheters
are placed in the antecubital vein and advanced into the central venous
ft. L
**
r
r
0
0
i
Ct
j- 3
i
145
area A shorter polvethvlene catheter may be placed in the central venous
area via the subclavian vein, but this-procedure presents more nsks
(pneumothorax, hemothorax, air embolism). Fluctuation of the pressure
with respiration suggests successful placement of the catheter in the area
of the right atrium, but the exact location of the catheter should be as
certained with an x-ray of the chest. This precaution will also serve to
detect those instances in which catheter placement has caused pneumo
thorax. The central venous pressure (CVP) normally ranges between 2 and
12 cm of water. In volume-depleted states, values of zero or below can be
expected. Before vigorous volume repletion is begun, a fluid challenge of
200 to 300 ml of normal saline should be attempted over a 10- to 20-niinute
period In an otherwise uncomplicated volume-depleted patient, this amount
of saline will have little effect on the CVP reading. A CVP nse greater
than 5 cm of water suggests cardiac failure, and the infusion should be
immediately discontinued. Venous thrombophlebitis, a major late com
plication of central venous catheterization, can be avoided m large part
by removing the central line after resuscitation is complete or after a max
imum of 36 hours.
. , . ,
b Balloon-tipped catheter. When a volume deficit must be repairea in the
presence of tricuspid stenosis, acute or chronic pulmonary disease, or an
unstable cardiovascular system, the central venous pressure does not give
a reliable index of left ventricular performance. In this situation, a baboontipped catheter (Swan-Ganz) can be wedged in a pulmonary artery. Tins
gives an indirect measurement of left ventricular end-diastohc pressure
and thus is a better guide to the~adequacy and speed of fluid replacement.
Because of the complications of infection, pulmonary infarction, and hemopneumothorax, this device should be inserted and placed only by trained
professionals.
B. Acute renal failure
Diagnostic and therapeutic use of diuretic agents. Osmotic diuresis witr
1.
mannitol and, in more recent years, the potent loop diuretics (furosemide anc
ethacrynic acid) has been used almost routinely to prevent or reduce the sevent?
of acute renal failure (Table 9-2). However, no human studies clearly documen
that this therapv is effective. Available evidence suggests that these agent
are effective only if given early in the initiation phase of acute renal failur
(e g., immediately after a mismatched blood-transfusion or crush injury- wit)
rhabdomyolysis). There are no data to support their use in established acut
1
1
d
1*
Inpatients' in whom volume deficits have been repaired with isotonic salin
or its equivalent and oliguria persists, 50 ml of 25% mannitol (12.5 gm) i
generally given and repeated after 30 minutes if a diuresis of 40 ml per hoc
does not ensue. If a diuresis does not occur, no more mannitol should be givei
since the hypertonic mannitol will increase the plasma volume and may pr»
cipitate pulmonary congestion. If a diuresis occurs, it should be sustained wit
repeated boluses of mannitol or an infusion of 5% mannitol until the patiei
Table 9-2. Diuretic Agents in Acifte Renal Failure
3
a:
Rationale for use
Convert oliguric to nonoliguric acute renal tailure
Prevent acute renal failure (unproven)
Dosages
Mannitol
Initial 12.5 gm <50 ml of 25% solution)
Repeat 12.5 gm
Maintain with 5% mannitol solution
Furosemide intravenous bolus 80-400 mg
146
9; The Patient With Acute Azotemia
9: The Patient With Acute Azotemia
147
i
.4
can maintain an adequate urine flow spontaneously. If mannitol fails to produce
a diuresis, furosemide may be used. Furosemide has the advantage of not
causing volume expansion. It is given intravenously in a dose of 80 to 400 mg.
Doses higher than this are rarely effective and add the risk of ototoxicity. The
chance of having a satisfactory diuretic response is small if (a) acute renal
failure is more than 36 hours old, (b) the 24-hour urine output is less than
200 ml per day, and (c) the serum creatinine is greater than 5 to 6 mg per
deciliter.
2. Fluid therapy
a. Oliguric acute renal failure (ARF). The use of dialysis therapy for oliguric
ARE may permit fluid intakes of 1.5 to 2 liters per day. depending on the
status of the card iovascular system. If hemodialysis or peritoneal dialysis
is not immediately available, fluid balance usually can be maintained by
replacing insensible losses (400 to 600 ml/day) with 10% dextrose in water
and measured losses (e.g., urine, gastric drainage, diarrhea) liter for liter
with 0.45% saline. If the plasma bicarbonate level falls below 20 mEq per
liter, one or two ampules of 7.5% sodium bicarbonate (45 mEq of bicarbonate
per ampule) should replace an equivalent quantity of sodium chloride in
these fluids. The best monitor of adequacy of fluid therapy is an estimate
of the ECF volume status and daily weights. A serum sodium determination
every other day is helpful in deciding whether water intake is appropriate
to solute intake (hyponatremia indicates excessive water intake and hy
pernatremia indicates too little water intake). Since hypokalemia is rarely
a problem with ARF, and because of the danger of cardiac arrhythmias
from hyperkalemia, potassium chloride is not added to intravenous fluids.
b. Nonoliguric ARF. In general, nonoliguric ARF represents a milder renal
injury and requires dialysis less frequently. As a result, fluid management
tends to be easier. These patients ordinarily should receive a volume of
water per day that equals their urine output plus insensible losses. The
salt content of their diets should be approximately equal to what is excreted
in the urine and lost’ in other measurable bodily fluids.
3. Parenteral hyperalimentation. This form of therapy may be effective in de
creasing mortality in ARF occurring in hypercatabolic surgical and trauma
patients, especially when complications have developed. The so-called renal
failure fluids consist of 50% dextrose as the source of carbohydrates and es
sential 1-amino acids as the nitrogen source. When ARF occurs in the absence
of the hypercatabolic state, parenteral hyperalimentation is not recommended.
4. Dialysis therapy. Indications for dialysis therapy are as follows:
Absolute indications z
(1) Central nervous system dysfunction
(a) Asterixis
(b) Neuromuscular irritability
(c) Somnolence z
(d) Coma
I
(e) Seizures
(2) Gastrointestinal complications
(a) Nausea and vomiting
(b) Hemorrhage
(3) Pericarditis
Relative indications x
(1) Cardiovascular complications
(a) Pulmonary edema
(b) Hypertension
(c) Arrhythmias
1 (2) Metabolic complications
(a) Hyperkalemia <
(b) Hyperuricemia
(c) Hyponatremia
125 mEq/L or symptomatic)
/
•L
er.
i
eb
e
e
e
It is now generally accepted that in the patient with acute renal failure, dialysis
therapy should be used as often as necessary to maintain the BUN below 100
mg per deciliter. Dialysis should also be used to prevent symptoms of uremia
(irritability, insomnia, failure to concentrate, anorexia, vomiting). Thus, iTa
65-year-old patient has uremic symptoms with a BUN of 70 mg per deciliter,
dialysis should be begun. In severely catabolic patients /e.g., crush injury, burns)
daily dialysis may be required. The type of dialysis therapy for a particular
patient—hemodialysis versus peritoneal dialysis—depends on the clinical sit
uation. Patients with severe tissue breakdown (e.g., rhabdomyolysis, trauma,
bums, sepsis, postoperative) have enhancecFurea production and usually require
hemodialysis. Hemodialysis may also be indicated in methanol or ethylene
glycol poisoning to remove the toxin and control the accompanying metabolic
acidosis. In other types of ARE in which the catabolic component is less prom
inent, such as when renal failure occurs secondary to antibiotics or x-ray con
trast, peritoneal dialysis may be adequate. However, these patients often can*
be managed successfully without dialysis, using the conservative measures
described above.
C. Postrenal failure. In large part, the therapy of urinary tract obstruction is surgical
and requires early urologic consultation. Foley catheter drainage is usually suc
cessful for acute obstruction secondary to prostatic hypertrophy and may be fol
lowed in several weeks by prostatic resection. With ureteral obstruction, cystoscopy
and placement of ureteral drainage catheters may allow passage of obstructing
stones, sludge, or pus, but if this fails operative intervention will be required.
D. Acute interstitial nephritis. When a therapeutic agent is identified as the cause
of acute interstitial nephritis, removal of the agent is the obvious first step in
therapy. When renal impairment is minor, nothing more need be done. In more
severe cases, high-dose, short-term prednisone therapy (60 mg day for 1 to 2 weeks)
may speed recovery of renal function and normalize urinary sediment. The extent
i
Table 9-3. Therapy of Acute Azotemia in Primary Renal, Systemic, and Vascular
Diseases
Disease
Therapy
Acute poststreptococcal glomerulonephritis
Rapidly progressive glomerulonephritis
and Goodpasture’s syndrome
No specific therapy
Pulse methylprednisolone 1 gm IV over 20
minutes for 3 days and/or prednisone
1-2 mg/kg/day
Cyclophosphamide 1-3 mg/kg/day
Plasmapheresis 4 L/day for 1-3 weeks
Prednisone 1-2 mg/kg/day
Cyclophosphamide 1-3 mg/kg/day
Antibiotics
Systemic lupus erythematosus
3
-3
£ 3
Subacute bacterial endocarditis
Necrotizing vasculitis
Large vessel polyarteritis
Small vessel polyarteritis (leukocyto
clastic vasculitis, hypersensitivity vas
culitis)
Henoch-Schonlein purpura
Wegener's granulomatosis
Malignant hypertension
Postpartum ARE
Prednisone 1-2 mg/kg'day and/or
cyclophosphamide 1-3 mg/kg/day
Prednisone 1-2 mg/kg/day and/or
cyclophosphamide 1-3 mg/kg/day
No specific therapy
Cyclophosphamide 1-3 mgzkg/day
Antihypertensives
Dialysis, if required
No specific therapy
■
ARE = acute renal failure.
I
r J
/
9: The Patient With Acute Azotemia
148
-
and severity of the nonrenal manifestations (e.g., fever, dermal eruption) will
-^r
■
J
r
The Patient With Chronic
Azotemia, With Emphasis
on Chronic Renal Failure
I
Ronald B. Miller
assess
<1
and includes the joint Participation of a rhe^1^
£
3>
el
el
a
granulomatosis, cyclophosphamide is the agent of choice.
Suggested Reading
I
^nt usual
Sly dieted how Ion; high-dose therapy should be
Uss. Response to therap,
.
„
should be tapered. Ordinarily, a positive
continued and how rap dly the drugsjnou
Although there is not
response to therapy will be aPParen
un:tv regarding the usefulness of each
complete agreement in the
re^ntless, progressive nature
of these agents or protocols, thepo p gn
h some form of ag.
of these diseases when untreated usually dic^cyclophosphamide,
Henrich. w. L„ Miller, T. R., Gabow, P.
el ‘ a
-al failure. N. Engl. J.
e -
1977
Cronin R. E. Aminoglycos.de nephrotoxicity: Pathogenesis and preventton. Chn.
Nephrol. 11:251, 1979.
v
• a q
P Havnes B F., and Wolff, S. M. Cyclophosphamide therapy of
S syst™:N.
J. Med.
1979.
Grossman, R. A., Hamilton, R. W Morse B. M et al. Nontraumatic rhabdomyoiysts
and acute renal failure. A. Engl. J. Med. 291.8 .
,
j n X*
A t Pinching A J., et al. Plasma-exchange and immunosuppression in’the tmatme^t of fulminating immune complex crescentic nephnfs.
I
Lancet 1:63, 1977.
Miller, T. R., Anderson, R. J., Linas, S. L et al. Urinary- diagnosttc indices m acute
renal failure. A prospective study. Ann. Intern. Med. 89.47, 1978.
5
Schrier, R. W„ and Cronin, R. E. Acute Renal
3
Little, Brown. In press.
i
I
Azotemia literally means an increase in the concentration of nitrogenous compounds
in the blood. These include proteins, peptides, amino acids, creatinine, urea, uric
acid, and ammonia. In common usage, however, the term chronic azotemia implies
prolonged (months to years) retention of waste products of protein metabolism that
would normally be excreted in the urine, particularly urea and creatinine. Thus, the
term may be used simply as a synonym for chronic renal insufficiency or it may be
used to imply an abnormal concentration of urea in the blood without an equivalent
elevation of serum creatinine. The latter circumstance obtains when there is an in
ordinate generation of urea, as in patients with massive protein intake or significant
catabolism, or when there is inordinate renal tubular reabsorption of urea, as in
partial urinary tract obstruction or in cardiac failure. Severe azotemia (blood urea
nitrogen concentration above 50 to 75 mg/dl) rarely occurs without retention of cre
atinine as well as urea, and is due to either_renal failure or obstructive uropathy.
1. Clinical setting
A. Causes of chronic azotemia. The causes of chronic azotemia are chronic renal
failure, obstructive uropathy, cardiac failure, massive protein intake, and catabolic
stst^s.
1. Chronic renal failure. The common causes of chronic renal failure (Table 10li in both children and adults are glomerulonephritis (including hereditary
nephritis), polycystic kidney disease, and interstitial nephritis (including pye
lonephritis). In adults additional common causes are diabetes and hypertension
(nephrosclerosis). In children additional common causes are renal hypoplasia,
obstruction, and a variety of hereditary disorders, each of which is itself un
common or even rare, such as medullary cystic disease, cystinosis. and oxalosis.
Some infrequent causes of severe renal failure are amyloidosis, sickle cell ane
mia. tuberculosis, hemolytic uremic syndrome, and renal artery or vein oc
clusion; there are many others.
2. Obstructive uropathy. Urinary tract obstruction is common, particularly at
the extremes of life. A variety of congenital obstructive disorders (frequently
with associated vesicoureteral reflux) occur in infants and young children and,
unfortunately, often result in chronic azotemia, because either#the diagnosis
of obstruction is not made for a long period of time or there are complications
(surgical or infectious). Renal damage may result from prolonged unrelieved
obstruction, recurrent (or even aggravated) obstruction following surgery, or
complicating infection. Obstructive nephropathy (i.e., obstruction resulting in
severe renal dysfunction) may progress over a period of months to years to
end-stage renal disease (ESRD) in children and occasionally in adults. At the
other extreme of life, the commonest obstructive nephropathy in the aged is
that due to benign prostatic hypertrophy. Fortunately, surgery for this disorder
is usually successful and sustained renal failure is rare, even in patients with
chronic infection. There are, of course, several other causes of obstruction in
both children and adults (such as urinary stones, tumors, surgical misadven
ture, and retroperitoneal fibrosis or tumor), and the prognosis of these disorders
is variable.
3. Cardiac failure. Cardiac failure causes edema (which is of paramount impor
tance) and also azotemia (which is usually mild and thus relatively unim149
10: The Patient With Chronic Azotemm
150
151
10: The Patient With Chronic Azotemia
the administration of a cataboiie drug such as Utracyline or adrenal corti-
Table 10-1. Relative Frequency of Causes of Chronic Renal Failure in Adults
£
and Children
Cause
Adults
Children
Glomerulonephritis
Polycystic kidney disease
Interstitial nephritis
Diabetes
Hypertension (nephrosclerosis)
Obstructive uropathy
Renal hypoplasia
Hereditary disorders*
3+
4+
1+
2+
Rare
Rare
3+
2+
1+
2+
2+
4+
2+
1+
Rare
Rare
may present with a request for
tercurrent illness or for routine periodic
tients may present with unrelated
discovered by chance, a circumstance
examination, and their azotemia
y
rcening panels of laboratory tests,
mcreasingly common because of the
present because they have sympThe minority of patients with
a“‘ ationPtn;)v be nonspecific (e.g.. failure
toms of uremia and even then the p
or aduitsl or even misleading
e >
■■m
order.
"■ rgKsr™-*
♦Excludes Alport’s syndrome (hereditary nephritis with nerve deafness), which
is included in the glomerulonephritis category, and polycystic disease, both
of which are listed above.
portant, except that its cause must be distinguished from other causes of azo
temia). To the extent that edema is associated with a decrease in glomerular
filtration rate, there is a proportionate rise in blood urea nitrogen (BUN) and
serum creatinine. Salt and water retention in congestive heart failure may
also be due to secondary aldosteronism and increased fractional proximal renal
tubular reabsorption of salt and water, and these disturbances may account
for sufficiently slow flow of filtrate down the nephron that there is enhanced
renal tubular reabsorption of urea as well. This presumably accounts for the
disproportionate rise of BUN compared with serum creatinine in most patients
with heart failure such that many patients with chronic congestive failure
have a BUN in the range of 30 to 60 mg per deciliter but a serum creatinine
concentration usually less than 2.5 mg per deciliter and not infrequently within
the normal range.
4. Massive protein intake. Dietary protein is an uncommon cause of azotemia
in an otherwise healthy person. When protein intake is massive there may
be a rise in BUN without a proportionate rise in serum creatinine, but the
rise in BUN is relatively mild. This phenomenon is seen in obese persons with
extreme dietary restriction of carbohydrate and fat, but either no restriction
or more commonly, supplementation of protein intake. Occasionally the phe
nomenon is seen in persons who are not restricting calories, carbohydrate, and
fat but are simply ingesting inordinate amounts of protein. More common than
these voluntary causes of chronic azotemia are iatrogenic causes of acute azo
temia One iatrogenic cause of azotemia is parenteral hyperalimentation (the
intravenous infusion of amino acids as well as carbohydrate in a patient unable
to assimilate them from the gastrointestinal tract), and this results m a dis
proportionate rise in BUN, particularly in patients who already have renal
insufficiency. Another iatrogenic cause of azotemia (in which BUN may be
disproportionately elevated to creatinine) is the use of high-protein tube feed
ings in a patient who is comatose .or otherwise unable to communicate thirst
and who is given insufficient water and solute to offset the urea diuresis that
occurs from administration of inordinate amounts of protein. These iatrogenic
disorders-are usually of short duration and, except in very unusual circum
stances, do not rfSftlt ;n chronic azotemia.
• 5. Catabolic states. Catabolism (with increased endogenous protein breakdown)
is a more freq'tient'cause of azotemia than is increased protein intake. Most
catabolic states, however, are not of sufficiently long duration to cause chronic
azotemia, although in exceptional circumstances they may. The increased urea
generation due to catabolism may result from an underlying illness or from
:
ass
U.,.).
and the existence of complications.
obstruction. If obstruction is due to a
1. Features related to the cause o the obst uct on^
or
renal tumot, the patient may have lo 1
anemia lf obstruction is
hematuria, or systemic symptoms su
personal history of stones or
h. H.«„=
eitancy, intermittency, sensation of
e!
s
s
3
3.
obstruction (or unilateral
Higher levels of obstruction,
be
>.»• -r-a-Kssn"
in a pati^nt with two kidneys,
^comphcated by infection ^“^SStom Pain is much more
SR.“S'SS"—- "■> 4
volume, a nearly diagnostic. sigm
_
|on infection is probably the
□ ^ySSn“re ^prolonged fiartia! obstruction as well as w.th
complete obstruction.
r-
152
10: The Patient With Chronic Azotemia
10: The Patient With Chronic Azotemia
153
Table 10-3. Specific Clinical Features that Suggest the Cause of Chronic Azotemia
^ Chronic glomerulonephritis: history of acute nephritis or nephrotic syndrome, symptoms
lO^However,
occasionally
there are specific
that
the
■
of systemic
lupus erythematosus
(SLE),physical
deafhesssigns
(Alport
’s suggest
syndrome)
Diabetes:
polyuria,
polydipsia,
family
history
cause of *0 Parent’s di^e (Table 10-3K
a
1
Polycystic disease: family history
Nephrosclerosis: hypertension before proteinuria or renal failure
Interstitial nephritis: recurrent urinary infection, analgesic abuse
Obstruction: symptoms of bladder dysfunction, stones
\
Physical examination
Diabetes: retinopathy, neuropathy
Polycystic disease: palpable kidneys, hematuria
ST .E- facial rash, arthritis
Alport’s syndrome: deafness, ocular abnormalities
Obstruction: large prostate, palpable kidneys
Gout: tophi
Laboratory tests
Chronic glomerulonephritis: nephritic or nephrotic sediment
Diabetes: hyperglycemia
Polycystic disease: diagnostic intravenous pyelography (IVP) or ultrasonography
Interstitial nephritis: diagnostic IVP if pyelonephritis
Obstruction: diagnostic IVP or ultrasound study
ST ,F.: positive antinuclear antibody, nephritic or-nephrotic sediment
SSSsSBSS
testinal symptoms, many have itching,
some have neuromuscular symptoms,
nonspecific, a history of a relatively
l
10f: Such
previous elevation of blood pressure,
notte mteSuf if the patient is asked about
the military service,
differentiate
insufficiency
has reached
reacneu end-stage, even 1renal biopsy may fail toexaminations
insufficiency has
Symptoms
General: fatigue, weakness
vomiting, abnormal taste, hiccoughs
Gastrointestinal: anorexia, nausea,
Ne^^uiaSlss legs, numb feet, muscle cramps or twitching, inability to con-
centrate,- insomnia, irritability
Genitourinary’: loss of libido or potency, nocturia
Cardiovascular: dyspnea, edema, pencardial pain
I
i
th
Laboratory Findings
Azotemia
Acidosis, metabolic
Anemia, usually normochromic, normocytic
Leukopenia and occasionally thrombocytopenia
Hypophosphatemia, at times hypocalcemia and hyperphosphatasia^
Radiographic osteomalacia or osteitis fibrosa
Proteinuria
Cylindruria
___________________________
L
4"
j
b
0
3
3
e-
Table 10-2. Nonspecific Clinical Features of Patients
with Chronic Azotemia (Uremic Manifestations.
j
£ I
Rit
e-.
f.-
temia is due to renal parenchymal disease). As indicated above, an elevation
of BUN disproportionate to serum creatinine suggests obstruction, cardiac
failure, high protein intake, or catabolism, whereas proportionate elevations
of urea and creatinine suggest renal parenchymal disease.
When azotemia is severe, whether due to obstructive nephropathy or renal
parenchymal disease, there usually are many abnormalities of laboratory tesis.
although they may be nonspecific ‘see Table 10-2). There may also be more
specific laboratory findings (Table 10-3) that provide etiologic information.
For example, a strongly positive antinuclear antibody (ANA) test is diagnostic
of systemic lupus erythematosus (SLE) and severe carbohydrate intolerance
of diabetes mellitus. It must be remembered that mild carbohydrate intolerance
is common in patients with renal insufficiency of any cause, but also that
diabetic nephropathy can occur in patients who have sufficiently mild car
bohydrate intolerance not to require insulin. Other clinical laboratory findings,
such as a nephritic or nephrotic urinary sediment, are somewhat less specific
(e.g.. a nephritic sediment may occur in subacute bacterial endocarditis ([SBE J.
SLE, and malignant hypertension as well as chronic glomerulonephritis, and
a nephrotic sediment may occur in congestive heart failure, malignant hy
pertension, preeclampsia, sickle cell aqemia, myeloma, and other malignancies
as well as in chronic glomerulonephritis), but at least they place the patient
within a category of diseases and exclude other types of diseases.
Often the most specific laboratory features in the patient with chronic azotemia
are radiographic. Although there is a risk
iLiliiiJ^U^t^nal failure
by intravenous urography (particularlvii^a^Wtl WithJdM^^^rnultiple
cnaghe^is^i^g renal
myeloma), it may not be possible to
and
disease without radiographic study, »Ktgjugfi cqeimSyV^ude
/bight thin& that renal bi^ppy jLouid
detect cysts with ultrasonography
be invariably definitive; although^ may be in early stagesisf cly-otntfrenal
parenchymal disease, it usually is not• in end-stage disease in vvhich Bxe his
tologic damage may be so severe that it is nonspecific.
zz
10: The Patient With Chronic Azotemia
154
155
10: The Patient With Chronic Azotemia
HI.
ill is to determine whether the renal failure is phrenic or acute. Chronic disorders
are more likely to be stable and thus less of an immediate threat to the patient
than acute renal failure, but, unfortunately, chromcity often implies irreversibility
Irreversibility is not, however, invariable, and the second question to be aske
is even if the7basic disease is chronic, is it remediable? Even if it is irreversible
Jin ite progress at least be slowed? The third question to be asked is even if the
basic disorder is not remediable, are there remediable complications (i.e., factors
that contribute to, or aggravate, the azotemia)?
B
of ^nd-stage renal failure by chronic dialysis or renal transplantation).
Evidence Riat renal failure is chronic. The most reliable ev\denc®tpIaJtNr^
' failure is chronic is documentation of previous sustained elevation of BUN and
or serum creatinine. Such data should be sought in every PatlJnt’ however inconvenient even if the expeditious approach of radiographic determination
renal size demonstrates kidneys smaller than normal. The reason
to obtain previous laboratory data even in patients with small kidneys
that
thp relation between structure and function is variable; patients may have had
surprisingly goTd renal function despite substantial reduction in renal mass^
The converse !i.e.. poor function despite normal-sized or even large.kidneys; may
also be true with polycystic kidney disease, diabetic nephropathy, malignant
nephroscTeroS7s multiple myeloma, rapidly progressive glomerulonephritis, and,
occasionally chronic glomerulonephritis. Particularly m patients who have nor
mal-sized kidneys despite renal failure, renal biopsy may be necessary to demonstrate the nature of the disease and whether or not it is chronic. Yet another
diagnostic approach that may yield reaBonaWy re^in Bvtdenre of chroiuc^
is x-ray of the bone, demonstrating renal osteodystrophy, particularly osteitis
fibrosa Even this however, may be unreliable in the rare patient who has a paraffiyreTd adenoma’and deterioration of renal function due to previous hyperTTie7™re other data that may suggest chronicity, but they are less reliable than
■
4
j
,
-3
calcemia is a somewhat more reliable indicator of chronic renal insufficiency,
“may occur in acute renal failure, particularly in association with rhabdomyolysl Anemia can occur with acute renal insufficiency but is more typmal
of chronic renal insufficiency. Patients with severe chronic renal insufficiency,
however may not have profound anemia until they become frank y uremic.
C Screen for remediable causes of chronic renal failure. Table 10-4 lists a number
C’ !fXnic but remiiabte causes of renal failure as well
m
features of these disorders. There are also some acute didders that can
to
permanent renal failure, including rapidly progressive glomerulonephritis (eg ,
antiglomerular basement membrane nephritis or Goodpasture s 8ynd™™ ' a"d'
rarely" antibiotic nephrotoxicity (particularly that caused by cephalofldine and
amphotericin).
*
Table 10-4. Remediable Causes of Chronic Renal Failure
*
Causes
1
|
Diagnostic Features and Tests
Obstruction
Bladder neck or prostate
,
|
I
!
documentation of previous azotemia, renal x-ray, renal biopsy and bone x-ray.
Apatient with a family history of an inheritable renal disorder such as adult
polvcystic kidney disease or Alport’s syndrome is likely to have the same
A history of prolonged nocturia, polyuria, itching, or neuropathy is suggestive of
; f
tome renJl insufficiency, but at times is misleading. The same is true of a
history of hypertension, since chronic hypertension does not invariably result m
renaHnsufficiency Stigmata of uremia, hypertension, or hypercalcemia on phys,
ical examination (e.g., pigmentation, neuropathy, retinopathy, and
5
topathv) are reasonably convincing evidence of chromcity. So, too, is the presence
J
ot severe azotemia without uremic symptoms. Stability of azotemia is suggestive
I
of chronicity since the BUN and creatinine usually rise when the disorder
*7, , acute and progressive, but with chronicity the converse is of relevance.
■
of urea disproportionate to creatinine has been previously discussed. Except
patients with ato disease who are capable of, and foreed to have, a water diuresis, *
«
a serum creatinine disproportionately elevated to urea almost invariably indicates
chronic renal insufficiency with reduced urea generation due to either anorexia
and impaired protein intake in the absence of significant catabolism or dietary
nreferenXs such as those of a vegetarian. The patient with acute renal failure
secondary to rhabdomyolysis and myoglobinuria also may have a disproportionate -J
rise in serum creatinine. The presence of severe acidosis, with tolerance for it
is often evidence of chronicity. Hyperphosphatemia may imply chron c: ty, but it
is common in acute renal insufficiency when there is hypercatabohsm. Hypo-
' Jo
Nocturia, hesitancy, intermittency, de
creased caliber or force of urinary
stream, postvoiding residual
History of pelvic surgery or radiation
Therapeutic misadventure
Retroperitoneal fibrosis or tumor Intravenous pyelography (IVP), use of
methysergide (Sansert), lymphoma,
myeloma
Colic, hematuria, passage of stone, plain
Calculi
x-ray of abdomen, IVP
Stone
passage
Stone formation
KUB for radiopaque calcium or magne
sium stone in kidney or ureter
IVP for nonopaque uric acid stone
Renal tubular acidosis, hyperparathy
Stones and/or nephrocalcinosis
roidism *
Hyperparathyroidism, milk alkali syn
Hypercalcemic nephropathy
drome, other causes of high serum cal
i
cium
Pyelonephritis with active infection IVP, urine sediment, culture
or papillary necrosis
History of analgesic abuse, other drugs or
Interstitial nephritis
toxins (lead, cadmium)
Serum and urine electrophoresis or light
Multiple myeloma
chain testing, bone marrow
Angiography,
bruits, rise in serum creat
Bilateral renal artery stenosis
inine if captopril is administered
Hypertension, retinopathy, renin
Malignant nephrosclerosis
Extrarenal manifestations of lupus (skin
Lupus nephritis
rash, hair loss, arthritis)
Upper
and lower respiratory tract manifes
Wegener’s granulomatosis
tations of Wegeneris, e g., sinusitis, pul
monary infiltrates
Elevated
sjerum uric acid, history of
Gouty nephropathy
podagra
Low serum potassium, history ot diuretic
Potassium depletion
or laxative use
ii
-j
i|
I
1
KUB = Kidney, ureter, and bladder x-ray.
/
p
!
156
It would be far better to prevent chronic renal insufficiency than to treat it, but,
unfortunately, many of the most common causes of end-stage renal failure either
go undetected for such'long periods of time that irreversible damage results or
are not amenable to prevention. At our present stage of knowledge the latter is
true of most forms of chronic glomerulonephritis, diabetic nephropathy (although
lhe vascular complications of diabetes may be less when blood sugar is tightly £
controlled), polycystic kidney disease, and many other inherited or >d>opathic
i
■h
10: The Patient With Chronic Azotemia
10: The Patient With Chronic Azotemia
when it occurs in a child with vesicoureteral reflux) may not be preventable, and
certainly chronic pyelonephritis can progress long after bactenuna is erad1cate<k
Nerertheless, there are several common causes rfchronicrenarfailure that^should £
Table 10-5. Remediable Contributors to Azotemia in Patients with Chronic Renal Failure
Laboratory error or chemical interference with laboratory determination
j
Heart failure: congestive, low-output, pericarditis with tamponade or constriction
Hypertension: severe, especially malignant; overtreatment of hypertension
I
I
I
[
1.
athies of most types, and nephropathy due to analgesic abuse.
It should be evident that it is mandatory for a physician seeing a patient with
i
chronic
chronic’renal
renaf insufficiency
insufficiency to
to make
make aa spednc
specific diagnosis
diagnosis if
if it
it is
is possible
possible to
to do
ao so
so
...................
isonable risk
without
unreasonable
nskto
tothe
thepatient.
patient.Many
ivu»iyoiagnostic features~and approaches
are suggested in Table 10-4, but diagnostic approaches for disorders that areno
remediable'are not listed. Those approaches for polycystic kidney disease diabetic
i
neohropathy\and renal hypoplasia are relatively self-evident. Details of the patient’s history, meticulous examination of the urinary sediment, excretory urography and percutaneous renal biopsy are the mainstays of
C
of parenchvmal renal disease. Occasionally, immunologic, bactenolgic, or blood
■ i
chemistry determinations allow a specific diagnosis to be made
It is well known that the majority of patients with acute renal failure will recover
essentially normal renal function if they tan be sustained through their acute
.
illness by dialysis and bv appropriate medical a^d surgical therapy of the condition
t"useT^^^ renal failure. This is true even when acute renal failure
is prolonged. It is less well known that there are several causes of chronic renal
I
failure that even if severe enough to require dialysis for a substantial period o
time (even many months), occasionally improve sufficiently that dialysis ib not
i
reouired for a period of months (or even years'. Such disorders include malignan
nephrosclerosis, lupus nephritis, Wegeners granulomatosis, multiple myeloma, V,
h
I'
3
I
and disorders in which a reversible complication is discovered.
D Screen
Screen for
for remediable
remediable complications
complications or contributors to azotemia in patie
‘ "
Although
the principle of parsimony (reluctance to
with chronic renal’ failure.
A'. ’ a young
person) mav be helpful in arriving at
make more than one diagnosis in
■ect unliving aiagnu^o .u a patient wuh multiple symptoms, the principle
a correct unifying diagnosis in a
is dant
I
I
I
!
fi
It
^EreoneoLsX^o^data not only may cause
■ !LaUe
to (he physkian
padeat. but aiso
alaa may
may a'mO’laPP™P",t“
hysician and pauenuoui
The physician must not only be alert to the possibility
3
3
3
_
|
,
ticularlv drugs, may interfere with various chemical methods, tor examp e,
an artifactually elevated serum creatinine may result from hyperglycemia,
ketonemia albumin infusion, or ingestion of arginine, ascorbic acid cefoxitin
levodopa and methyldopa. Some drugs may increase serum creatinine, not
bv decreasing glomerular filtration rate but by interfering with the tubular
secretion of creatinine. Examples are trimethoprim and cimetidine. An arti
factually elevated blood urea may result from infusion of dextran or ingestion
of acetohexamide, ammonium salts, aspirm. chloral hydrate, chloramphenicol.
m heart faffure and pericardial
______________________
2 Congestive
disease Heart failure may cause a
Tn creXfineUclearanre
of approximately 50
percent ina
in a patient with
,
__________________________
^llnprrpnf
docrcHsc 1
it may
may in
in patients
patients who
with nuimurua.
normal renal funcchronic renal insufficiency, just as it
tion. Renal failure may cause pencaraiUb,
PeHcardiUs. which
may be f^^d
bytemwmcu may
—7
---- ’*
in turn additionally impair renal function and
ponade, and tamponade may i
157
Ct V? ;
7
ip
Urinary obstruction:
Intrarenal: uric acid, papillary necrosis
Ureteral: bilateral, unless patient has only one kidney
Bladder outlet
Vascular obstruction: arterial or venous
Infection: renal or extrarenal
Catabolism: infection, surgery, gastrointestinal bleeding, steroid, tetracycline
Drugs: diuretics, antibiotics, radiographic dyes, anesthetics, analgesics, vitamin D, alkali,
phenazopyridine (Pyridium), magnesium antacids, prostaglandin inhibitors, captopril
Salt depletion: restriction, diuretics, anorexia and nausea, vomiting, diarrhea, laxatives
Electrolytes: salt, water, or potassium depletion; hypercalcemia, hypermagnesemia,
hyperphosphatemia, hyperuricemia, acidosis
Hypoproteinemia: nephrotic syndrome, cirrhosis, peritoneal dialysis, plasmapheresis
Uncontrolled diabetic glucose diuresis
Pregnancy: especially toxemia, preeclampsia
Acute renal failure of any cause
precipitate flagrant uremia. If pericarditis is complicated by defective blood
coagulation, life-threatening intrapericardial hemorrhage may result.
3. Hypertension. Hypertension must be severe, often accelerated or malignant,
to impair renal function acutely and reversibly. Another cause of worsening
renal function in a hypertensive patient with chronic renal insufficiency is
overtreatment of the hypertension. Reversible renal failure may also occur
when patients with bilateral renal artery stenosis are treated with captopril.
4. Urinary tract infection, obstruction, and catabolism. Kidney infection without
obstruction rarely causes a profound disturbance of renal function unless it is
so fulminant as to produce microabscesses throughout the kindeys, or papillary
necrosis. The latter is particularly common in diabetics, especially when there
is coexisting obstruction. Extrarenal infection with septicemia and/or catab
olism is as frequent a cause of progressive azotemia in patients with chronic
renal insufficiency as infection of the kidney itself. Innumerable other causes
of catabolism, including infection, surgery, gastrointestinal bleeding, steroids,
and tetracycline, may similarly complicate chronic renal insufficiency.
5. Drugs. Drugs may cause azotemia in a variety of ways, including direct neph
rotoxicity, catabolism with increased urea generation, diuretic loss of salt and
water with consequent volume depletion, reduction of blood pressure even in
the absence of volume depletion, prostaglandin inhibition, and interference
with the excretion of other substances or drugs that are nephrotoxic. Drugs
may also complicate chronic renal insufficiency by causing complications other
than azotemia (e.g., hyperkalemia). Drugs that cause hyperkalemia include
salt substitutes (which may provide a dietary load greater than the patient
can excrete), spironolactone, amiloride and triamterene (which interfere with
potassium excretion),.and succinylcholine (which causes release of potassium
from muscle).
.
6. Electrolyte imbalance. Numerous electrolyte disturbances, either known or
suspected to impair glomerular filtration rate are listed in Table 10-5. Most
ominous, because it is frequently insidious and unrecognized, is salt depletion.
It is instinctive to treat the patient with hypertension or congestive failure
with salt restriction and/or diuretics, but this can be dangerous in the patient
10: The Patient With Chronic Azotemia
158
159
!
’
10: The Patient With Chronic Azotemia
==ss==g=
=s===ESssg?:
their obligatory excretion. This is often more than half a gram of sa t per day.
The volume depletion may be subclinical yet sufficient to impair glomerular
4}
filtration seriously.
,. ,
_ „
E. Assessment of severity of chronic renal failure For many patients onre the
renal failure is substantial, the cause of the underlying renal disease is less im
portant than its severity with regard to manifestations, complications
Thus when the physician has excluded remediable causes of chronic renal failure (
and remediable aggravating factors, he or she must shift attention to assessment
of the severity of the renal failure and, thus, to its proper m+anaSeme^1 Symptoms. The symptoms of renal insufficiency depend not only on its seventy
’ hut also on the rate at which it develops. If uremic symptoms are present, the
physician can be reasonably certain that renal insufficiency is severe However
if symptoms are absent, the renal insufficiency may nevertheless be equally
severe and on occasion even life-threatening. Thus, the physician must not
.
rely on symptoms alone but must repeatedly obtain extensive laboratory data
to follow a patient with chronic renal insufficiency.
2. Physical findings. The physical examination of patients with renal insufficiency
may also reveal evidence of severe renal disease. If there is uremic frost, per
icarditis (particularly with tamponade), neuropathy (particularly motor rather
than simply sensory), or evidence of bone disease (deformities in children, tendemess or pathologic fractures in adults), the renal insufficiency is severe.
Other stigmata, such as hypertension, hyperpigmentation, retinopathy, and
even ecchymoses, do not necessarily correlate with the severity of the renal
insufficiency and may correlate better with its duration
3. Laboratory data. Aside from the history, physical examination, and observation
of urine volume (oliguria invariably represents severe and potentially litethreatening disease), definitive assessment of the seventy of renal insufficiency
is dependent on laboratory findings. Anemia, acidosis, hypeiyhosphatemia,
hypocalcemia, and hyperuricemia are all important but less useful m assessing
severity than are measurement of BUN, creatinine, and creatinine clearance. — I
Creatinine clearance is the most important clinical test. However it overestimates glomerular filtration rate (GER) when GFR is reduced below 5 to 10 —
percent of normal, and in this circumstance a mean value of creatininei and w I
urea clearances (since the latter underestimates the extremely low GFR) ^ves
a more accurate value. Despite the overestimation of the very low GFR by
creatinine clearance, it is adequate for all clinical purposes. Except for errors
related to improper timing and collection (e.g, a patient with variable emptying
of the bladder or who is confused may be unable to collect a timed sample
reliablv), creatinine clearance is superior to measurement of serum creatinine
i
alone. This is particularly true of malnourished and elderly patients whose
muscle mass may be difficult to estimate to interpret the clinical implication
of their serum creatinine level. Furthermore, if the patient is not severely
catabolic or anabolic (e.g., a growing child), once an accurate
creatinine
excretion has been obtained, creatinine clearance can ever after be calculated
from that value together with serial serum creatinine determinations.
Creatinine clearance is not always necessary for clinical purposes if it,is> appreciated that a large, muscular, young man should have a significantly higher
serum creatinine than a small, elderly woman. Furthermore, any change in Ww—r
serum creatinine concentration reasonably reflects a change m glome^^ ^-4^
filtration rate, since renal tubular secretion of creatinine is a relatively' s
r
I and minor factor (except in advanced renal failure) and since the othe
f pendent variable_is the production of creatinine, which varies less than 10
percent unless there is a change in muscle mass.
_
The BUN is a less accurate measure of GFR because the production of urea
is much more variable than the production of creatinine and because ren
mav be even more important than knowledge of the GFK itselt. tor’ exar“P >
altered production of urea (decreased with inadequate protein ^take or very
qpvere liver dysfunction increased with catabolism or gastrointestinal bleeding)
^absorpthm of urea (with decreased fluid1 intake hypovo
imnaired cardiac function, or urinary obstruction) changes the BUN r
to L serum creatinine. Thus, a serum creatinine
tn iirea (normal ratio 1 :10) suggests inadequate protein intake, *ater diuresis,
e15
c:
■■«
teen convincingirdemonstrated to be more than a hilar pattern of pulmonary
edema) Renal x-ray (with or without radiographic contrast^ renal scintiscans
^nd ultrasound may all assess the severity of renal
size and may also detect obstruction. Bone x-ray, particularly ot hands ano
of the S£verity of renal
F Varybig^natural history of different causes of chronic renal failure The rate of
' pr^reLon of renal insufficiency expected for a given P8116^
^orSnce. If serial determinations of serum.creatinine are notavail able the
^12
i
ffinctionunexpected for the underlying disorder dictates a
complications After the physician has followed a patient for a pe
however, the patient should serve as his or her own control•
“ can
"a ^ughly “slope, and'any abrupt change in rate demands an expla-
.
-J"by hbw’ptajtel
of uremia should be followed to know when dietary protein restriction must be
160
10: The Patient With Chronic Azotemia
t
Table 10-6- Parameters to Folloy in Patients with Renal Failure
■
History
Symptoms of uremia
P Weight^Z™-
10: The Patient With Chronic Azotemia
standing blond pressure, retinopathy, skin turgor, cardiac size, pros-
tate, edema, reflexes, sensation
^Bk^Tureardtrogen, c^atinine, potassium, HCOf, uric acid, phosphate, calcium albu
I
min hematocrit, platelets, serum iron or femtm, alkaline phosphatase, parathyroid
hormone, urine sediment and culture; 24-hour urine volume, creatinine, protein, sodium
X-ray tests
Chest, bone, kidney size
;ts ■
Nph^iral exlminatmnor neree conduction velocity, electroencephalogram, psychomet-
rics
j
rH
■I
■ I
t
\
-•
■•
t' 1 s
1 3
___ _________
initiated and, after it has failed, when dialysis and'or transplantation should be
initiated The signs, symptoms, and radiographic manifestations of hypertension
and cardiac dysfunction should be followed to assess the need for antihypertensive,
diuretic, antiarrhythmic, and cardiotonic drugs and also eventually to appreciate
when dialytic therapv may be required to control circulatory overload that may
aggravate hypertension and/or cardiac dysfunction. Laboratory parameters such
as potassium mid bicarbonate should be followed to know when dietary therapy
or other drugs are required, and parameters such as calcium, phosphorus para
thyroid hormone, and bone x-ray or densitometry to know when to modify the
diet and to use medications such as phosphate binders and vitamin D analogues.
Other tests, such as serial determination of body weight, urine sediment ano
culture, and serum iron or ferritin, are important to detect complications such
as salt depletion, urinary infection, and iron deficiency, to make therapeutic ma
neuvers to prevent rapid deterioration of function or to treat complicating illness.
IV. Treatment of patients with chronic renal failure
A Conservative management
.
' 1. Measures to prevent aggravating renal failure and complications
a Careful drug usage. As in all medicine, pnmum non nocere Renal failure
may 'be aggravated or complicated, particularly by the injudicious use of
medications or inappropriate manipulation of the diet Many drugs depend
on renal excretion and have excessive or toxic effects if employed in r«>rma
do=ave in patients with renal disease. Other medications must be used
cautiously because of the impaired homeostatic mechanisms m patients
with renal failure. Nonsteroidal antiinflammatory agents are prostaglandin
synthesis inhibitors that may cause serious renal insufficiency, presumably
by decreasing renal blood flow. At times they may cause even more serious
and less rapidly reversible renal insufficiency by causing interstitial ne
phritis with or without nephrotic syndrome. Other drugs which may cause
interstitial nephritics include phenylhydantoin, cimetidine, captopril
methicillin, allopurinol, and furosemide. Such agents may be more likely
to cause interstitial nephritis in patients who already have some degree
of renal insufficiency. A detailed discussion of drug use in renal failure is
beyond the scope of this chapter, but tables for modificationrof drug.dosage
are readilv available in the current literature and m Chapter 11. fo sum
marize briefly, a few medications are so toxic or dangerous that they should
be avoided altogether; these include nitrofurantoin (which may cause pe
ripheral neuropathy); spironolactone, amiloride, and triamterene (which
may cause lethal hyperkalemia); cephaloridine (which may cause severe
renal failure); phenformin (which may cause severe lactic acidosis); and
sulfonylureas (which may cause severe hypoglycemia).
s
3
L
€'■
4
r t
J.
1
>
c
Ju
161
Many medications must be used in decreased dosage, with Monitoring of
blood levels whenever possible;' these include digoxin, many antibiotics,
cytotoxic medications, cimetidine, clofibrate, long-acting barbiturates, and
insulin. The physician must be particularly cautious in using drugs that
are potentially nephrotoxic and ototoxic, such as gentamicin, kanamycin,
and vancomycin. A few medications require increased dosage in patients
with renal insufficiency to be effective; these include diuretics and some
antibiotics when used to ti*eat urinary infection.
b. Avoid volume depletion and hypotension. In patients with renal insuf
ficiency, it is particularly important to avoid excessive treatment of hy
pertension and edema. Thus, special care is necessary' in the use of anti
hypertensive medications and diuretics. Upright as well as supine blood
pressure should be monitored to detect postural hypotension, whether due
to an antihypertensive drug or to volume depletion. Even restriction of
dietary sodium is potentially dangerous and generally should be avoided.
Vomiting and diarrhea are particularly hazardous to the patient with renal
insufficiency because the renal ability to reabsorb sodium and bicarbonate
is limited; these symptoms are danger signals requiring prompt diagnostic
and therapeutic intervention, at times including intravenous fluid therapy.
c. Avoid electrolyte imbalance. Although the ability to excrete potassium'is
sufficient to handle the potassium in a normal diet until chronic renal
disease has progressed to an oliguric stage, the ability to excrete extra
potassium loads is not. Thus, supplemental medicinal potassium is rarely
required, and salt substitutes (KC1) as well as potassium-sparing diuretics
should be avoided in patients with chronic renal disease. Patients with
hyporeninemic hypoaldosteronism may require potassium restriction or
9a-fluorohydrocortisone. In diabetic patients with renal insufficiency, care
must be taken to avoid extreme hyperglycemia as well as acidosis to avoid
shifts of potassium out of ceils and dangerous hyperkalemia.
d. Avoid indiscriminate protein restriction. Dietary protein restriction is
highly effective in ameliorating early uremic symptoms, but indiscriminate
protein restriction may result in malnutrition. Thus, when the quantitv
of dietary protein is restricted, the remaining protein should be of high
biologic value (i.e.. rich in essential amino acids).
e. Avoid pregnancy in high-risk patients. Although many patients with renal
insufficiency are infertile, some are not, and these women should be advised
against pregnancy (which may accelerate renal failure, at times irrever
sibly) or at least cautioned of the high risk to the mother as well as fetus.
Risks are greatest in patients with hypertension, serum creatinine greater
than 3.0 mg per deciliter, or both. If pregnancy is not interrupted, extremely
close observation is mandatory.
$
f. Avoid instrumentation and radiographic contrast studies. Some diagnostic
maneuvers are potentially hazardous in patients with renal insufficiency.
Catheters and other urinary tract instrumentation should be avoided if at
all possible because of the risk of urinary infection. Radiographic contrast
studies are potentially dangerousd-o all patients with renal insufficiency,
particularly to patients with multiple myeloma, diabetes mellitus, hype
ruricemia, or dehydration. Serum uric acid as well as BUN and serum
creatinine should be measured before any contrast study: if the serum uric
acid is elevated, the patient should be pretreated with allopurinol unless
the x-ray study is urgent. Fluid intake should not be restricted before uro
graphic or angiographic studies, and at times additional fluid should be
administered. Patients with cholecystitis are frequently dehydrated, and'
volume repletion is indicated before cholecystography or cholangiography.
A cholecystogram should not be repeated in a patient with renal insuffi
ciency without a substantial interval of time between studies.
2. Approaches to slow the progression of renal failure
a. Control hypertension. Control of hypertension, most particularly of ma
lignant hypertension, may slow the progression of renal insufficiency
whether the hypertension is primary or secondary. With initial therapy
■ . ..
10: The Patient With Chronic Azotemia
162
10: The Patient With Chronic Azotemia
^4^
e ;>
there may be transient worsening of renal function, but this should not
dissuade ke physician from achieving control of the hypertension, even
if the patient is on the borderline of uremia and might require temporary
dialysis On the other hand, as previously mentioned, overtreatment of
hypertension is to be avoided since it is as dangerous as inadequate treat
ment- syncopal episodes, aggravation of azotemia, and even modest re
duction’ of blood pressure with captopril may cause reversible renal in
sufficiency in patients with bilateral renal artery stenosis
b. Treat urinary tract infection. Treatment of urinary infection is less frequently effective in slowing the progression of renal insufficiency. Some
patients with severe renal infection have substantial
function with effective therapy, but treatment of patients whose ntfection
is restricted to the lower tract is unlikely to have a beneficial effect on
.renal function. Nevertheless, since there are other reasons to treat infection
'and since there is no sure way to tell which patients have only lower-tract
infection, all patients should be treated unless the treatment is judged to
J
eebr
u
ItCResfrict phosphorous and protein; treat with ultraviolet irradiation, diphenhydramine
Gastrointestinal symptoms
.
Restrict protein; correct acidosis; treat with frequent small meals, prochlorperazine
^tSsis; restrict and b.nd phosphate; treat w.th calcium supplementation, vitamin
D, or 1,25(OH)2D3
Neuropathy
Treat with vitamins
A Treat with iron, anabolic steroids, and, if severe, with transfusions
High-quality protein when quantity of protein is restricted
^trirt and bind pfiosphate; treat with allopurinol, phenylbutazone______________
e
3.
renal function fads and symptoms develop^dietary protein restriction is indicated because uremia is large
due to the production of protein catabolites whose excretion is ^paired,
i
slow the progression of renal failure and even, perhaps, improve renal
treated for this reason as well.
e. Treat severe hyperuricemia (> 10 mg/dl). Although not as well demon
strated a pathogenetic factor in progressive renal msuffidency ihyper
phosphatemia, hyperuricemia also causes renal parenchymal damage by
interstitial inflammation and scarring. Thus, its treatment may ako slow
the progression of renal insufficiency even in patients who do not have
f Treat severe metabolic acidosis. Metabolic acidosis should be treated, at
bicarbonate’falls below 17 mEq per liter, not only to
least when serum biu<n
—----- -- ——•* «
_ ,
provide a buffer reserve
serve against acidogenic insults, but also to protect the
skeleton from demineralization.
zation; It seems possible that acidosis may impair
function.
renal function as well as cardiovascular
------ —
-------- If edema or aggravation
-..
of hypertension results from sodium bicarbonate therapy, dietary'sodium
restriction or diuretics mav be required to allow continued alkali therapy.
g Control blood sugar in diabetic patients. Just as high protein intake may
sesssxass^
in young diabetic patients.
Tab!e 10-7. Therapy to Alleviate Uremic Symptoms
diazepam, sedatives, anticonvulsants
be more dangerous than the infection.
. .
.
c Limit dietary protein. Protein ingestion or amino acid 'nfusmn inc\e^s?
’ renal blood flow and GFR and may increase renal size. A substantial body
of evidence—albeit much of it indirect or in experimental ammals-suggests that the rate of progression of renal insufficiency of any cause even
ageing may be greater when protein intake is high. Conversely, protein
restriction may slow the progression of renal disease. Whether considerable
slowing can be achieved by modest reduction of dietary protein rema*ns
to be seen, but presently it seems reasonable to limit dietary protein to 1
gm per kg body weight per day in patients whose creatinine clearance is
less than 30 ml per minute. Some advocate more stringent restriction even
earlier in the course of renal disease.
d Control hyperphosphatemia. It is now well known that hyperphosphatem
sufficient to initiate parathyroid hyperplasia and hyperparathyroidism oc
c^rsrelatNely
curs relatively early"in
early in renal
renal insufficiency
insufficiency (when
(when glomerular
glomerular filtration
filtration is
is
reduced bv only
onlv approximately 30 percent); thus, to protect the skeleton
reuuceu
, , hazards hvneroarathvroidism,
use use
of
and
to preventel-other -potential
of hyperparathyroidism,
phosphate-binding medication and avoidance of excessive PhosPhat®
(primarily, dairy products) are appropriate. It is also likely that hjptr
phosphatemia mediates renal damage by enhancing ^lclum'pkoSbpk^0^
deposition and hastens the progression of renal insufficiency, it should be
insulin before meals or with an insulin pump should be advised, partic
1S3
3
3
3
/
©
y
x
Dietary protein restriction should not be severe (i.e., should not be less
than
gm protein/kg body weighVday) until uremic symptoms develop,
since the beneficial effect in slowing progression °f ^^^^rtion
the risk of malnutrition. Furthermore, reserving marked proteini restnrt on
to the uremic stage of renal insufficiency generally allows the Phys^ian
to know that there is still time to prepare for end-stage
a^ement without undue haste or alarm, since marked protein
usually allows one to several months of sufficient amelioration of symptoms
bXWysisT transplantation is required^To initiate
restriction before the onset of symptoms, and thereby to deUy their^ap
pearance until very late in renal failure, obliterates this important signal
to the physician that referral for end-stage renal disease care is indicated,
thereby exposing the patient to greater risk of life-threatening comphb
tPoe ^protein restriction a variety
b- If mSion^ usually required to prevent or allev.ate aymi,toms ones
uremia has supervened. Itching is a common and particularly unpleasant
problem that is not always amenable to conservative therapy. Restriction
of dietary protein and restriction or binding of dietary phosphate may suf
fice. If dlyless of the skin contributes, avoidance of frequent or
bathing, use of mild soaps, and application of skin creams may be help .
Ultraviolet irradiation has occasionally ^een highly ettective ?ther ‘
tipruritic medication may be helpful in selected patients but diphenhy
dramine is usually the drug of choice both because it often decreases itching
a ui because it is sedative. Itching is particularly bothersome to thei uremic
patient at night when activities of the day no longer distract attention
from what is often relatively mild pruritus.
8
I
10: The Patient With Chronic Azotemia
|
164
e
otherv.7ise abnormal taste, nausea
symptoms are usually reearly satiety, and, occasionally ,d.arr.^
aUowed
lieved by dietary P™161”re®‘^
’ ustomary diet. As renal failure adbe less appealing than t. e p
additional measures may be indivances, however, symptoms^recurt
he4 b decreasing orai bacteria
cated. The abnormal ta’^m^
ijh ha!f.Btrer.gth hydrogen peroxide
(which convert urea to
anunonia with small amounts of lemon
u“!-
«i. a..
or trimethobenzamide.
qvmctoms. Neuromuscular symptoms are
Treatment of neuromuscular s/mpt^
legg par.
d.
perhaps the next most ccinun
u
other symptoms of peripheral neu-
™S“a
3
c 3
s «s
3
$
e.
§
/•!
.? ,’nss.
on radiographic survey, calcium carto
appropriate. provided
and 1,25 dihydroxy-vitam'"D. I-gerum calcium is followed
that sc™n',rph,0S^°^ induced osteomalacia
aluosteomalacia is demonstrated by
oy an amregularly. If alummum-inauveM ■enal, osteodystrophy
, __ u., may ro«non<
respond to al
minimi stain on bone biopsy, the
fortunately infrequent
m
,e. Arthritis is fortunately
^quent^
minum removal oy desferrox
periartlcular hydroxyapatite depuremia, but several forms may
’ ented by dietary restriction and
osition and inflammation may
P
-tQ henylbutaione.
binding of phosphate o^P^”81" may-=-• -- —W with
Goul may I
colchicine or phenyibutozo
ylbutazone or----------with 'mmob;llza'Xa The anemia
Ja of renal insufficiency is a particularly
f. Treatment of anemia. The ane
erythropoietin
vexing problem. II.is
b'een synthesized and is
deficiency. Unfortunately, ery
™ .
cnnically. Patients should be
available for treatment of P" ct
ironS deficiency with serum
not
screened for other forms of ’“^^rm of anem.a is found the only
iron or ferritin, but if no
. adnllnistration of anabolic steroids
practical therapy is the^pa
t Because of risk and short-lived
whose efficacy is. iinfortu 1
jy
avoided exCept in patients with
benefit, transfusions shoulcI ge
rerebrovascuiar disease, or cardiac
symptomatic “JL^Xhig to these cardiovascular diseases improve
failure, whose symptoms relating
with transfusion.
Finally it should be noted that the
g. Treatment of intercurrent "lne“n
many other disorders.
czssi
b
A' -
165
10: The Patient With Chronic Azotemia
1
|
T*
€
Ri-
45
“ ’I.
be amenable to
Br When to refer the patient with renal failure to a nephrologist
1. In renal insufficiency of any stage (earty to advanced) when there are con
cerns regarding the evaluation or management of the patient. When no longer
comfortable in caring for the patient, the primary physician should seek nephrologic consultation. This may be because he is not confident of the evaluation
of the underlying disease or of possible superimposed complications, or the
primary physician may not be confident that he is providing optimal con
servative management. Such confidence is understandably shaken when there
is unexpected, unexplained progression of renal insufficiency, when compli
cations develop, or when manifestations are not controlled by therapy.
When temporary dialysis may be required. Dialysis for a relatively short period
of time may be indicated in a patient with moderate, suburemic renal insuf
ficiency who develops an intercurrent illness or catabolic stress that precipitates
symptomatic uremia. Preoperative preparatory dialysis may be indicated in
patients who require elective surgery that might cause uremia. Temporary
dialysis may also be required in a patient with moderate renal insufficiency
who has had surgery, complicating intraabdominal infection, or intestinal fis
tula necessitating parenteral alimentation, any of which may precipitate
symptomatic uremia. In these situations the need for temporary dialysis can
be predicted, and it can be applied prophylactically before the development of
uremic symptoms. In other circumstances the need for temporary dialysis may
not be anticipated, such as in the patient who requires emergency surgery or
who, for whatever reason, develops an abrupt and severe deterioration of renal
function that results in uremia.
Temporary dialysis may also be required for a patient who presents already
uremic but who has not been adequately evaluated for the duration, cause,
reversibility, or complications of renal failure. Similarly, a patient may present
with uremia, with known, chronic, irreversible renal disease, who has not
been adequately evaluated for the appropriateness of chronic dialysis or trans
plantation. Specifically, the patient may not have been evaluated for such
problems as metastatic disease, end-stage heart failure, intractable pain, and
psychosocial misery, any of which might contraindicate definitive ESRD care.
Such a patient should be dialyzed until the evaluation is complete.
3. To consider, plan, and prepare for definitive ESRD therapy
a. Indications for initiating chronic dialysis or transplantation for a patient
with otherwise suburemic severe renal failure include:
d) Circulatory overload, congestive heart failure or hypertension that fails
to improve with medication
(2) Severe, progressive peripheral neuropathy, especially motor neuropathy
(3) Pericarditis
(4) Severe renal osteodystrophy
(5) Progressive physical debility or malnutrition
(6) Progressive emotional discouragement or psychosis
(7) Early, but progressive, diabetic retinopathy
(S) Severe diabetic neuropathy, gastroenteropathy, or vascular disease
(S) Creatinine clearance less than 4 ml per minute
(10) Irresponsible or noncompliant patient and danger of death from hy
perkalemia or other complication
(11) Bleeding diathesis
b. Indications for initiating chronic dialysis or transplantation for a patient
with uremic ESRD include: !
(1) Conservative management fails to sustain quality of life or productivity
(2) Patient emotionally as well as intellectually prepared
c. Patients should be referred to a nephrologist when any of these indications
exists. Preferably, to allow for a smooth transition so that the patient has
adequate time to become acquainted with the new physician and to adjust
to the frightening and awesome transition from conservative to radical
management of renal failure, the patient should be referred before the
development of these indications. A signal that the time for referral is
auspicious is the onset of symptoms in a patient before the initiation of
ilk - • > -
166
10: The Patient With Chronic Azotemia
c.
10: The Patient With Chronic Azotemia
-I
1
marked dietary protein restriction. Creatinine clearance may also serve
as a guide; referral is generally indicated when the clearance has fallen
to 10 ml per minute or in the diabetic patient when it has fallen to lo ml
per minute. Early referral is desirable not only for the reasons just men
tioned, but also to allow time for maturation of an arteriovenous fistula
for vascular access for hemodialysis or for preparation of the patient for
transplantation. If there are willing related donors, time for their evaluation
and preparation is also necessary.
Definitive ESRD therapy (chronic dialysis and transplantation)
1. Indications to initiate chronic dialysis or transplantation. Indications that
the time has arrived or passed for proper initiation of ESRD therapy are listed
above and are for the most part self-explanatory. A few, however, deserve
a. Neuropathy. Sensory neuropathy is common, frequently only mildly dis’ 'tressing to the patient, and not a cause for Undue alarm. However, even
early motor neuropathy is an indication that dialysis or transplantation
should be initiated without delay, especially since dialysis rarely reverses
peripheral neuropathy but may halt its progress. In fact, if motor neuro
pathy has progressed considerably, transplantation may be preferable to
dialvsis because it may allow regeneration of peripheral nerves.
b. Uremic pericarditis. Uremic pericarditis is often mild and as such does
not cause tamponade. However, there are occasional patients in whom
pericarditis is fulminant, particularly those whose uremia is also compli
cated by a hemorrhagic diathesis. Hemorrhage into the pericardium may
precipitate tamponade, and a fibrinous, hemorrhagic pericardial exudate
may not be easilv drained by pericardiocentesis. Thoracotomy with drain
age. at times pericardiectomy, may be required. Indomethacin frequently
ameliorates the pain of uremic pericarditis, and if initiated early it may
possibly lessen the risk of tamponade and hemorrhage.
c. Malnutrition and physical debility. Malnutrition and physical debility often
develop insidiously in uremic patients, and the conscientious physician
who sees patients at short intervals may be at a disadvantage in appre
ciating these affiictions.-Malnutrition and debility predispose patients to
intercurrent illness and impair their ability to recover from such illness.
d. Emotional considerations. The various complications of uremia were
common in the early days of dialysirwhen it was less available and when
conservative therapy was prolonged beyond what we now know to be a
reasonable time. Thereafter, the pendulum swung to early initiation ot
dialysis, even at the inception of uremic symptoms, and nephrologists took
pride in the fact that they were able to initiate definitive therapy with
minimal uremic symptoms. It is now apparent, however, that dialysis can
be initiated too early as well as too late, and that the patient who has not
had to endure unpleasant uremic symptoms finds it extremely difficult to
I
accept emotionally the time-consuming, expensive, and at times unpleasant
demands of chronic dialysis or transplantation.
vqdta
The patient must be emotionally as well as intellectually prepared for hbitlJ
therapy and thus probably should be allowed to experience early uremic
symptoms to accept dialysis or; transplantation and thereby, in the long
run, to suffer less. The physician should, nevertheless, initiate dialysis or
transplantation when conservative management fails to sustain a reason
able quality of life and health or fails to sustain productivity. The inability
of a person to continue work or school activities or to enjoy retired life is
an important signal that dialysis or transplantation should be deterred no
2. Contraindications to initiating chronic dialysis or transplantation or to con
tinuing chronic dialysis. An absolute contraindication to initiation of dialysis
or transplantation is the patient’s decision against such action, if the parent
is mentally competent and well informed. Specifically, the patient should be
given an opportunity to consider the pros and cons of prolongation of life by
167
dialysis or
have severe difficulty adjusting even to a sheltered existoce Anoth
"XSJ 'h: &- a*-
wPould cause severe and prolonged suffering of an incompetent patient.
3'
a^AncX^ffierepy and technical aspects. Although the adequacy of.dialysis
■
heTth^ietary and
|
hemSysfe
fib 3
a
soluble vitamins (B and C), folic acid, and phosphate binders (aluminum
hydroxide or carbonate). For many patients therapy also..lnclud“ anti
hypertensive
r&nsive medications, supplemental calcium andor
ano-or active
acu.e vitam ^,
and periodic transfusion of blood. Occasional patients require subtotal
iron,ihvrJidectomv
:
because of bone disease, and rare patients require
of ^r= 'Although there are fewer
problems with arteriovenous fistulae than with external shunts, vasculai
access fails periodically in most patients. The forearm veins of many pa
tients are inadequate to create adequate fistulae, and interposition seg
ments of bovine carotid artery, microporous Teflon ilmpra or Goretexi,
e
itation less «Xre to hepatitis, less expense than center dialysis and,
“e’ehTd, a more natural setting. The disadvantages of home dialysis
ai-e the added psychological stress for the patient and assistant the dis^
3 '
<*5
i-l
1’^
!
, .
required bv illness or technical misadventure, and the lesser frequency of
ov-duation of the oatient by nurses and physician.
b Efficacy of chronic dialysis. Uremic manifestations and how they are con-
1
I
f
3
i
Jhe time rtui^ed for treatment and for medical evaluation and supervision
The vast majority of patients are well enough to enjoy reasonably normal
Hves and half rfthem can continue full-time work school or ret.remerd
activities. A minority of patients, generally 10 to 20 percent depending 0
acceptance criteria of the individual center, remain seriously ill and ha
a Questionable quality of life. Nearly all such patients have serious extraXl! diX that is primarily responsible for their failure to be restored
-
to reasonable health or to be rehabilitated.
better —
As might be anticipated, elderly and retired patients
' |
to the demands of chronic hemodialysis than do younger Patients,
prisingly, many elderly patients have fewer medical problems than their
younger counterparts.
v
10: The Patient With Chronic Azotemia
■
10: The Patient With Chronic- Azotemia^
168
T.hle
Control
Neurologic symptoms
Gastrointestinal symptoms
I
Bleeding
Table 10-9. Complications of Hemodialysis
Efficacy of Chrome Dialysis in Contig
_
Sodium, water, potassium
balance*
Hypertension*
Circulatory overload*
Acidosis
Hyperuricemia
Arthropathy
Osteodystrophy
Anemia*
Neuropathy
Pericarditis
Hyperlipidemia
Carbohydrate intolerance
i
1
i
Poorly Controlled
Cardiovascular disease
e
e
Growth
Development
Maturation
Sexual interest and func
tion
Muscle cramps
Anephric anemia
< 1 3
13
3
eA
Pruritis
Amenorrhea
Strength and endurance
3
i
I
1
iritoneal dialyse than by hemodialysis.
♦Better controlled by continuous pe;
S' Sy-
superficial forearm ccpha
access fistula or shunt surgery
cephalic vein internal
Agoing hemodialysis on a
is a period.c requirement forpatients
lifeofbovlne
long-term basis,
carotid arteries and of
have made it rare that
alysis for lack
p
p
3
3
st
e
ous Tefkm tubes as interposition grafts
continue long-term hemodiFvt^mal arteriovenous shunts are
basis but are rarely employed as the
- ?
■ i“r
™ XS
kidneys) requiredpatients with gastrointestinal ulfeared but rarely occurred
routine tQ employ reg10nal
ceration. Under such c
npulra|12v the heparin in blood returning
anticoagulation-thatis toneutrahj^ P
hag
m the patient with pro—
Se"
5UrpriSinB,y’ hem°
S‘C
complications are now airanprocedure. More patients are
(2) Complications related to
' y. ink Fortunately, serious illness,
made ill by dialysis than we li
is rare; however,
such as septicemia.
cramps (related in part to the
unpleasant symptoms s
jve fluid intake between dialyses),
ultrafiltration required by .
dialysis, or a “washed out
headache, nausea, and vomiting
s
11
Sa
w
o
169
_
Vascular access: hemorrhage, thrombosis, embolus, infection, aneurysm, arterial steal,
venous congestion, high flow (strain on heart)
t
Technical misadventure: impure water, improper dialysate, air embolism, ruptured
dialyzer, excessive anticoagulation, excessive ultrafiltration
Hepatitis and carrier state
Removal of nutrients, medications, other solutes
Anemia and impaired oxygen delivery ,
Neutropenia and eosinophilia
Bleeding and clotting tendencies
Cardiovascular: cardiac stress, hypotension, hypertension, arrhythmias, endocarditis
Gastrointestinal: phosphate depletion, obstipation, ascites
Genitourinary: sexual dysfunction, oliguria, stones, papillary calcification, acquired cystic
disease (often with tumor)
Neuromuscular: muscle cramps, seizures, disequilibrium, dementia, carpal tunnel syn
drome, intradialysis headaches, nausea, vomiting, hypotension, muscle cramps
Postdialysis hypotension or "washed out” feeling
syndrome following dialysis, are common. Symptomatic hypotension
is also common during dialysis, jjarticularly now that high-performance
dialyzers are commonly used to remove the accumulated solute waste
in short periods of time (4 hours or even less). This necessitates the
removal of fluid gained between dialyses in the same short period of
time. Transfer of fluid from interstitial and cellular spaces to the in
travascular compartment may not proceed at a rate sufficient to prevent
hypotension.
.
(3) Disequilibrium syndrome. The disequilibrium syndrome consists oi
headache, nausea, vomiting, and even convulsions, with or without
increased intracranial pressure. It has been thought, although not
demonstrated, that a b.ood-brain barrier to urea transfer results in
greater removal of urea from blood than from cerebral tissues during
dialysis and that the resulting osmotic gradient causes an influx of
water to the brain (i.e., cerebral edema). Thus disequilibrium is more
likely to occur when BUN is very high (e.g., when hemodialysis is
initiated or when a patient has gastrointestinal bleeding or has missed
dialyses). Symptoms of disequilibrium may be prevented by infusion
of mannitol during dialysis. Fortunately, severe disequilibrium is in
frequent despite the short, 4-hour dialyses that patients prefer.
(4) Dialysis dementia. A much more serious and lasting*disturbance of
the brain, so-called dialysis dementia, has become a major problem in
many dialysis centers. After the patient has been undergoing dialysis
for a period of time, often several years, this syndrome may begin in
sidiously, usually with minor disturbances of speech. Thereafter, the
disturbance progresses to incomprehensible speech or even mutism,
an apraxia of gait as well as speech, epileptiform and slow-wave ab
normalities on EEG, and at times, convulsions. There is a tendency
for all manifestations to be aggravated by dialyses. At times the de
velopment of flagrant psychosis or progressive and disabling dementia
occurs with dialysis. The cause of this disorder is not known, although
excessive aluminum in the grey matter of the brain has been implicated
in some patients. Unfortunately there is no effective remedy, apparently
not even transplantation, although there is hope that removal of alu
minum through chelation with desferrioxamine may be therapeutic
and has been reported to be effective in some patients.
-k-l ,
10: The Patient With Chronic Azotemia
170
I
171
10: The Patient With Chronic Azotemia
i
Table 10-10. Causes of Death of 557 Chronic Hemodialysis Patients
Cause
Sepsis
Cardiac
Myocardial infarction
Cerebrovascular
Miscellaneous
Withdrawal or suicide
Dialysis-related
Pericarditis
Gastrointestinal bleeding
Percentage*
22
21
18
10
10
8
5
3
3
*
(C1 Refusal of blood transfusion. This tenet of Jehovah's Witnesses
makes hemodialysis potentially angeraw.
M Si".EX
(f) Diabetes. Peritoneal dialysis .may
.
e!
i
*Thirty percent of deaths occurred in the first month of dialysis.
PSc
that following their initial stabilization on dialysis patients spent a mean
of 2 to 3 days per month (median of 1 day per month) in the hospita .
In the same study, the causes of death of 557 patients were cf^efu y re
viewed (Table 10-10). It should be emphasized that 30 percent of the d®atf^
occurred in the first month of dialysis. Other studies indicate that the
annual mortality of chronic hemodialysis patients is 10 to 15 percent m
the first year and 5 to IQ.percent annually thereafter. Only a minority ot
deaths relates directly to renal failure or dialysis. This is especially true
now that patients with serious extrarenal disease are commonly (and ap
propriately) accepted for chronic dialysis therapy.
4 Chronic peritoneal dialysis. In the past several years chronic intermittent
peritoneaHlialysis has become an acceptable alternative te ^nic hemcrialysis for many patients, and continuous ambulatory pentoneal dialys
7nt'uous cyding peritoneal dialysis (CCPD) may
the treatment of end-stage renal disease and become the treatment of choice
^ndi?aflonsyfor,Pand contraindications to, chronic peritoneal
(1) Indications. Even though pentoneal dialysis became firmly established
in the treatment of acute renal failure years before hemodialysis was
used the reverse was true for treatment of chronic renal failure, thus,
the indications for chronic peritoneal dialysis remain for the most part,
even today, contraindications to hemodialysis. In the next several years
development of more positive indications for chronic peritoneal dialysis
can be anticipated, especially if CAPD and CCPD find widespread ap
plicability because of the development of technologic means to decrease
the frequency of complicating infections. Currently, indications for
peritoneal dialysis as opposed to chronic herfiddialysis include.
(a) Home dialysis. Peritoneal dialysis may be preferable for a patient
who desires to undergo dialysis at home but who has no available
I
assistant for home hemodialysis. Although assistance is desirable,
it is unneccessary for home peritoneal dialysis.
(b) Severe cardiac arrhythmia, angina, intravascular volume insta
bility, or autonomic neuropathy. Each of these conditions may make
hemodialysis technically dangerous or difficult.
h rigk of limb
SSSSS5S
“ i j:
better contro lied by i^aperitoneaHiBuhm
of
caL infection and anasaortic prosthesis because per to 1
peritoneal and pleural spaces
tomotic rupture. Communication be
jis may cause massive
is rare, but when it is present. p
of the diaphragm
hydrothorax and atelectasis, h
,ous for patients with severe
from peritoneal dialysis mak
1 £ h irrhosis and ascites may lose
pulmonary dysfunction. Patient i t if ritoneally dialyzed. Patients
unacceptably large “te rf P^'"^
adhesions may
!
■ of 1800 patients in California and Minnesota several years ago revealed
a £5
P
,a’ dialysis is theoretically
J
und^^
in a patient
*
C
I
I
i
J
H
T.=s:“.^
ej
.
.
‘ 1
e1
a
ii
b. to be carried out for an
th‘ skin to the peritoneum can be
■ 1
mandatory. The entry of hMte
bonded to the catheter and located min
I
impeded by two Dacron fe
Th u(fe aljow ingrowth of tissue to
properitoneal subcutaneous tunnel ‘
patien, must pre
prevent a fistulous tract from skin pe conne<
connect
ions between the peritoneal
.tions
meticulous
mkdelivery
^connect
.
meticulous aseptic
aseptic ^nique
^h^“alin
‘"ate
and drainage system, lor un
.
catheter and the closed dia
dla ysate d
“ rltoneal dialys}s
dialysis (IPD)>
(IPD), an automated,
attended, overnight, intenmttcn
intermitten p
produces'pure
pnxiuces'pure water
water by
by reverse
reverse
monitored
deli^ry^nage
monitored delix
'er>'<Jrain^e.SyiSvl,ate concentrate) was developed. This al
al-.
osmosis and mixes it-with d^lysate wn en^Jsl
for 10 to 12 hours,
lowed dialysis to be performed wh It t P 1
ittent, overnight dialysis
3 to 4 nights each week. The machines tor inter
2
bottle wlth
proportion 100 ml of diaiysnte ^cen Changes and require connections
1900 ml of purified water for each of 20 exchange^
and disconnections only at ee
g Capd) is a promising technique
Continuous ambulatory ^Xe^areZ^d each day, continuously
in which 3 to 5 dialysis etxch^g®®
^plicated by peritonitis because
for 24 hours. Presently it u.too oftfind disconnections required
of the greater number of tubing conn
, . r p/ or 2-1
2-1iter
iter bags
bags
than for IPD. For CAPD,
and a disconnection at the end
that require a connection at the b► g
^rries out three 5-hour, 2-hter
of each exchange. The ave^k t£ emplY dialysate bag and tubing rolled
exchanges during the day (with
P dialysate is in the peritoneum)
up and worn under the dothmg
at, night. Thii provides .
and one 9-hour, 2-liter^xchang 7*“^^
excellent chemical and fluid con
ass^tant and only a short training
It requires no additional equipment, no assistant, an
/-“LTwS—“^e^tm^tP^
V
F
172
H'
(I
10: The Patient With Chronic Azotemia
10: The Patient With Chronic Azotemia
period; also, it entails less expense than other forms of dialysis and provides
considerable mobility for the patient.
A modification of CAPO called continuous cycling peritoneal dialysis
(CCPD) has been developed using a cycling device for automatic delivery
of a number of exchanges of dialysate during the night. These cyclers are
easier to set up and use than the machines for IPD, and in addition patients
leave an exchange of dialysate in the abdomen each morning so that dialysis
and ultrafiltration can continue (albeit slowly) during the day. CCPD is
preferred to CAPD by patients who want to avoid the inconvenience or
’
time necessary to do exchanges during she day or who wish to cap off their
peritoneal catheter rather than wear the rolled-up dialysate bag and tubing
during the day. Even using 2-liter bags of dialysate and thus the same or
greater number of connections and disconnections than with CAPD. CCPD
is reported to have decreased the incidence of peritonitis, perhaps because
aseptic technique is more strictly adhered to when almost all the connec
tions and disconnections are done at a single time. The incidence of per
itonitis may be additionally reduced with larger (3- or 5-liter) bags of di
alysate for’the cycler and with semiautomated connections made under
ultrviolet light. Such large bags of dialysate could not be used for the CAPD
technique because the volume is too great to infuse into the abdomen for
a single dialysis exchange (a large bag of dialysate is used for more than
one of the nighttime exchanges using the CCPD technique), and thus the
patient would have to carry about a partially filled bag of dialysate rather
than an empty bag that can be rolled up along with the tubing and carried
conveniently on the body.
c. Complications of chronic peritoneal dialysis.
(1) Infection. The most serious complication of chronic peritoneal dialysis
is infection, either of the skin exit site, of the subcutaneous catheter
tunnel, or of the peritoneum itself. In several series, CAPD patients
averaged two episodes of peritonitis annually. Although these patients
usually can be treated on an outpatient basis, sometimes they require
hospitalization. Sometimes peritonitis does not clear without removing
the catheter, and of course patients then have to be hemodialyzed for
a month or more.
(2) Inadequate peritoneal clearance and ultrafiltration. Repeated episodes
of peritonitis can so diminish peritoneal surface area and clearance of
solute that peritoneal dialysis becomes ineffective. With prompt rec
ognition and treatment of peritonitis, howeverj it is now rare for a
patient to return to hemodialysis for this reason. Occasional patients
inexplicably lose the ability to ultrafilter and to maintain fluid balance
even though solute clearance is not diminished.
(3) Catheter failure. Catheter failure in peritoneal dialysis is a problem
comparable to failure of vascular access in hemodialysis, although less
frequent. It usually is due to infection, but occasionally to spontaneous
repositioning of the end of the catheter to a nondependent area in the
peritoneal space, fibrin clotting of the catheter, or omental encasement
of the catheter.
- , •
u
(4) Excessive removal of fluid or electrolytes. As with hemodialysis, the
goal to control fluid and electrolyte balance may be exceeded to the
point of depletion. Therefore, the physician may need to liberalize di
etary' or fluid intake, alter dialysate concentration of glucose or po
tassium, decrease the duration or frequency of dialysis with IPD, or
decrease the number of exchanges with CAPD.
Malnutrition. Malnutrition (due to loss of protein in peritoneal dialysis
(5)
effluent) can develop if the patient fails to ingest an adequate quantity
of protein, especially if he has frequent bouts of peritonitis, which
greatly increase the peritoneal loss of protein.
(6) Hypernutrition. Conversely, some patients become hypernourished,
even obese, from absorption of dialysate glucose. Glucose is present in
peritoneal dialysate to effect osmotic removal of fluid (ultrafiltration),
s
e s
e; 5
i
1l
I
-t
f
e s
e *
li!
r
tC
-
i’
P
c; bI
i '
173
since the patient ingests more fluid than can be excreted in urine.
stool, sweat, and insensible losses. —
(7) Hypernatremia. When a patient’s fluid intake and thus qltrafiltration
requirement is large, he or she must employ a high dialysate glucose
concentration (2.5% or 4.25% glucose rather than the customary J.5%
glucose dialysate). The absorbed glucose may provide excessive calories,
and the unabsorbed glucose may remove so much water that hyper
natremia develops. If substantial, the hypernatremia may in turn re
quire the use of low-sodium dialysate or the provision of solute-free
water, which attenuates the effectiveness of the intended ultrafiltration.
(8) Hyperglycemia. In the diabetic patient, the absorbed glucose may result
in hyperglycemia, which may require additional insulin during each
dialysis with IPD or each day with CAPD. Many CAPD patients add
some or all of their daily insulin to their dialysate.
(9) Insomnia. Occasionally insomnia complicates overnight, unattended
peritoneal dialysis.
5. Renal
transplantation
_________
1
a. Indications for transplantation. It has long been hoped that a scientific
breakthrough in immunologic matching, manipulation, or suppression
would allow the uniform success of transplantation so that the indication
for renal transplantation would become end-stage renal disease itself (i.e.,
tansplantation would be preferable to dialysis for all patients). Major ad
vances in transplantation in the past decade have decreased mortality and
increased graft retention, but transplantation is still not preferable even
for the majority of patients. These advances include restraint in immu
nosuppressive therapy, especially of acute rejection episodes; preparation
of cadaver-transpl ant recipients with multiple, random, third-party trans
fusions; preparation of living-related donor transplant recipients with
donor-specific transfusions; DR histocompatibility matching; and intro
duction of cyclosporine, a semiselective immunosuppressive agent. Pre
vention or treatment of rejection might be equally or more effective, yet
less toxic, if nonimmunogenic human monoclonal antibody to selected Tlymphocyte subsets (helper, suppressor, cytotoxic) were developed. Tissue
typing for the endothelial-monocyte antigen system as well as HLA antigens
may prevent hyperacute rejection not prevented by present crossmatch
techniques.
(1) Absolute indication. The only nearly absolute indication for trans
plantation of a patient with end-stage renal failure is the existence of
either a healthy identical twin or an HLA-identical sibling willing to
donate a kidney. HLA-identical sibling transplantation, although re
quiring prednisone and azathioprine, has nearly the success of identical
twin transplantation.
(2) Relative Indications. Transplantation should be seriously considered
for the following:
(a) A recipient who has a willing and healthy sibling, parent, or child
donor, who is ABO-compatible and shares an HLzA. haplotype and
to whom the recipient does not develop antibodies after three blood
transfusions from the prospective donor
(b) A recipient who does not have a relative to donate a kidney but
who:
(0 Prefers a cadaveric transplant to dialysis and is well informed,
and/or
Has adapted poorly to dialysis, and/or
(ii)
(Hi) Is a child (because dialysis interferes with the active life of
youngsters) and/or
(iv) Is an insulin-dependent diabetic.
-y no£
another, and
What is an acceptable risk to one person,—
may
patient and physician may not always agree; nevertheless, a reasonable
and informed patient's preference should be a major factor in the de
cision whether to transplant or dialyze the patient.
•
174
■
■
10: The Patient With Chronic Azotemia
To oversimplify perhaps, the patient must decide whether he prefers
dialysis, which offers a slightly greater chance of survival but a lesser
chance of full restoration of health, or transplantation, which involves
a slightly greater chance of death or of requiring prolonged hospital
ization but—if successful—a greater chance of excellent health.
b. Contraindications to transplantation. Contraindications to transplantation
are listed below. For the most part they are either self-explanatory or suf
ficiently technical to require the nephrologist rather than the family phy
sician to explain them to the patient considering transplantation.
(1) Absolute contraindications
(a) ABO incompatibility
(b) Positive crossmatch, except B-cell or D-locus crossmatch (i.e., lecipient serum is cytotoxic to donor T-lymphocytes)
(c) Previous cytotoxic antibody in recipient to an HLA antigen of donor
(d) Active infection: disseminated histoplasmosis or coccidioidomycosis,
active tuberculosis, active urinary infection, recent hepatitis or re
cent development of HBsAg
(e) Active peptic ulcer disease
(f) Oxalosis
(g) Malignancy
(2) Relative contraindications
(a) HLA antigen in donor for subsequent transplant also present in
donor of a previously rejected transplant
(b) Antiglomerular basement membrane antibody
(c) Malignancy in recipient within 2 years
(d) Debilitation and malnutrition
(e) Cytotoxic antibodies over 50 percent
(f) Unsuitable bladder and/or urethra
(g) Diverticulosis
(h) Recurrent peptic ulcer disease
(i) Antibody to cytomegalovirus (CMV) in donor if not present in re
cipient
c. Recipient evaluation and preparation
(1) Evaluation. Recipient evaluation includes testing for the various ab
solute and relative contraindications to transplantation, particularly
to exclude patients (at least temporarily) who have active infection,
peptic ulcer, malignancy, debilitation, or an unsuitable lower urinary
tract (although transplantation is technically possible with an ileal
conduit or other diversion).
(2) Preparation. Preparation of the transplant recipient may require any
of several additional surgical procedures before or at the time of trans
plantation. These procedures include:
(a) Bilateral nephrectomy, if malignancy is the primary renal disease
and is bilateral, if malignant hypertension cannot be controlled,
or if there is persistent infection with reflux or polycystic disease,
or if the renal disease is tuberculosis
(b) Splenectomy if marked leukopenia or thrombocytopenia is present
(c) Urologic surgery (e.g., prostatectomy, ileal conduit)
(d) Vagotomy and pyloroplasty if previous peptic ulcer disease, or colon
resection if there is severe diverticulitis
(e) Parathyroidectomy if calciphylaxis, or if hyperparathyroidism is
very severe, since it will not regress even after successful trans
plantation.
(f) Transfusion. A surprising finding verified in centers throughout
i
the world is that blood transfusion with packed cells or whole blood
I
improves the success of cadaveric transplantation. Since blood
transfusion can presensitize a patient to transplant antigens and
thereby cause rejection and failure of a transplant, at first it was
thought that the improved graft survival of transfused patients
F
e!
10: The Patient With Chronic Azctemia
175
specificAntibodies to the donor kidney with a positive crossmateh.
This is not th» entire explanation, however. It appears that trans
fiwfon artudlv has a positive effect, although the meohanism is
unknown, in decreasing the chance of rejertior1 of a ‘Xnfiy
Thus, patients who.do^Vr
by t^e
e >
S^dlXXea more units of nonfr^n . nonsaline,
washed red blood cells over weeks to months preceding transplan
e! -3
(g) oXAspecffic
j^g^'^ns^antation,
ei
ggsssfflSFE
e
centage of
i
1I
X— /^fusions of stored
donor blood ^or giving azath.opnne concurrent with transfustons.
*
I
i
for an acceptable living related renal
I
the risk of having only a single kidney
arterv)
(b) Two kidney*, both healthy (preferably with single renal arteiy)
(c) No disease'that might be adversely affected (e.g„ nephrolithiasis
e',
or hypertension)
(d) No active urinary infection
(e) ABO blood group compatibility
(g) HLA UTi^to^ify double or single ^'XoX^matches
d sufficiently good to justify removal of a kidney from a hetiltby donor,
4 _______
no matter how willing or anxious the relative
is to donate.
of
renal
There aonears to be no greater success of renal transplantation
transpianiauvu from
..u...
Pliving rmrekted donor than from a cadaver, and such transplants
(2)
c.,
mechanically ventilated cadaver with beating
heart is thought to be the optimal cadaveric organ donor since goo
renal perfusion reduces the probability of acute renal failure in the
early ^si-transplant period. Such cadavers are those with brain death
(usuahy due ^ vehicular accidents or gunshot). Criteria for brain death
are in the absence of hypothermia or central nervous system depressan
drugs 'a» no'response to external stimuli, (b) no spontaneous muscle
—ent or respiration, (c) no elicitable brain
’ J
donation
I
,
.
:
./
f
176
I
10: The Patient With Chronic Azotemia
10: The Patient With Chronic Azotemia
y4
(b) Age of 10 to 65 years, preferably
(C) No potentially transferable disease such as malignancy (except central nervous system), sepsis, hepatitis, or urinary tract in-
it
(d) Heafthy kidneys: no previous renal disease or severe hypertension,
no prolonged ischemia, blood urea nitrogen less than 30 mg per
deciliter, creatinine less than 2 mg per deciliter, urine voiume more
than 20 ml per hour, urinalysis near normal
(e) ABO blood-group compatibility
(Kg) HLA^yping wfth^iatching desirable (especially at B. locus) but
not necessary; serologic DR typing, which allows rapid determi
nation of similar compatibility factors to those tested by the much
more time-consummg MLC technique for living-related donors, also
H
i
fi
!
I
■
jl
1
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(h) Experimental: pretreatment of donor with 5 gm of cyclophospha
mide and 4 gm of methylprednisolone, intravenously
These criteria are also self-explanatory, except for the pretreatment
of donors with cyclophosphamide and methylprednisolone. The theo
retical rationale for this experimental pretreatment is the destruction
of passenger leukocytes (i.e., lymphocytes land perhaps other cells] m
the donor organ that might mediate or augment sensitization to donor
antigens, thereby increasing the risk of rejection).
Management and follow-up of transplant reclplenu Two agents have been
used for 2 decades to prevent transplant rejection: prednisone and aza
thioprine. Prednisone may be initiated at 200 mg daily, tapered to 40 mg
per day over 2 weeks, and thereafter to 15 mg per day or 30 mg on alternate
days (occasionally to even lower dosages, particularly m HLA-identical
sibling transplant recipients). Azathioprine is generally employed m a
dosage of 2 to 3 mg/kg/day, which is usually continued unless there are
complications. If hepatic toxicity develops, cyclophosphamide may be sub
stituted for azathioprine, usually in a dosage two-thirds that of azathioprine.
Cyclosponne, a fungal peptide formerly called cyciosporin A, is.a mor
, “selective” immunosuppressant than prednisone (which affects monocytes
and blocks interleuken I) or azathioprine (which blocks proliferation of
rapidly dividing cells such as immunologically competent cells). Cycloshorine inhibits interleuken II (T-cell growth factor); a mediator squired
for differentiation and proliferation of cytotoxic and helper T cells (but
spares suppressor T cells). Thus, cyclosporine suppresses both cellular and
humoral (antibody) immunity. This drug is best used without azathioprine^
and although some use it without prednisone, probably it is wise to use
prednisone in reduced dosage. Although serum creatinine may be higher
than in patients treated with prednisone and azathioprine, the percentage
of patients with adequate graft function is higher, and patient survival is
superior, with cyclosporine. There is also much less marrow suppression
with cyclosporine, but there are a variety of adverse effects ^eluding
nephrotoxicity and hepatotoxicity (both of which are dose-related), deve opment of lymphomas (especially if azathioprine is given concurrently),
and infections, hypertension, hirsutism, gum hyperplasia, and tremor Cy
closporine (Sandimmune) may be given orally or intravenously, and the
dosage should be adjusted according to blood levels.
All other therapies to prevent transplant rejection, such as the adminis
tration of antilymphocyte serum and thoracic lymph duct dramage. must
be considered experimental because they are not unquestionably efficacious.
Such theraoies are listed in Table 10-11The mainstay of treatment of acute transplant rejection is an increase> m
adrenal corticosteroid dosage for 3 to 5 days, usually oral prednisone (1 JO
mg day)or intravenous methylprednisolone (1 gm/day). An experimental
therapy of acute steroid-resistant rejection is plasmapheresis ior lympho
plasmapheresis). The theoretical rationale is the removal of cytotoxic an-
e->
3
€
3
e
e 3
<g
■ s
ch
177
Table 10-11. Immunosuppression for Renal Transplant Recipients
Standard
Prednisone 200 mg/24 hr tapered to 40 mg per day over 2 weeks and
thereafter to 15 mg per day or 30 mg q.o.d.
Azathioprine 2 to 3 mg/kg/day
Cyclophosphamide, especially if recipient is intolerant of azathioprine
Cyclosporine
Experimental
f
Extracorporeal irradiation of recipient blood
Thoracic duct drainage to deplete lymphocytes
Total lymphoid irradiation
Antilymphocyte serum or globulin, antithymocyte globulin
Local x-irradiation of kidney (150 rads for three doses)
Heparin, sodium warfarin, dipyridamole
Solu-Medrol 1 gm per day for 3 to 5 days
Lymphoplasmapheresis
Monoclonal antibody
tibodies to transplant antigens (and/or the removal of lymphocytes), but
preliminary results with this therapy are equivocal. Other experimental
therapies for acute rejection include the use of cyclosporine, antilymphocyte
globulin, and anticoagulants. ——
The transplant recipient is generally followed in the hospital with daily
laboratory tests for 2 or 3 weeks. Acute tubular necrosis or other compli
cations may require longer hospitalization. Thereafter, the patient is fol
lowed as an outpatient, initially with laboratory tests every 2 to 3 days.
The most crucial parameters to follow are urinary volume. BUN and serum
creatinine, urinary protein excretion, weight and blood pressure, and—to
detect excessive dosage of azathioprine—white blood count, platelets, and
hematocrit. Other parameters, such as serum potassium, bicarbonate, cal
cium. and phosphate, and urine culture and sediment, are also followed.
Fever is an ominous sign that requires prompt evaluation for infection
and/or rejection, the former sometimes triggering the latter.
f. Efficacy of transplantation. Uremia is “cured” with successful renal trans
plantation, but preexistent disease (e.g., diabetes) and preexistent com
plications of uremia (e.g., hypertension, cardiovascular disease, hyper
parathyroidism) may be aggravated. Furthermore, the original renal
disease may recur in the transplant. Diseases that may recur include ox
alosis, glomerulonephritis (particularly antiglomerular basement mem
brane nephritis, rapidly progressive glomerulonephritis, meaangiocapillaiy
glomerulonephritis, and focal glomerular sclerosis), diabetes, and cystinosis.
g- Complications of transplantation
(1) Technical complications. Early technical complications of renal trans
plantation include:
(a) Acute tubular necrosis x
(b) Wound infection
(c) Vascular anastomotic leak or occlusion
(d) Ureteral anastomotic leak or obstruction
(e) Ureteral rupture (which may be due to rejection)
Late technical complications include lymphocele (which may cause
ureteral obstruction) and renal artery stenosis (which may cause hy
pertension). The one complication worthy of discussion is acute oliguric
renal failure. It often occurs after cadaveric transplantation and in
frequently after living related donor transplantation. Oliguria in the
immediate post-transpl ant period complicates detection of rejection
since the hallmark of acute rejection is a decrease in urinary volume.
Nevertheless, several tests, including ultrasound, renal scan, and frac
tional sodium excretion, allow distinction between acute tubular ne-
ML
178
i
a « is
?S 2 £1
10: The Patient With Chronic Azotemia
crosis and hyperacute or acute rejection, and thus appropriate man
agement can be provided. Ultrasound is normal, renal blood flow
generally well preserved, and fractional sodium excretion is high with
acute tubular necrosis; the opposite'is true in patients with renal
transplant injection.
.
(2) Drug-related complications. Complications of prednisone, immuno
suppressive agents, and antacids are as follows:
(a) Steroid: infection, masking of infection, Cushings syndrome, psy
chosis, peptic ulcec, pancreatitis, cataracts, osteonecrosis
(b) Azathioprine: infection, bone marrow depression, liver damage,
malignancy
.
.
(c) Cyclophosphamide: infection, bone marrow depression, ovarian fi
brosis, aspermia, hemorrhagic cystitis, pulmonary fibrosis, alopecia,
malignancy
r
(d) Cyclosporine: infection, renal and liver damage, lymphoma, tremor,
hirsutism and gum hyperplasia
.
,
(e) Antilymphocyte globulin: thrombocytopenia, anemia, disseminated
intravascular coagulation, fever, .arthritis, glomerulonephritis,
anaphylaxis if given intravenously, pain if given intramuscularly,
infection
(f) Antacid: hypophosphatemia
Hypophosphatemia is a complication that may be due to decreased renal
tubular reabsorption of phosphate, which in turn is due to secondary
hyperparathyroidism failing to resolve in the early post-transplant pe
riod; it may also be drug-related, particularly secondary to antacids
used to lessen the risk of peptic ulceration from prednisone.
(3) Immunologic complications. Four types of immunologic complications
of renal transplantation are:
(a) Rejection: hyperacute, acute, chronic
(b) Infection: common or esoteric pathogens
(c) Malignancy: reticulum cell sarcoma, lymphoma, cancer
(d) Recurrent glomerulonephritis: 5 percent of allografts, 65 percent
of isografts
Of these, transplant rejection deserves discussion since it may occur
in any transplant other than between identical twins. Hyperacute re
jection, which occurs within minutes to hours (occasionally days) fol
lowing a transplant, is due to preformed circulating antibody and results
in fulminant vascular disease of the renal graft. It may also cause
microangiopathic hemolytic anemia, thrombocytopenia, hemorrhage,
and even renal rupture. It is unresponsive to therapy, and nephrectomy
should be performed without delay.
Acute (or classic) transplant rejection may begin as early as several
days or as late as years following a transplant, but is most common
within the first 2 months. Sometimes it appears to be triggered by
intercurrent infection. Acute rejection may result in fever, tenderness
over thQ graft, hypertension, decreased urinary volume, increased BUN
and creatinine, an active urinary sediment, and a decrease in urinary
sodium concentration. Fortunately, this form of rejection may respond
to an increase in oral prednisone or an infusion of methylprednisolone
for several days. Unless the patient is severely oliguric, azathioprine
dosage is not decreased. If steroid therapy does not abrogate the re
jection, antilymphocyte globulin, cyclosporine, heparin infusion, or
lymphoplasmapheresis should be tried. If rejection fails to respond,
nephrectomy may be necessary for fever, pain, or thrombocytopenia.
I
Chronic rejection does not begin for months to years following trans
plantation and occurs in either of two forms: a proliferative glomer
ulonephritis or an interstitial nephritis with fibrosis. Both forms are
relentless, irreversible, and unresponsive to therapy, but nephrectomy
is rarely necesary.
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10: The Patient With Chronic Azotemia
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180
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181
10: The Patient With Chronic Azotemia
Table 10-13. Causes of Renal Transplant Graft Failure
Table 10-12. Results of Transplantation and Chron.c Dialysis
Functioning Graft
Donor (if transplant)
i
Identical twin
HLA-identical sibling
1-Haplotype-identical
relative15
Continuous peritoneal
dialysis
Chronic hemodialysis
Cadaver6
i
i
I
1 Year
(%)
5 Years
(%)
1 Year
(%)
5 Years
(%)
95
90
80
80
80
70
98
98
95
90
85
75
90c
60
40
^'4
Surviving Patient’
•-'e
a
c
e I4
J4
e 9
to be substantially improved with
cyclosporine and prednisone
Miscellaneous complications^ Add^onal c°^hocrat^°ithout rejection;
(4)
(a) “at usualTy transient; distal, often persistent or recurrent;
(b) SKo"r^other causes of hypophosphatemia are ant(c)
phlebotomy
(d) Situational depression, even suic
(e) Nephrotic syndronie
nUge of recipients of four classes of
h. Results of transp.anUtion.
P?
relationship
who have
relationship to
to donor)
donor^who
have
istly in the United States. For
“d
—“
j i
chronic te^’^transpuXaft failure and of death following renal
The causes of renal transplan fe
transplantation are listed mTaMes iv
hemodiaiys!s and transComparlson
of
morbidity
a
"
1
dialysis
and
transplantation
is difficult
6. plantation. The overall morbidity of,di
in
hospI ]
u> quantify. However the
- be^uantified. A study of a relatively
is a definable form of mor
y
54 cadaver donor transplants, 21 living
e! 3
L
I9
1a
I
c s
■■3
from living related
tution several years ago
^XanA"
appreciated that the minority
hosp-Uluation following transplantation
- >
’tients with cadaver trans-
d'ed'
Rejection
Death of patient
Technical
Acute tubular necrosis
Recurrent disease
60
25
10
4
1
T
Table 10-14. Causes of Death After Renal Transplantation
transplantation is 5 to 10 percent
ind 15 to 20 percent worse at 5
i—"
Percentage of Cases
re jS
d
60
60
85
85
Cause
-a
'IT
Cause
Percentage of Cases
Sepsis
30
10
10
10
10
8
5
5
4
2
2
1
1
1
1
Rejection and sepsis
Rejection
Immunosuppression
Technical
Other
Unrelated to transplant
Cardiovascular
Gastrointestinal hemorrhage
Cerebrovascular
Suicide
Pulmonary embolus
Neoplasm
Hepatitis
Pancreatitis
60
the percentage of renal grafts functioning at 1 year was 72 percent for living
related donor transplants and 64 percent for cadaver transplants.
A newer study of the mortality of transplant and dialysis patients at a single
institution revealed significantly better survival in patients transplanted with
a graft from a living related donor (98% at 1 year, 75% at 5 years) than in
those transplanted with a cadaveric graft (85% at 1 year, 63% at 5 years) or
in those undergoing chronic hemodialysis (90% at 1 year, 55% at 5 years). The
differences in survival between cadaveric transplant and chronic hemodialysis
were not significant, and it was concluded that a patient’s decision betw’een
cadaveric transplantation and chronic hemodialysis should be based on pyschosocial rather than medical grounds. The paper noted that differences in
survival of home hemodialysis versus, center hemodialysis patients are not yet
known.
7. A proposed schema for choice of therapy for ESRD. Figure 10-1 is the author’s
proposed schema for choice of therapy for ESRD. To recapitulate briefly, the
physician should urge renal transplantation for children and particularly for
patients with a healthy identical twin or HLA-identical sibling who is a willing
donor. The physician should also offer transplantation to patients who have
a 1-haplotype-matched relative willing to donate, or to informed patients who
prefer it to dialysis. Conversely, the physician should recommend dialysis for
patients incapable of successful transplantation and for elderly patients. The
majority of these patients do not have contraindications to hemodialysis or to
10: The Patient With Chronic Azotemia
^2
■!
183
10: The Patient With Chronic Azotemia
..
peritoneal dialysis. After the patient is informed of the advantages and dis
advantages of each, the choice between hemodialysis and peritoneal dialysis
usually should be the patient’s preference. Technologic developments in aseptic
technique may so reduce the frequency of peritonitis that chronic peritoneal
dialysis (CPD) may become the preferred mode of dialysis for all patients with
ESRD who do not prefer transplantation.
Although progress in the simplification of dialysis and in transplantation im
munology has been slower than desired, it should be appreciated that in less
than 25 vears, not one, not two, but three forms of therapy (transplantation,
hemodialysis, and peritoneal dialysis) have become available for patients who
previously would have die< Furthermore, these therapies are availab e
throughout the world, and in this country are available to virtually all patients
who can benefit from them. No longer does the physician select the proper
patient for the treatment; rather, one selects the proper treatment for the
patient.
-
Suggested Reading
Articles and Chapters for Extended Reading
Anderson, R. J.. Bennett, W. M., Gambertoglio J. G.. and Schrier R. W. Fate of
Drugs in Renal Failure. In B. M. Brenner and F. C. Rector, Jr. (Eds.), The Kidney
(2nd edj. Philadelphia: Saunders, 1981.
Bennett, W. M., Muther, R. S., Parker. R. A., Fieg, P., Morrison, G., Golper, T A.,
and Singer I. Drug therapy and renal failure: Dosing guidelines for adults. Ann.
Intern. Med. 93:62, 286, 1980.
Brenner, B. M., Meyer, T. W„ and Hostetter, T. H. Dietary protein intake and the
progressive nature of kidney disease. N Engl. J. Med. 307:652, 1982.
Canadian Multicentre Transplant Study Group. A randomized clinical trial of cy
closporine in cadaveric renal transplantation. N. Engl. J. Med. 309.809, 1983.
Carpenter, C. B. Immunology and Genetics of Transplantation. In S. G. Massry and
R. J. Glassock (Eds.), Textbook of Nephrology. Baltimore: Williams & Wilkins, 1983.
Carpenter, C. B., and Strom, T. B. Transplantation: Immunogenetic and clinical as
pects. Hosp. Pract. 17:125, 1982; 18:135, 1983.
European Multicentre Trial Group. Cyclosporine in cadaveric renal transplantation.
One-year follow-up of a multicentre trial. Lancet II: 986, 1983.
e 3
3
<4-3
^-.3
ej 3
c
ei
The Kidney (2nd ed.). Philadelphia: Saunders, 1981.
Vaziri, N. D. Acquired renal cystic disease in dialysis patients. J. Artif. Organs 5.336,
1982.
TEXTS FOR REFERENCE
Anderson. R. J., and Schrier. R. W. Clinical Use of Drugs in Patients with Liver and
Renal Disease. Philadelphia: Saunders, 1981.
Bennett, W. M. Porter, G A., Bagby, S. P and McDonald, W, J. Drugs and Renal
Disease. New York: Churchill-Livingstone. 1978.
Brenner, B. M„ and Rector, F. C. Jr. (Eds.). The Kidney (2nd ed.). Philadelph.a:
Saunders, 1981.
Earley, L. E„ and Gottschalk, C. W. (Eds.). Strauss and Welt's Diseases of the Kidney
(3rd ed.). Boston: Little, Brown. 1979.
Edelmann, C. M), Jr. (Ed.). Pediatric Kidney Disease. Boston: Little, Brown, 1978.
Friedman, E. A. (Ed.). Strategy in Renal Failure. New York: Wiley. 1978.
e
5
3
-3
Massry, S. G. and Glassock, R. J. (Eds.). Textbook ofNephrology. Baltimore: Williams
& Wilkins, 1983.
Massry, S. G. and Sellers, A. L. (Eds.). Clinical Aspects of Uremia and Dialysis.
Springfield, Ill.: Thomas, 1976.
Nissenson, A. R„ Fine, R. N„ Gentile, D. E. (Eds.) Clinical Dialysis. Norwalk, Conn..
Appleton-Century-Crofts, 1984.
Papper, S. Clinical Nephrology (2nd ed.). Boston: Little, Brown, 1978.
Schrier, R. W. (Ed.). Renal and Electrolyte Disorders (3rd ed.). Boston: Little, Brown.
c! >
$
SUim J.' H. (Ed.). Nephrology. In J^ Dietschy (Ed.) The Science and Practice of
Clinical Medicine, Vol. 7. New York: Grune & Stratton, 1980.
Gulyassy P F., Yamauchi, H., and Detner, T. A. Conservative Management of
Chronic Renal Failure. In L. E. Earley and C. W. Gottschalk (Eds.), Strauss and
Welt’s Diseases of the Kidney (3rd ed.). Boston: Little, Brown, 1979.
Haussler, M. R., and Cordy, P. E. Metabolites and analogues of vitamin D. JAM A.
247: 841,’1982.
Henderson, L. W. Hemodialysis. In L. E. Earley and C. W. Gottschalk (Eds.), Strauss
and Welt’s Diseases of the Kidney (3rd ed.). Boston: Little, Brown, 1979.
1
v>
Kopple. J. D. Nutritional Management. In S. G. Massry and R. J. Glassock (Eds.),
Textbook of Nephrology. Baltimore: Williams & Wilkins, 1983.
Lajuer, A., Saccaggi, A., Ronco, C., Belledonne, M., Glabman, S., and Bosch, J. P.
Continuous arteriovenous hemofiltration in the critically ill patient. Ann. Intern.
Med. 99:455, 1983.
Noiph, K. D., Boen. F. S. T., Farrell, P. C., and Pyle, K. W. Continuous ambulatory
peritoneal dialysis in Australia, Europe, and the United States: 1981. Kidney Int.
23:3, 1983.
Oreopoulos, D. G. Peritoneal Dialysis. In S. G. Massry and R. J. Glassock (Eds.),
Textbook of Nephrology. Baltimore: Williams & Wilkins, 1983.
•a
/
I
/
».•. T.--
"rg.
/
Approach to Drug Use
in the Azotemic
iS
William M. Bennett
e
ei 3
ee 3
J
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e
i
I
k
e i’
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e o
There are increasing numbers of patients with renal dysfunction who require therapy
for intercurrent medical problems. Since most drugs or their metabolites undergo
renal excretion, compromised renal function may allow accumulation of a drug to
toxic levels unless proper dosage adjustments are made. Furthermore, the physiologic
abnormalities of renal failure may alter the expected pharmacologic response of a
drug resulting in an untoward reaction. The goal of therapy in the patient with
renal dysfunction is to tailor the dosage regimen to the individual patient’s clinical
situation to simulate normal therapeutic conditions.
5. principles of prescribing to azotemic patients: stepwise approach
A Assessment of renal function—step 1. The extent of accumulation of drugs given
in the usual doses to patients with renal failure depends on the degree of renal
dysfunction. For the proper adjustments to be made, the level of renal function
must be known. Blood urea nitrogen (BUN) is an unsuitable parameter for this
purpose, since it is influenced bZextrarenal factors such as diet, steroid therapy,
and gastrointestinal bleeding) Instead, measurement or approximation of glo‘ merular filtration rate is necessary to prescribe optimally for patients with renal
disease. The endogenous creatinine clearance is customarily used. Although
measurement of creatinine clearance is widely available and convenient, the re
quirement of carefully timed urine collections limits its usefulness m acutely ill
patients. Since creatinine excretion is proportional to lean body mass and inversely
proportional to age, formulas and nomograms have been developed to estimate
creatinine clearance from the serum creatinine without the need for urine col
lection. One convenient formula is:
j
creatinine clearance =
i!
i
^/j 3
Vi.
>' ■ ’
■
-
??
-.a*1
(140 - age)(body weight in kg)
x
creatinin8
( (The calculated value should be multiplied by 0.85 for women).
If renal function is decreasing rapidly, the measured creatinine clearance or the
estimated value will overestimate the actual value. Thus, in patients with acute
renal failure dosage adjustments should be based on creatinine clearance of less
than 10 ml per minute. Otherwise, serious overdosage may result. Conversely,
if the patient has improving function, care should be taken to avoid underdosing,
since serum creatinine may remain elevated for several days after urine output
has increased. In this chapter a creatinine clearance of less thanJOjnl per minute
will be considered advanced or severejrenal feilure-.
B. "Determining the need forBbsage adjustment—step 2. Drugs that have a normal
renal route of elimination or that are transformed to active metabolites requiring
intact renal function for excretion are the agents that generally require major
dosage adjustments in renal insufficiency. Thus, some knowledge of a drugs
pharmacology is essential to rational prescribing for these patients. This is es(pecially true for drugs with a narrow toxic-therapeutic ratio, such as cardiac
Lglycosides, antiarrhythmics, and aminoglycoside antibiotics. The situation is more
Complex when metabolites with pharmacologic activity are accumulated but the
parent compound is normally metabolized by the liver. An example of this is
normeperidine accumulation in patients with renal failure, which results in sei185
-
186
v&!SESB.. ^i- -il.W.
-«I_M.—x
MSW^
11: Approach to Drug Use in the Azotemic Patient
187
Table 11-2. Serum Drug Levels and Changes Produced by Decreased Protein Bin
g
11: Approach to Drug Use in the Azotemic Patient
despite normal hepatic biotransformation of the parent compound
zures and coma
.meperidine.
For measured or estimated creatinine clearances above 30 ml per minute it is
x
• .
1•n
.1 .
.
__________ 1.
—nnrr]iAtrnoniilor Hmirrcl
seldom
necessary to
modify
doses
except for ~antibiotics
and cardiovascular drugs)
Ugs
Wilii
HiicumawivB.vcxxxj
------------Common drugs with pharmacologically active ortoxic
toxicmetabolites
metabolitesare
arelisted
listedinin
In situations in which the clinician is in doubt about the need for
__4-/,it is safest to look up ♦Via
dosage modification
the ticnol
usual r>ht»Kmarnlncrir
pharmacologic hnndlintr
handling of
of
the compound or specific recommendations in a standard reference source.
C. Choosing the loading doses of drugs—step 3. When patients receive multiple
m close intervals, the average plasma concentrationjdses
concentration rises
drug doses at uniform
concentration
time
required
to reach apuntil a steady state c
-- ------------- is reached.QThe
’ ’
‘
J
int nf
proximately 90 percent
of thic
this rnnrpnfratinn
concentration is 3.3 times the half-life of drug
elimination) Since the half-life may be markedly prolonged in renal failure, ef
fective therapy may be greatly delayed if dosage is simply adjusted for a prolonged
half-life. Therefore, a large initial dose, or loading dose, is usually required. This
is of particular relevance in antibiotic, antiarrhythmic, and digitalis therapy, in
_
Tn nrartirp
usual initial
dose
be Eriven.
which
efficacythp
is needed
quickly.
Incan
practice,
the usual | initial dose can be given.
If there are adverse hemodynamic factors, such as extracellular fluid volume
depletion or dehydration, it may be prudent to reduce the initial dose to 75 percent
of that usually prescribed. This applies in particular to cardiac glycosides such
as digoxin or ototoxic aminoglycoside antibiotics.
D. Finding a maintenance dosage—step 4. In practice, the desired dosage regimen
can be reached either by lengthening the interval between doses to correspond
to the delayed excretion of the particular drug in renal failure or by reducing the
size of the individual dose prescribed at the same interval as usual. The interval
extension method is particularly convenient for drugs with relatively long serum
half-lives, whereas the dosage reduction method is preferred when a more constant
serum level is desirable. The clinician usually uses a combination of these methods,
on guidelines published in the literature. Any fixed formula must be adapted
to the individual situation since many complex variables may modify the rec
ommendations.
E. Use of the serum drug level to monitor therapy—step 5. A standard drug dosage
will lead to a variety of therapeutic effects in individual patients. To avoid serious
over- or underdosage, serum drug concentrations can be used as therapeutic guides.
Ranges of concentrations associated with safe, yet efficacious, therapy are being
increasingly identified for most categories of drugs used to treat patients with
renal failure. Therapeutic ranges of some common agents that can be used in
clinical practice are shown in Table 11-2. Serum levels can be interpreted fully
..a
'■
in Renal Pailiirp
Failure
e
5
Parent Drug
Active Metabolite
Adriamyan
Allopurinol
Azathioprine
Cephalosporins
Chlordiazepoxide
Clofibrate
Diazepam
Meperidine
Primidone*
Procainamide
Propranolol
Propoxyphene
Sulfonamides
Adriamycinol
Oxypurinol
6-mercaptopurine
Desacetylcephalosporins
Oxazepam
Chlorophenoxyisobutyrate
Oxazepam
Normeperidine
Phenobarbital
N-acetylprocainamide
4-hydroxypropranolol
Norpropoxyphene
Acetylsulfonamides
Therapeutic
Serum
Concentrations
Antibiotics
Aminoglycosides
Amikacin
Gentamicin
Netilmicin''
Tobramycin
Cephalosporins
j
22
c'
e
e
I *
.1
2 -»
Serum levels not
clinically useful
No effect
Penicillins
Carbenicillin
100-300 mg/L
Penicillin G
1-25 mg/L
Ticarcillin
100-300 mg/L
Some decreased binding in
uremia
Some decreased binding in
uremia
Some decreased binding in
uremia
Sulfonamides
Cardiovascular Drugs
Digoxin
Digitoxin
Disopyramide
Furosemide
Lidocaine
Procainamide
Propranolol
Quinidine
Miscellaneous drugs
Carbamazepine
Ethosuximide
Lithium
Nortriptyline
Phenobarbital
Phenytoin
Salicylate
Theophylline
Serum levels not
clinically useful
Decreased binding in uremia
0.8-2 ng/ml
10-25 ng/ml
No effect
Decreased binding in uremia
and with heparin therapy
during dialysis
No effect
Decreased binding in uremia
2-7 mg/L
Serum levels not
clinically useful
1.5-5 mg/L
4—8 mg/L
20-50 ng/ml
2-6 mg/L
2-6 mg/L
40-80 mg/L
0.5-1.3 mEq'L
50-150 pg/L
15-30 mg/L
10-20 mg/L
6-12 mg/L
200-300 mg/L
8-20 mg/L
L
f
No effect
No effect
No effect
No effect
Primidone
£
Effect of Renal Disease
on Protein Binding
15-30 p.g/ml
4-10 pg/ml
4-10 pg/ml
4-10 p-g/ml
I
Vz
Table 11-1. Common Drugs with Active or Toxic Metabolites Dependent on Renal
Excretion
«
«
Drug
e
I
I
■h
H
3!
No effect
No effect
No effect
No effect
No effect
No effect .
No effect
No effect
Decreased binding in uremia
Decreased binding in
uremia; side effects can be
seen at “therapeutic”
levels
Decreased binding in uremia
of major metabolite,
phenobarbital
Decreased binding in uremia
Increased toxicity with low
serum albumin
-
I
11: Approach to Drug Use in the Azotemic Patient
188
189
11: Approach to Drug Use in the Azotemic Pat.er.1
Table 11-3. Drug Interference With Laboratory Tests in Nephrology
Test
Drug
Effect
Serum creatinine
Ascorbic acid
Para-aminohippurate
Methyldopa/levodopa
Elevates total chromogen
Elevates total chromogen
Reducing agents interfere with au
toanalyzer; increases when blood
level > 2 mg/ml
Raises serum level by competition
for tubular secretion
May raise serum level by secretory
competition
Increases serum level by interfer
ence with Jaffe reaction
Increases serum level by secretory
competition
Increases; mechanism unclear
Increases in nonenzymatic methods
Increases in nonenzymatic methods
Increases in nonenzymatic methods
Increases with phosphotungstate
method
Increases in nonenzymatic methods
Interference in autoanalyzer
Red-brown
Red-brown
Red-brown
Darkens on standing
Darkens on standing
Darkens on standing
Blue-green
Blue-green
False-positive reaction
False-positive reaction
False-positive reaction
False-positive reaction
False-positive reaction
False-positive reaction
Fa Ise-positive reaction
False-positive reaction
Salicylic acid method only
3
bloodstream. bound
XXicns determine the total drag eontlinical Sittons
Nations in
in which
which th^is
there is a,
a low
low serum
serum albumin,
albumin, such
sucn as
as
nephrotic syndrome.^
in which drug affinity for plasma.
aLZ therapeutic rangers
pr?a
I
Trimethoprim .
Acetylsalicylic acid
— levels withm the
Cefoxitin
“X torenal disease are
effects. taPOTt"* 2 These should be kept in mind in interpreting serum levels
Cimetidine
-JI
3
Serum urea nitrogen
Serum uric acid
41
I
3
as ~
I
Psince interaction with many compoundsjmndtsplaee v^nn^
c
tein-bmding sites. The drug interaci bleeding. Other „
amDies are
examples
are the
the poor
poor oral
oral it a
defect of urenua
ofga'strointestinal binding by ant/absorption 0
interference with methotrexate ex
acids prescribed forh^7^natreatrnent, which can potentiate bone marrow
: •
2
5
'i
i
K—a
5TP
lude increases in serum creatinine proauceu uv mLd cimetidine which
which compete
sites of
of tubular
tubular secretion.
compete for
for transport
transport sites
secretion.
’
" *
o.
1
E:
_ ..
’"h
’in Emulating a therapeutic
1___ :__ j;nhMia tHp nnsl steo ir
W
— «!««« xvithnut
/
5S5
j?
Change in urine color
Urinary protein deter
minations
Acetohexamide
Ascorbic acid
Salicylates
Aminophylline
Methyldopa
Acetaminophen
Levodopa
Rifampin
Sulfasalazine
Phenothiazines
Metronidazole
Methyldopa
Nitrofurantoin
Amitriptyline
Triamterene
Aminosalicylic acid
Acetylsalicylic acid
Cephalosporins
Contrast media
Penicillins
Sulfonamides
Acetazolamide
Tolbutamide
Tolmetin
i
J----- ------------ -----
t
binding and molecular size, removal of a drug during dialysis depends on the
type of artificial kidney employed; most clinically used dialyzers have cuprophane
or cellulose membranes, which have similar characteristics. In general, regularly
scheduled drug doses should be given after dialysis to minimize removal. For
drugs with considerable removal, it is best to replace a full maintenance dose
following dialysis (Table 11-4). Since hemodynamic factors and various other pa
tient variables make precise adjustments difficult in clinical situations, it is best
to check serum levels before the next regularly scheduled dose. A serum level
measured immediately postdialysis may not accurately reflect the total body bur
den since equilibration from intracellular pools may occur for several hours.
There has been a recent resurgence of interest in chronic peritoneal dialysis.
Because of the relatively large surface area available for transfer, the peritoneal
membrane is five to ten times more permeable to large-molecular-weight solutes
PL
190
11: Approach to Drug Use in the Azotemic Patient
11: Approach to Drug Use in the Azotemic Patient
-J
Table 11-4. Common Drugs Requiring Supplemental Dosage After Conventional
Hemodi alysis
Antibiotics
Aminoglycosides:
Cephalosporins:
-—
Table 11-5. Drugs Cleared by Peritoneal Dialysis that Require
Supplementary Doses During Clinical Therapy
A--------- . • 1
~
'
Antiarrhj-thmic agents
Antimicrobial Sgents
Procainamide*
Amikacin
Quinidine
Carbenicillin
Cephalothin
Antihypertensive agents
Cephradine
Methyldopa
Ethambutol
Flucytosine
Neurologic agents
Gentamicin
Diphenylhydantoin
Isoniazid
Gallamine
Streptomycin*
Sulfamethoxazole
Sedatives, hypnotics, tranquilizers
trimethoprim*
Lithium carbonate
Sulfisoxazole
Phenobarbital
Ticarcillin
Tobramycin
Miscellaneous
Analgesics
Aminophy 11 ine*
Acetylsalicylic acid
*In vivo data are lacking, but indirect evidence strongly supports placing the drug in
Amikacin, gentamicin, netilmicin, streptomycin, tobramycin
Cephalothin, cefamandole, cephazolin, third-generation
Penicillins:
■
than clinically used hemodialysis membranes. However, the relativelyTow■ bi^l
Row to the peritoneum limits the removal
cently the use of continuous ambulatory peritoneal diaiy sis (CAPD) has g
e
3
I
Lurce1 Adapted from T. A. Golper, Drugs and peritoneal dialysis. Dialysis and Transplantation. 8:41, 1979.
B- “XX^amam.de is metabolized to a pharmacologically active .
'I
IS
given every 8 to 12 hours in patients with end-stage rena disease. tanan de
and //-acetylprocainamide are readily removed by dialysis, and a full main
tenance dose should be given following a dialysis treatmentflH^e^ of
rhythmias, and conduction disturbances may occur as a consequence oi
following systemic administration are inconsistent. Table 11-5 lists drugs tn
require supplemental doses during peritonea dialysis.
2. Udocainl6 Lidocaine undergoes extensive hepatic
antiarrhythmics. No increased central nervous system toycity h as bam ot>
served in patiente with renal disease. The drug is not dialyzable, and it can
be used in the usual way for azotemic patients.
Table 11-6. Cardiac Glycosides in Renal Failure
—========
Drug
Digitalizing Dose
Maintenance Dose
Dialysis
With normal renal function and 4.4 days m anuric patients. After a digitanz g
Digitoxin
Customary
No change required
Digoxin
75-90% of usual
Creatinine clearance > 50
ml/min, 0.25-0.5 mg/
day; 10-50 ml/min,
0.125-0.25 mg/dpy;
< 10 ml/min, 0.06250.125 mg/day
Keep dialysate K’ at 3.0
mEq/L; monitor serum
level if heparin is used
Keep dialysate K+ at 3.0
mEq/L; monitor serum
level
of digitalis glycosides in renal failure are shown in Table 1
h
A
Ak .
“
AmoxiciUin'^mpicillin, azlocillin, carbenicillin, mezlocillin,
penicillin, piperacillin, ticarcillin
5-flucytosine v
Antifungal drugs
Antituberculous drugs Ethambutol, isoniazid, cycloserine
Acyclovir, chloramphenicol, metronidazole, sulfisoxazole,
Miscellaneous
trimethoprim-sulfamethoxazole.
antiinfective drugs
Acetylsalicyclic acid, acetaminophen
Analgesics
Sedatives, hypnotics, Phenobarbital, lithium
and tranquilizers
Cardiovascular drugs
Antiarrhythmics:
-dolol, sodium
Antihypertensives:
nitroprusside
Azathioprine, cyclophosphamide, ethosuximide, 5-fluorouracil,
Miscellaneous drugs
gallamine, methotrexate, primidone, theophylline
191
!
1
11: Approach to Drug Use in the Azotemic Patient
195
11: Approach to Drug Use in the Azotemic Patient
phalothin is given in the usual loading dose followed by maintenancedoses
every 8 to 12 hours for end-stage renal patients. For the orally active agents
suchks cephalexin, adequate blood levels are achieved by a 1-gm load fo^ed
by 500 mg every 12 hours, in patients with creatinine clearances less than
rffi per mfnute. Usual doses are necessary for urinary tract infections. Cep
alosporins are removed from plasma by hemodialysis. A ma^tenanc®,
given after hemodialysis returns plasma concentrations to within the therapeutic range. The third-generation cephalosporins have characteristics sim
to other d^gs in the same cTass. An exception is cefoperazone, which undergoes
nonrenal elimination and thus requires no dosage adjustment in renal disease.
4 Miscellaneous antibiotic, antifungal, and antituberculous drugs
a Chloramphenicol. No alteration in dose is necessary for chloramphenicol,
/ even in oatients
patients with severe renal insufficiency. However,
However dose-related.
reversible, hematopoietic depression is more common in patients with im
paired renal, function. This may be related to accumulation of toxic metabolites normally excreted by the-kidneys.
....
Erythromycin and clindamycin. Erythromycin and
metabolized primarily by nonrenal mechanisms are prescribed in
therapeutic doses to patients with impaired renal function.
c Lincomycin. Lincomycin exhibits a prolonged half-life m renal ‘n8^"
ciencv The normal dose of lincomycin should be reduced by one-half n
patients with advanced renal failure. Hemodialysis does not significantly
alter the plasma concentrations of erythromycin, clindamycin, or linco-
d
Nitrofurantoin. Nitrofurantoin should be avoided in patients with renal
■ insufficiency. It is ineffective therapy when the creatinine clearance de
creases to less than 30 ml per minute. Moreover, toxic metabolites may
cause peripheral neuropathy in patients with far advanced renal disease
Sulfonamides. Most sulfonamides are ineffective in patients with rena
failure because their elimination and urine concentration is dependent
largely on glomerular filtration. The sulfamethoxazole-tnmethopnm com
bination has recently been shown to be efficacious in the therapy of Pneu
mocystis carinii infections in immunosuppressed patients. Dosage ‘"Arvais
should be extended to 24 hours when creatinine clearance is less than 10
ml per minute. Hemodialysis removes the drug from plasma; therefore, a
maintenance dose should be given after dialysis.
f. Tetracyclines. Tetracyclines have well-known antianabohc effects that
y
aggravate azotemia. They should be avoided if possible in patients with
uremia. If a tetracycline is specifically indicated, doxycycline is the drug
of choice. No alteration in the dosage schedule of this agent is required
g. Vancomycin^Vancomycin may cause damage to the eighth nerve if the
high (greater than
80 mg/ml).
It is .eliminated
serum levels are Lign
------ ------o
. j- primarily
leys and dosage modification is needed jn
in renal disease.
disease, pie
by the kidneys,
long half-life, and dosage intervals should be extended to 3 to
drug has a
—------ , —
r
ed renal
6 days in advanced
renal failure.
failure. Since
Since the
the drug
drug is
is not removed by dialysis,
popular
agent
in
the
treatment
of vascular access-related
vancomycin is a
------- ------------m rnncpntrations
should be
obtained to
ensure optimal
infections. Serum
concentrations should
be obtained
---------
I
I
h Amphotericin. Amphotericin B, a nephrotoxic agent, is widely used for
treating systemic mycotic infections. Although decreases in renal function
are commonly observed, serum drug concentrations do not rise. Dosag
need not be altered except in severe renal failure. !n suchi patien^ 1
dose may be decreased by one-fourth. Amphotericin B is high,., protein
bound and is not removed by hemodialysis.
I Flucytosinen Miconazole and Ketoconazole. Flucytosine is excreted by
the kidneys Dosage intervals should be extended to 24 hours in patients
with severe renal failure. Flucytosine is removed from plasma by hemo-
dialysis. Single doses of 25 to 50 mg per kilogram body weight postdialysis
produce nontoxic, therapeutic concentrations in patients undergoing he
modialysis every 48 to 72 hours. Frequent monitoring of serum concen
trations is recommended. Miconazole and ketoconazole require no dosage
adjustment in patients with renal failure.
j. Antituberculous drugs. Isoniazid is eliminated from the body predomi
nantly by hepatic acetylation to an inactive metabolite. In most patients
no dosage alteration is required in renal insufficiency. However, in patients
with reduced hepatic metabolism (slow acetylators), the dosage should be
reduced by approximately one-third if the creatinine clearance is less than
10 ml per minute. Isoniazid is removed by hemodialysis. Serum concen
trations may be followed as a guide to dosage. The dose of rifampin need
not be altered in renal failure or adjusted for dialysis. Isolated case reports
of nephrotoxicity have been reported in patients receiving rifampin. Renal
function should be monitored in such patients. Ethambutol is excreted only
through the kidneys. The dosage interval needs to be extended 24 to 48
hours for severe renal failure. Supplemental doses should be given after
dialysis.
5. Treatment of urinary tract infections in patients with renal disease. In patients
with renal dysfunction, effective treatment of urinary tract infection is difficult
to achieve. Delivery of antibiotics in adequate concentration to sites of infection
in the diseased urinary tract may not be possible.
Drug therapy for urinary infection in patients with poor renal function needs
to be selective to achieve effective antibiotic concentrations in the urine or
renal parenchyma. Penicillins and cephalosporins, both of which undergo tu
bular secretion, seem to achieve adequate urinary levels despite severe re
ductions in creatinine clearance. Trimethoprim-sulfamethoxazole has also been
reported to achieve clinical urinary sterilization in patients with severe re
ductions of renal function. It should be emphasized that the customary dosage
adjustments for renal failure will prevent high blood concentrations of antibiotic
but may reduce the concentrations achievable in the urine. Thus, ampicillin,
cephalexin, and trimethoprim-sulfamethoxazole should be used in full dosage
for urinary tract infections in patients with concomitant, severe renal disease.
Aminoglycoside antibiotics do not penetrate well into diseased renal paren
chyma or achieve reliable urinary tract levels in patients with severe renal
failure (i.e., with creatinine clearances less than 10 ml/min). Thus, they should
be reserved for patients with septicemia.
6. Treatment of dialysis-access infections. Of the infectious problems encoun
tered in patients with chronic renal failure, infections of dialysis vascular access
sites are most troublesome. External shunts have a much higher incidence of
infection than internal arteriovenous fistulae. Although the predominant or
ganism causing these infections is Staphylococcus aureus, there are increasing
numbers of infections with gram-negative bacteria, especially Pseudomonas
aeruginosa. In addition to definitive surgical management, antibiotics are often
indicated. Penicillinase-resistant penicillins or vancomycin is preferred for
staphylococcal infections, whereas an aminoglycoside is used for gram-negative
involvement. Vancomycin, because of its long half-life and failure to be removed
by dialysis, is particularly useful in a dose of 1 gm every 5 to 6 days admin
istered after a dialysis.
7. Treatment of peritonitis in patients undergoing peritoneal dialysis. Chronic
peritoneal dialysis is fast becoming a popular alternative for a growing number
of patients with end-stage kidney disease. Peritonitis remains a major limiting
complication. Once peritonitis is suspected on clinical grounds or after routine
cultures, peritoneal fluid should be obtained for Gram stain, total and differ
ential white blood count, and culture with antimicrobial sensitivity testing.
Peritoneal dialysis should then be begun and antibiotics added on the basis
of bacteriologic studies or Gram stain. Some typical regimens are outlined in
Table 11-8. If the patient has systemic signs and symptoms it may be prudent
to add appropriate parenteral antibiotics according to dosage guidelines de
scribed above.
>
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11: Approach to Drug Use in the Azotemic Patient
3. Quinidine. Quinidine half-life is similar in uremic patients and normal persons.
No dosage adjustment is required for renal failure, and the drug is not sig
nificantly dialyzed.
4. Propranolol. Propranolol has found widespread use not only as an antiarrhythmic agent but also as symptomatic treatment for angina .pectoris and
hypertension. The dosage need not be changed in patients with renal disease,
because increased hepatic metabolism counterbalances reduced uptake of the
drug by the liver. No significant amount of propranolol is removed by he
modialysis or peritoneal dialysis.
5. Other drugs. Disopyramide is excreted by the kidney and metabolized to a
compound with antiarrhythmic activity. For this reason, the interval between
doses should be extended to 12 to 24 hours in patients with end-stage renal
failure. Calcium entry blocking drugs are metabolized by the liver and require
no dosage adjustments for renal failure.
C. Antibiotic therapy
1. Aminoglycoside antibiotics. These widely used drugs (gentamicin, amikacin,
kanamycin, tobramycin and netilmicin) have a narrow toxic-therapeutic ratio.
In patients with renal disease, drug accumulation may lead to ototoxicity and
additional'renal damage. With very high blood levels, neuromuscular blockade
may occur. This may be of importance to anesthesiologists, since aminogly
cosides potentiate the neuromuscular blocking properties of the paralyzing
drugs used in surgery. Loop diuretics such as furosemide and ethacrymc acid
are known to enhance irreversible ototoxicity associated with aminoglycoside
therapy of patients with renal disease. Serum levels are widely used to ensure
antibacterial efficacy. It is not clear that maintaining serum levels in the
therapeutic range prevents toxicity; however, a rising serum level drawn 1
hour following a dose (peak) or just before the next dose (trough) indicates
renal dysfunction, since aminoglycosides depend primarily on glomerular fil
tration for excretion. Because aminoglycosides are removed by hemodialysis,
supplements of 0.5 to 1.0 mg per kilogram after dialysis are necessary to
maintain therapeutic effects. The addition of 5 mg of gentamicin or tobramycin
to each liter of peritoneal dialysate maintains adequate serum concentrations
during concomitant parenteral therapy.'Suggested initial and maintenance
regimens for aminoglycosides are given in Table 11-7.
2. Penicillins. The penicillins as a group are generally safe to administer to pa
tients with renal failure since little clinical toxicity is noted despite drug ac
cumulation. Isoxazoyl penicillins (cloxacillin, dicloxacillin, nafcillin) do not
require dosage modification, nor are they significantly dialyzed. If penicillin
G is prescribed for patients with creatinine clearance lesfe than 10 ml per min
ute, half the usual loading dose should be given every 8 to 12 hours after the
usual initial dose. Ampicillin and amoxicillin maintenance dosing intervals
should be extended to 12 to 16 hours when treating extrarenal infections in
patients with creatinine clearances less than 10 ml per minute. In the treatment
of urinary tract infections, usual doses are required to achieve adequate an
tibiotic concentrations in the urine and renal interstitium. The doses of car*
benicillin and ticarcillin should be reduced when creatinine clearance decreases
to 25 to 30 ml per minute. In patients with end-stage renal disease the carbenicillin dose is 2 gm every 8 to 12 hours. Toxic effects of penicillins in renal
failure include neurotoxicity at high serum levels, extracellular fluid volume
expansion (carbenicillin contains 5 mEq sodium/gm), and hyperkalemia (1
million units of penicillin contain 1.7 mEq potassium). Hypokalemic metabolic
alkalosis may also occur, since urinary excretion of large amounts of anion
(carbenicillin or penicillin) enhances potassium and hydrogen ion excretion.
The interval between doses of the new penicillins, azlocillin, mezlocillin, and
piperacillin, should be extended to 8 hours in patients with end-stage renal
disease to avoid drug accumulation.
3. Cephalosporins. Cephalothin and its related compounds are well-tolerated,
effective antibiotics for patients with renal failure. Although they are primarily
excreted by the kidneys, nephrotoxicity is rarely observed. Major dosage mod-
11: Approach to Drug Use in the Azotemic Patient
is:
Table 11-7. Aminoglycoside Dosing Chart
e
1. Select loading dose in mg/kg (ideal weight) to provide peak serum levels iij range ustec
below for desired aminoglycoside.
Expecte ’ °ea
Serum 1 ^els
Usual Loading Doses
Aminoglycoside
3
Netilmicin
Tobramycin
Gentamicin
Amikacin
Kanamycin
1a
€
a
Creatinine
Clearance
(ml/min)
50
e
e
9
3
<
I i.
:/n-
5.0 to 7.5 mg,'kg
15 to 3C
g/ir
2. Select maintenance dosage (as percentage of chosen loading dose) to contini >ea
serum levels indicated above according to desired dosing interval and the patient
corrected creatinine clearance.
90
80
70
60
e
.V
4 to 10
Percentage of Loading Dose Required For Dosage Interval Selected
e
C'
I
1.5 to 2.0 rag/kg
3
40
30
25
20
17
15
12
10h
7
5
2
0
Half-life
(hr)a
8 Hr
12 Hr
3.1
3.4
3.9
4.5
5.3
6.5
8.4
9.9
11.9
13.6
15.1
17.9
20.4
25.9
31.5
46.8
69.3
84%
80
76
71
65
57
48
43
37
33
31
27
24
19
16
11
8
91%
88
84
79
72
63
57
50
46
42
37
34
28
23
16
11
H
a 2%
°1
.5
0
67
A
'6
47
1
^0
21
aAlternatively, one-half of the chosen loading ^ose may be given at an interval appro
mately equal to the estimated half-life.
hDosing for patients with Oct < 10 ml/min should be assisted by measured serum icveli
Source: Adapted from F. A. Sarubbi and J. H. Hull, Amikacin serum concer
tio
Prediction of levels and dosage guidelines. Ann. Intern. Aled. 89:612, 19/8.
f
.■■•■
■ittMTirg- . ... .
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-•
■•
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■
..'.
.
- -%
i
Gentamicin8
Amphotericin Bf
Clindamycin4
8
2-4
10
0.5-3.5
10
20-40
Chloramphenicol is the only parenteral preparation that does
does not
tot lead to adequate intraperitonea!
intraperitoneal JeveK
levels,
Tetracycline and erythromycin are not recommep^a
Hours to Attain
Therapeutic
Serum Levels
Drug Stabil
ity in the
Dialysate
3-18
3-7
4
6-20
4-6
8-20
1-6
6-12
10-20
240
4-6
8-12
8-12
(probably)
8-12
36 hr
12 hr
8-24 hr
Stable if
acid pH
36 hr
36 hr
Stable
i
24-48
40
1.5-3.5
5-7
10-12
End-Stage Renal
Disease, Half-life
in Hours
24-50
not become active intraperitoneally, and oral or
8
I
36 hrb
Stable
Stable
parenteral administration
——
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»«M ”« ““l; 5
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I. Antibiotics Used to Treat Peritonitis During Dialysis
Table IK
Serum Level Attained
Safe Serum
Intraperitoneal
With Routine Parenteral
Level
Dose (mg/L or
Generic
Doses (/xg/ml)
(gg/ml)
gg/ml)
Name
10-30
50-100
20-50
Cephalothin
50-100
50
50
Ampicillin
16-72
100-200
100
Methicillin
15 U/ml
80
U/ml
1000-50,000 U/L
Penicillin G
(1 p.g « 1.6 U) >
110-170,
200
200
Carbonicillin
,23-40
15-25
15
Vancomycin8
3-14
10-12
8
Tobramycin*
.'.
3
E
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if*
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0Q
d
8
5*
r
£
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i
198
ft
11: Approach to Drug Use in the Azotemic Patient
of thiocyanate toxicity, which include nausea, vomiting, myoclonic movements,
and seizures, can be rapidly alleviated by dialysis. Because of the potentia
for accumulation of thiocyanate, nitroprusside infusions to patients with renal
failure are best terminated within 48 hours. Although no dose
d™ adjustments
- :
; “
LA
----- v
* ;• hydralazine,
»
for renal failure are
required AV*
for clonidine, -methyldopa
prazosin,’
it may be wise to omit a dose just before dialysis
guanethidine, or minoxidil,
i
ire likely
to have hypotension
during the procedure.
in patients who are
----- J----..
js onen
often used
usea In
in pmiwma
patients with
«««• renal
•«<•— failure3
F. Miscellaneous drugs
be- used in patients with Cr—..
1. Anticonvulsants.i. Standard
J doses of phenytoin may- u
i • __ i______ a. AUL«.,/»k
JonroacpQ nhpnvtxiin nindinfiT
all UCgrctiS
degrees ui
of renal
uremia
decreases
binding
i eiicii impairment.
xiiipcxn nivuv. Although
a
*— - ------- —
-- ----*phenytoin
x r
i
il.
xx
F1O QTTIAllTll AT
plasma proteins, accelerated
metabolism
by4-L.
the
liver 1/nnnc
keeps ♦the
amount ot
:e drug
dm2 at relatively therapeutic levels. Even so,, either lower than therapeutic
*
free
or toxic total phenytoin plasma levels may occur in patients with renal failure.
Phenytoin is not removed
i---- . significantly
. by. hemodialysis, and supplemental
arp not necessary. No good data —
are -------------------available on the didoses postdialysis, are
afyzability of other anticonvulsants.
For the long-acting barbiturates, empiric decreases in drug dosage are needed,
with close monitoring of plasma levels and observation for toxic effects. Phen
obarbital is dialyzable. For treatment of status epilepticus, usual doses of par
enteral diazepam may be administered.
2. Immunosuppressive and antlneoplastic agents. The drugs most commonly
used in therapy of immunologically mediated renal diseases and renal trans
plantation are azathioprine and cyclophosphamide. Considerable dosage reduction of cyclophosphamide is required in patients with renal failure since
significant renal excretion of active alkylating metabolites occurs. In patients
with renal insufficiency, empiric decreases in cyclophosphamide dosage are
indicated in association with evidence of toxic effects (e.g., leukopenia), borne
data suggest an increased pharmacologic effect when azathioprine is admin
istered to patients with advanced renal failure, so careful monitoring is required
when these drugs are used in patients with renal failure. Some cyclophos
phamide and azathioprine may be lost during hemodialysis.
The antineoplastic drugs actinomycin D, bleomycin, cis-platinum, 5-fluorouracil, melphalan, methotrexate, and streptozocin all undergo considerable
renal elemination of either-parent drug or active metabolites and therefore
require empiric dosage decreases with evidence of toxic effects in patients with
compromised renal function. Considerable dialyzability has been demonstrated
for 5-fluorouracil and methotrexate, whereas bleomycin does not appear to be
significantly dialyzable.
3. Other drugs
t
a. Cloflbrate. Clofibrate is used as a hypolipidemic agent m uremic patients.
Because of the high degree of protein binding and considerable renal elim
ination of clofibrate, use of this drug may be associated with a high frequency of skeletal muscle damage when administered in standard doses
to either nephrotic patients or patients with renal insufficiency. The drug
probably can be used to lower serum triglycerides safely in patients
undergoing maintenance hemodialysis if reduced doses are prescribed.
b. Anticholinergic agents. The anticholinergic drugs are often used in treating
gastrointestinal disorders. Little modification of dosage is needed in renal
patients. Care must be taken with these agents to avoid urinary retention
that may additionally compromise renal function.
c. Metoclopramide. Metoclopramide, a dopamine antagonist, has proved
useful for management of nausea and vomiting associated with uremia or
diabetic gastroparesis. The dose should be 50 percent of normal in patients
with advanced renal failure.
3
d. Cimetidine. Cimetidine, currently in widespread use for treatment and
prophylaxis of peptic ulcer disease, undergoes considerable renal elimi
1nation. A dose of 300 mg every 12 hours should produce adequate inhibition
of gastric acid output in anephric patients.
XWX
********••,**—•—*•** — “ ' ■
. — — —- ----------
V
...
11: Approach to Drug Use in the Azotemic Patient
ManageJ^
of forced diuresis, dialysis, and hemoperfuslon.
* Active measures to remove exogenous poison or drugs taken in overdoses are compu?x.
Undoubtedly the major factor in patient survival is exP€rt ^ePslv®t‘ L,
To be useful in treating poisoning, toxic drug effects should be rela^^ejla
concentration or the duration of the drug in the body. The amount of.drug
by diuresis, dialysis, or hemoperfusion should represent a
the drug’s or poison’s usual elimination route. Pentoneal dialysis, because of relatively
low clefrance rates, has little role in acute overdoses. Resin and charcoal
fusion are absorbent procedures in which blood passes directly over absorbent ma
terials Compounds poorly removed by conventional hemodialysis are ofteneffectively
eliminated. Exact indications are not yet established Drugs that may be
from the body effectively by forced diuresis, hemodialysis, and hemoperfusion are
listed in Table 11-9.
'
.
Table 11-9. Drugs Removed by Forced Diuresis. Hemodialysis, and Hemoperfusion
3
43
*3
Drug Removal
Forced diuresis: Intravenous fluid
(plus osmotic agents such as
mannitol, 25-50 gm, every 2-4
hr) to achieve urine flow of 3-6
ml/kg'hr
Alkaline diuresis. Sodium bicar
bonate l-j-2 mEq/kg IV
Acid diuresis. Add ascorbic acid,
500 mg to 2 gm IV or am
monium phloride, 75 mg/kg/day,
in four divided IV doses
Hemodialysis
Immediate therapy indicated
■«
>
199
1
Indicated for severe overdoses or if
usual elimination routes un
available (i.e., liver or kidney
disease)
Hemoperfusion: May be used in se
vere overdoses only
Drug
Comment
Bromide
Follow electrolytes; re
place fluid losses with
0.45% NaCl to avoid
z hyperosmolarity
Isoniazid
Phenobarbital
Salicylates
Amphetamines
Phencyclidine
Strychnine
Quinine/quinidine
Follow electrolytes closely, j
with early potassium ,
supplementation
’
Contraindicated in liver
and renal disease
Ethylene glycol,
methanol if blood
level >50 mg/dl
Ethyl alcohol if
blood level > 90
mg/dl
Salicylate blood
level >100
mg/ml
Long- and short
acting barbitu
rates
Digoxin
Glutethimide
Meprobamate
Methaqualone
\ IV ethanol may be adjunc. tive therapy
Blood levels are only
guides; clinical judg
ment must be exercised
Most reports are anec
dotal; procedure lowers
blood platelets by
25-30%; contraindi
cated in patients at risk
of bleeding
I
/
11: Approach to Drug Use in the Azotemic Patient
Suggested Reading
n
-
» w v ♦
r
GambertogUo, J. G.t and Schrier, R. W. Fate of
S
The Patient With
Kidney Disease and
Hypertension in
Pregnancy I1
Marshall D. Lindheimer
and Adrian I. Katz
■
K P^n “
’Am-
y
"cheZa^ p” ^bZ,' D. C. Nomograms for drug use in renal disease. CUn.
pharrnacoki.net- 6:193, 1981.
rrp
Cockcroft, D. W„ and Gault, M. H. Prediction of creatinine clearance for serum
atinine. Nephron 16:31,1976.
phnrG.bson, T. P .and Nelson, H. A. Drug kinetics and arfficml kidneys. CUn. Pha
|
f;t
i
I
lb
!
i
H i
1
1
macokinet. 2:403, 1977.
.q7q
Golper T. A. Drugs and peritoneal dialysis. Dialyse Transplant. 8.41, 1979.
u
j Winchester J F Hemodialysis and hemoperfusion for drugs
Knepshield,J.H.,and Wmc.
, JOrgans 28:666,1982.
and poisons. Trans. Am. Soc. Artif. intern, u B
Mawer, G.E. Dosage adjustment in renal insufficiency. Br. .Can. oar
1982‘ •
a
Ju H T H Amikacin serum concentrations: Predictions of levels
Sarubbi, F. A., and Hull, J. H.
and dosage guidelines. Ann. Intern. Med. 89.612, 18.
Sher P P Drug interferences with clinical laboratory tests. Drugs 24.24,
■
failure; Pharmacokinetic and clinical impucau
C!
A k
eh
'l
Gestation in women with preexisting renal disease, regardless of type or severity,
alarms physicians. Their concern is frequently shared by consultant nephrologists,
whose experience may be based on patients referred after complications have occurred.
As a result, pregnancies are often interrupted and contraception advised. Such views,
however, are unduly pessimistic. It is now apparent that in most instances gestations
in women with renal disorders end successfully, especially when kidney function is
well preserved and hypertension absent.
I The kidney and blood pressure in normal pregnancy. The anatomy and function
’ of the kidneys and lower urinary tract are altered in gestation. There are also phys
iologic alterations in volume homeostasis and blood pressure control, recognition of=
which is a prerequisite for the appropriate interpretation of data from pregnant pa
tients with renal disease or hypertension _(Table 12-1).
A Anatomic and functional changes in the urinary tract. Kidney length increases
approximately 1 cm during normal gestation. The major anatomic alterations of
the urinary tract during pregnancy, however, are seen in the collecting system,
where calyces, renal pelves, and ureters dilate, often giving the erroneous
impression of obstructive uropathy. The dilatation is accompanied by hypertrophy
of ureteral smooth muscle and hyperplasia of its connective tissue, but whethex
bladder reflux is more common in gravidas is unclear. The cause of the uretera.
dilatation is disputed; some researchers favor hormonal mechanisms, wherea*other researchers believe that it is obstructive in origin. It is clear that as preg
nancy progresses, assumption of a supine or upright posture may cause uretera
obstruction when the enlarged uterus entraps the ureters at the pelvic brim (Fig
12-1). These morphologic changes have considerable clinical relevance. Stasis ii
the dilated urinary tract may contribute to the propensity of pregnant womei
with asymptomatic bacteriuria to develop frank pyelonephritis. The widenec
ureters contain substantial volumes of urine, which may lead to collection error
in tests that require timed urine volumes. These errors may be avoided by th
following simple protocol: gravidas to be tested receive a water load and reman
in bed positioned in lateral recumbency for 1 hour before the start of the collectior
This procedure minimizes inaccuracies by standardizing the procedure as web
as by producing a modest water diuresis, so that residual urine is dilute and c
recent ori gi n Acceptable norms of kidney size should be increased by 1 cm if estimated durin
pregnancy or the immediate puerpenum, and reductions of renal length note
several months postpartum need notbe attributed to renal disease. Also sine
dilatation of the ureters may persist until the twelfth postpartum week electiv
radiologic examination of the urinary tract should be deferred, if possible, unt
after this time.
_
B. Renal hemodynamics. Values considered normal in nongravid women may retie*
. decreased renal function during pregnancy. For example, in gravid women coi
centrations of serum creatinine exceeding 0.8 mg per deciliter or of serum ure
nitrogen greater than 13 mg per deciliter suggest the need for additional evaluatio
of renal function.
j nn
1. Glomerular filtration rate (GFR) and renal plasma flow (RPF). GFR and HP
increase to levels 30 to 50 percent above nongravid values. Increments th?
are already present during the days following conception become maximal t
2fr
f
\
202
12: The Patient With Kidney Disease and Hypertension in Pregnancy
12:
Table 12-1. Renal Changes in Normal Pregnancy
Alteration
Manifestation
Clinical Relevance
Increased renal size
Renal length approxi
mately 1 cm greater on
roentgenograms
Postpartum decreases in
size should not be mis
taken for parenchymal
loss
Dilatation of pelvic calyces
and ureters
Resembles hydronephrosis
on intravenous pyelog
raphy Ctnore marked on
right)
Not to be mistaken for
obstructive uropathy;
elective pyelography
should be deferred to the
twelfth postpartum week;
upper urinary tract infec
tions are more virulent;
retained urine leads to
collection errors
Increased renal hemody
namics
Changes in acid-base me
tabolism
Renal water handling
Glomerular filtration rate
and renal plasma flow in
crease 35-50%
Renal bicarbonate
threshold decreases
Osmoregulation altered
£ - ■
-3
0
e
Serum creatinine and urea
N values decrease during
normal gestation; so
values > 0.8 mg% Cr and
13 mg % urea N are al
ready suspect; albumin,
amino acid, and glucose
excretion all increase
Serum bicarbonate is 4-5
mM/L lower in normal
gestation
Serum osmolality decreases
10 mOsm/L (serum
sodium I 5 mEq/L) dur
ing normal gestation
% s
3
r
3
postmortem studies. Note the iliac sign at the pelvic brim on the right (From P.
'Dure-Smith, Pregnancy dilatation of the urinary tract. Radiology 96.545, 19/0.)
e.
C
3
the end of the first trimester. According to some authors, these increments
are sustained until term, whereas other investigators have observed a decline
in creatinine clearance during the last four weeks of pregnancy.
The increase in GFR has important clinical implications. Since creatinine pro
duction is unchanged during pregnancy, increments in its clearance result in
decreased serum levels. Using the Hare method, one group of investigators
observed that true serum creatinine, which averaged 0.67 mg per deciliter in
nongravid women, decreased to 0.46 mg per deciliter during gestation. In
studies that also measured creatinine chromogen (resembling results reported
in most clinical laboratories), values were 0.83 mg per deciliter in nonpregnant
women and decreased to 0.74, 0.58, and 0.53 mg per deciliter in the first, second,
and third trimesters, respectively.
2. Blood urea nitrogen. Similar changes occur in the mean value of blood urea,
but some of these alterations may be due to enhanced protein synthesis in
addition to increments in the clearance of this solute. In a serial study of 83
gravidas, blood urea nitrogen averaged 9.8, 9.2, and 9.2 mg per deciliter in
each trimester and rose to 12.1 mg per deciliter 6 weeks postpartum.
3. Other hemodynamic alterations. Several other changes that occur in gestation
may be due to altered hemodynamics. Excretion of glucose, most amino acids,
and several water-soluble vitamins increases. Increments in urinary nutrient
content, for instancey may be a factor in the enhanced susceptibility of gravidas
to urinary tract infections. Urinary protein excretion also increases during
gestation.
Acid-base regulation in pregnancy. Renal regulation of acid-base is altered during
gestation. The bicarbonate threshold decreases, and early
unnes
often more alkaline than those in the nongravid state. In addition,
carbonate concentrations decrease approximately 4 mM per i er, averag g
*
diminished, pregnant women are in theory at a disadvantage w.en
bv sudden metabolic acidosis (e.g., lactic acidosis in preeclampsia, diabetic ke
toacidosis, or acute renal failure). However, they respond with appropriatej in
crements in urinary titratable acid and ammonia after an acid load, and proton
regeneration is already evident at blood pH levels higher than those in similarly
3
.a
€
>3
D.
Water excretion. After conception there is a rapid decrease in plasma osmolality
that levels off at 5 to 10 mOsm per kilogram below that of nongravid subjects.
If this decrease occurred in a nonpregnant woman, she would cease secreting
antidiuretic hormone and enter a state of water diuresis. However, gravidas
maintain this new osmolality, diluting and concentrating their urine appropriately
when subjected to water loading or dehydration. This suggests a resetting of
the osmoreceptor system, and indeed recent data demonstrate that the osmotic
thresholds for both thirst and vasopressin release are decreased in pregnant
There are also reports that women with diabetes insipidus who become pregnant
require increments in their vasopressin injection (Pitressin) or dDAVP (1 des
amino, 8 D-arginine vasopressin) dosage. Whether this relates to increased renal
hemodynamics and/or prostaglandin production or to a placental enzyme that
« -!
! \
12: The Patient With Kidney Disease and Hypertension in Pregnancy
204
12; The Patient With Kidney Disease
and Hypertension in Pregnancy
^4^
described;
destroys vasopreffiin
4S
vasopressin or dDAVP, and the other rs due to m
,
vivo destruction or renal resistance to ^^^^proximatelv 12.5 kg during the
E. Volume regulation. Most healthy
pregnancies. Generations of
first pregnancy, and 1 kg less <
ga
r limits of permissible weight
physicians have considered these
to deyiat
ions about
leviauons
auvuv a
a mean,
■eight
gain, and their salt
gains, forgetting tha
folded for excessive wt*
6^,
|
r
_I J
r
c
“SSX. a-SSSw -
I ■
g
VvrvH\7
during midpregnancy, wnereas mere
cumulative retention of approxiin the third ta™es(.ter,T^erien'remanc^that is distributed between the product
mately 900 mBq of sod.um P^^uyular ^ce. These alterations in maternal
of conception and the maternal jproduce a physiologic hypervolemia,
intravascular and interstitial
changes as normal, and when salt
yet the gravidas volume recepto
nse ^ physiologic expansion, maternal re
restriction or diuretic therapy hmto^.
'regna* women. This is one comsponses resemble those n salt P
g de<;ade agojwhereby gravidas
II
r
u
V
GFR means that up to 10,000 addrt
iderablv greater than the expected
the renal tubules each day,^a'y^ ^^rticoids ’(aWosterone, desoxycorticossalt-retaining potency °
e j ofwhich increase in pregnancy,
terone, estrogen), the blood level
Dressurc starts to decrease early m gesF. Blood pressure regulation. Mean
Pav
ing 10 mm Hg less than meastation, diastolic tevels >n ™'dP p nCT blood pressure increases, gradually apurements postpartum. In 'a^r Pre^since cardiac output rises quickly in
proaching prepregnancy vatees nea
constant thereafter, the decrease in
the first trimester and r®™?’d^^ent in peripheral vascular resistance. The
pressure is due to a ma^
following a midtrimester nadir is interesting,
c, .3
e
e
A V A.
1
■I
il
i; id
-J
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I series) may also
° „ angiotensin levels, increase sub
renin, its activity, and its ^bstrate
g ressor effects of angiotensin
Stantially. but gravidas are ex^Xbe^na?tered in gestation.
II. Catecholamine levels^in blood pres6®re during normal gestation
Lack of awareness of the tluctuau.
with ml]d essential
may lead to ^^Pf^^X^Aence the normal decrease in blood
hypertension who m the first to®;n pregnancy They are then erroneously
pressure display near nonnal level., ear^
8aranyly el(!V!lted pressures occur,
labeled preeclamptic m the■las
.
jn the 5econd and 85
W
"^ered as upper limits of normal.
II. Clinical evaluation ol' r®"®1
f^of proteinuria with eclampsia was first
*&’a
€*
4
205
detection of excessive protein excretion or microscopic hematuria during a routine
Heakhy nonpr^nt women excrete considerably less than 100 mg of protein
in the urine daily, but due to the relative imprecision and variability of testing
methods used in hospital laboratories, proteinuria is not considered abnormal
until it exceeds 150 mg per day. During pregnancy protein excretion increases
and excretion up to 300 mg per day (some authors accept 0.5 gm/day) may still
be normal. On occasion, a healthy gravida can excrete more than that amount.
The problem is compounded by the fact that about 5 percent of healthy adolescents
and young adults have postural proteinuria, which may become apparent only
during pregnancy. In addition, postural proteinuria may increase near term, when
gravidas tend to assume a more lordotic posture, which augments excretion. An
other cause of increased proteinuria in pregnancy may be compression of the
renal veins by the enlarged uterus, especially when gravidas he supine, thus,
when the gravida is tested for postural proteinuria (see Chap. 8, sec. I.D, under
Proteinuria), she should be positioned in lateral recumbency.
There have been few attempts to quantitate urine sediments m pregnancy, lhe
excretion of red blood cells may increase during normal gestation. Whether in
creased leukocvturia also occurs during pregnancy is not clear. Since microscopic
examination of the urine sediment is an important and nonmvasive technique,
it is unfortunate that so little has been done to standardize this test for pregnant
B Renal function tests. The clearance of endogenous creatinine, the most satisfactory
approximation of GFR in nongravid subjects, is equally useful for assessing renal
function in gravidas. Gravidas as well asmonpregnant women show lithe variation
(approximately 10 percent per day) in urinary creatinine excretion and presum
ably in creatinine production, which in a given woman is similar both during
and after gestation. The lower limit of normal creatinine clearance during ges
tation should be 30 percent greater than that of nongravid women, which m most
hospitals averages 110 to 115 ml/min/1.73 sq m.
....
.,
,
Acid excretion and urinary concentration and dilution are similar m gravid and
nonpregnant women. Thus, tests such as ammonium loading (rarely indicated m
gestation) give values similar to those in nongravid women. When examining
urinary diluting ability, the clinician should be aware that supine posture can
interfere with this test. Therefore, studies to detect minimal urinary osmolal
concentrations should be performed with the patient lying on her side. However,
although lateral recumbency is the required position for prenatal measurement
of most renal function parameters, this posture interferes with tests of concen
tration. For example, a urine osmolality that was 800 raOsm per kilogram after
overnight dehydration may decrease to 400 mOsm per kilogram within an hour
when a lateral recumbent position is assumed. Such changes may be explained
by fluid mobilization from the extremities during bed rest, resulting in either
volume-induced inhibition of vasopressin secretion or a mild osmotic diuresis.
Such observations demonstrate the importance of upright posture, such as quiet
sitting, when maximum urinary concentration is measured in pregnancy.
C. Role of renal biopsy In pregnancy. Percutaneous renal biopsies were introduced
in the 1950s. and subsequent investigations correlating light, electron, and immunofluorescent microscopy with alterations in renal function have revolutionized
our understanding of the pathology and natural history of Kidney disease in non
pregnant populations. Few such studies have been reported on renal disease in
pregnancy mainly because clinical circumstances rarely justify the Slight risks
of biopsy during gestation and the procedure is usually deferred to the postpartum
period. Another reason may have been a report of excessive bleeding and other
complications in gravid women that led some physicians to consider pregnancy
a relative contraindication to renal biopsy. These views, however were based on
the earlier practice of performing prepartum and intrapartum (i.e., during cesarean
section) biopsies in women who were hypertensive, and at a time that predates
current understanding of the coagulation abnormalities occasionally seen in
206
12: The Patient With Kidney Disease and Hypertension in Pregnancy
12: The Patient With Kidney Disease and Hypertension in Pregnancy
preeclampsia. It is now evident that if the biopsy is performed in the immediate
puerperium in a woman with well-controlled blood pressure and normal coagu
lation indices, morbidity is similar to that in nongravid patients.
There are relatively few indications for antepartum renal biopsy, one being ne
phrotic syndrome of unknown cause first diagnosed in midpregnancy or early in
the third trimester. Diagnosis of preeclampsia may influence decisions concerning
termination of pregnancy, whereas demonstration of other pathology by biopsy
helps in the determination of appropriate therapy. Renal biopsies should not be
performed after gestational week 32 since at this stage the fetus will probably
be delivered in any case, and the decision usually has to be made quickly and
independent of biopsy results.
D. Clinical application. Some of the normal morphologic and physiologic adjustments
that affect the kidney during pregnancy and the application of such information
to detecting disease are illustrated in the following case report.
Example: A 25-year-old multipara with known hypertension was hospitalized at
31 w^eks of gestation with a blood pressure of 200/140 mm Hg. Treatment included
a single 20-mg dose of hydralazine, 2 mg trichlormethiazide daily for 3 days, bed
rest in the position of lateral recumbency, and restriction of dietary sodium. After
2 weeks, weight decreased 4.6 kg and diastolic blood pressure now averaged 90
to 100 mm Hg. Unfortunately, urine volumes declined, and the creatinine clear
ance decreased from 106 ml per minute on the sixth to 82 ml per minute on the
sixteenth hospital day (Table 12-2). Simultaneously, blood urea nitrogen increased
from 8 to 25 mg per deciliter. Interruption of gestation was considered, since
deteriorating renal function was regarded as a sign of superimposed and pro
gressing preeclampsia. However, a diagnosis of salt depletion was also entertained.
A trial period in which sodium intake was increased to 206 mEq per day followed.
After sodium intake was liberalized, weight increased 1.5 kg, but diastolic blood
pressures remained between 90 and 100 mm Hg and the creatinine clearance
increased to 118 ml per minute. Serum creatinine and urea nitrogen decreased
to 0.9 and 16 mg lOO ml, respectively. The gestation was allowed to continue
until labor ensued spontaneously.*
This report demonstrates the advantage of estimating GFR from serum creatinine
rather than plasma urea levels. Alterations in serum creatinine mirrored changes
in its clearance, whereas this relation was less clear in the case of urea nitrogen.
The GFR was low for pregnancy, illustrated by the serum creatinine values of
0.9 to 1.3 mg per deciliter, which are acceptable in nonpregnant women but ab
normal during gestation. On the other hand, there was a normal plasma urea
nitrogen on admission, perhaps reflecting poor nutrition. It is also interesting
how easily this patient became dehydrated (a fact not appreciated by many who
manage pregnant women). With dehydration and oliguria the concentration of
urea increased threefold while the serum creatinine clearance decreased only 23
percent. However, when GFR increased to values greater than those measured
on admission, urea nitrogen was still 16 mg per deciliter, probably reflecting a
good hospital diet.
III. Renal disease in pregnancy
A. Asymptomatic bacteriuria. Urinary tract infection is the most common renal
problem occurring in pregnancy. The urine of gravidas supports bacterial growth
better than that of nonpregnant women, due to its increased nutrient content.
This, as well as ureteral dilatation, stasis, and occasional obstruction, would be
expected to increase the susceptibility of pregnant women to urinary tract in
fection. Surprisingly, this is not the case, and, with the exception of certain highrisk groups (diabetics and gravidas with sickle cell trait), prevalence of asymp
tomatic bacteriuria during gestation varies between 4 and 7 percent, a value
• similar to that of sexually active nonpregnant women. The natural history of
asypptomatic urinary tract infections is, however, quite different in pregnancy.
* Adapted from J. Palomaki and M. D. Lindheimer, Sodium depletion simulating deterioration in a
toxemic pregnancy. N. Engl. J. Med. 282:88, 1970.
207
Table 12-2. Renal Function During Hospitalization
e.
3
e. 3
e 3
e-,
3
C:
3
3
e;
3
*X7-
Function
Day 6
Day 16
Day 26
Creatinine clearance (ml/min)
Serum creatinine (mg/dl)
Serum urea nitrogen (mg/dl)
Maximal urine flow, < ml/min)
106.0
1.1
8.0
82.0
1.3
25.0
2.3
118.0
0.9
16.0
8.7
Although in the nonpregnant state the situation is quite benign, progression to
overt cystitis or pyelonephritis occurs in up to 40 percent of affected gravidas
(Table 12-3). Therefore, it is important to screen all pregnant women for the
presence of asymptomatic bacteriuria and to treat those with positive urine cul1. Method of urine collection. Pregnant women contaminate midstream urine
specimens more frequently than do nonpregnant persons. The incidence can
be reduced by the use of multiple vulval washings combined with carefully
supervised collection procedures. There are some women in whom suprapubic
aspiration is required to differentiate contamination from true infection. There
is no contraindication to this procedure in pregnancy.
If the urine is sterile at the beginning of pregnancy, it usually remains so
until term. Still, a small number (1 to 2 percent) of gravidas Whose original
urine cultures are negative subsequently have bacteriuria. Abnormal urinalysis
and the presence of dysuria do not differentiate between contamination and
true infection. For example, dysuria occurs in 30 percent of gravidas whose
urines are sterile, and the urine may be infected and still contain fewer than
two leukocytes per high power field.
2. Method of treatment. There is some controversy about the optimum treatment
of asymptomatic bacteriuria in gestation. Some authors, believing that gravidas
have a high relapse rate, recommend prolonged antibiotic treatment. However,
approximately 50 percent of patients have bladder involvement only, and most
infections appear to respond to a simple 8- to 12-day course of therapy. Thus,
we recommend a 2-week course, preferring the initial use of short-acting sulfa
drugs or a nitrofurantoin derivative and reserving the more potent agents
(ampicillin, cephalosporins, or carbenicillin) for treatment failures and for
symptomatic infection. Of course, the choice of antibiotic agent in both situ
ations should always be based on the sensitivity of the isolated organism.
3. Importance of postpartum evaluation. Asymptomatic^urinary tract infection
• has been linked to premature labor, hypertension, and anemia during gestation,
but these assertions have not been proved. On the other hand, there is an
increased incidence of occult urinary tract pathology in these gravidas. Therefore, women with bacteriuria during pregnancy may benefit from evaluation
of their urinary tract postpartum by excretory urography.
i
j
]
|
|
1
I
i
■
Table 12-3. Relation Between Asymptomatic Bacteriuria
and Antenatal Symptomatic Urinary Tract Infection
,
Patient Status
Number
Followed
Number
Symptomatic
Percentage
Untreated bacteriuric
Treated bacteriuric
Nonbacteriuric
1609
421
13,742
464
15
246
28.8
3.6
1.8
/
Source: M. D. Lindheimer and A. I. Katz, Renal Function and Disease in Preg
nancy. New York: Lea & Febiger, 1977.
A-4
' \
12: The Patient With Kidney Disease and Hypertension in Pregnancy
' 3
««*>
* is.
1
*
3
Ut
mJ
3
3
3
3
Fig. 12-2. Transverse sonogramwhich W3S first discovered and
corresponded to an enlarf^’^
The uterus is on the left, the
subsequently became infected dur g P £
y
Kidney Function and
v”>?£ i
Ih
**’3
°,J ”■B"*
B. symptomauc bacter^rla. The clinical
infection during gestation differs from that wrasjp^
of aU
t. Acute pyelonephritis.
‘Antibiotic era. and 3
pregnancies was a
of ™aternabdeath^
45
I H
Most patients with
i
]|
I,. Hjy
■ it
U to g/avidas with asymptomatic
normal within 48 to
hours),
,
become reinfected. Therefore,
hacteriuria, they are very likely to ^aP^0^^iUin) such WOmen should
aftor initial therapy ^.^^4 wZksXr which their urine should
receive appropriate antibioticsTo r3
Some authors
be screened frequently during
_
prophylaxis to term in such patients,
also recommend continuous dntib>o p Pd
j abscess formation
2. perirenal and renal abscess
sh™ld
con'
or carbuncle, although m^uennt .^^fP^^um fever (Fig. 12-2). The insidered in the differential
percent during the first
cidence of positive urine cultures .
thPthird postpartum day.
days after delivery amb^bably reflects the inability to prevent
Tins apparent spontaneous
hSi i^dence of infection. Thus, when
n^uAof the puerperium. suprapubic
i it
aspiration of urine Js
3-
f
I’
be’ used in pregnancy.
near term as they may precipitate kernicterus
£ $
r -9
^;b
i p
er
209
in the newborn. Ampicillin, the cephalosporins, and carbenicillin. are the agents
most commonly used in the treatment of symptomatic infections during preg
nancy. The combination of trimethoprim and sulfamethoxazqle is gaining in
popularity, but we await more careful scrutiny of its effect on the fetus. Nat
urally, the drugs chosen should preferably be those that have stood the test
of time for safety in pregnant women.
C. Acute renal failure
1. Incidence. Two decades ago the incidence of acute renal failure in pregnancy
was estimated at between 1 in 2060 and 1 in 5000 gestations and represented
a considerable proportion of cases reported in large series. More recently the
number of patients with acute renal failure from obstetric causes has declined
markedly and the incidence is now estimated to be less than 1 in 10.000 preg
nancies. This trend, attributed to liberalization of abortion laws and improve
ment of prenatal care, has not been shared by the poorer and less industrialized
nations, in which such patients comprise up to 25 percent of referrals to dialysis
centers and in which renal failure in pregnancy continues to be an important
cause of maternal and fetal mortality.
The frequency distribution of acute renal failure during gestation is bimodal,
with one peak early in pregnancy (12-18 weeks) comprising most of the cases
associated with septic abortion, and a second peak between gestational week
35 and the puerperium, primarily due to preeclampsia and bleeding compli
cations, especially placental abruption.
2. Causes. Most gravidas with acute renal failure have acute tubular necrosis.
Rarely, glomerular disease or obstructive nephropathy is also seen. IrTcontradistiriction to the etiologic breakdown in nonpregnant populations, there
is a greater incidence of acute cortical necrosis during pregnancy. The latter
entity is most likely to occur late in gestation, as it is frequently associated
with abruptio placentae. Although the necrosis may involve the whole renal
cortex and cause irreversible anuria, the “patchy” variety occurs more often
in pregnancy. This patchy necrosis has a distinctive course, with an initial
episode of severe oliguria followed by a variable return of function, characterized
by a stable period of moderate renal insufficiency. However, after several years
(and for obscure reasons) renal function again declines, often leading to terminal
kidney failure.
There are two rare forms of acute renal failure specific to pregnancy. One is
associated with acute fatty liver of pregnancy and is characterized by jaundice
and severe hepatic dysfunction in late gestation or the immediate puerperium.
Renal failure in this condition may be due to hemodynamic factors (analogous
to the hepatorenal syndrome), and some cases have been associated with in
travascular coagulation and hepatic fibrin deposition. The mortality rate is
high and is due primarily to liver failure, but a substantial number of these
patients recover following rapid termination of the pregnancy.
The second disease, known by a variety of names, is best labeled idiopathic
postpartum renal failure. Such patients have uncomplicated pregnancies and
deliveries, but present 3 to 6 weeks in the puerperium with uremia, severe
hypertension, and often, evidence of microangiopathic hemolytic anemia. The
cause of the condition is unknown, although viral agents, ergot compounds,
oral contraceptives, and retained placental fragments have all been suggested.
Most of the affected women succumb, or if they survive do so with severe
ly reduced renal function, but recoveries have been recorded. Since there
are claims that the disease has been contained and/or reversed with anticoagu
lant therapy, this therapeutic approach combined with dilatation and curet
tage of the uterus, may be tried. Poststreptococcal glomerulonephritis sec
ondary to endometritis may cause acute renal failure postpartum and there
is also an increased incidence of thrombotic thrombocytopenic purpura post
partum.
3. Management. The management of acute renal failure occurring in gestation
or immediately postpartum is similar to that in nongravid subjects (see Chap.
9), but several points peculiar to pregnancy deserve emphasis. Since uterine
210
12: The Patient With Kidney Disease and Hypertension in Pregnancy
12: The Patient With Kidney Disease and Hypertension in Pregnancy
hemorrhage near term may be concealed and blood loss underestimated, any
overt blood loss should be'replaced early. Gravidas should be slightly over
transfused to forestall the development of acute tubular or cortical necrosis.
Both peritoneal dialysis and hemodialysis have been successfully used in pa
tients with obstetric acute renal failure. Neither pelvic peritonitis nor the
enlarged uterus is a contraindication to the former method. However, when
circumstances dictate the use of peritoneal dialysis rather than hemodialysis,
the catheter should be inserted high in the abdomen, preferably under direct
vision. Finally, since urea, creatinine, and other metabolites that accumulate
in uremia traverse the placenta, dialysis should be undertaken early, with
the aim of maintaining the blood urea nitrogen at approximately 30 mg per
deciliter. The advantages of early dialysis in nongravid patients are even more
important in pregnancy, making arguments for prophylactic dialysis quite
compelling.
.
,
D. Pregnancy in women with preexisting renal disease. The current approach to
pregnancy in women with chronic renal disease is primarily based on retrospectiv e
studies, and more definitive views must await prospective data from large series
in which clinical, pathologic, and functional observations are correlated. Never
theless, several generalizations can be made and guidelines presented regarding
gestation in women with chronic kidney dysfunction (Table 12-4).
1. Prognosis
,,
a. Degree of renal impairment. The ability to sustain a viable pregnancy
decreases as renal function declines, and when serum creatinine and urea
nitrogen exceed 3 and 30 mg per deciliter, respectively, before conception,
normal gestation is rare. Contraception or early termination of pregnancy
is generally recommended in women w’hose serum creatinine exceeds 2
mg per deciliter, but it should be noted that women with moderately severe
disease manifesting azotemia greater than that described above have borne
viable infants. There are even rare instances in which women undergoing
maintenance hempdialysis have conceived and the gestation has ended
successfully.
b. Level of blood pressure. The blood pressure level at time of gestation is
an important prognostic-index. In the absence of hypertension, the natural
history of most established renal parenchymal diseases is unaffected by
gestation (although preeclampsia may occur more readily). In contrast,
when renal disease and hypertension coexist the gestation is more likely
to be complicated, either by severe increments in blood pressure or by ad
ditional reductions in renal function. Such women should be counseled to
avoid conception and if they do become pregnant to terminate the preg
nancy. If they wish to continue the pregnancy and to take the risks ex
plained to them, these gravidas must be seen weekly and should understand
that their gestation must be terminated if renal function deteriorates or
if their blood pressure becomes difficult to control.
I c. Proteinuria. Urinary protein excretion, which increases in normal preg
nancy, may increase markedly in pregnant women with underlying pa
renchymal renal disease. In one large series one-third of the patients de
veloped nephrotic-range proteinuria during gestation. In most instances,
however, these increments do not reflect worsening of the underlying kidney
disease.
d. Renal hemodynamics. Gravidas with kidney disorders who have only
minimal renal dysfunction usually experience increments in GFR during
gestation, even though levels do not reach those seen in normal pregnant
women. Thus a decrement in serum creatinine level early in pregnancy is
a good prognostic sign. If serum creatinine levels before conception exceed
j 1.4 mg%, decrements during gestation are less common and the prognosis
of such pregnancies is more guarded.
2. Glomerulonephritis. Absence of gravidas in large epidemiologic surveys of
poststreptococcal glomerulonephritis is remarkable and has led to speculations
that pregnancy protects women from this disease. However, this form of im-
3
3
c.
3
ST,
3
Table 12-4. Summary of Pregnancy in Women with Preexisting Renal Disease*
Disease
Comments
Chronic glomerulonephritis, noninfectious
tubulointerstitial disease ‘e.g., polycystic
kidneys)
Lupus nephropathy
Usually no adverse effect in the absence of
hypertension; urinary tract infections
may occur more frequently
Controversial; prognosis favorable if
disease in remission at conception;
monitor complement levels during
gestation and increase treatment when
values decrease; steroid dosage should
be increased in the puerperium
Probably no adverse effect on the renal le
sion, although frequency of leg edema,
preeclampsia, and perhaps urinary tract
infection is higher
Tolerated well; infants may have low
birth weight. Diuretics should not be
used
Bacteriuria during pregnancy leads to
more frequent exacerbation
Infection may be more frequent; otherwise,
ureteral dilatation and stasis do not
seem to affect the natural history
Pregnancy usually well tolerated; dystocia
has been attributed to pelvic kidneys
Most pregnancies succeed, but hyperten
sive and infectious problems are more
frequent than in normal gravidas;
immunosuppressive therapy may cause
fetal adrenal failure and congenital
anomalies
Diabetic nephropathy
3
€
3
3
3
211
Nephrotic syndrome
Chronic infectious pyelonephritis
Urolithiasis
Status postnephrectomy; solitary and pel
vic kidneys
Transplanted kidneys
*Generalizations are for women with only mild renal dysfunction (serum creatinine
level <1.5 m^/dl). The natural course of renal disease in women with greater
functional impairment remains to be determined.
^3
3
\
mune complex nephritis does occur rarely in gestation, in which it may mimic
preeclampsia. Its prognosis is favorable, since in those instances in which the
occurrence of acute poststreptococcal glomerulonephritis during gestation was
properly documented, renal function recovered rapidly and the pregnancy
usually had a successful outcome.
The prognosis of chronic glomerulonephritis during pregnancy is difficult to
evaluate because most reported cases are poorly documented, especially the
prepregnancy level of renal function and blood pressure. Still it appears that
if proteinuria or abnormal urinary sediment is the sole manifestation of the
disease, pregnancv will proceed normally. Gravidas with membranoproliferative glomerulonephritis, especially those with dense intramembranous de
posits demonstrated ultrastructurally and women with IgA nephropathy, may
be especially prone to hypertensive complications. Although C3 nephritic factor
may pass from mother to fetus, the neonate appears unaffected and maternal
complement levels may actually rise in gestation.
Hereditary nephritis is an uncommon disorder that may first be manifested
during pregnancy, when women with this disease develop frank nephrotic
syndrome. A variety of hereditary nephritis accompanied by platelet abnor
malities has been described. Pregnancy in these women has been successful
r.
213
12: The Patient With KidneyDiseaseandHypert^n^^
C^4ar ■
complicated by bleeding
tom a renal standpoint, but then gestahons have been
problems.
vascular diseases
^-Hable effects on lupus nephropathy,
3. Collagen
a. Lupus nephritis. Pregnancy’ hasj*n*bte ettec
Qf
with either transient
* , S*apse. ^appears that the longer the
the disease, or a tendency to f ^n^Dt;on the greater the likelihood
disease has been in remission^
should be closely
’*“■
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212
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becomes malignant m nature^
reported cases end in materns.
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12: The Patient With Kidney Disease and Hypertension in Pregnancy
12: The Patient With Kidney Disease and Hypertension in Pregnancy
saliuretic therapy could conceivably compromise uteroplacental perfusion or
aggravate the increased tendency to thrombotic episodes.
6. Tubolo-interitltial disease
a. Chronic pyelonephritis. Dilatation and stasis in the urinary tract make
chronic pyelonephritis in gravidas more prone to exacerbation. These
women should have a high fluid intake prescribed and should be told to
rest frequently on their sides. Prognosis of pregnant women with noninfectious interstitial nephritis seems similar to that of pregnant women
with glomerular disease. Renal functional deterioration may occur rapidly
in this group of patient^when they are inadvertently salt restricted during
gestation.
b. Polycystic disease. Polycystic kidney disease may remain undetected in
gestation. Careful questioning of gravidas for a family history of renal
problems and judicious use of ultrasonography may lead to its earlier de
tection. Patients with minimal functionaljmpairment have few compli
cations, but a greater propensity toward preeclampsia exists. Hypertension
usually accompanies the onset of increased functional deterioration, and
pregnancy in such gravidas is more hazardous. Of interest is a report of
pregnancy in a woman with the infantile variety of polycystic disease who,
although hypertensive before conception, had a successful gestation.
c. Renal tuberculosis and solitary and pelvic kidneys. Renal tuberculosis
does not seem affected by pregnancy. Women with solitary kidneys appear
to tolerate gestation well. However, if the nephrectomy was performed for
nephrolithiasis or chronic pyelonephritis, the remaining kidney is often
infected. Patients with these conditions must be carefully scrutinized by
frequent examination and culture of the urine throughout pregnancy and
in the puerperium.
Pelvic kidneys are apparently associated with decreased fetal survival,
often due to the presence of other malformations of the urogenital tract of
the’ mother. In addition, dystocia may occur when the kidney is in the true
pelvis.
7. Urolithiasis. Prevalence of stone disease in gestation varies between 0.03 per
cent and 0.35 percent in the Western hemisphere. The older literature stressed
the dramatic complications that occur in pregnancy when calculi cause ob
structive uropathy and infection supervenes. However, a recent survey of non
selected stone formers indicates that the course of the disease is unaffected
by pregnancy, although urinary tract infections may be more common. Still,
renal calculi are the most common cause of nonuterine-related abdominal pain
severe enough to require hospitalization during pregnancy. Clinicians should
not be deterred from pyelographic x-ray examinations because the patient is
pregnant when complications suggest the need for surgical intervention.
E. Renal transplantation
1. Fetal and maternal complications. Pregnancy in women who have received
renal allografts is becoming more common. As expected, prognosis is better
when the transplanted kidney comes from a living donor. Most gestations suc
ceed, but both maternal and fetal complications, due in part to the immuno
suppressive therapy, can be anticipated; these include steroid-induced hyper
glycemia, severe hypertension, septicemia, ectopic pregnancy, and uterine
rupture. Fetal problems such as intrauterine growth retardation, congenital
anomalies, prematurity, hypoadrenalism, hepatic insufficiency, thrombocy
topenia, and serious infection in the neonate have been reported.
2. Suggested criteria for pregnancy. The following criteria for transplant re
cipients wishing conception are suggested.
a. Good health and stable renal function for 2 years after transplantation
ft. Stature compatible with good obstetric outcome
<c. Absent or, at most, minimal proteinuria
d. No hypertension
e. No evidence of pelvicalyceal distention on an excretory urogram performed
before attempting pregnancy
1 3
r.
3
4 3
Jr5
& *
215
f. Serum creatinine of 2 mg per deciliter or less and preferably < 1.5 mg/dl
g. Drug therapy, prednisone 15 mg per day or less; azathioprine 2 mg/kg/day
er less
Although stringent, these criteria constitute appropriate prudence until more
information on pregnancy in transplant recipients becomes available.
F. Case history. The following example of two successful gestations in a woman
with diffuse lupus glomerulonephritis demonstrates certain principles in the
management of gravidas with chronic renal disease.
Example: A 24-year-old white gravida 3 para 1 abortus 1 was electively admitted
for induction of labor. Five years previously, she developed fever, arthritis, pleuritic
chest pains, and a malar skin rash 2 weeks after a miscarriage. Systemic lupus
erythematosus was diagnosed, based on a positive LE test and presence in her
serum of antinuclear and DNA antibodies. Her blood pressure was 115/75 mm
Hg. Laboratory examination revealed anemia and leukopenia. Serum creatinine
and urea nitrogen were 1.0 and 15 mg per deciliter, respectively. Protein excretion
(qualitative) was negative, and the creatinine clearance was 110 ml per minute.
A renal biopsy demonstrated diffuse glomerulonephritis. She was treated initially
with prednisone 100 mg per day, which was slowly tapered to 30 mg per day.
Therapy was complicated by development of a gastric ulcer.
The patient became pregnant one year later while in remission and after her
predinsone dosage had been additionally tapered to 15 mg per day. Her prenatal
course was uneventful. During gestation her serum creatinine and urea nitrogen
decreased to 0.8 and 11 mg/100 ml, respectively. Her diastolic blood pressures
ranged between 70 and 80 mm Hg. Prednisone was discontinued during her fifth
gestational month, at a time when all clinical and serologic parameters were
normal.
—
Labor was induced at 40 weeks gestation, resulting in the delivery of a healthy
3420-gm baby. The patient received hydrocortisone 100 mg during labor and 50
to 75 mg everjrG to 8 hours for the next 2 days. During the third postpartum day
she developed transient hypotension, which apparently responded to hydration
and 150 mg ofadditional hydrocortisone. Oral prednisone was then restarted and
maintained at 20 mg per day.
One year after delivery she was operated on for acute appendicitis. Serum cre
atinine was 0.9 mg per deciliter and the blood pressure 136/70 mm Hg. The pa
tient’s third pregnancy occurred in 1977, 4 years after the initial diagnosis of
systemic lupus erythematosus. At that time she was in clinical remission and
her prednisone dosage was increased to 15 mg daily. During gestation the blood
pressure was in the 125/80 mm Hg range, and serum creatinine, urea nitrogen,
and uric acid were 0.8, 7, and 4.6 mg per deciliter, respectively. Urine protein
excretion (qualitative! ranged between negative and 'trace. Inulin and paminohippurate clearances during her seventh gestational month were 157 ml
per minute and 678 ml per minute.
The prenatal course continued uneventfully until gestational week 37, when dec
rements in her hemolytic complement and a rise in her antinuclear factor titer
led the patient’s physicians to increase the prednisone dosage to 30 mg per day.
The complement activity then increased to low normal values.
Delivery was induced at 39 weeks, resulting in a 3675-gm healthy baby. Again,
she received intravenous hydrocortisone during labor and in the immediate puerperium, after which oral prednisone was restarted.
Three months postpartum, the patient’s blood pressure was 100/65 mm Hg. Serum
creatinine and urea nitrogen were 0.9 and 17 mg per deciliter, respectively, and
urinary protein excretion was 350 mg in a 24-hour collection. Repeat inulin and
p aminohippurate clearances were 93.5 ml per minute and 405 ml per minute.
Her steroid therapy had been tapered to 5 mg per day.
The following points are illustrated in this case. The patient’s initial manifestations
of lupus erythematosus appeared to be related to gestation, and her renal biopsy
contained a lesion that has a guarded prognosis. Nevertheless, because functional
parameters and blood pressure were normal, she was allowed to conceive again
twice, and both gestations succeeded. During the first pregnancy steroid therapy
!
I
\
216
5
12: The Patient With Kidney Disease and Hypertension in Pregnancy
12: The Patient With Kidney Disease and Hypertension in Pregnancy___
was
ration, scru my
neajJtei™'
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wisely restarted in the puerperium. During the second gesaamln<nr factors sugg^twi
suggested the
the possibility
possibility of
ofexacerbation
exacerbation
. ,» tiierapy was judiciously increased. Finally, it is noteSice of a diffuse glomerular lesion, the patient ,
4
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PrSciampsla’eclampsla - hypertension peculiar to pregnancy)
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hvnertension, proteinuria,
1’ T^^-t ^T^a"^UUe8hS in la^pregnancy^
edema, and, at times -0^ tnmesUr hypertension is defined as a blood
primarily m nullip „
for 4 to 6 hours. Also, increments
ovTearlier systolic and diastolic pressures exceeding 30 and 15 mm Hg, re-
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present is sufficient reason to proceed
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hypertension, but in some
I
mortality
I
cfa
'nhe aorta. renal disease, pn-
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pheochromocytoma has such a catastrophic outcome
measurement1 of unAary catecholamines or vanillylmandehc
4-^
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4,4
r^ L^torrnvXlar coagulation. It represents a rapidly developing
mS'emergency. Should the patient conceive again, there is a strong proo-
i.
4.
gory includes a numuei ui pauvu«
y
develop hypertension only in the
otherwise difficult to f^^p^e^bmbW pressure normalizes
<
rj;.
V
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I
;X"reL°nt women destmed to have essential hypertension develop
later in life.
X
217
B Pathophysiology and pathology of preeciampsia. The increment in blood pressure
m preeclampsia is characterized by its lability, especially when compared to other
hypertensive disorders. This probably reflects the intense sensitivity of these
women’s vasculature to changing concentrations of their own endogenous pressor
peptides and catecholamines. Whereas normal pregnant women are extremely
resistant to the pressor effects of infused angiotensin, those destined to develop
preeclampsia manifest increased pressor responsiveness to the infused peptide
weeks before the appearance of abnormal blood pressure, weight gain, or signs
of coagulopathy.
.
.
.
In the past much attention was given to edema occurring in preeclampsia. How
ever, preeclampsia can occur in the absence of fluid retention. Even when inter
stitial edema is present, plasma volume is decreased and hemoconcentration is
present.
. . ,
, , .
The incidence of coagulation abnormalities m preeclampsia is debated; in our
experience disordered coagulation occurs in only a minority of patients and usually
in those with the most severe disease.
C. Kidney function and morphology in preeclampsia
1. GFR and RPF. Both GFR and RPF decrease in preeclampsia. The decrements
approximate 25 percent in most instances, so the GFR of preeclamptic women
often remains above pregravid values. However, in rare instances large de
creases in function may occur and, on occasion, lead to acute tubular or cortical
necrosis.
'
.
2. Uric acid. There are changes in the renal handling of urate m preeclampsia.
A decrease in the clearance of uric acid, accompanied by increments in blood
levels of this solute, may occur weeks "before any clinical signs of the disease
aopear. In pregnancy, serum urate levels above 4.5 mg/100 ml are suspect.
The level of hyperuricemia also correlates with the severity of the preeclamptic
renal lesion, as well as with fetal outcome.
3. Proteinuria. Increased proteinuria, which may be moderate or heavy, is a fea
ture of preeclampsia, and the diagnosis is suspect in its absence. The magnitude
of proteinuria does not appear to affect maternal prognosis, but protein ex
cretion in the. nephrotic range is associated with greater fetal loss.
4. Glomerular capillary endotheliosis. Preeclampsia is accompanied by a char
acteristic lesion, glomerular capillary endotheliosis (Fig. 12-3). In women di
agnosed clinically as preeclamptic, this lesion is present in only about 75 .percent
of biopsies obtained from primiparas and in considerably fewer biopsies from
multiparas; the remainder of patients have evidence of nephrosclerosis or an
other parenchymal disease. The usefulness of postpartum renal biopsy in
preeclamptic patients is underscored by observations that renal vascular ab
normalities may have prognostic implications for future pregnancies. Women
with glomerular endothehosis alone tend to have uneventful subsequent ges
tations, but when alterations in the renal vessels are present, hypertension
is more likelv to recur in later pregnancies.
___________of
‘ preectampsia
.
i
D. Management
1. Hospitalization. Ambulatory treatment has no place in the management of
preeclampsia. All suspected preeclamptic patients should be hospitalized. This
approach diminishes the frequency of convulsions and other consequences of
diagnostic error. In general, fetal maturity is evaluated; if the gestation is
near term, induction is the therapy of choice, whereas attempts to temporize
are made if the pregnancy is at an earlier stage. Rest is an extremely important
part of the therapeutic regimen, which must be prescribed rather than sug
gested. Termination of pregnancy should be considered when hyperreflexia
develops or persists; blood pressure cannot be controlled; serum creatinine,
urea nitrogen, or uric acid rise; laboratory evidence suggests disseminated
intravascular coagulation or abnormal liver function (increased transaminases);
or specific obstetric tests suggest fetal jeopardy. When signs oi impending con
vulsions (eclampsia) are present, parenteral magnesium sulfate is the drug of
choice in most obstetric centers.
2. Treatment of hypertension. The approach to treatment of high blooa pressure
in gravidas is disputed. Results of morphologic examination of placentae dem-
Btl
- - ±r
218
12: The Patient With Kidney Disease and Hypertension in Pregnancy
12: The Patient With Kidney Disease and Hypertension in Pregnancy
3
Ci
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Fig. 12-3. (Left) Electron micrograph demonstrating complete capillary obliteration by
a swollen endothelial cell. Note, however, that the basement is normal and the foot
processes are intact. (Right) Micrograph showing glomerulus from a preeclamptic’s
kidney. Swollen endothelial and mesangial cells that display prominent vacuolization
encroach upon the capillary lumina. (Courtesy of B. H. Spargo, M.D.)
onstrating trophoblastic invasion of the uterine spiral arteries, as well as observations by investigators who use unanesthetized sheep or primate models,
suggest that uterine arteries behave like rigid conduits or are normally maximally dilated. These authors believe that reduction in maternal blood pressure
decreases uteroplacental perfusion (i.e., poor autoregulation of uterine blood
flow) and caution against large decrements in the mother’s mean pressure,
especially in acute emergencies. They are especially cautious in preeclampsia,
since placental flow is already compromised. In contrast, investigators working
with anesthetized rabbits note that autoregulation of uterine flow is rapid and
complete, and they suggest an aggressive approach to human hypertension.
Data in human pregnancy are limited, but they suggest that drops in maternal
pressure may reduce placental perfusion. Assuming that autoregulation of
uterine blood flow exists, a critical but unanswered question is how quickly
it takes place, since fetuses may be damaged by short periods of ischemia.
There are documented instances in which precipitous decreases of pressure in
response to diazoxide (even to diastolic levels above 85 mm Hg) were followed
by immediate monitor signs of fetal distress. Thus, we prescribe the careful
use of parenteral hydralazine when acute hypertension exceeds diastolic levels
of 105 mm Hg, along with close maternal scrutiny and fetal monitoring. This
approach is successful in most gravidas, and diazoxide is restricted to the oc
casional case resistant to this therapy. Diazoxide should be administered in
j small doses (30 mg at a time), because hypertensive gravidas are usually conf trolled with a total dosage one-third that required in nongravid women. Dia
zoxide causes uterine atony, which is easily reversed with the judicious use
of oxytocin.
There is debate as to whether or not women with mild essential hypertension
should be treated during gestation since fetal outcome in this group seems no
C .3
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219
different than in normotensive gravidas. Current practice is to withhold therapy
until diastolic levels reach 95 mm Hg in the second trimester and 100 mm
Hg in the third trimester. Some authorities suggest even slightly higher values.
Methyldopa, which can be combined with hydralazine, is the agent most fre
quently used in gravidas with chronic hypertension. Data from trials testing
a variety of beta-blocking drugs appear promising, and such agents can also
be used when those listed above are not sufficient. Finally, since diuretic ther
apy limits the physiologic increment in plasma volume, these agents are not
usually prescribed to hypertensive gravidas. However, there are some instances
in which vasodilating agents alone fail and, faced with the choice of terminating
a gestation, diuretics may be prescribed as a last alternative.
Suggested Readin*
A V
3
£31
■
3
3
' A
» r--
A
Andriole, V. T. Bacterial Infections. In G. B. Burrow and T. F. Ferris (Eds.), Medical
Complications of Pregnancy (2nd ed.). Philadelphia: Saunders, 1982.
Chesley, L. C. Hypertensive Disorders of Pregnancy. New York: Appleton-CenturyCrofts, 1978.
Chesley, L. C. The control of hypertension in pregnancy. In R. M. Wynn (Ed.), Ob
stetrics and Gynecology Annual. New York: Appleton-Century-Crofts, 1981.
Coe, F. L., Parks, J. H.. and Lindheimer, M. D. Nephrolithiasis During Pregnancy.
Philadelphia: Lea & Febiger, 1977.
Davison, J. M., and Lindheimer, M. D. Pregnancy in women with renal allografts
Semin. Nephrol. 3:240, 1984.
Kitzmiller, J. L., Brown. E. R., Phillippe, M., Stark, A. R., Acker, D., Kaldany, A..
Singh, S., and Hare, J. W. Diabetic nephropathy and perinatal outcome. Am. J. Obstet.
Gynecol. 141:741, 1981.
Lindheimer, M. D., and Katz, A. I. Kidney Function and Disease in Pregnancy. Phil
adelphia: Lea & Febiger, 1977.
Lindheimer/M. dI, and Katz/ A. I^The Renal Response to Pregnancy. In B. M. Brenner
and F. C. Rector, Jr. (Eds.), The Kidney (2nd ed& Philadelphia: Saunders, 1980.
Lindheimer, M. D., and Katz, A. I. The kidney in pregnancy. Kidney Int. 18:147,
1980.
Lindheimer, M. D^ and Katz, A/^Ii Hypertension and Pregnancy. In J. Genest, O.
Kuchel, P. Hamet, and M. Cantin YEds.), Hypertension (2nd ed.). New York: McGrawHill, 1983.
Lindheimer, M. D., Katz, A. I., Ganeval, D., and Grunfeld, J. P. Acute Renal Failure
in Pregnancy. In B. M. Brenner and J. M. Lazarus (Eds.), Acute Renal Failure. Phil
adelphia: Saunders, 1983.
McFayden, J. R., Eyken. S. J., Gardner, N. H. N., Vanier, T. M., Bennet, A. E., Mayo.
M. E., and Lloyd-Davies, R. W. Bacteriuria in pregnancy. J. Obstet. Gynecol. Br.
Comm. 80:385, 1973.
Redman, C. W. G. The management of hypertension in pregnancy. Semin. Nephrol.
3:270, 1984.
■
T
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I
\
Use of Radiologic
Techniques in the Patient
With Renal Problems
i
Robert A. Older,
Daniel E. Wertman, Jr.,
Larry M. Crane, and
Hector J. Hidalgo
Diagnostic imaging of the urinary tract is undergoing rapid expansion. This provides
a wtder choice of examinations for any individual problem, but it also necessitates
an understanding of each study and a knowledge of its indications. In the first part
of this chapter we discuss each of the imaging studies currently available and their
general indications. The second part of the chapter is problem oriented; here we
present a rational approach to using the various imaging techniques when faced
with a particular diagnostic problem.
e.
i. Urographic procedures providing information about the urinary tract
A. Abdominal film. The routine abdominal film provides considerable information
e
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e.
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i*
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about disease processes involving the urinary tract. These can be considered in
four main categories.
1. Bone. Changes of renal osteodystrophy and either lytic or blastic metastatic
lesions can be demonstrated.
2. Soft tissue changes. Obliteration of the psoas outline, the renal outline, or
both of these gives a clue to the presence_of pathologic processes such as in
flammation, hemorrhage, tumor, or urincma.
3. Abnormalities of “air.” Dilated small or large bowel will be evident in cases
of ileus or obstruction. Areas in which there is decreased abdominal air may
indicate displacement by a mass.
Air outside of the normal intestinal tract indicates considerable pathology.
Intraperitoneal air is best visualized just under the diaphragm on an upright
chest film. Intraperitoneal free air is usually related to bowel perforation,
trauma, recent abdominal surgery, or a severe infectious process such as ab
scess. Retroperitoneal air outside of the intestinal tract also occurs; this can
be visualized in several areas, including in and around the kidneys, in and
around the bladder, and along the lateral abdominal walls. Air within the
kidneys or bladder may be due to severe infections, particularly in diabetic
patients. Trauma to the retroperitoneal portions of the intestines can also pro
duce free retroperitoneal air, as can the postoperative setting.
4. Calcifications
?
t-
1
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C-
i I:
MfM
t;4
a. Renal. Collecting structures—nephrolithiasis
5
(1) Medulla. Nephrocalcinosis (hypercalcemic states, medullary sponge
kidney, papillary necrosis)
(2) Cortex. Chronic glomerulonephritis, acute cortical necrosis
b. Ureter. Calcified stones
c. Bladder. Tuberculosis, schistosomiasis, bladder stones
B. Renal tomograms without contrast media. Renal tomography provides an es
timation of renal size and may also .reveal renal calcification not observed on the
plain abdominal film.
C. Excretory urography. Excretory urography is the primary study for evaluation
of the urinary tract. The diagnostic information obtained is directly related to
the quality of study performed.
1. Factors determining quality of excretory urography. Factors that influence
the quality and, therefore, the diagnostic capabilities of the excretory urogram
are:
a. Bowel preparation
b. Fluid restriction
247
243
249
14- Use of Radiologic Techniques m the Patient With Renal Problems
14: Use of Radiologic Techniques in the Patient With Renal Problems
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emphysematous cystitis.
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nephrogram allows detection of a small hypovascular mass (arrows).
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Amount of contrast used-50 to 100 ml of 50 to 60% contrast media for
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Eicreto^uro^tphy'^ln accurate diagnostic procedure when ProP^^r'
fo™^d mdTXlized for each patient. The use of
.
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f. Abdominal compression
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Fig. 14-2. Medullary calcification typical of renal tubular acidosis or
hyperparathyroidism.
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14: Use of Radiologic Techniques in the Patient With Renal Problems
251
in the Patient With Renal Problems
14: Use of Radiologic Techniques
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has markedly declined. Although many institutions have almost completely
eliminated the use of the retrograde pyelogram. it does have a place in urologic
diagnosis.
Uses of retrograde pyelography are:
1. Additional evaluation of possible filling defects not definite on excretory
urography
2. Selective cytologic studies and cultures
3. Additional delineation of an obstructing lesion, especially the length of the
obstruction and ureter distal to the obstruction
4. To rule out obstruction if all poninvasive studies are inconclusive
5. Cases of ureteral trauma (Fig. 14-5)
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1. Indications for retrograde cystography
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a. Vesicoureteral reflux. Retrograde cystography, performed after filling the
bladder with iodinated contrast media through a catheter, is used primarily
for the evaluation of vesicoureteral reflux in children with recurrent urinary
tract infections. The yield of demonstrating reflux in the adult with urinary
tract infection is low, especially if there are no abnormalities of the kidneys
demonstrated with excretory urography.
b. Anatomic delineation of bladder in patient with reduced renal function.
The retrograde cystogram provides somewhat better anatomic delineation
of the bladder in instances in which there is reduced or even absent, renal
function and the bladder cannot be demonstrated with excretory urography.
An example of this is the evaluation of the bladder of a potential tx-ansplanl
recipient before surgery.
Other indications for retrograde'cystography include:
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(1) Pelvic trauma
(2) Possible vesicovaginal or vesicoenterlc fistulas
(3) Postoperative evaluation
“ Nonna! collecting system using compressmn.
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• arrows) from a partially transected right ureti
the degree of extravasation are apparent.
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14: Use of Radiologic Techniques in the Patient With Renal Problems
252
2. Indications for voiding cystourethrography. Voiding cystourethrography can
be performed as part of retrograde cystography or as part of excretory urography
(Fig. 14-6). Indications for this procedure are:
a. Posterior urethral valves in male children
b. Strictures of either the posterior or anterior urethra in both children and
adults
F. Retrograde urethrogram. Retrograde urethrography is a limited, but useful, ex
amination. Indications are:
1. Evaluation of strictures of the anterior urethra
2. Pelvic trauma. This is an important study in patients with severe pelvic trauma
and should be performed before attempted catheterization of the bladder.
G. Nuclear cystography. This technique provides an alternative method for eval
uation of vesicoureteral reflux in infants and children. 99n' Technetium pertech
netate is instilled directly into the bladder via catheterization. Continuous imaging
allows detection of reflux. A major advantage of this technique is a considerable
reduction in radiation dose to the child, a factor that is of particular concern when
multiple follow-up studies are necessary. It does not, however, provide clear an
atomic evaluation of the bladder or urethra. Routine cystography with iodinated
contrast media is usually performed as the initial study, with isotope examinations
used for follow-up.
II. Ultrasound in evaluation of renal disease. Because of its simplicity, noninvasiveness,
low risk, and relatively low cost, ultrasound has found considerable use in the urinary
tract. Results, however, are dependent on operator expertise and experience. The
following are clinical circumstances in which ultrasound may be of value.
14: Use of Radiologic Techniques in the Patient With Renal Problems
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a
A. Renal mass lesions. Ultrasound is not a screening method, but once the mass
has been identified it is the simplest modality for establishing whether the mass
is cystic or solid (Fig. 14-7).
B. Patients for whom an IVP is appropriate
1. Renal failure. When an elevated serum creatinine is indicative of renal failure,
intravenous contrast for an intravenous pyelogram (IVP) may be hazardous.
Ultrasound can distinguish between obstruction and parenchymal disease as
a cause of the failure. An absent or atrophic kidney can also be discovered.
2. Allergic patients. Patients who have a serious allergic history to iodinated
contrast media can be studied with ultrasound, from which important infor
mation regarding renal size and contour, parenchyma, and collecting system
may be obtained.
C. Peripheral space. The perirenal and pararenal spaces can be well evaluated with
ultrasound, specificallv for the presence of abnormal fluid, as in urinoma, he-
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echoes are present and the overall echogenicity is similar to the normal kidney. Open
arrows = upper and lower pe.cs of the kidney; P = posterior.)
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and upper kidney. Even without the use of contrast media the adrena.» are we
visualized (arroius). (L = liver; S - spleer; B. Computerized tomographic scan
through the level of the midkidneys (black arrows). (Arrow 1 - the aorta; arrow the inferior vena cava.)
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14: Use of Radiologic Techniques in the Patient With Renal Problems
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Urge solid tumor with density similar to the kidney (black arrows). Kidney (k) is
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(arrow) in the region of the right adrenal gland. This lesion measures 3.5 cm in
diameter. The normal kidney (white arrow) is seen posterior to the lesion.
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1. Staging of the bladder carcinoma
2. Evaluation of pelvic masses (tumor, abscess, hematoma)
3. Post-transplant evaluation
4. Confirmation of pelvic lipomatosis
IV. Radionuclide evaluation of renal disease. Radionuclide imaging of the kidneys for
both morphology and function is somewhat controversial. Its use vanes considerably,
depending on the institution and the experience and interest of the persons responsible
for the studies. There are three basic areas in which isotope studies of the kidney
can be helpful. These are (a) renal function studies, (b) rejial morphology, and (c)
localization of inflammatory processes.
A. Evaluation of renal functon. Renal function has traditionally been evaluated
using the Hippuran renogram, and curves characteristic for obstructive versus
parenchymal disease have been described. Unfortunately, in clinical practice these
entities often overlap, and the renogram curves have only limited usefulness in
making these differentiaticns. At some institutions the Hippuran renogram study
has been extended to include serial measurements of blood and urine activity.
With these data more gnantitative information, such as effective renal blood flow,
can be evaluated. Relative function of each kidney as well as function of parts
of the kidney can also be evaluated. This information can be helpful in determining
therapy in a number of disease states, such as congenital anomalies, vesicoureteral
reflux, stone disease, and neurogenic bladder. The use of this more extensive
study, however, is limited- In a number of institutions "mtechnetium DTPA has
replaced 13II Hippuran for assessing function. Although it does not provide as
much functional information, the technetium study has the advantages of pro
ducing images of the kidney and of being somewhat easier to perform. It provides
functional information similar to that obtained with excretory urography and is
of particular use in patiesis in whom iodinated contrast is contraindicated.
B. Evaluation of renal morphology. Normal and abnormal renal anatomy can be
evaluated with radionuclides. There are currently a number of excellent imaging
3
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14: Use of Radiologic Techniques in the Patient With R< na^Problems
With Renal Problems
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ei~ ' » n-rmwis including renal and pennenhric disease, pyelonephritis,
of ^^^P^^^tsefXess gallium relates to its accumulation in
and subphremc abscess. The usefulnrf
rad,oactivity.
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B
Fiq 14-12 A. Selected right renal ateriography demonstrates post-traumatic
extravasation of contrast in a branch of the renal artery (arrows.) B. F ollowmg
injection ofclotting material to embolize the renal artery, the bleeding has steppea.
studies indicate a renal tumor. Here arteriography is used to conf-rm the nature
of the mass, to determine extension into the vascular structures, and to pi ovide
a vascular road map for the surgeons.
B. Evaluation of renal vascular hypertension. When available the procedure of choice
in screening for renovascular hypertension is now digital subtraction angiography.
Computer-enhanced imaging allows visualization of arterial anatomy following
intravenous administration of contrast. Thus, the study can be performed on an
outpatient basis with less risk and discomfort for the patient. Renal arteriography
and renal vein catheterization for renin samples, however, continue to be the
definitive tests for evaluation of renal vascular hypertension (see Chap. 13, V.B.
I.b.).
.
.
C. Renal transplantation evaluation. Renal arteriography is used for preoperative
evaluation of the donor kidney. It is also used in the evaluation of the recipient
kidney if the clinical course suggests arterial occlusion. Digital subtraction an
giography is a less invasive alternative to arterial injection in evaluating the
renal vasculature in the transplant patient.
D. Traumatized kidney without function. Changes in therapeutic approach to a more
conservative method of handling blunt renal trauma have reduced the need for
renal arteriography. It is, however, indicated in the traumatized kidney that shows
no function with urography. Arteriography will outline the specific renal lesions
more clearly and may be of particular help if the less invasive studies, such as
urography, are indefinite or if the patient s clinical course is unstable.
E. Interventional angiography. Interventional uses of angiography are increasing^
This includes the use of special catheters and embolization techniques to cont rol
hemorrhage (Fig. 14-12) or to occlude entities such as arteriovenous fistulae, which
can be either congenital or traumatic. Embolization techniques are also used to
infarct renal cell carcinomas before surgery and occasionally as the only therapy.
Interventional angiographic techniques are now used in the management of re
novascular hypertension. Hypertension in transplant recipients caused by excess
renin production from the patient’s native kidneys can be treated by renal ablation
with intraarterial absolute ethanol. Intraluminal renal angioplasty has rapidly
260
14: Use of Radiologic Techniques in the Patient With Rena’ Problems
14: Use of Radiologic Techniques in the Patient With Renal Problems
261
A
gained acceptance as an alternative to surgery in the management of renovascular
hypertension (Fig. 14-13A, B. and C). Success in treatment of renovascular hy
pertension due to fibromuscular dysplasia exceeds 90 percent, and angioplasty
is now considered the treatment of choice in the management of this condition.
Angioplasty is also effective in most instances of renal artery stenosis due to
atherosclerosis. Clinical improvement in the severity of the patient’s hypertension
is seen in about 70 percent of cases; in unsuccessful cases surgical correction can
then be undertaken.
F. Renal vein thrombosis. Both renal arteriography and renal venography can es
tablish the diagnosis of renal vein thrombosis.
VI. Renal puncture techniques: cyst puncture, antegrade pyelography, and percuta
neous nephrostomy
A. Cyst puncture. Cyst puncture is used for the definitive diagnosis of a simple cyst.
The combination of the radiographic images and the fluid samples is highly re
liable. Although it is used routinely in some institutions, in others it is used only
in specific instances. The indications include:
1. Probable but not definite cyst after ultrasound and computerized tomography
2. Patients under 50 years of age
3. Patients whose clinical presentation suggests neoplasm
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Fig. 14-13. Renal artery angioplasty in a renal transplant patient. The patient was a
15-year-old male with progressive hypertension 6 months following renal allograft
transplant. A. Aortogram reveals 80 percent stenosis of transplant renal artery
(arrow). Pressure gradient was 30 mm Hg. B. Angioplasty balloon inflated in region
of stenosis. C. Postdilation arteriogram with improved blood flow to kidney. Pressure
gradient across stenosis is decreased to zero.
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14: Use of Radiologic Techniques in the Patient W ith Renal Problems
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Fia 14-14 Ultrasound examination of a nonvisualized kidney at excretory urography
shows marked dilatation of the collecting structures and rena.
indicating significant hydronephrosis. (P = posterior: C = ciphalad.) B. Antegrade
pyelography performed with a direct puncture to the calyceal structures was used to
demonstrate the kidney, ureter, and the exact point of obstruction (arrow).
Retrograde pyelography was not technically possible m this patient.
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ide pyelography. This study u1 perfonned< 4
contrast media. It can be performed under ultrasonic guidance or w>th fluoroscopy.
It is indimed when evaluation of the anatomy of the upper urinary tract is necS and when this cannot be done with excretory urography or retrograde
nyetography (Fig. 14-14). In addition to diagnosing a site of obstruction, antegrade
pyeXaphy ’may be used in conjunction with pressure measurements to teip
obstruction and persistent hydronephrosis without obdifferentiate between true g^.
struction.
C. Percutaneous ncMi«iv=«v»v.y.
nephrostomy. This procedure, which consists of gpnoperative
into the renal pelvis under imaging control, is gaining
placement of a catheter
tvgreater acceptance bv both radiologists and urologists. It provides an alternative
Nephrostomy for drainage of an obstructed kidney. It can be
method to surgical m
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used for both short- and long-term drainage, and either small or large catheters
can be used, depending on the consistency of the material to be drained. Material
for diagnostic culture can be obtained and antibiotics can be directly instilled
into the infected kidney. Although ultrasound may be useful in the initial an
tegrade pyelogram to outline the calyceal system, especially if there is no uro
graphic visualization, we prefer to place the nephrostomy tube under fluoroscopic
visualization..
D- Endo-urology. With percutaneous access to the kidney the interventional ra
diologist now can provide a useful array of therapeutic procedures. A percutaneous
nephrostomy tract can be enlarged to accept a 26 French sheath. This sheath
allows percutaneous access to the collecting system by the urologist. Using this
technique, small stones can be removed directly and larger ones fragmented by
an ultrasonic lithotriptor and removed in pieces. Stents can be placed by tl>e
264
14: Use of Radiologic Techniques in the Patient With Renal Problems
14: Use of Radiologic Techniques in the Patient With Renal Problems
fistulae can be treated with stent placement and percutaneous drainage.
VII. Problem-oriented approach to radiologic evaluation of urinary tract
A. Factors determining choice of procedure. The use of diagnostic imaging studies
in any given situation depends to a large extent on the fol.owing four factors.
1. Need for information to determine patient management
2. Accuracy and reliability of a given study
3. Invasiveness of the study (i.e.. risks)
4. Cost of the study
x
.
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In general, this means the simple noninvasive studies are performed first, but
the diagnostic yield from these simpler studies is sufficiently low, then more= ex
pensive and invasive procedures may be warranted. In the schemes that follow
we have tried to balance these four factors. Although a number of studies may
be ljsted for a given problem this does not necessarily imply that any imaging
studies are required. This must be a clinical decision.
B. Evaluation of the renal mass. Evaluation of renal masses involves more than a
’ scheme of imaging modalities, such as that given in Fig. 14-15. In each case‘ t. e
overall clinical condition of the patient must be considered. The outline below
acts only as a guide to the use of imaging modalities. These studies fall essentially
into two groups: screening procedures (excretory urography, radionucli e rena
scanning) and diagnostic procedures (ultrasound, computerized tomography, cyst
C. Evaluation oHthe patient with renal failure. In patients with renal failure, imaging
techniques are used primarily to define the size and shape of the kidney and o
exclude obstruction as the cause of renal failure. Defining the renal size will in
most cases allow differentiation of the acute processes, which may be associated
with normal or large kidneys, from the chronic states, which produce bilaterally
small kidneys. This differentiation and the exclusion of obstruction can provide
the basic information necessary to determine additional management The outline
below presents an imaging approach to certain categories of renal failure, with
the studies listed roughly in order of preference.
.
1. Chronic renal failure without acute exacerbations. Obstruction is not a strong
clinical consideration.
.
a. Nephrotomography without contrast media. This procedure provides in
formation regarding kidney size and shape, and calcification.
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Solid mass
ANGIOGRAPHY
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Cystic or uncertain mass
RADIONUCLIDE
ULTRASOUND <— Mass — RENAL SCAN
Cystic
\lndeterminant Normal
Jndeterminant
PUNCTURE
OR STOP
CT SCAN
orANGIOGRAPHY
Fig. 14-15. A suggested approach to the evaluation of a renal mass.
STOP
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265
b. Ultrasound. This procedure allows evaluation of kidney size and shape as
well as providing evidence of hydronephrosis.
c. Computerized tomography. Size, shape, and evidence regarding obstruction
can be obtained. This procedure is reserved for cases in which this infor
mation cannot be obtained with the simplerand less expensive studies.
2. Acute renal failure, chronic renal failure with acute exacerbation, or unknown
duration of renal failure
a. Serum creatinine 4 mg 100 ml or below
(1) Ultrasound. If urography is considered high risk or felt to provide in
adequate visualization of the calyceal structures, ultrasound can be
used to exclude the presence of obstruction. Accuracy will depend on
the expertise of the operator.
(2) Computerized tomography. Computerized tomography may exclude
obstruction without use of contrast, but accuracy in this situation is
not established.
(3) Excretory urography. Excretory urography with a high dose of radi
ocontrast media (100 ml of 50 to 60% solution) and tomography will
generally provide information regarding size, shape, and status of the
collecting structures, ureters, and bladder. Patients must be well hy
drated before urography and the information to be gained must be
balanced against the increased risk of renal toxicity from iodinated
contrast. Urography will, however, provide the most information and
should be used if this information is necessary for patient management.
(4) Retrograde pyelography. Retrograde pyelography provides definitive
evaluation of the collecting systems and ureters, but generally is not
necessary unless the above procedures are equivocal or unavailable,
or if confidence levels in these studies are not optimal due to lack of
operator experience.
(5) Radionuclide studies. Radionuclide studies are not as specific but can
be useful, especially in patients in whom excretory urography presents
a high risk.
b. Serum creatinine greater than 4 ml/100 ml
(1) Ultrasound. Ultrasonography allows the exclusion of obstruction and
determines kidney size and shape. Fine detail of the calyceal structures
and parench.vma is not provided but generally is not necessary in this
situation.
(2) Computerized tomography. Computerized tomography provides the
same information as ultrasound without the use of contrast. It should
be used if the more simple ultrasound examination is not definitive.
(3) Retrograde pyelography. The use of retrograde'pyelography will de
pend on the confidence level of ultrasound in excluding obstruction. It
also may demonstrate the presence of papillary necrosis and calyceal
abnormalities not evident on ultrasound or computerized tomography.
Both retrograde pyelography and computerized tomography may dem
onstrate retroperitoneal fibrosis as the cause of renal failure.
(4) Excretory urography. The information from excretory urography is
variable, depending on degree of visualization; the test is probably not
worth performing if other imaging modalities are available.
This outline, as with all outlines, cannot include all possible exceptions. All of
the studies vary in their quality from one institution to another, and the reliability
and expertise with which any given study is performed in an institution must
be strongly considered when making the choice of imaging modalities in renal
failure as well as in al! other forms of renal disease. As a general statement, the
problem usually faced with acute renal failure is to exclude obstruction, and the
least invasive study that will accurately and reliably do this should be used.
Di Evaluation of urinary tract obstruction in the absence of renal failure. The fol
lowing sequence is suggested (Fig. 14-16):
1. Abdominal film. Passible stones or soft tissue masses causing obstruction with
marked hydronephrosis can be demonstrated on the preliminary abdominal
film.
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14: Use of Radiologic Techniques in the Patient With Renal Problems
266
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L
Obstruction
No obstruction
•h
in
Ii j
II
i
ULTRASOUNP
ANTEGRAPfi \
PYELOGRAM
Further definition
of the anatomy
related to the
obstruction
(if necessary)
Baseline for
' follow-up
Retrograde or
Antegrade
Pyelography,
possible
Computerized
Tomography
Stop
~
KU
,f s
a”0™3
in the
Z
°fu£dtofollow
»- e
Computerized tomography is of most benefinn
* %“•—... ...............
|
„„atlb. s-ggsfi
jstSSSS.*.”
sxsss
y/'
-r-
b. Collecting systems with tumor, stones, leukoplakia, submucosal hemor
rhage, or papillary necrosis
2. Cystoscopy or renal biopsy. Cystoscopy allows evaluation of bladder lesions,
however, if clinical evidence suggests acute glomerular inflammatory lesions,
such as those with associated proteinuria, renal biopsy may be of most value
=3^■—
E|i
[1
Sk -wr
Fia 14-17. Computerized tomographic examination of the kidneys without contrast
„i pelvis fZong
rirx-nct black
klnnb nrrau'}
media*showsUdilatation of the right renal
arrow) and
and thp
the c.alvceal
calyceal
system (short
(short black
black arrows)
arrows) in
in a
a patient
patient whose
whose kidney
kidney was only poorly visualized with
system
Xrrptorv
indicates the normal appearance of the left.
excretory urography. The open
openarrow
------- acollecting system. CL = liver.)
arenChyma as dense
; ssX'jKxjssSESsss
h
.. .
ft ft.
in most cases
“ncludZ
trast-fdled pelvis or ur<*er
iodinated “n^1
I
3. CompXVized tomography. With persistent hematuria and the above studies
negative, it is reasonable to perform computerized tomography specifically for
relatively hypovascular and small tumors. Computerized tomography'is also
used to evaluate solid masses and their extent before surgery fFig. 14-18).
4 Bilateral retrograde studies with cytologic study. This procedure provides
information regarding small lesions with abnormal cytologic results that may
not yet be visible and can also provide another evaluation of the collecting
structures in case any small lesions were not seen at urography. If the above
studies fail to delineate the cause of hematuria, the yield with additional studies
will be very low.
.
5. Selective renal angiography. Vascular lesions such as arteriovenous malfor
mations and small renal cell carcinomas can produce hematuna and not be
visible on any of the above studies. In these cases the lesions may be observed
F. Evaluation of the^renal transplant. Evaluation of the renal transplant is best
performed by comparison with baseline examination obtained in the immediate
IIE.
L
Normal
oach to the e’
Fig. 14-16. A suggested approach
absence of renal fatlure.
2. Excretory ^^S^^^nc^and^rf obstruction
noint of obstraction.
• \
Indeterminant
——
5
'
■- 3
Temporary drainage
and will documeni p
■
ULTRASOUND
Obstruction
II !
if
Indeterminant
Stop
RETROGRAD£_OS-
’
-b ■
gXCRETORVJJROGBAPHY
1
■
267
postoperative period.
1. Baseline studies after renal transplantation
a Radionuclide studies. ""Technetium DTPA provides estimation of both
vascularity and function of the transplanted kidney. I Hippuran renograms add additional functional information.
„a,
Evaluation of hemaWlap
tory urography is the primary s • . dernonslrate:
® parenchyma* ie^ion >
s„f the kidneys
I
14: Use of Radiologic Techniques in the Patient With Renal Problems
14: Use of Radiologic Techniques in the Patient With RenaUProblems
5
3
5
e
9
-3
e
Fig. 14-18. Noncontrast co?=ed
S
computerized tomography. (L - liver, £>
arrou; = calcified aorta.)
spieeu, rv
=
b Ultrasound Ultrasonography has been used more in recent years and is
Sent fo’r evaluating of abnormal fluid collections around the kidney
as well as of renal size. Collecting system obstruction can tdso be v'sual^±
igraphy allows evaluation of
Excretory urography; Excretory urography
of anatomy,
anat0™> ’
and size of the kidney, exclusion of obstniction and exj.ravasati^.
HLIVM*
*******
£----
#
>
-
r
, , ___ J___ whon Hrncrranhv IS
trast media, urography should nttot be used routinely. When urography is
5 to 7 days post-transplantation.
ana evaiudiiuii Ui ui
rnavte''testfora"s^dfi7transplant complication, it is often
necessary
Combination
ofr studies
the mnlt.inlft
multiple variables.
. .
*__ 4.^ to separate iVio
to use a cuuiuiiidLivu vx
-------.r—
- ..^ as those related to
-i r _x:----a. Radionuclide
studies. Unanges
Changes
in reneljunctien
such
6 Studies.
icua*
—
-i as
acute tubular necrosis are best evaluated with renal radiorejection or
—-------specific, these isotope studies may provide
/uj
“r.—
b. UlbaXbi’. OlwX^grapby Is used to assess additionally Any sospostod
I\
t
I
c Excretory urography^Exmtory urography provides only gross evaluation
uroi
of renal functmn, but the presence of a functioning kidney excludes major
arterial lesions. Urography is primarily used to exciude the developmen
of an obstructive process or the presence of extravasation. Masses such as
hematomas or lymphoceles may be detected but only if they are of sufficient
d Renal angiography. If any of the above studies or strong clinical suspicions
suggest the^resence of a major arterial lesion, dig.tai venous subtract.on
I
t
ter -r-
angiography or renal arteriography may be necessary.
gj-
269
i
e. Computerized tomography. Computerized tomography can provide ex
cellent information regarding the renal anatomy and surrounding structufts. Additional data are needed to determine whether it will replace any
of the other modalities or add new information.
f. Scheme for evaluation of oliguria and anuria in the transplant patient
(Fig. 14-19)
G. Evaluation of renal and perirenal Infection. In many instances it is impossible
clinically to separate the various forms of renal infection. Without renal imaging
it may only be possible to suspect that an inflammatory process is occurring. The
separation into specific entities, therefore, is somewhat artificial, yet helpful in
understanding the usefulness of the various imaging techniques.
1. Acute pyelonephritis. Imaging studies are not always indicated.
a. Abdominal film. The abdominal film will exclude radiopaque urinary tract
calculi as the underlying cause and allow evaluation of the retroperitoneal
soft tissues for evidence of inflammatory change, such as loss of renal out
lines and/or psoas margins.
b. Excretory urography. Excretory urography is the primary imaging mo• dality even though radiographic changes may be minimal or nonexistent
in the majority of patients with acute pyelonephritis. Bindings may include
increased renal size due to swelling, decreased concentration of contrast,
asymmetry of function, spidery calyces, mucosal striations, and an irregular
nephrogram. The procedure is not generally indicated acutely unless a
complicating factor, such as urinary tract obstruction, is suspected.
c. Ultrasound. Ultrasonography can detect focal and generalized areas of
swelling, but it is of more use in the evaluation of a well-defined renal
abscess or perinephric inflammation.
d. Retrograde cystogram. The retrograde cystogram is primarily used in
children with recurrent bouts of pyelonephritis. It is not usually performed
during the episode of acute pyelonephritis.
2. Chronic urinary tract Infection
a. Abdominal film. The abdominal film will reveal the 90 percent of ne
phrolithiases that are radiopaque. Uric acid stones are radiolucent.
b. Excretory urography. The ability of this study to demonstrate both pa
renchymal scars and calyceal blunting makes it the most useful study
diagnostically.
c. Retrograde cystogram. This procedure will exclude vesicorenal reflux and
underlying causes of chronic urinary tract infection in children and is es
pecially important if upper tract changes are demonstrated.
3. Renal abscess
a. Abdominal film. The plain abdominal film may reveal loss of soft tissue
outlines, thus suggesting inflammation.
b. Excretory urography. Excretory urography may demonstrate a mass lesion,
possibly associated with loss of renal outline if there has been extension
of the inflammation.
c. Computerized tomography. This study can define a mass as solid but can
not always separate an inflammatory from a neoplastic lesion. CT is ex
cellent for guiding percutaneous aspiration to make this distinction.
d. Ultrasound. Ultrasonography allows additional assessment of the renal
mass detected with urography. The clinical characteristics of the mass as
well as perirenal extension can be evaluated. Diagnostic puncture and
drainage can be performed with ultrasonography.
e. 67Ga!lium scanning. This procedure may be helpful in localization of renal
and perirenal inflammatory lesions when these are not defined with other
studies.
f. Arteriography. Renal arteriographic patterns suggesting an inflammatory
lesion as opposed to a neoplastic lesion have been described, but the spec
ificity and accuracy of this differentiation is very variable.
4. Perinephric abscess
a. Abdominal film. The abdominal film will demonstrate loss ot renal and/
or psoas margins.
1
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Decreased Perfusion
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OUGUWA^^
necrosis (ATN)
Rejection. Acute tubular
wmrpc OTPA
___
Excretion Study
UltraBoobtaP^limea^
features, serial
ic
Nearly Norrnal_Perfvision
11 ■ ~~ Decreased Excretion
Absent Rcna£E£Lr-ui’1
No Excretion; Causes:
Rejection
ATN
Ultrasound or delayed
WmTC DTP A
Nonviable kidney,
renal arterial thrombosis,
hyperacute rejection
No obstruction
Obstruction
Acute tubular necrosis
± Arteriography
No fluid
collection
With fluid
collection
11
. gss’.stUi^
CAT scan, aspiration
ureteral kinks
SSssr
I
Hematoma,
abscess,
_ ___ urjnoma,
lymphocele.
I
Radiology of Renal Failure. In M . Resnick
t> irtaMad
,1982.)
...........
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272
14: Use of Radiologic Techniques in the Patient With Renal Problems
14: Use of Radiologic Techniques in the Patient With Renal Problems
c. Sudden onset or acute exacerbation of hypertension
d. Abdominal or flank bruit on examination.
hypertension. An infusion or bolus injection of saralasm follow^ by a b ood
pressure decrease of greater than 10/8 mm Hg has been used for selection
of patients for urography and arteriography. The results, however, have
been variable, and the test has not become widely used.
b. Excretory urography. Ttie excretory urogram demonstrates anatomic dis-
3
3
13
*4 3
masses. Hypertensive patients are studied with the rapid-sequence excre
273
Magilner, A., and Ostrum. B. Computed tomography in the diagnosis of renal masses.
Radiology 126:715, 1978.
Resnick, Mt I. (Ed.). Symposium on Advances in Laboratory and Intraoperative Di
agnostic Techniques. The Urologic Clinics of North America, Vol. 6. Philadelphia:
Saunders, 1979.
Resnick, M. I., and Older, R. A. (Eds.). Diagnosis of Genitourinary Disease. New
Y’ork: Thieme-Stratton. 1982.
Rosenfield, A., Glickman, M., and Hodson, J. Diagnostic Imaging in Renal Disease.
New York: Appleton-Century-Crofts, 1979.
Smith, A. D. (Ed.). Symposium on Endourology. The Urologic Clinics ofNorth America,
Vol. 9, No. 1. Philadelphia: Saunders, 1982.
Stables, D. The scope of kidney radiology. Kidney 10:7, 1977.
i following findings:
(1) Disparity in renal length (>2 cm difference)
W
*
(2) Difference in time of opacification of the collecting structures
Delayed hyperconcentration of contrast media in the collecting sys(3) I
tern ot
tem
of xne
the affected
anecieu Kiuucy
kidney
(4) Ureteral notching due to collateral arterial supply
i
c. Digital subtraction angiography. Digital subtraction angiography, using
intravenous
contract
Mus
for
imaging
of
arterial
stnictures,
an intravenous contrast bolus for imaging of arterial structures, is
is concon
sidered by many to be the procedure of choice in screening for renovascular
hypertension. The procedure can be performed on an outpatient basis and
is usually followed with a conventional excretory urogram to evaluate for
structural abnormalities and tumors.
.
----d Radionuclide studies. Renograms and scintiphotos obtained with either
' orthoiodohippurate (131I Hippuran) or ""Tc-DTPA are also used asprehm-____
inary studies to evaluate renal blood flow. These are currently used infrequently at our institution.
i
e Renal angiography. Selective renal arteriography provides the definitive
diagnosis of renal arterial lesions. Atherosclerosis that involves the main
renal artery at or near its origin is most common in the older population.
*
Fibromuscular hypertrophy is the most common cause of renovascular hypertension in patients under 40 years of age and occurs more jenpherally
g
Arteriography can also additionally define renal parenchymal disease, rena
?
masses, renin-secreting tumors, and other forms of vascular disease.
f. Renal vein renin assay. Renal vein renin assay provides a me*s^ement
of the causal relation of renovascular lesions and hypertension. Both re
ft
veins and the inferior vena cava below the renal veins are sampled begmental renal vein sampling is indicated if localized arterial or parenchyma
abnormalities are present. Renal vein renin ratios of 1.5 :1.0 are the upper
limits of normal; a ratio of 2 : 1 is diagnostic of severe renovascular■ pa
thology. Suppression of renal vein renin in the contralateral kidney (i.e.,
a value comparable to the vena cava renin) is predictive of a good surgical
outcome, as is an elevated peripheral plasma renin activity.
Syllabus Genitourinary Tract Radiology. Oak Brook, Ill.: The Radiological Society
of North America, 1978.
Tegtmeyer, C. J., et al. Percutaneous transluminal angioplasty: The treatment of
choice for renovascular hypertension due to fibromuscular dysplasia. Radiology
143:631, 1982.
J
Suggested Reading
'
Colapinto, R. F , et al. Percutaneous transluminal dilatation of the renal artery:
Follow-up studies on renovascular hypertension. AJR 139./z/, I9»z.
Ellenbogen, P., Scheible, F„ Talner, L., and Leopoid, G-Sensitivity of gray ^ale
ultrasound in detecting urinary tract obstruction. Am. J. Roentgenol. 130.731,1978.
GreJn, W., King, D., and Casare'lla, W. A reappraisal of sonolucent renal masses.
Radiology 121:163, 1976,
Korobkin, M„ White, E„ Kressel, H„ Moss, A., and Montagne, J Computed tomography in the diagnosis of adrenal disease. Am. J. Roentgenol. 132.231, 19/9.
275
index
li
2^
^3
1
"S
I
a!
\
:i i
I
/
I
*
*
Ri
IV,.
.
I
f
Abdominal films, 247
in obstructive uropathy, 265
in perinephric abscess, 269
in pyelonephritis, acute, 269
in renal abscess, 269
in urinary tract infections, 269
Abscess
renal and perinephric
in pregnancy, 208
radiology in, 269-271
visceral, diagnosis of, 126
Acetazolamide, 7
in hyperphosphatemia, 82
in uric acid stones, 94-95
Acid-base equilibrium
disorders of, 49-61
clinical signs of, 51
definitions and terminology of.
50-51
mixed, 51, 55-56
recognition of, 51
regulation in pregnancy, 203
Acidemia, 50
Acidosis
alcoholic ketoacidosis, 55
diabetic ketoacidosis, 55
hyperchloremic, 53-54
hyperkalemia in, 43
hypokalemia in, 33, 37-39
lactic acid, 54-55
metabolic, 50, 53-57
in bicarbonate loss, 53
from ammonium chloride, 54
increased anion gap in, 54-55
metabolic alkalosis with. 56
normal anion gap in, 53-54
in overdosage of drugs, 55
in renal insufficiency, 55, 162
respiratory alkalosis with, 56
in starvation, 55
treatment of, 56-57
in tubulo-interstitial renal
disease, 54
renal tubular, 53-54
bicarbonaturia in, 19
differential diagnosis of, 91
distal, 54
hypokalemia in, 37
proximal, 54
respiratory, 50, 60-61
metabolic alkalosis with, 59
treatment of, 61
Acromegaly, hyperphosphatemia in,
80
Addison’s disease
hypercalcemia in, 65
hyperkalemia in, 19, 45
hyponatremia in, 19
Adrenal disorders, hypertension in,
232-235
Adfenergic agonists
hypokalemia from, 36
and potassium uptake by cells, 31
Adrenergic blockers
hyperkalemia from, 43
in hypertension, 239-242
Adrenocorticotropic hormone (ACTH)
production, ectopic, and
hypokalemic alkalosis, 41
Age
and blood pressure, 221
and hyponatremia development,
15
Air, abdominal visualization of, 247
Albright’s hereditary osteodystrophy,
71
>
Albumin depletion
hypocalcemia with, 70
in nephrotic syndrome in
pregnancy, 213
x Alcohol, abstinence from, in cirrhosis,
9
Alcoholism
hypophosphatemia in, 77
ketoacidosis in, 55
Aldosterone
hypoaldosteronism, hyperkalemia
in, 45
and potassium excretion, 31, 33
serum levels of
in hypokalemia, 36
in hypokalemic alkalosis, 41
275
A—
*
Index
276
■
in renal abscess, 269
Aldosteronism, hypertension in,
in renovascular hypertension, 231,
232-234
259, 272
Alkalemia, 50
in transplant complications, 268
Alkali therapy. See Bicarbonate,
Anion excretion, and potassium
replacement therapy
excretion, 33
Alkalosis
Anion gap
hypokalemia in, 33, 36, 39
increased, and metabolic acidosis,
metabolic. 50, 58—60
54-55
bicarbonaturia in, 19
normal and metabolic acidosis,
metabolic acidosis with, 56
53-54
respiratory acidosis with, 59
Antibiotics
respiratory alkalosis with, 59
interstitial nephritis from, 138
sodium chloride-resistant, 59
nephrotoxic effects of, 137
sodium chloride-responsive,
in peritonitis during dialysis, 196
58-59
in pregnancy. 208-209
treatment of, 60
in renal failure, 192—196
respiratory, 50, 57-58
therapeutic serum levels of, 187
hypophosphatemia in, 77
in urinary tract infections, 106, 195
metabolic acidosis with, 56
Antibody-coated bacteria test, 104
metabolic alkalosis with, 59
Anticholinergic agents, in renal
treatment of, 58
failure, 198
Allopurinol, in hyperuricosuria, 93,
Anticonvulsants
94
in renal failure, 198
Alport’s syndrome, nephritic sediment
therapeutic serum levels of, 187
in, 127
Antidepressants, tricyclic, in renal
Amikacin
failure, 197
in renal failure, 192, 193
Antidiuretic hormone, inappropriate
therapeutic serum levels of, 187
secretion of, 20—21
Amiloride, 7, 240
Arthritis in uremia, treatment of, 164
hyperkalemia from, 46
Artifacts in laboratory date, 156, 188, I
Aminoglycosides
189
in renal failure, 192
Ascites in cirrhosis, 4
therapeutic serum levels of, 187
diuretics in, 9—10
Ammonia
LeVeen shunt in, 10-11, 144
and potassium metabolism, 33
Atenolol, in hypertension, 241
production in hypokalemia, 36
Azathioprine, in renal failure, 198
Ammonium chloride, hyperchloremic
Azotemia
acidosis from, 54
acute, 135—148
Amoxillin, in urinary tract infections,
in acute renal faiure, 137-138,
106
145-147
Amphetamine, in idiopathic edema,
biopsy in, 143
12-13
developed inside of hospital,
Amphotericin
139-140
in peritonitis during dialysis, 196
developed outside of hospital, 139
in renal failure, 194
differential diagnosis of, 138-143
Ampicillin
diseases with, 138, 148
in peritonitis during dialysis, 196
drug-induced, 139-140
in urinary tract infections, 106 <
evaluation of patient in, 138
Analgesics
in interstitial nephritis, 138
abuse of
physical examination in, 140-141
hematuria in, 130
radiography in, 142
pyuria in, 132, 133
testing procedures in, 141-143
in renal failure, 197
treatment of, 143—148
Ariemia in renal insufficiency,
ultrasonography in, 142-143
treatment of, 164
urinary studies in, 141-142
Angiography, renal, 258-261
chronic, 149-182
in azotemia, acute, 142
in catabolic states, 150—151
in hematuria, 267
in cardiac failure, 149—150
interventional uses of, 259-261
■
V
Index
e s
e
277
3
« 3
e.3
I
j.
e
r1
in chronic renal failure, 149
clinical features of, 151-153
from.massive protein intake, 150
laboratory tests in, 152—153
in obstructive uropathy, 149
physical examination in, 152
remediable contributors to,
156-158
uremic manifestations of, 152
drug usage in, 160—161, 185-200
postrenal, 136-137
treatment of, 147
prerenal, 135—136
in cardiac failure. 143
central venous pressure in,
144-145
drug-induced, 139
in hepatic disease, 143-144
in nephrotic syndrome, 144
Swan-Ganz catheter use in, 145
treatment of, 143-145
Bacteriuria, 97
asymptomatic. 97-98
in pregnancy, 206-207
treatment of, 105
biochemical tests for, 104
symptomatic, 98-99
in pregnancy, 208—209
Barium poisoning, hypokalemia in,
37
Bartter’s syndrome, hypokalemia in,
39
Bendroflumethiazide, 240
Bicarbonate
plasma levels of, 49
elevated, 58-61
reduced, 53-58
replacement therapy, 57
complications of, 57
in hyperkalemia, 46
in uric acid stones, 94
Bicarbonaturia, and hyponatremia, 19
Biopsy of kidney
in azotemia, acute, 143
in hematuria, 125, 267
in nephrotic syndrome, 120
in pregnancy, 205—206
Bladder
disorders of, hematuria in, 131
radiology of, 251-252
Blood, buffer system in, 49
Blood pressure
elevated. See Hypertension
in hypokalemia, 35
normal, 221
in pregnancy, 204
Blood transfusions, for renal
transplant recipients, 174-175
Brain, idiogenic osmoles in, in
hypernatremia, 25, 28
Bronchodilator drugs, in renal failure,
199
Buffer system in blood, 49
Bumetanide, 240
in renal failure, 197
Calcinosis, tumoral,
hyperphosphatemia in, 81
Calcitonin, in hypercalcemia, 68
Calcium
forms in plasma, 63
hypercalcemia, 63-70
hypercalciuria, 85, 90-91
idiopathic, treatment of, 92-93
hypocalcemia, 70-75
regulation of plasma levels, 63
replacement therapy, 74
stones of, 83, 85
idiopathic, 94
treatment of, 92-94
Calcium gluconate therapy, in
hyperkalemia, 46
Calculi, renal, 83-95
calcium, 83, 85
idiopathic, 92-94
chronic renal failure in, 155
clinical assessment of, 86-87
cystine, 83, 85, 86, 95
hematuria in, 131
metabolic evaluation in, 87-90
interpretation of data in, 90—92
in pregnancy, 214
radiology in, 247
struvite, 83, 85, 86, 95
symptoms of, 84
treatment of, 92-95
types of, 84-86
uric acid, 83, 85, 86, 91, 94-95
urinalysis in, 87
Candiduria, treatment of, 110
Capillary endotheliosis, glomerular,
in preeclampsia, 217
Captopril
in heart failure with edema, 14
hyperkalemia from, 45
in hypertension, 241, 243
Carbamazepine, therapeutic serum
levels of, 187
Carbenicillin
in peritonitis during dialysis, 196
potassium depletion from,. 41
therapeutic serum levels of, 187
in urinary tract infections, 106
Carbon dioxide
hypercapnia and respiratory
acidosis, 60
partial pressure of, 49
;
i
Index
-
278
Index
hazards of. 105.137-138, 140. 161,
Carbonic acid-bicarbonate buffer
system, 49
/
i
Cellulose phosphate therapy,
calcium stones, 93
during » 196
in renal failure, 192-194
therapeutic serum levels of 18/
in urinary tract infections, 106
Cerebrovascular accidents tn
hypertension, 227-228
Chemotherapy, in renal fa. ure W8
Chloramphenicol, m renal failure,
194
Chlordiazepoxide, in renal failure.
I
197
^deptetmn of, and hypokalemia. 39
Iif
i ■
i
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I
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Hi
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27.
hvperchloremic acidosis, 53-M
Chlorothiazide, 240
Chlorpromazine, m renal failu ,
Chlorthalidone, 7, 240
Chvostek’s sign m tetany, 72
Cimetidine, in renal failure, 198
Cirrhosis of liver
edema in, 4
treatment of, 9-11
LeVeen shunt in, 10'1^ 144
portacaval shunts in, 10
prerenal azotemia in, 143-144
Cis-platinum, potassium depletion
/
from, 41
C1interitodtis during dialysis’ 196 ■
in renal failure, 194
Clofibrate, in renal failure J 9.
Clonazepam, m renal failu Clonidine, in hypertension, 240-241
Collagen vascular diseases in
pregnancy. 212
o
Colloid osmotic pressure, plasma, .
Color of urine
abnormal, 114
drugs affecting, 189
Computerized tomography, 2o4-2o/
in hematuria, 267
in obstructive uropathy, 2bt>
in perinephric abscess, *71
in renal abscess, 269
in renal failure, 265
in transplant complications. 269
Conn’s syndrome, hypertension in,
232-234
.
Connective tissue disease, mixe ,
diagnosis of, 126
Contrast media
allergy to, 250
250
Coronary vascular disease, in
hypertension. 228
Corticosteroids. See Glucocorticoids
Creatinine
C"mc renal fadure, 1.58
in pregnancy, 205
serum levels of
Q
drugs affecting tests tor. 189
in hypertension, 230
in pregnancy, 202
Cryoglobulinemia, essenldial, nephritic
sediment in, 127
Crystalluria, 83, 87
in acute azotemia, 142
Cult ures of urine, 100-101
Cushing’s syndrome
hypertension in, 234
hypokalemic alkalosis in 41
Cyclophosphamide, in renal failure,
3a
A'
Cb
198
Cvstic disease in kidney. See also
Polycystic kidney disease
hematuria in, 130
proteinuria in, 115,120, 121
puncture technique in diagnosi
261
pyuria in, 133
Cystine stones, 83, 85. 86
treatment of, 95
Cystitis, 97
hematuria in, 131
pyuria in, 133
treatment of, 106
Cystography
nuclear, 1252
retrograde, 251
’
in acute pyelonephritis, 269
in urinary tract infections,
Cystoscopy, in hematuria, 267
Cystourethrography, voiding,
252
Demeclochlortetracycline, in
hyponatremia with
inappropriate antidiuretic
hormone secretion, 21-2Z
Dementia, dialysis. 169
Dextroamphetamine, in idiopathi
edema, 12-13
Diabetes insipidus
central, 23.
complete, 27
partial, 27
nephrogenic, 23-24
in pregnancy, 203-204
a
Diabetes mellitus
chronic renal failure in, 149
treatment of, 162
hematuria in, 130
hypophosphatemia in, 71
ketoacidosis in, 55
nephrotic syndrome in, 122
in pregnancy, 212
and renal failure from radiographic
contrast media. 137-138, 140
Dialysis therapy, 165-173
in acute renal failure, 146-147
contraindications to, 166-167
dementia from, 169
disequilibrium syndrome from, 169
drug dosage in. 188-190, 191
in drug overdosage. 199
hemodialysis, 167-170
complications of, 168-169
efficacy of, 167—168
morbidity and mortality from,
170, 180-181
vascular access for, 168
in hyperkalemia, 46
in hyperphosphatemia, 82
indications for. 165-166
infections of. 195
peritoneal, 170—173
complications of, 172-173
continuous ambulatory, 171
continuous cycling, 172
contraindications to, 171
at home, 170
indications for, 170-171
intermittent, 171
peritonitis in, 172
treatment of, 195--196
technical aspects of, 171-172
temporary, 165
Diazepam, in renal failure, 197
Diazoxide
in malignant hypertension, 244
in pregnancy with hypertension,
218
in renal failure, 197
Diet
and azotemia from massive protein
intake, 150
in calcium stones, 92, 93
and dialysis affecting nutrition,
172-173
in nephrotic syndrome, 124
and oxalate in foods, 92
and parenteral hyperalimentation
in acute renal failure, 146
azotemia from, 150
potassium intake in, 33
inadequate, 37
protein in
azotemia from, 150
in chronic renal failure, 161. 162
163
sodium in. See Sodiufti, intake of
Digitalis preparations
in heart failure. 8
hyperkalemia from, 45
and potassium balance, 35
in renal failure, 190, 191
therapeutic serum levels of, 187
Diphosphonates
in hypercalcemia, 68
hyperphosphatemia from, 81
Disequilibrium syndrome, in dialysis
patients, 169
Disopyramide
in renal failure, 192
therapeutic serum levels of, 187
Diuretics, 5-8, 240
action of, 6
in acute renal failure, 145-146
in cirrhosis of liver, 9—10
complications from, 6
in hyperkalemia, 47
in hypertension, 238-239
hypokalemia from, 39
hyponatremia from, 17-19
hypophosphatemia from, 77
in idiopathic edema, 13
indications for, 5-6
in nephrotic syndrome, 122
potassium replacement with, 42
potassium-sparing, 43
in renal failure, 197
thiazide. See Thiazide diuretics
Drainage of kidney, percutaneous
nephrostomy in, 262-263
Drug-induced conditions
acidosis, 55
in analgesic abuse
hematuria in, 130
pyuria in, 132, 133
azotemia, 139-140, 157
diabetes insipidus, nephrogenic.
24
edema, 4
hypercalcemia from thiazides,
65
hyperkalemia, 43, 45. 46
hypocalcemia, 71
hypokalemia, 36, 37, 39, 41
hyponatremia, 17—19, 20
hypophosphatemia, 77
interstitial nephritis, acute, 138
laboratory errors, 156, 188, 189 in laxative abuse
hyperphosphatemia in. 79
hypokalemia in, 37
hyponatremia in. 17
fca^sr
280
Index
Drug-induced conditions—Continued
nephrotic syndrome, 122
nephrotoxic disorders, 137-138,
139-140
Drug usage in azotemic patients,
160-161,185-200
affecting laboratory data, 156, 188,
189
antiarrhythmic agents, 191-192
antihypertensive agents, 197-198
and assessment of renal function,
185
in dialysis patients, 188-190, 191
digitalis glycosides, 190
diuretics, 197
do^ge adjustment in, 185-186
interactions of drugs in, 188
miscellaneous agents in, 194-195
overdose in, 199
and prescribing for pain and
sedation or sleep, 197
and serum drug levels as
therapeutic guides, 186-188
Dysuria, 99
Edema, 1-14
in chronic renal failure, treatment
of, 161
in cirrhosis of liver, 4, 9-11
clinical features of, 2-3
disorders with, 3—5
diuretics in, 5-8, 13
drug-induced, 4
formation of, 2
generalized, 1-2
in glomerulonephritis, acute, 4, 12
in heart failure, 3^4, 8-9, 14
in hyponatremia, 17
idiopathic, recurrent, 4, 12-13
incipient, 3
localized, 1
in nephrotic syndrome, 4, 11-12, 13
in pregnancy, 213
pitting or nonpitting, 2-3
refractory, 13-14
bed rest in, 13
compression stockings in, 13
diuretics in, 13
sodium intake in, 5
<
in toxemia of pregnancy, 5, 13
treatment of, 5-13
Electrocardiography
in hypercalcemia, 66
• in hyperkalemia, 43
in hypocalcemia, 72
in.hypokalemia, 35
Embolism, renal, hematuria in, 130
Emotional stress, hyponatremia in,
20
Index
Endocarditis, bacterial
diagnosis of, 126
treatment of, 147
Endotheliosis, glomerular, in
. preeclampsia, 217
Endo-urology, 263-264
Eosinophils in urine, 142
Ephedrine, in renal failure, 199
Erythromycin, in renal failure, 194
Ethacrynic acid, 7, 240
in renal failure, 197
Ethambutol, in renal failure, 195
Ethosuximide, therapeutic serum
levels of, 187
Ethylenediaminetetraacetic acid
(EDTA), in hypercalcemia, 69
Extracellular fluid volume
depletion of
and azotemia, 135-136, 140
treatment of, 143-144
in hypernatremia, 25
in hyponatremia, 16-17
Fanconi syndrome
bicarbonaturia in, 19
hypophosphatemia in, 77
Flucytosine, in renal failure, 194-195
Fluid therapy
in acute renal failure, 146
in prerenal azotemia, 143-144
Flurazepam, in renal failure, 197
Furosemide, 7, 240
in acute renal failure, 146
in hypercalcemia, 68
in hypernatremia, 27
in hyponatremia, 22
in renal failure, 197
therapeutic serum levels of, 187
Gastrointestinal disorders
hypophosphatemia in, 76
in uremia, treatment of, 164
Gastrointestinal fluid losses
and hypokalemia, 37
and hyponatremia, 17
Gentamicin
in peritonitis during dialysis, 196
in renal failure, 192, 193
therapeutic serum levels of, 187
Glomerular capillary endotheliosis, in
preeclampsia, 217
Glomerular filtration rate
in chronic renal failure, 158
in preeclampsia, 217
in pregnancy, 201-202
Glomerulonephritis
acute, edema in, 4
treatment of, 12
azotemia in, 138
281
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treatment of, 147
chronic renal failure in, 149
diagnosis of, 126
hematuria in, 124-125
hypertension in, 231
nephritic sediment in, 126
nephrotic syndrome in, 12, 122
in pregnancy, 210-211
proteinuria in, 121
treatment of, 147
Glucocorticoids
deficiency of, hyponatremia in, 20
as therapy
in hypercalcemia. 68
in lupus nephritis, 124, 128
in nephrotic syndrome, 122-124
Glucose
hyperglycemia in dialysis patients,
173
therapy with insulin, in
hyperkalemia, 46
utilization test in bacteriuria, 104
Glucosuria
and hypernatremia. 24
and hyponatremia, 19
and hypophosphatemia, 77
Glycosides, cardiac, 8. See also
Digitalis preparations
Glycyrrhizic acid, hypokalemic
acidosis from, 41
Goodpasture’s syndrome
azotemia in, 138
treatment of, 147
I
nephritis sediment in, 127
treatment of, 128
Gout
nephropathy with, chronic renal
failure in, 155
in uremia, treatment of, 164
Guanabenz, in hypertension, 239
Guanethidine, in hypertension^ 241,
243
Gynecomastia, from spironolactone, 43
Haloperidol, in renal failure, 197
Heart, conduction disorders of
in hyperkalemia, 43
in hypokalemia, 35
Heart failure
chronic azotemia in, 149-150, 156157
edema in, 3-4
treatment of, 8-9,14
in hypertension, 228
prerenal azotemia in, 143
Hematuria, 124-129
in glomerular disease, 124-125
biopsy in, 125
treatment of, 125, 128
nonglomerular causes of, 125, 130131
clinical features of, 129
diagnosis of, 132
evaluation of patient in, 128-129
treatment of, 129
radiology in. 266-267
in renal stones, 87
three-glass maneuver in, 128
Hemodialysis, 167-170. See also
Dialysis therapy
Hemolytic uremic syndrome, nephritic
sediment in, 126
Henderson-Hasselbalch equation,
49
Henoch-Schonlein purpura, treatment
of, 147
Heparin, hyperkalemia from, 45
Hepatitis, viral, diagnosis of, 126
Herpes infections, dysuria in, 99
Hydralazine, in hypertension, 241,
242-243
Hydrochlorothiazide, 7, 240
triamterene with, 7
Hydrostatic pressure, capillary, 2
Hyperalimentation, parenteral
in acute renal failure, 146
azotemia from, 150
Hypercalcemia, 63-70
acute, 69
in Addison’s disease, 65
calcitonin in, 68
chronic, 69-70
chronic renal failure in, 155
diagnosis of, 66-67
diphosphonates in, 68
EDTA in, 69
familial hypocalciuric, 65
glucocorticoids in, 68
in hyperparathyroidism, 63
in malignancies, 63-65
in milk-alkali syndrome, 65
mithramycin in, 68
and nephrogenic diabetes insipidus,
24
in Paget’s disease, 65
phosphate therapy in, 67—68
saline and furosemide in, 68-69
in sarcoidosis, 65
I
symptoms of, 65-66
treatment of, 67-70
in vitamin D intoxication, 65
Hypercalciuria, 85, 90-91
idiopathic, 85, 91
treatment oC 92-93
Hypercapnia, and respiratory acidosis,
60
Hyperglycemia, in dialysis patients,
173
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Index
Index
Hyperkalemia. 43-47
in Addison’s disease, 19, 45
differential diagnosisM, 43-46
drug-induced, 43, 45, 46
from potassium salts, 43
in hypoaldosteronism, 45
in mineralocorticoid deficiency, 45
and periodic paralysis, 45
■ pseudohyperkalemia, 43
in pseudohypoaldosteronism, 45—46
in renal failure, 45
symptoms of, 43
treatment of, 46—47
Hypernatremia, 22-28
in diabetes insipidus
central, 23, 27
nephrogenic, 23-24
diagnosis of, 25-27
in dialysis'patients, 173
disorders with, 23—24
euvolemic, 25-27
hypertonic salts inducing, 24
hypervolemic, 25
hypodipsia and hypertonic urine
with, 27
hypovolemic, 25
idiogenic osmoles in, 25, 28
in osmotic diuresis, 24
prognosis of, 24
symptoms of, 24-25
treatment of, 27-28
water deprivation test in, 27
Hyperoxaluria, 85, 91
treatment of, 93-94
Hyperparathyroidism
differential diagnosis of, 91
hypercalcemia in, 63
hypercalciuria in, 85
hypophosphatemia in, 77
Hyperphosphatemia, 79-82
acute, 82
causes of, 79-81
chronic, 82
diagnosis of, 81-82
hypocalcemia with, 72, 81
symptoms of, 81
treatment of, 82
in renal insufficiency, 162
Hypertension, 221-245
adrenal causes of, 232-235
adrenergic blocking agents in, 239242
in aldosteronism, 232-234
and antihypertensive agents in
renal failure, 197-198
and azotemia with chronic renal
failure, 157
treatment of, 161-162
captopril in, 241, 243
cerebrovascular accidents in, 227228
clinical features of, 224-226
coronary vascular disease in, 228
in Cushing’s syndrome, 234
diagnosis of, 228-235
epidemiology of, 222-224
guanethidine in, 241, 243
heart failure in, 228
hydralazine and minoxidil in, 242—
243
laboratory tests in, 228-230
malignant
definition of, 243-244
diazoxide in, 244
nitroprusside in, 244-245
pathophysiology of, 244
and prognosis after therapy,
235
treatment of, 147, 244-245
and mortality, 221., 223
natural history of, 227
in pheochromocytoma, 234—235 /
physical examination in, 228
plasma renin activity in, 230
in pregnancy, 216-219
treatment of, 217-219
renal function in, 228
in renal parenchymal disease, 231
renovascular, 231-232
angiography in, 231, 259, 272
intravenous pyelography in,
231
' radiology in, 271-272
renal vein renin in, 231-232
saralasin screening test in, 272
secondary, 225-226
diagnosis of* 230-235
screening tests in, 230
sodium intake affecting, 223, 238
symptoms of, 224
target organs in, 225
thiazide diuretics in, 238-239
treatment of, 235-245
benefits of. 235-236
recommendations for, 236-238
stepped-care approach in, 238243
Hyperthyroidism
hypercalcemia in, 65
hyperphosphatemia in, 80
Hyperuricemia
in preeclampsia, 217
treatment of, in renal insufficiency,
162
Hyperuricos uria
and calcium stones, 85, 91
treatment of, 93
and uric acid stones, 91, 94
cs
c>
Mk
$
hypocalcemia with, 70
in nephrotic syndrome in
pregnancy, 213
Hypocalcemia, 70—75
acute, 74
chronic, 74-75
diagnosis of, 72—73
in hyperphosphatemia, 72, 81 f
in hypoalbuminemia, 70
in hypomagnesemia, 71
in osteoblastic metastases, 72
in pancreatitis, 72
in parathyroid disorders, 70-71
in renal failure, 75
symptoms of, 72
treatment of, 74-75
in vitamin D deficiency, 71-72
Hypocalciuric hypercalcemia, familial,
65
I
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ter
Hypodipsia, and hypernatremia, 27
Hypokalemia, 34-43
in acidosis, 33, 37-39
aldosterone levels in, 36
in alkalosis, 33, 36, 39
ammonia production in; 36
in barium poisoning, 37
cardiac effects of, 35
and chloride depletion, 39
chronic renal failure in, 155
and diabetes insipidus, nephrogenic,
24
differential diagnosis of, 36-42
disorders with, 34
diuretic-induced, 239
extrarenal causes of, 37
hemodynamics in, 35
in hypertension, 230
and hyponatremia, 36
in insulin excess, 36
insulin release in, 36
in mineralocorticoid excess, 39-41
neuromuscular disorders in, 35
and periodic paralysis, 36
and plasma renin activity, 36
pseudohypokalemia, 36
pyuria in, 133
renal causes of, 37-42
renal function in, 35—36
symptoms of, 34-36
in toluene intoxication, 37
treatment of, 42-43
Hypomagnesemia
hypocalcemia with, 71
and hypokalemia, 41-42
Hyponatremia. 15-22
in Addison’s disease, 19
and azotemia with chronic renal
failure, 157-158
283
demeclochlortetracycline in, 21
diagnosis of, 16-21
disorders with, 15
j
in diuretic abuse, 17-19
drug-induced, 20
edema in, 17
in emotional stress, 20
euvolemic, 20—21
extracellular fluid volume in, 16-17
furosemide in, 22
in gastrbintestinal fluid losses, 17
in glucocorticoid deficiency, 20
hypertonic saline in, 22
in hypothyroidism, 20
hypovolemic, 17-20
in inappropriate antidiuretic
hormone secretion, 20-21
lithium in, 22
and osmolality of extracellular
fluid, 16
osmotic diuresis in, 19-20
and potassium depletion, 36
pseudohyponatremia, 16
in salt-losing nephritis, 19
symptoms of, 15—16
treatment of, 21—22
water intake restriction in, 21
Hypoparathyroidism
hyperphosphatemia in. 80
hypocalcemia in, 70-71
Hypophosphatemia, 76-79
in alcoholism, 77
diagnosis of. 78
in diuretic therapy, 77
in Fanconi’s syndrome; 77.
in gastrointestinal disorders, 76
in glycosuria, 77
in hyperparathyroidism, 77
symptoms of, 77-78
treatment of, 79
in Vitamin D-resistant rickets, 76
Hypothyroidism, hyponatremia in, 20
Immunosuppressive agents, dosage in
renal failure, 198
Indomethacin, hyperkalemia from, 45
Infections
of dialysis vascular access sites, 19u
peritonitis during dialysis, 1 /2
treatment of, 195—196
renal and perirenal, radiology in,
269-271
of urinary tract, 97-110
and asymptomatic bacteriuria,
9,7-98
and azotemia with chronic renal
failure, 157
biochemical tests for bactenuna
in, 104
Index
284
Infections, of urinary tract—
Continued
and care of urinary catheters,
108-110
clinical features of, 99-100
laboratory diagnosis of. 100-104
localization of infection site in,
104
microscopic examination of urine
in, 103-104
microorganisms in. 100-101
in pregnancy. 206-209
prostatic secretions in, 102-103
pyuria in, 103-104. 132
radiology in, 104—105, 269
reinfection in, 97
relapse in, 97
symptomatic, 98-99
treatment of, 105-110
in renal insufficiency, 162
urine cultures in, 100-103
Insulin
deficiency of. hyperkalemia in. 43
excess of, hypokalemia in, 36
hypophosphatemia from, 77
and potassium entry into cells, 31
release in hypokalemia, 36
Interstitial nephritis
chronic renal failure in, 149, 155
drug-induced, 138
diagnosis of, 142
treatment of, 147-148
Ischemia, acute renal failure in, 137
Isoniazid, in renal failure, 195
Kanamycin, in renal failure, 192, 193
Kayexalate, in hyperkalemia, 46, 47
Ketoacidosis
alcoholic, 55
diabetic, 55
in starvation, 55
Ketonuria, and hyponatremia, 20
Kidney
diseases of. See specific disorders
failure of. See Renal failure
in hypertension, 228
in hypokalemia, 35-36
in pregnancy, 201-204
stone formation in. See Calculi,
renal
<
i
I
285
Index
Laboratory data, artifacts in, 156,
188, 189
Lac|ic acidosis, 54—55
Laxative abuse
hyperphosphatemia-from, 79
and hypokalemia, 37
and hyponatremia, 17
Lead poisoning, pyuria in, 133
Lesch-Nyhan syndrome, 86
Leukocytoclastic vasculitis
nephritic sediment in, 126
treatment of, 128, 147
Leukocyturia, in renal stones, 87
LeVeen shunt, in ascites with
cirrhosis, 10-11, 144
Licorice ingestion, hypokalemic
acidosis from, 41
Liddle’s syndrome, aldosterone levels
in, 41
Lidocaine
in renal failure, 191
therapeutic serum levels of, 187
Lincomvcin, in renal failure, 194
Lipid levels, in nephrotic syndrome in
pregnancy, 213
Lithiasis. See Calculi, renal
Lithium
in hyponatremia with inappropriate
antidiuretic hormone secretion,
22
therapeutic serum levels of. 187
Liver, cirrhosis of
edema in, 4
treatment of, 9-11
prerenal azotemia in, 143-144
Lupus erythematosus
azotemia in, 138
treatment of, 147
chronic renal failure in, 155
and corticosteroids in nephritis,
124, 128
nephritic sediment in, 126
nephrotic syndrome in, 12, 124
pregnancy in, 212, 215-216
Magnesium depletion
hypocalcemia with, 71
and hypokalemia, 41-42
Malaria, diagnosis of, 126
Mannitol diuresis
in acute renal failure, 145
hypernatremia in, 24
and hyponatremia, 19
Medullary cystic disease, renal
hematuria in, 130
proteinuria in, 120, 121
pyuria in, 133
Methenamine mandelate, in urinary
tract infections, 108
Methicillin, in peritonitis during
dialysis, 196
Methyldopa, in hypertension, 240, 241
Metoclopramide, in renal failure, 198
Metolazone, 7, 240
in renal failure, 197
Metoprolol, in hypertension, 240,
241
Milk-alkali syndrome, hypercalcemia
in, 65
Mineralocorticoids
deficiency of, hyperkalemia in, 45
excess of, hypokalemia in, 39-41
and potassium excretion, 33
as therapy in hyperkalemia, 47
Minoxidil, in hypertension, 241, 242243
Mithramycin, in hypercalcemia, 68
Mononucleosis, diagnosis of. 126
Morphine, in renal failure, 197
Myeloma, multiple, chronic renal
failure in, 155
Myoglobinuria with rhabdomyolysis
acute renal failure in. 137
diagnosis of, 142
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Nadolol, in hypertension, 241
Narcotics, in\renal failure, 197
Necrosis, acute tubular, 137
in pregnancy, 209
Nephritic urinary sediment. 125
causes of, 126-127
Nephritis
hereditary, in pregnancy, 211-212
interstitial. See Interstitial
nephritis
salt-losing, 19
Nephrocalcinosis, 83
chronic renal failure in, 155
pyuria in, 133
radiology in, 247
Nephrolithiasis. See Calculi, renal
Nephrosclerosis
chronic renal failure in, 149, 155
proteinuria in, 115, 121
pyuria in, 133
Nephrostomy, percutaneous, 262-263
Nephrotic syndrome, 120—122
differential diagnosis of, 123
edema in, 4
treatment of, 11-12, 13
in glomerulonephritis, 122
idiopathic, 144
in lupus erythematosus, 12
in membranous glomerulopathy, 12
nil or minimal-change disease, 1112, 122
in pregnancy, 212-214
prerenal azotemia in, 144
treatment of, 122-124
Nephrotoxic disorders, acute renal
failure in, 137-138, 139-140
Netilmicin
in renal failure, 192, 193
therapeutic serum levels of, 187
Neurologic disorders
in hypernatremia, 24
in hyponatremia, 15
in hypophosphatemia, 78
Neuromuscular disorders
in hyperkalemia, 43
in hypocalcemia, 72
in hypokalemia, 35
in hypophosphatemia, 77
in uremia, treatment of, 164
Nitrite indicator strips, in bacteriuria,
104
V
Nitrofurantoin
in renal failure, 194
in urinary tract infections, 106
Nitroprusside
in malignant hypertension, 244245
in renal failure, 197-198
Nortriptyline, therapeutic serum
levels of, 187
Nutrition. See Diet
Obstructive uropathy
azotemia in, 137, 139, 140, 149, 157
chronic renal failure in, 149, 155,
157
clinical features of, 151
computerized tomography in, 254
hematuria in, 130
radiolog)' in, 265—266
treatment of, 147
Osmolality
of extracellular fluid, and
hyponatremia, 16
of plasma, in hypernatremia, 25
of urine, in pregnancy, 205
Osmoles, idiogenic, in hypernatremia,
25, 28
Osmostat, reset, 27
Osmotic diuresis
hypernatremia in, 24
hyponatremia in, 19
Osmotic pressure, colloid, 2
Osteodystrophy
Albright’s hereditary, 71
renal, treatment of, 164
Osteomalacia, in hypophosphatemia,
78
Oxalate
in foods, 92
hyperoxaluria, 85, 91
treatment of, 93-94
stones of, 83
Paget’s disease, hypercalcemia in,
/ 65
Pain
hyponatremia in, 20
relief of, in azotemic patients, 197
Pancreatitis, hypocalcemia in, 72
if'
288
Index
(
r I
!J ■
H
I
R
Mi
Paralysis, periodic
hyperkalemic, 45
hypokalemic, 36 Parathyroid disorders. See
Hyperparathyroi di sm;
Hypoparathyroidism
Parathyroid hormone levels,
measurement of, 66-67
D-Penicillamine, in cystine stones, 95
Penicillin
in peritonitis during dialysis, 196
potassium depletion from, 41
in renal failure, 192
therapeutic serum levels of, 187
Periarteritis. See Polyarteritis nodosa
Pericarditis, and chronic renal failure,
156-157
Peritoneal dialysis, chronic, 170-173.
See also Dialysis therapy
Peritonitis during peritoneal dialysis,
172
treatment of, 195-196
pH
normal values for, 49-50
and potassium balance, 33
and potassium distribution,
transcellular, 31
Phenobarbital, therapeutic serum
levels of, 187
Phenothiazines, usage in renal
failure, 197
Phenytoin
in renal failure. 198
therapeutic serum levels of, 187
/Pheochromocytoma, hypertension in,
234-235
Phosphate
external balance of. 75
hyperphosphatemia, 79-82
hypophosphatemia, 76-79
internal balance of, 75
normal levels of, 75
replacement therapy, 79
in hypercalcemia, 67-68
Pindolol, in hypertension, 241
Plasma flow, renal
in preeclampsia, 217
in pregnancy, 201-202
Plasmapheresis
in Goodpasture’s syndrome, 128
in lupus nephritis. 128
Polyarteritis nodosa
nephritic sediment in, 127
pregnancy in, 212
treatment of, 128, 147
Polycystic kidney disease
chronic renal failure in, 159
hematuria in, 130
hypertension in, 231
Index
in pregnancy, 214
proteinuria in, 115, 121
Polythiazide, 240
Portacaval shunt, in cirrhosis of liver,
10
1
Posture
and test for orthostatic proteinuria,
115
and ureteral obstruction in
pregnancy, 201
Potassium
dietary, 33
inadequate, 37
hyperkalemia, 43-47
hypokalemia, 34—43
renal regulation of, 32-34
stores in body, 31
therapy with
administration of, 42
complications from, 43
in diuretic |herapy, 42
transcellular distribution of, 31
alterations p, 36-37
in hyperkalemia, 43—45
Prazosin, in hypertension, 239, 241,
242
1
Preeclampsia, 212, 216-219
management of, 217-219
pathology of, 217
renal function in, 217
Pregnancy, 201-219
abscess of kidney in, 208
acid-base regulation in, 203
acute renal failure in, 209-210
idiopathic postpartum, 209
antibiotic use in, 208-209
/
bacteriuria in
asymptomatic, 206-207
symptomatic, 208-209
biopsy of kidney in, 205-206
blood pressure regulation in, 204
blood urea nitrogen in, 202
calculi in, 214
in chronic renal disease, 210-214
risks in, 161
in collagen vascular diseases, 212
creatinine levels in, 202
diabetes insipidus in, 203-204
diabetes mellitus in, 212
glomerular filtration rate in,
201-202
glomerulonephritis in, 210-211
hereditary nephritis in, 211-212
hypertensive disorders in, 216-219
treatment of, 217-219
in lupus nephritis, 212, 215-216
nephrotic syndrome in, 212-214
pelvic kidney in, 214
in polyarteritis nodosa, 212
polycystic kidney disease in, 214
preeclampsia in, 212, 216-219
pyelonephritis in
acute, 208
chronic, 214
renal disease in, 206-216
renal function in, 201-204
evaluation of, 204-206
in preeclampsia, 217
in renal transplant recipients,
214-215
in scleroderma, 212
solitary kidney in, 214
toxemia of, edema in, 5
treatment of, 13
tuberculosis of kidney in, 214
tubulo-interstitial disease in, 214
urinary tract in, 201
urine examination in, 204-205
volume regulation in, 204
water excretion in, 203-204
Primidone, therapeutic serum levels
of, 187
Procainamide
in renal failure, 191
therapeutic serum levels of, 187
Propoxyphene, in renal failure, 197
Propranolol
in hypertension, 240, 241-242
in renal failure, 192
therapeutic serum levels of, 187
Prostate
collection of secretions, 102-103
hypertrophy of, hematuria in, 131
Prostatitis, 97, 99
treatment of, 108
Protein, dietary
azotemia from. 150
in chronic renal failure, 161, 162,
163
Proteinuria, 114-124
in chronic interstitial nephritis,
120, 121
drugs affecting tests for, 189
evaluation of patient in, 114-115
functional. 115, 121
heavy. 120-122
idiopathic, 115, 121
low-grade. 115-120, 121
in medullary cystic disease, 120,
121
moderate, 120
in nephrosclerosis, 115^ 121
in nephrotic syndrome, 4
in pregnancy, 213
in obstructive uropathy, 120
orthostatic, test for, 115
in polycystic kidney disease, 115,
121
287
in preeclampsia, 217
in pregnancy, 204-205. 213
Pruritus in uremia, treatment of, 163
Pseudogout in uremia, treatment of,
164
Pseudohyperkalemia, 43
Pseudohypoaldosteronism,
hyperkalemia in, 45-46
Pseudohypokalemia, 36
Pseudohyponatremia, 16
Pseudohypoparathyroidism
hyperphosphatemia in, 80
hypocalcemia in, 70-71
Psychoactive drugs, in renal failure,
197
Pyelography
antegrade, 262
in obstructive uropathy, 266
intravenous, 104-105. See also
Urography, excretory
in hypertension, 231
retrograde, 250-251
in obstructive uropathy, 266
in renal failure, 265
Pyelonephritis, 97
acute, 97
jn pregnancy, 208
radiology in, 269
treatment of, 107
chronic, 97
in pregnancy, 214
treatment of, 107-108
chronic renal failure in, 155
hypertension in, 231
pyuria in, 133
Pyuria, 129-133
causes of, 133
clinical features of, 132
in infections of urinary tract.
103-104, 132
treatment of, 132
Quinethazone, 240
Quinidine
in renal failure, 192
therapeutic serum levels of, 187
'Radiation nephritis, pyuria in, 133
Radiology, 247-272
abdominal films in, 247
angiography in, 258-261
in azotemia
acute, 142
chronic, 153
choice of procedure in, 264
computerized tomography in.
254-257
cyst puncture in, 261
cystography in
Index
289 I
Index
Radiology, cystography in—Continued
nuclear, 252
retrograde, 251
endo-urology in, 263-264
excretory urography in, 247-250
and hazards from contrast media,
105, 137-138, 140, 161, 250
in hematuria, 266-267
in infections, 269-271
in obstruction of urinary tract,
265-266
percutaneous nephrostomy in,
262-263
pyelography in
'antegrade, 262
intravenous, 104-105
retrograde, 250—251
radionuclide imaging in. 257-258
in renal failure
acute, 265
chronic, 159, 265-266
in renal masses, 264
in renovascular hypertension,
271-272
tomograms in, 247
in transplant evaluation. 267-269
ultrasonography in, 252-254
urethrography in, retrograde, 252
in urinary tract infections,
104-105 —
voiding cystourethrography in, 252
Radionuclide imaging, 257-258
in cystography, 252
in perinephric abscess, 271
in renal abscess, 269
in renal failure, 265
in renovascular hypertension, 272
in transplant complications, 268
in transplant evaluation, 267
Reflux, vesicoureteral, cystography in,
251, 252
Renal artery stenosis
chronic renal failure in. 166
hypertension in, 231-232
Renal failure
acute
acute azotemia in, 137-138
dialysis in, 146-147
diuretics in, 145-146
fluid therapy in, 146
hyperphosphatemia in, 80
in ischemic disorders, 137
in nephrotoxic disorders,
137-138, 139-140
I
nonoliguric, 146
t
oliguric, 146 —
postpartum, idiopathic, 209
in pregnancy, 209—210
I
i
4
II
Lh
radiology in, 265
treatment of, 145—147
chronic, 149
acidosis in, 55
approach to drug use in, 160—161,
185-200
conservative management of,
160-164
in diabetes, treatment of, 162
diagnostic approach in, 154-160
dialysis in, 165-173
edema in, treatment of, 161
electrolyte balance in, 161
hypertension in, treatment of,
181-162
laboratory data in, 158-159
nephrologic consultation in,
165-166
parameters for monitoring in,
159- 160
physical examination in, 158
pregnancy in, 210—214
as risk, 161
prevention of complications in,
160- 161
protein intake in, 161, 162, 163
radiology in, 265—266
rate of progression of, 159
remediable causes of, 155—156
severity of, assessment of,
158-159
symptoms of, 158
therapy of end-stage disease in,
165-182
transplantation of kidney in,
173-182
treatment of, 160—182
uremic symptoms in
dialysis in, 167-168
treatment of, 163-164
Renal vein thrombosis
angiography in, 261
in nephrotic syndrome, 124
Renin
activity in plasma
in hypertension, 230
in hypokalemia, 36
in hypokalemic alkalosis, 41
renal vein, in renovascular
hypertension, 231—232, 272
Renovascular hypertension, 231-232
Reserpine, in hypertension, 239, 241, 242
Rhabdomyolysis with myoglobinuria
acute renal failure in, 137
diagnosis of, 142
Rickets, vitamin D—resistant,
hypophosphatemia in, 76
Rifampin, in renal failure, 195
t') 3
<^3
A
C' *
Terbutaline, in renal failure, 199
Tetany, in hypocalcemia, 72
therapeutic serum levels of, 187
Tetracycline
in renal failure, 197
in renal failure, 194
Saline infusions
in urinary tract infections, 106
in hypercalcemia, 68-69
Theophylline
in hypernatremia, 27
in renal failure, 199
hypernatremia from. 24
therapeutic serum levels of, 187
in hyponatremia, 22
Thiazide diuretics, 7, 240
Saralasin screening test, in
hypercalcemia from, 65
renovascular hypertension, 272
in hypercalciuria, idiopathic, 92
Sarcoidosis, hypercalcemia in, 65
in hypertension, 238-239
Scleroderma
in renal failure, 197
nephritic sediment in, 126
Thiocyanate toxicity, in nitroprusside
pregnancy in, 212
therapy, 197-198
Sediment in urine, 113-114
Thirst
in azotemia, acute, 141-142
and hypernatremia, 24, 27
nephritic, 125
and hypokalemia, 36
causes of, 126-127
Thoridiazine, in renal failure, 197
in pregnancy, 205
Three-glass maneuver in hematuria,
Sickle cell anemia, hematuria in, 130
128
Sjogren’s syndrome, nephritic
Thrombocytopenic purpura,
sediment in, 126
thrombotic, nephritic sediment
Sodium
in, 126
/
hypernatremia, 22—28
Thrombosis
hyponatremia, 15-22
in nephrotic syndrome in
intake of
pregnancy, 213
in cirrhosis of liver, 9
renal vein
in edema, 5, 13
angiography in, 261
hypertension related to, 223, 238
in nephrotic syndrome, 124
in hypokalemia. 42
Thyroid disorders
in pregnancy, 204
hyperthyroidism. See Thyrotoxicosis
and potassium excretion, 32-33
hypothyroidism, hyponatremia in,
Spironolactone, 7, 240
20
in cirrhosis of liver, 10
Thyrotoxicosis
gynecomastia from, 43
hypercalcemia in, 65
hyperkalemia from, 46
hyperphosphatemia in, 80
in hypokalemia, 42
Ticarcillin, therapeutic serum levels
Starling forces, and edema formation,
of, 187
2
Timolol, in hypertension, 241
Starvation, ketoacidosis in, 55
Tobramycin \
Stone formation. See Calculi, renal
in peritonitis during dialysis, 196
Streptococcal infections,
in renal failure, 192, 193
glomerulonephritis from. See
therapeutic serum levels of, 187
Glomerulonephritis
Toluene intoxication, hypokalemia in,
Struvite stones, 83, 85, 86
37
treatment of, 95
Tomography, renal, 247
Succinylcholine, effects in
in chronic renal failure, 264
hyperkalemia, 45
computerized, 254-257
Sulfate excretion, and potassium
Toxemia of pregnancy, edema in, 5
excretion, 33
treatment of, 13
Sulfisoxazole, in urinary tract
Transfusions, for renal transplant
infections, 106
recipients, 174—175
Sulfonamides, in renal failure, 194
Sulfosalicylic acid test for proteinuria, Transplantation of kidney, 173—182
and angiography of donor kidney,
114, 120
Swan-Ganz catheter, measurements
259
complications of, 177-180
with, 145
Syphilis, diagnosis of, 126
contraindications to, 166-167, 174
Index
Index
i'
i
-
■
I
drugs affecting tests for. 189
Transplantation of kidney
in pregnancy, 202
Continued
.
Uremia, 152
donor evaluation and preparation
dialysis in, 167-168
treatment of, 163-164
in, 175-176
Ureteral disorders, hematuria in,
efficacy of, 177
evaluation and preP^1011 of
131
Urethral syndrome, acute, 99
recipient in, 174-175
indications for, 165-^66’H^ 180_
Urethritis. 97, 99
morbidity and mortality from, 1
hematuria in, 131
pyuria in, 133
and pregnancy in recipients, 214-215
Urethrography, retrograde, 2
radiology in. 267-269
Uric acid
hyperuricosuria. See
rejection of, 178
prevention of, 1 /o-i / /
Hyperuricosuria
serum levels of
results of, 180
drugs affecting tests for, 189
ultrasonography ot,
in preeclampsia, 217
Trauma
\
9(-q
angiography of kidney in, 259
stones of, 83, 85, 86, 91
treatment of, 94-95
azotemia in, 139
treatment of hyperuncemi,ia in renal
hematuria in, 131
Triamterene, 7, 240
«
insufficiency, 162
gastrointestinal side effects of, 43
Urinary tract
hvdrochlorothiazide with, I
infections of, 97-110. See also
hyperkalemia from, 46
Infections, of urinary tract
Tricyclic antidepressants, in renal
in pregnancy, 201
failure, 197
Urine
Trimethoprim, in urinary tract
in azotemia, acute, 141
infections. 106
biood in. See Hematuria
sulfamethoxazole with, 106
collection of samples, 113
Trousseau’s sign in tetany, 72
for cultures, 100
in pregnancy, 207
Tuberculosis, renal
■edle
aspiration,
by suprapubic nec
------in pregnancy. 214
pyuria in, 133
’101-102
techniques for, 90
Tubular necrosis, acute, io
timing of, 87-90
in pregnancy. 209
TubuVinterstitial rena! diseases
color of
4
hyperchloremic acidosis with, 54
abnormal, 114
drugs affecting, 189
in pregnancy, 214
cultures of, 100-101
colony counts in, 101
interpretation of, 101-103
eosinophils in, 142
microscopic examination of, 103
Tumoral calcinosis,
hyperphosphatemia in, oi
1°4
in pregnancy, 204-205
See also Proteinuria
Ulcers, gastrointestinal, from
protein in, 114.. Sc:
potassium salts, 4d
pyuria, 129-133
Ultrasonography, 252"^
in renal stones, 87
in azotemia, acute, 142-143
sediment in, 113-114
142
in azotemia, acute, 141-142
in obstructive uropathy, 266
in perinephric abscess 271
nephritic, 129
in pyelonephritis, acute, 269
causes of, 126-127
in pregnancy, 205
in renal abscess, 269
Urography, excretory. 247-250
in renal failure, 265
in renal transplantation, 268
in azotemia, acute, 142
in hematuria, 266-267
Urea diuresis
in obstructive uropathy, 266
and hypernatremia, 24
in perinephric abscess, 2/1
and hyp°natremia’ 19
in pyelonephritis, acute, 269
Urea nitrogen, blood
in chronic renal failure, 158-159
m renal abscess, 269
in renal failure, 265
in renovascular hypertension, 272
in transplant complications, 268
in transplant evaluation, 268
in urinary tract infections, 269
Lt
Vaginitis, dysuria in, 99
Vancomycin
in peritonitis during dialysis, 196
in renal failure, 194
Vesicoureteral reflux, cystography in,
251, 252
Vitamin D
deficiency of, hypocalcemia in, 7172
intoxication from, hypercalcemia in,
65
as therapy iri ^p^lcemiag74^-7 5
fe /
I® (
291
Volume regulation, in pregnancy,
204 '
I
Water
'
compulsive drinking of, 27 .
deprivation test, 27
excretion in pregnancy, 203-204
insensible losses of, and
hypernatremia, 24, 25-27
negative balance in hyponatremia.
22
replacement in hypernatremia, 2728
restriction in hyponatremia, 21
Wegener’s granulomatosis
chronic renal failure in, 155
nephritic sediment in, 126
treatment of, 128
Weight gain in pregnancy, 204
" MIt
tie
e
a
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