ST. JMC JOURNAL OF MEDICINE ISSN 0970-4221 VOL. IV NO. 2 JUNE 1991.pdf
Media
- extracted text
-
COMMUNITY HEALTH CEU
320, V Main, I Block
Keffenangala
•»HI«r«-&60Q34
India
ISSN 0970 - 4221
ST. JOHN'S MEDICAL COLLEGE
JOURNAL OFMEDICINE
VOL IV No 2
June 1991
EDITORIAL
19
NEPHROLOGY SYMPOSIUM
-
-
Hemolytic Uremic Syndrome Current Concepts in
Pathology and Management
22
Acute Renal Failure
28
ESSAY
-
The Leprosy Vaccine - An Exercise in Futility
SELECTED SUMMARIES
37
40
CASE REPORT
An unusual Case of Acute Pancreatitis
42
INFORMATION FOR CONTRIBUTORS
EDITOR-IN-CHIEF
Ashley. J. D'Cruz
Submitting the Manuscript
EDITORIAL BOARD
The St. John's Medical College Journal of Medicine accepts scientific contributions from all fields of
modern medicine and from all institutions and health care professionals. The journal is a quarterly
publication which will be published in March, June, September and December. It is owned by the
C.B C.l. Society for Medical Education and published by the Principal, St. John's Medical College. The
journal is a part of it's commitment to continuing medical education. Articles and all editorial
communications should be addressed to the Editor, Alumni Office, St. John’s Medical College,
Bangalore-560 034.
Rajini Macaden
Ravi C. Nayar
A.B. Kilpadi
A.S. Arvind
Anil Abraham
Original articles, short case reports and review articles are accepted for publication. Review articles
and editorials are usually on invitation by the Editorial Board. Letters to the Editor will be considered
for publication only if received at least six weeks prior to the next publication.
PREPARING THE MANUSCRIPTS
All manuscripts should be submitted in 3 copies (including the glossy prints). They should be neatly
typewritten on bond paper, one side of the paper only, with double spacing and margins of at least
2.5 cms. Please be sure to include an accurate address for editorial communications and for reprint
requests.
A brief abstract of the material of the paper should precede the body of the paper, to run no more than
500 words. INDEX WORDS for the purpose of indexing and computer programming, should appear
on the same page.
The format for articles suggested is as follows: INTRODUCTION, MATERIALS AND METHODS,
RESULTS, DISCUSSION, REFERENCES.
Measurements should be in metric system.
OVERSEAS
R.R. Baliga
A.V. Kurpad
ILLUSTRATIONS AND TABLES
Figures and tables should be cited in order in the text; their position should be marked in the margin
of the manuscripts. Arabic numbering should be used for both figures and tables. All line drawings
should be submitted in duplicate as clear, glossy, black and white, 5“ x 7" photographs. Photomicro
graphs should also be submitted in duplicate, with allowance made for the effects of reduction if
necessary. Legends for illustrations should be typewritten, double-spaced, on a separate sheet, and
included at the end of the manuscripts. A legend must accompany each illustration. Each table should
be typed on aseparate sheet and appropriately numbered. Legend should be typed on the samesheet
as the tables. The contributors must bear all the costs connected with printing colour illustrations.
REFERENCES
PUBLISHER
Prof. A.F.A. Mascarenhas
Principal
References should be compiled at the end of the articles according to the order of citation in the text,
not alphabetically. They should be typewritten, double-spaced under the heading REFERENCES.
Abbreviation for titles of medical periodicals should conform to those used in the latest edition of Index
Medicus. Give inclusive page numbers.
EXAMPLES OF REFERENCES
Journal Articles upto six authors, list all names:
Kurpad AV, Shetty PS: Dietary Fibre and the colon. StJohn's J Med, 1988:1:5-12.
Journal Articles more than six authors, list three authors followed by et al:
Complete book
Gallagher JR: Medical Care of the Adolescent (ed 2). New York, Appleton, 1966; pp 208-215
Subscription
Single Copy
Rs. 30/Annual
: India Rs. 100/Abroad U.S. $ 20/Payable in cash/bank drafts/ cheques to the St. John's Medical College Journal of Medicine, I Floor,
Robert Koch bhavan, St. John's Medical College, Bangalore 560 034.
PUBLICATION COMMITTEE
The advertisement charges:
C. Ramachandra
Cover (back age): Rs. 3000/- Inside Cover (back page): Rs. 2000/-
S.C. Rajendra
All contributions towards the Journal come under 80 (G) exemption.
J. Alapatt
Founded by the Alumni Association of St. John's Medical College In 1988.
St. John’s Medical College Journal of Medicine
EDITORIAL
======
THE BANGLADESH CYCLONE - A LESSON IN POST-DISASTER MANAGEMENT
The Bangladesh cyclone of April 29th-1991 left half a million dead, countless “eco-refugees” and irreparable ecological
and economic damage. It was a cruel trick played on one of the poor countries in the world regularly besiged by natural and
political calamities. The nation, in a state of political euphoria after just establishing its first democratically elected
government in its twenty year history, was caught tragically unawares.
The impact of a 10 metre high tidal wave at 230 km/hour sustained over 4 hours on the coastal areas which have an elivation
of only a few metres was devastating.
The ensuing media coverage catalyzed the formation of a 7-member medical relief team from St. John’s Medical College
Hospital and St. Martha’s Hospital comprising of 3 doctors, 2 nurses and 2 paramedical workers. The team was also
interested in assessing the impact of the disaster on epidemiological and social conditions. On arrival, the team was
unfortunately split up and placed with 4 NGO’s (non-governmental organisations) working in different areas. However, in
retrospect, this move enabled us to have a wider spectrum of experiences.
Surprisingly, there are over 10,000 NGO’s involved in developmental and health activities in Bangladesh. Most
responded promptly to deliver relief, although with a lack of co-ordination and clear cut policy directives. NGO’s are
viewed as negative forces - agents of external power seeking to dominate society and.its resources. Their collective funds,
unofficially stated, equal the national budget almost assuming the level of a parallel economy! A critical analysis by the
U.N. showed that they have had an insignificant impact on poverty alleviation so far. In contrast there seemed to be no
government involvement in relief apart from an initial army presence. This lead a prominent intellectual to remark that
there were 2 tragedies in Bangladesh - we the cyclone and the second the NGO’s!
The death toll could have been minimised if it were not for people refusing to evacuate for fear of losing their property.
Here occupation of land is proof of ownership. The highest (No.10) danger signal is not a reliable indicator as it implies
wind speeds ranging from as moderate as 80 km/hour to as serious as 350 km/hour. This signal proved to be a false alarm
last year leading to a differing threat perception among the population this time. The un-registered poorest sections were
the most affected having been pushed southwards into the eye of the storm by the more affluent north. They also had
no early warning systems, transport or alternative place to go. All this, coupled with a sense of religious fatality and a
situational immunity to such disasters, contributed to the high death toll.
AN APPROACH TO POST DISASTER MANAGEMENT
Based on our experience our conclusions on how to deal with apost cyclone situation would be to establish a time bound
3-tier programme of immediate rescue and short term relief, medical care and long term rehabilitation (Table 1).
TABLE -1
I
IMMEDIATE RESCUE AND SHORT TERM RELIEF
Evacuation and first aid
Population survey and relief card distribution
Relief distribution
Domestic - food, clothing, utensils, fuel, water
Occupational - fishing nets, paddy seeds, text books
Temporary shelter materials
Dead body disposal
Water sanitation
Reuniting and relocation of families
Maintaining of relations with - local elite
local people
army
“Food for work” programmes
June 1991
19 —
St. John’s Medical College Journal of Medicine
II
MEDICAL CARE
Vulnerable group targeting
Health education and promotion
III
REHABILITATION
Rebuilding - houses and schools
- cyclone shelters
- embankments
Tube wells
Income generation
Legal services to dispossessed, widows, orphans
Disaster - preparedness
The most crucial phase of immediate rescue and first aid was the most dis-organised, inadequate and delayed. Despite
satellite tracking of the cyclone path for a week prior - the people and government machinery were still taken by surprise.
All tele-communications and transport links were cut for 3 vital days when the area was flooded making even helicopter
landings impossible. Maximum number of preventable deaths occured during this stage.
Disasters are great social levellers and inter-personal bonders, with the situation bringing out the best in people. Hitherto
undisplayed qualities of altruism and self-sufficiency emerged but lasting only till relief teams arrived! Initiation of relief
requires planning and well defined objectives. Accurate surveying of the population after assessing the extent of damage
and grading level of need is vital to the programme. A family card may then be issued after personally seeing each individual
before recording their identity. Precise detailing of age, sex and occupation is necessary for a later equitable and corruption
free relief distribution. Actual distribution may be compartmentalised into domestic, occupational and shelter materials.
Disposal of dead bodies after an attempt at identification should be culturally acceptable and done so as to prevent spread
ofdisease. Cremation is impossible due to lack of fuel. Burial is a viable option provided it is not sited near drinking water
sources or too close to the sea or river, where it can resurface.
Drinking water ponds rendered saline by the cyclone need to be pumped out and allowed to refill with rain water. All other
sources should be disinfected.
An attempt needs to be made to re-unite and re-locate families, encourage refugees to return to their original area only
if adequate facilities are available.
Local elite may offer to “help” in relief distribution but instead take political credit for it and try to control operations.
They may even make false accusations of corruption against you if denied control. An attempt may be made by them to re
establish pre-disaster authority and appropriate property of the dead. This underscores the need for operating from a
neutral base. The tendency is to use the house of the local rich and powerful as those are the only concrete structures left
standing. This gives them more exploit potential.
Initially the local people are in a state of shock, desperate for life saving aid and extremely co-operative. They later become
more critical, demanding and manipulative. Due to “over-kill of relief” they usually become dependant and apathetic refusing
to work and preferring to wait in relief lines all day.
Since relief activities greatly disturb the existing political climate it is important to be sensitive to pre-disaster social
stratification. The people need to be involved in decision making about their own future as their approval and commitment
ultimately contributes to the success of the programme.
II
MEDICAL CARE
Vulnerable groups like women, children and the aged tend to be neglected in all phases of relief inspite of sustaining the
highest mortality and morbidity rates. The status of women in society was pitiable and explained away by terminology
like "conservatism, culture, religion and orthodoxy”. It was shocking to find that the majority had never visited q
doctor (usually male) after puberty. As a natural consequence, their attitudes to their own health was not surprising.
20
VOL IV No. 2 —
St. John’s Medical College Journal of Medicine
Passive acceptance of illness, yearly pregnancies, religious fatalism and reluctance to travel towards medical care was the
rule.
Drugs and surgical equipment may be selected according to prevailing disease patterns, level of need and professional
skill of the team. Sophisticated drugs like cephalosporins and Amoxycillin were being routinely dispensed by paprmedicals when cheaper alternatives could have been used. Reconstitution of paediatric powders were difficult in field
conditions. Seals of all medications need to be broken to avoid resale. Most of the attractively coloured UNICEF ORS packets
ended up in the local vegetable market! ORS packets invariably are counter-productive as water cannot be boiled.
Distributing a water purifying tablet with each packet seems reasonable.
Nutrition posed a major problem. People refused to eat fish because of a local rumour that they were eating dead bodies
in the sea. This cheap, abundant, protein rich source was left untapped inspite of information that carnivorous fish are
not edible!
Immunisations could not even be considered. Medical care was regarded as relief commodity where drugs and injections
were demanded as a right. This needed to be guarded against.
Often neglected is the mental health of the population and the medical team as well. In this regard placebos were invaluable
as most patients just needed a sympathetic ear and something to take back home.
Ill
REHABILITATION
During rebuilding of houses corrugated iron roofs should be avoided as they are dangerous in a storm. Thatching should
be encouraged as it is cheap, can be used to keep afloat in a flood and can be built in a day. Cyclone shelters should
have alternative functions between cyclones.
Tube wells should be sunk after establishing group ownership and maintenance commitments.
The main occupations of the affected coastal areas were shrimp farming, salt and jute production and smuggling. All but
the last were critically affected by the cyclone.
It seems reasonable to conclude that the 3-tiers of relief are inextricably linked and it is impossible to do purely medical
work in a post disaster scenario. Apart from being an educational experience, the Bangladesh cyclone has underscored,
the need for the formation of a core group, aware about disaster preparedness and able to respond promptly in the
event of another disaster.
Dr. Anne Rego
Emmaus - Swiss Project
Palamaner
June 1991
21 —
NEPHROLOGY
St. John’s Medical College Journal of Medicine
SYMPOSIUM - I
HEMOLYTIC UREMIC SYNDROME CURRENT
CONCEPTS IN PATHOLOGY AND MANAGEMENT
S.D. SUBBA RAO
DEFINITION
The Hemolytic Syndrome (HUS) first described by Von
Gasser in 1955, is a disease mainly of infancy and early
childhood characterized by acute renal failure, fever,
hemolytic anemia with micro angiopathic changes in the
erythrocytes and thrombocytopenia.1
Thrombotic thrombocytopenic pupura (TTP) and HUS
have many features in common and choice between the two
diagnosis is some times arbitrary especially in adults. HUS
and TTP are now thought to represent common etiopathologic responses to a number of different initiating events,
distinguished at present, by the clinical settings in which they
occur.
Both HUS and TTP are commonly seen in association
with pregnancy, cancer, infections (especially diarrhoea)
and toxins have been implicated in sporadic cases of
thrombotic micro angiopathy.2
which stools are often bloody. This type is called the epidemic
form by Barett et al to distinguish from the sporadic form in
which the prodromal illness may be an upper respiratory tract
infection or in which there is no definite prodrome. The
prognosis is this tends to be good.4
TABLE|1
Clinical Subtypes of Hemolytic Uremic Syndrome
Clinical features Typical (Epidemic)
Genetic factors
Age of onset
Rare
6-48 months
Not reported
Uncommon
Common
Babies & older
children
All round the year
Resp / nil
Insidious
frequent
Severe
arteriolar
cortical necrosis
Common
Common
Rare
Common
Season
Summer
Prodrome
Diarrhoea
Abrupt
Onset
Occasional
Neurologic
Hypertension
Mild io moderate
Renal Pathology Glomerular,
CLINICAL SUB GROUPS
Clinically 2 broad sub groups, the first is a disoder which has
become increasingly common, it typically follows a
prodormal illness of diarrhoea often bloody, occurs, more
often in summer months and 85% of these children can be
expected to make a good recovery. This contrasts apprecia
bly with a much rarer illness in which there is no obvious
prodrome and no seasonal incidence. In this heterogenous
group one finds patients with a relapsing form of the disease
or a positive family history. More than 70% progress to
chronic renal failure. The mnemonics D+ for diarrhoea as
sociated and D- for non prodromal form of the syndrome
are accepted and reflect an extrensic or intrinsic etiology
respectively.3
a.
The classic or typical form of HUS (Table 1)
This is the commonest formofHUS.lt occurs more often
in infants and growing children, but no age group is exempt,
The features of HUS are-preceded by a diarrhoeal illness in
DR. S.D. SUBBA RAO
ASSISTANT PROFESSOR
DEPT. OF PAEDIATRICS
ST JOHN'S MEDICAL COLLEGE AND HOSPITAL
BANGALORE560 034.
22
Relapse
End stage
Renal Disease
Death
Atypical (sporadic)
b. HUS associated
E.Coli (VTEC)
of
verocytotoxin
producing
Discovery of Verocytotoxin producing E Coli (VTEC) impli
cated in cases of D+ HUS by Karmali in 1983 was a major
break through. The verocytoxin is identical to shigatoxin
produced by Shigella dysentrae - 1. It is recognised that
glomerular endothelium the main site of injury in HUS and
verocytotoxin is shown to be lethal to human umbilical vein
in vitro.
c.
HUS associated with shigellosis (S. dysehtriae type I)
Although eases have occured in North America and Europe.
the definitive descriptions of this association have cbme from
India and' Bangladesh.5 Tip incidence of HUS in India is
unknown and the prevalence of HUS cases of Bacillary
dysentry has not been established clearly but it seems to
range from 0.88% and 3.7% to as high as.65%. There seems
to be no clear cut prodromal illness separated by a disease
free interval in this form of HUS. Very high leucocyte counts
including leukemoid reactions have been reported in shigella
VOL IV No. 2 -----
St. John’s Medical College Journal of Medicine
associated HUS. In typical cases circulating endotoxin has
not been found although in some atypical cases one may be
able to demonstrate circulating endotoxin prior to the onset
of HUS. These patients may also have evidence of
consumptive coagulopathy. The mortality rate ranges from
30 to 80%.
d.
HUS associated with S. pneumoneae
Neurominidase derived from pneumococci is thought to
cleave N-acetyl neuraminic acid on the surface of erythro
cytes, platelets and endothelial cells, thereby exposing the
T-F antigen. This results in hemolysis, thrombocytopenia
and acute renal injury.
e.
HUS associated with the other infectious agents
Cases of HUS have been reported following an infection with
many different bacteria including E. Coli, salmonella,
yersinia Campylobacter and clostredia. A large number of
viruses have been isolated from patients with HUS and at
times several different viruses have been found in the same
patient. Isolated cases of HUS following infectious mononucleosus and kawasakis disease have also been reported.
f.
a) Reduced erythrocyte antioxidant status
b) Evidence to suggest lipid peroxidation in the cell wall
c) Increased erythrocyte aggregation in patients with HUS
in whom there was an infection by the nuraminidase
producing pneumocci.
Thrombocytopenia
HUS associated with drugs & Chemicals (Table 2)
:
The duration of Thrombocytopenia ranges from 7-14 days.
The cause of platelet deficiency could be :
a)
b)
Familial HUS
Both autosomal dominant and recessive modes of transmis
sion have been reported. A prodromal illness is the excep
tion. Recurrent episodes can occur. These patients have a
defect in prostacycline production. Mortality is >90% in
dominant form and >70% in the recessive form.
g.
lobin and a reticulocyte response. Coombs test (direct &
indirect) are negative. Osmotic fragility and RBC enzymes
are normal. Laboratory and clinical observations implicate
a micro angiopathic process in which erythrocytes appear
to be damaged and fragmented by fibrin strands as they
traverse in the small vessels of the kidney. It has been
postulated that these fibrin stands develop as a conse
quence of localized intravascular coagulation. Although this
fibrin stand theory is well accepted, there may be other
reasons why erythrocytes are damaged and some of the
reasons can be summarised as follows :
Peripheral destruction/shortened platelet survival
Increased consumption or increased aggregation - local
ized intravascular coagulation and the micro angio
pathy.
Immunologic mechanisms have not been implicated
because of failure to demonstrate antiplatelet antibodies.
One of the often ignored mechanisms is the effect of
hemolysis on platelet aggregation. A substantial amount of
intracorpescular nucleotides may be released during trauma
to erythrocyte and then cause platelet activation.
PATHOGENESIS46
Hemolytic Anaemia
Hemolysis usually occurs rapidly with Hb levels falling to as
low as 4gm/dl. The anaemia is accompanied by increased
serum bilirubin concentration, decreased serum hepatog-
Platelets may have an important role in the pathogenesis
of glomerular injury and in the reduction of glomerular
filtration rate. Platelets release thromboxane A2 and sero
tonin among many other factors. These may cause vaso
constriction and play an important part in the reduction of
GFR and renal plasma flow. There is evidence in favour of
TABLE- 2
Agents Implicated in Thrombotic Microangiopathies
Chemotherapeutic Agents
Toxins
Other Drugs
Mitomicin
Cisplatin
Daunorubicin
Cytosine Arabinoside
Methyl ccnu
Chlorozoticine
Necocarcinostatin
Carbonmonoxide
Bee Sting
Arsinic
Sulfonamide
Iodine
Cyclosoprine A
Penicillin
Metronidazole
Penicillimine
Oral Contraceptives
June 1991
23 —
St. John's Medical College Journal of Medicine
a direct toxic injury to the platelets. The platelets also may
have a receptor for verocytoxin so that the thrombocy
topenia may also be the result of direct injury.
reported in adults, often in association with pregnancy or as
a secondary condition superimposed on essential hyperten
sion.
Prostanoids :
The Clinical picture5 :
Endothelial cells produce numerous prostanoids, enzymes
and factors which are vitally important to the maintenance of
normal glomerular function. These include prostocycline,
leukotrines, coagulation factors and fibrinocytic factors.
A week or few days before the onset of HUS there is usually
an episode of diarrhoea, with or without bloody stools and
vomiting, less frequently, the prodromal illness is that of an
upper respiratory tract infection and occasionally, illness
such as varicella, measles or urinary tract infection.
Alterations in the ratio of prostacycline produced by endo
thelial cells and thromboxane A2 produced by platelets and
possibly by mesnageal cells may be expected to cause a
reduction in renal plasma flow and a decrease in GFR.
Neutrophils
:
Several lines of arguements from clinical and experimental
studies indicate that neutrophil leukocytosis may be more
than an associated finding in many HUS patients. Some
observations have led to the proposal that neutrophil may
be involved in the pathogenesis of glomerular injury.
Neutrophils are capable of causing glomerular injury by
several mechanisms;
a)
The intracytoplasmic granules contain catabolic en
zymes. One of these, elastase has been considered to
account for nearly 60% of the endothelial injury caused
by neutrophils.
b) Activated neutrophils can generate reactive oxygen
radicles which are capable of causing oxidative damage
to the cell membranes.
c) Localized coagulation could be enhanced by release
of procoagulant from activated neutrophils.
Recently Walters et al described a strong association
between neutrophilia at onset and adverse outcome of
patients with D+ HUS.7
Acute Renal Injury:
Glomerular capillary endothelial cell injury is the most
consistent renal finding in ultrastructural studies. Endothelial
swelling and detachment from the basement membrane has
been best described in the glomerular capillaries but has
been found in other organs as well. The swelling of the
endothelium results in the reduction of the capillary lumen
and a decrease in the filtrating surface of the capillary which
also is the result of expansion of the measangium. The net
result of these changes is a decrease in the GFR.
EPIDEMIOLOGY :
The syndrome mainly occurs in infants and children and rarely
in neonates. The mean age of onset differs from one country
to another. An increasing number of cases are being
24
The Syndrome :
In addition to involving kidneys, erythrocytes and platelets,
HUS occurs in the gut, liver, heart and CNS. Mildly affected
patients have anaemia thrombocytopenia, azotemia and an
uncomplicated course. Severly affected patients are anuric
for more than 24 hours and frequently have seizures and
hypertension. Anuria may last for days to several weeks.
Some patients have an inexorable course with progressive
renal insufficiency severe and recurrent hemolysis and
thrombocytopenia. Some patients experience recurrences
and in some women recurrences were associated with
pregnancy. The HUS can mimic an acute abdomen in 20%
of cases. Some patients have presented with a picture
similar to ulcerative colitis with abdominal tenderness and
bloody diarrhoea. Perforation, gangrene, intussuption,
pseudo membranous colitis and colonic strictures have been
reported. Neurologic complications include seizures, drowsi
ness, personality changes and hemiperisis. Seizures may be
related to hypertension in some but in many they are related
to erythrocyte disturbances and microthombi. Jaundice is
uncommon. Hepatosplenomegaly occurs in many cases and
in some there is biochemical evidence of hepatitis. There
has been evidence of myocarditis reported in few cases.
MANAGEMENT8
Considerable success has been achieved in the management
of acute illness by the judicious use of blood transfusions, the
careful control of electrolyte and water disturbances and
normalisation of blood pressure.
The management approach can be broadly seen under two
headings, supportive therapy and specific therapy.
Although the benefits of newer therapies are problem
ortiented and comprehensive, supportive therapy plays a
major role in all forms of HUS though the specific therapy may
be refined to meet the challenges of various clinical sub
groups.
Supportive Therapy :
A comprehensive supportive therapy has been responsible
VOL IV No. 2 -----
St. John's Medical College Journal of Medicine
for the dramatic decline in the mortality rate from 40% during
1955 to the present rate of approximately 5% to 10%.
a)
bleeding or who have count of less than 50,000/mm3 and are
about to undergo invasive proceduals like CVP monitoring or
peritoneal dialysis.
Fluid and electrolyte management :
d)
Meticulous attention to salt and water management is
imperative.
i)
Patients dehydrated from vomiting and diarrhoea require
repletion therapy irrespective of renal function. Potassium
should however be witheld unless the patient has
hypokalemia.
ii)
If the child is euvolemic on admission, fluids should be
limited to insensible loss (350ml/m?) plus urine and stool
loss.
iii)
More often patients are edematous because of admini
stration of generous amounts of IV fluids in an attempt
to stimulate urine production. An edematous hyponatre
mic patient has not only an excess of sodium but an even
greater excess of water. These patients must be allowed
to go into negative salt and water balance to correct
edema and dilutional hyponatremia. This can be
achieved by giving no sodium chloride and allowing
gastrointestinal and insensible fluid less to exceed
intakes. Often however, the diarrhoea subsides shortly
after the onset of HUS and euvolemia can be achieved
only with dialysis.
iv)
Hyperkalemia commonly occurs. If hyperkalemia is
moderate with no changes in ECG, administration of a
cation exchange resin like sodium polystyrene sulfonate
(kayexalite) is sufficient. Dose oral or rectal is 1 gm/kg.,
plus 1 ml of 70% sorbitol for each gram of kayexalate to
prevent constipation. A foley urinary catheter can be
used to administer the drug rectally. A retention
edema for 20 and preferably 40 minutes is necessary
for effective rectal exchange. With more severe hyper
kalemia, the conventional use of calcium gluconate,
sodium bicarbonate or insulin glucose infusion to be
given, while child is prepared for peritoneal dialysis,
which might be inevitable and life saving.
v)
Hyperphosphatemia and secondary hypocalcemia are
best treated with dialysis, phosphate binders (Alumi
nium hydroxide) have little effect.
b)
Redcell replacement
Hemolysis can be brisk with a corresponding hematocrit dop
of 10% or more within 24 hours. Packed cell transfusion at 10
ml/kg if the hematocrit falls rapidly to less than 15% is advised.
c)
Platelet Transfusion
Platelet counts less than 10,000/mm3are unusual and the
thrombocytopenia rarly requires specific therapy. Platelet
transfusions are to be restricted to patients who are actively
June 1991
Hypertension
Hypertension is seen in approximately 50% of cases and is
usually labile and intermittent. Sublingual nefidepine (0.24
to 0.5mg/kg/dose) for systolic readings above 120 to 130 mm
of Hg depending on the childs age. For more persistant
hypertension oral methyl dopa, 10 to 15 mg/kg per day
or
parenteral hydrallazine
(0.2mg/kg/dose) or oral
hydrallzine (1 to 2 mg/kg/day) in divided doses is recom
mended.
If the child continues to have episodic hypertension while
receiving these drugs, then nefidipine can be used as a
supplimentary drug.
e)
Seizure control
Seizures occur in about 40% of cases and in usually gener
alized. Causes of seizures is either hyponatremia or severe
azotemia. In some children it is secondary to structural
damage in the brain (infarcts) presumably as a conse
quence of micro angiopathy. Seizures can be usually
controlled with IV diazopam (0.1% to 0.2 mg/kg/dose)
followed by loading dose of IV phenetoin (15 to20mg/kg).
f)
Control of Azotermia
The combination of renal insufficiency. Catabolism and
reabsorption from the Gl tract can cause the blood urea
nitrogen to rise as much as 50 mg/dl/day. Once the vomiting
and diarrhoea subside the oral administration of carbo
hydrate essential aminoacids can help limit the azotermia.
Many authors recommend early peritoneal dialysis (Anuria
or oliguria for longer than 24 hours) while some feel we
should wait till BUN exceeds 150mg/dl, unless there was
severe fluid over load, hyperkalemia, encephalopathy or
other clinical signs of uremia. Early dialysis coupled with ul
trafiltration allows more liberal fluid intake and full nutritional
support. The choice between peritoneal dialysis to hemodi
alysis should be based largely on the size of the child and the
experience of the dialysis team. Peritoneal dialysis is usually
preferable in infants and young children, because of the easy
access of the peritoneal cavity and safer and requires less
intensive nursing support.
g)
Nutrition
Once the vomiting and diarrhoea have resolved, enteral
nutrition should be restarted. Occasionally the colitis can be
severe and persistant. Severe bowel ischemia, and
occasionally bowel gangrene with perforation requiring
colectomy, may prelude the introduction of oral feeds for
extended periods. In these situations total parentral
25 —
St. John’s Medical College Journal of Medicine
nutrition will be necessary. Administration of generous
amounts of protein (2 to 3 gm/kg/day) in an effort to promote
positive nitrogen balance and perform dialysis as needed
to keep BUN below 100mg/dl is recommended. Children in
acute renal failure from HUS have very high serum triglyc
eride levels. Only enough fat to prevent essential fatty acid
deficiency (0.5 mg/kg three times a week) should be
administered.
SPECIFIC THERAPY (INVESTIGATIONAL):
A variety of strategies designed to inhibit or lyse the reputed
platelet-fibrin thrombi have been used in an effort to
favourably effect the clinical course of HUS.
a) Heparin Therapy:
The rationale behind using heparin followed the observation
of fibrin in the renal vasculature and the presence of fibrin
degradation products in the circulation. But controlled
studies have shown heparin to be of no use. The reason may
be because it might be too late to administer heparin once
the diagnosis of HUS has been estalished, because the bulk
of any fibrin related ischemic damage has probably already
occured and there is usually no laboratory evidence of on
going fibrin deposition. In addition systemic heparin admini
stration can cause life threatening hemorrhage and is
therefore not recommended.
response to vascular injury, could account for the thrombocytic microangiopathy. These observations have led to the
‘missing factor’ hypothesis and to the speculation that the
infusion of FFP replaces the factor and plasma exchange
might have an additional advantage of removing PGI2
inhibitors. A multicentric study in Italy has failed to show any
benifit from use of FFP.
Experience with plasma exchange in childhood has largely
been limited by risks and difficulties in acquiring and maintain
ing a vascular access. The FFP therapy is therefore not
currently recommended for treating classic childhood HUS.
Moreover, given the risk and expense of plasma exchange,
any recommendation for its use should await the results of
controlled randomized prospective clinical trials. One can
however make a stronger argument for use of FFP or plasma
exchange in non classic HUS, (familial or recurrent). If one
elects to use these therapies for non classic HUS, however,
it must be done with the realization that they are of unproved
value, not without risk, and in the case of plasma exchange
not without considerable expenses.
e)
Prostacycline (PGI2) Infusion :
The probability of HUS plasma to support PGI2 production
and the recognition of the platelet inhibiting properties of
PGI2 have led to trials of IV prostacycline infusion. These
small un controlled studied failed to show benefit. Moreover
PGI2 is a potent vasodilator and can cause hypotension.
b) Antiplatelet Agents :
f)
There is some evidence that the use of aspirin and dipyrridamolemay cause a rapid rise in platelet count, but there
is no evidence that the antiplatelet drugs favourably affect
the other out come variables. Failure to demonstrate
efficacy may be a matter of timing; their administration
would not be expected to inhibit the platelet thrombus once
the platelet activation has occurred.
c)
Fibriholytic Agents :
With the realization that it was too late to initiate
anticoagulant or antithrombotic agents once the diagnosis of
HUS has been established, it was but logical to think of
methods to facilitate lysis of the fibrin platelet thrombus.
Attempts have therefore been made to use plasinogen
activating enzymes (urokilase, streptokinase) in the hope of
digesting fibrin threads that entrap platelets and bond clots
to the damaged blood vessels. Studies comparing
streptokinase therapy to symptomatic therapy have failed
to show any benificial effect.
d)
Freshfrozen plasma (FFP) infusion and plasma
exchange
•**
».v* •
A decreased ability to produce normal amount of antithrom
botic and antiplatelet substance by the endothelial cells, in
26
Intravenous IgG infusion :
Although IgG may improve thrombecytopenia, it is difficult to
assess its effect on the need for dialysis, duration of renal
failure and outcome. Recommendation regarding the use
of intravenously administered IgG must therefore await
results of prospective clinical trials.
g)
Vitamin E, Therapy :
There is speculation that lipid peroxidation plays a role in
the pathogenesis of HUS. Red blood cell membrane
archinodinic acid, from which PG 12 is generated may be
deficient because of peroxidative damage, and depressed
vitamin E. activity plus depletion of red cell membrane
phospholipid had been described in children with HUS. These
observations have led to considerable enthusiasm to the use
of vitamin E. Although vitamin E. Administration is one of
the least dangerous and least expensive of the investigative
therapeutic strategy, there is no continuing evidence for its
efficacy.
To conclude there can be no doubt that meticulous attention
to fluid and electrolyte balance, the administration of packed
cells for severe anemia, the control of hypertension and
seizures, and the widespread availibility of dialysis for infants
and young children have had a dramatic effect on the
outcome of HUS.
VOL IV No. 2 -----
St. John’s Medical College Journal of Medicine
It is more difficult to assess the effects of newer therapies
because there are a few seizable well designed prospective
randamized trials. It may first be necessary to deliniate the
pathophysiology and natural history of the various sub sets
before developing specific therapeutic stategies.
REFERENCES
1. Richard Aster 'Thrombocytopenia due to enhanced platelet
distraction'- Hematology*. Ed. Williams WJ, Beutler E, Erslev AJ.Lichtmann
MA, 3rd Edition McGaraw Hill Book Co. 1983;pp1308-1309.
2. Ives HE, Daniel TO : 'Vascular Disorders of kidney' - The Kidney Ed.
Brenner, BM, Rector Jr FC, 4th Ed. WB Saunders Co. 1991 ;pp1519-1527.
4. Kaplan BS, Vedanarayan VV : ‘Pathogenesis of Hemolytic Uremic
Syndromes-Current concepts. Indian J. Pediatrics 1988;55:512-525.
5. Raghupathy P, Date A, Shastri JCM : 'Hemolytic uremic syndrome
complicating shiegalla dysentry in South Indian Children*. Br. Med. J.
1978,1:1518-1521.
6. Jack SC, Fong, Jean-Pierce DE, Chandarevian, Bernard S. Kaplan :
Hemolytic Uremic Syndrome - Current concepts and Management, Ped.
Clin. N. Am. 1982;29:pp825-856.
7. Walter ND, Matthei U, Kayar, Dillan MJ, Baratt TM: The polymorphonu
clear count in childhood HUS Pediatric Nephrology 1989;ii:411-421.
8. Siegler RL: Management of hemolytic Uremic Syndrome. J.Pediatr.
1988;112:1014-1020.
3. Milford DV, Tailor CM : 'New insights into the hemolytic uremic
Syndrome*. Arch. Dis. Child 1990 65:713-715.
NOTICE
The Executive Committee of the Alumni Association has decided that
the journal will be available only on subscription, from March 1992.
Subscriptions may be remitted to the Alumni Office.
COMMUNITY HEALTH CELb
326, V Main, I Block
Kownbngala
Bangiloro-560034
India
27 —
June 1991
NEPHROLOGY
St. John’s Medical College Journal of Medicine
SYMPOSIUM -1
ACUTE RENAL FAILURE
T.S. RAM KUMAR
Acute renal failure (ARF) is a syndrome that can be broadly
defined as rapid deterioration of renal function resulting in the
accumulation of nitrogenous wastes such as urea and
creatinine1. To be detectable as a departure from the limits of
normal by a simple blood test this accumulation usually
implies at least a 50% decrease in the glomerular filtration
rate (GFR). If the ARF is superimposed on a pre-existing
renal insufficiency (acute on chronic renal failure) detectable
rises in serum creatinine require smallerdecrements in GFR.
Such a definition encompasses a variety of parenchymal
renal diseases and of extra renal abnormalities classified
and defined in Table I.
TABLE 1
Definitions of six major syndromes associated with an
acute decline in GFR
Pre renal azotaemia : Decrease in GFR resulting from
renal hypoperfusion immediately reversed upon restoration
of renal blood flow and not associated with structural
damage in the kidney.
Acute (intrinsic) renal failure : Decrease in GFR resulting
from renal hypoperfusion or nephrotoxin, not immediately re
versed upon discontinuation of insult and associated with
some tubule cell damage.
Acute interstitial nephritis : Decrease in GFR resulting
from interstitial inflammation.
Acute Glomerulonephritis or Vasculitis : Decrease in
GFR resulting from glomerular or vessel inflammation.
Acute renovascular disease : Decrease in GFR resulting
from obstruction of renal artery orvein in a single functioning
kidney or with bilateral kidney disease.
Obstructive uropathy : Decrease in GFR resulting from ob
struction in the urinary collecting system.
ARF is commonly used to describe acute intrinsic renal
failure (AIRF), otherwise referred to as acute tubular necro-
DR. T.S. RAM KUMAR
ASST. PROFESSOR AND IN-CHARGE
DEPT OF NEPHROLOGY
ST. JOHNS MEDICAL COLLEGE AND HOSPITAL
BANGALORE 560 034
28
sis (ATN). This is a syndrome defined as an abrupt and
sustained decline in GFR occuring within minutes to days
in response to an acute ischemia or nephrotoxic insult.
There is a typical delay of 1 -2 weeks for recovery after the
insult is corrected2 indicating persisting renal damage
awaiting cell regeneration for function recovery. This defini
tion of ARF includes 1) prerenal azotaemia, immediately
reversed by improving renal perfusion. 2) Post renal
azotaemia rapidly corrected by relieving obstruction: and 3)
Primary Parenchymal disease defined as nephritis. This
classification is useful to the therapist where extra-renal
causes should be rapidly identified and corrected or where
histologically defined nephritis may be amenable to specific
therapy as opposed to AIRF when the management is
mainly supportive.
FEATURES OF SYNDROMES ASSOCIATED WITH
ACUTE RENAL FAILURE
PRE RENAL AZOTAEMIA :
Some combination of hypotension, hypovolaemia and
diminished renal perfusion is the most common cause of
acute azotaemia in hospitalised patients3 Table2. The renal
response to volume depletion is multiphasic. There is
initially an increased reabsorption of salt and water by the
tubules, mediated by hormones and nerves. The resulting
decrease in urine flow produces a disproportionate increase
in blood urea at a time when the preserved GFR maintains a
normal creatinine. More advanced hypovolaemia will cause
a decrease in the renal blood flow with a re distribution from
the cortex to the medulla. Subsequently GFR, heretofore
maintained by the complex balance between angiotension
II, prostaglandins and renal nerves, will decline.
Causes of pre renal azotaemia not associated with a decline
in GFR are conditions of increased urea production: large
protein intake and increased protein catabolism (fever,
surgery, steroids,
severe
illness)
and
decreased
anabolism (tetracyclines). In patients with gastrointestinal
bleeding, the combination of high protein load and contracted
circulation leads to an increased blood urea production.
ACUTE INTRINSIC RENAL FAILURE
AIRF can be induced by renal hypoperfusion (ischaemia)
and nephrotoxins (exogenous and endogenous), and fre
quently by a combination of both.
RENAL HYPOPERFUSION
Hypoperfusion of the kidney is the most frequently recog
nised single insult leading to AIRF in the setting of trauma,
surgery, haemorrhage or dehydration3. In clinical, situations
VOL IV No. 2 -----
St. John’s Medical College Journal of Medicine
listed in table 2, a critical decrease in RBF may cause a mild
reduction in GFR (pre renal azotaemia) or frank ischaemic
damage (established ARF). This can occur in the absence
of remarkable systemic hypotension, which is documented
in less than 50% of the cases of post surgical ARF3.
TABLE - 2
Cause of renal hypoperfusion associated with ARF
6)
Interference with renal autoregulation
Prostaglandin synthesis inhibitors
Angiotensin converting enzyme inhibitors
Hypoperfusion is associated with a graded parenchymal
injury ranging from none in pre renal azotaemia to frank
ATN and cortical necrosis. It is therefore evident that the
same clinical setting can produce prerenal azotaemia or
ARF, or sequentially both, depending on the severity of the
renal ischaemia, rather than on the type of insult.
1)
Intravascular volume depletion
Major trauma, burns, crush syndrome
Haemorrhage (postpartum, gastrointestinal, surgical)
Pancreatitis, vomiting, diarrhoea, peritonitis, dehy
dration, hypoalbuminaemia
volume depletion secondary to renal losses (dia
betic ketoacidosis, diuretic use, adrenal insufficiency)
2) Decreased cardiac output
Severe congestive cardiac failure or low cardiac output
(myocardial, valvular or pericardial disease)
Pulmonary hypertension, massive pulmonary embolism
positive pressure mechanical ventilation
3) Increased renal / systemic vascular resistance ratio
Renal rasocontrictors
Alpha adrenergic agonists (nor epinephrine)
Others: hypercalcaemia, amphotererin.
4) Systemic vasodilation
After load reduction
Antihypertensives
Anaphylactic shock
Anaesthetics
Drug overdosage
Sepsis
5) Liver failure
Among the causes listed out in Table 2, I would like to
elaborate on two causes which are increasing in incidence
as causes or renal hypoperfusion.
Inhibitors of prostaglandin synthesis such as salicylates,
propionic acid derivatives (Ibuprofen, naproxen) Indoleacetic acid derivatives (indomethacin) have been reported
to produce acute deterioration of RBF and GFR in patients
with reduced effective blood volume or renovascular disease
such as congestive cardiac failure4, decompensated
cirrhosis5 nephrotic syndrome6 volume depletion7, triamter
ene administration, vasocontriction, hypoalbuminaemia,
sepsis and preexisting renal disease. As depicted in Fig
1, vasodilatory prostag land ins play a pivotal protective com
pensatory vasodilatation in the setting of renal hypoperfu
sion, when activation of renin-angiotensin cascade alone
would threaten the kidney with further vasoconstriction.
The converting enzyme inhibitors, (Capropril, enalapril)
have been reported to produce a consistant and severe
deterioration in renal function with renal artery stenosis8.
Converting enzyme inhibition in cardiac failure may cause
ARF in the presence of risk factors such as hyponatraemia,
Fig 1 : Increased circulating All level
Factors
Vasoconstriction^^
Promoting------------ >
All generation
(eg) Hypotension
Circulating ——
All level
Low salt intake
Anaesthesia
Vasodilatation--------
t
Synthesis of
Vasodilatory
Prostaglandins
Increased circulating All level + Indomethacin
Factors
Vasoconstriction^
Promoting
All
Vasodilatation ---------
Generation
June 1991
Normal or
Renal
* I Resistance
Renal f
* resistance
Synthesis of
Vasodilatory
Prostaglandins
29 —
St. John’s Medical College Journal of Medicine
diuretic induced salt depletion and diabetes mellitus.
NEPHROTOXIC INJURY
Because of its natural function of waste exertion with high
blood flow and efficient mechanism for concentrating the
urine, the kidney is exposed to large fluxes and high
concentrations of blood - borne substances, frequently
greater by one or two orders of magnitude than the rest of the
body. Accordingly, the renal tubule cells are often the first
target of direct toxicity for a wide variety of drugs, solvents,
heavy metals and other exogenous and endogenous prod
ucts. Nephrotoxic ARF is usually reversible, preventable or
correctable if it is identified and if exposure to the offending
material is avoided. Thus when evaluating a patient with
ARF, an initial search fora potential nephrotoxin is essential.
The extent of the injury is related not only to the concentration
of toxin and the duration of exposure but to multiple
predispensing and conditioning factors. This is particularly
true in elderly individuals or against a background of
dehydration, vascular insufficiency and circulatory failure,
or in the presence of subliminal amounts of other injurious
agents.
Tables 3 and 4 enumerate toxins associated with the clinical
picture of AIRF.
TABLE - 3
Common causes of exogenous toxic ARF
1)
Antibiotics
Aminoglycosides
Cephalosporines
Sulpha Cotrimoxazole
Quinolines
Tetracyclines
Amphotericin B
2) Anaesthetic agents
Methoxy flurane
3) Contrast media
Diatrizoate
Iothalamate
lopanoic acid
lopamidol
4) Anti-ulcer agents
Cimetidine
5) Analgesics
6) Diuretics
Mercurials
7) Chaemotherapeutic agents
Cisplatin
Methotrexate
Mitomycin
Cyclosporin A
D-Penicillamine
30
8)
Recreational drugs
Heroin
Amphltamines
TABLE - 4
ARF related to endogenous nephrotoxic products
Pigment nephropathy
Myoglobin
Haemoglobin
Methaemoglobin
Intrarenal crystal deposition
Uric acid
Calcium
Oxalate
Tumor specific syndromes
Tumor lysis syndrome
Plasma cell dyscrasias
I would like to touch upon aminoglycoside nephrotoxicity as
ARF complicates 10 to 26 percent of therepeutic courses,
of gentamycin, tobramycin and amikacin, even when
monitoring of plasma drug levels is optimal9. Correlation
between drug levels and nephrotoxicity is inconsistant but
there is a general relationship between cumulative dose and
toxicity ARF due to aminoglycosides is usually non-oliguric
and not clinically obvious, before 5-10 days of drug
administration unless the presence of multiple risk factors
precipitates its occurence. (Table 5) Aminoglycosides differ
in their ability to cause nephrotoxicity, neomycin being the
most and streptomycin the least nephrotoxic. There isn’t
much difference between the other drugs as far as the
propensity to cause toxicity is concerned'0.
TABLE - 5
Risk factors in aminoglycoside nephrotoxicity
High dosage, prolonged or repeated courses
Preexisting renal insufficiency
Advanced age
Concomitant drug administration
Cephalosporins
Indomethacin
Contrast agents
Furosemide
Volume depletion or hypotension
Liver cirrhosis
Renal ischaemia
Potassium depletion
Metabolic acidosis
The mechanism of nephrotoxicity remains speculative.
Aminoglycosides inhibit phospholipaseA2, and so may
VOL IV No. 2 —
St. John's Medical College Journal of Medicine
reduce formation of prostaglandins by limiting availability of
their arachidonic acid precursor11. Membrane alterations
involving the release of destructive enzymes from intracel
lular lysosomes, phospholipidosis, mitochondrial dysfunction
and secondary immune response may act in concert to
produce tubule damage.
COMBINATION OF HYPOPERFUSION AND TOXINS
A key feature of ARF is the frequent combination of multiple
factors. Using multivariate analysis, several studies12 have
identified acute and chronic conditions that independently
contribute to the development of ARF (Table 6). Synergism
between renal hypoperfusion and toxic insults may predis
pose to more severe oliguric ARF.
TABLE - 6
Risk factors associated with development of ARF
Acute risk factors
Volume depletion
Aminoglycoside use
Radio contrast exposure
Septic shock
Dehydration
Hypotension
Pigmenturia
Chronic risk factors
Pre-existing renal disease
Hypertension
Congestive cardiac failure
Diabetes mellhus
Gramnegative organisms
Brucellosis
Fungi
Viruses including
haemorrhagic fever
Indirect effects:
Streptococcus
Pneumococcus
Typhoid
Diphtheria
Legionnaire’s disease
TABLE 7
Interstitial Nephritis causing ARF
Infections
Direct invasion:
Staphylococcus
June 1991
Infiltration
Lymphoma
Leukaemia
Drugs
Penicillins
Cephalosporines
Sulphonamides
Rifampicin
NSAID
Thiazides
Furosemide
Cimetidine
Allopurinol
We will not discuss glomerulonephritis, renal vascular
disease and post renal azotaemia (obstruction) as they are
beyond the scope of this article. But it is vital, to look for
these problems aggressively when confronded with a patient
with ARF as these are eminently curable and treatment has
to be started immediately.
PATHOPHYSIOLOGY OF ACUTE RENAL FAILURE
The pathogenesis of the suppression of kidney function in
ARF has been attributed to several mechanisms
demonstrated in experimental models of ARF in animals and
involving glomerular, vascular and tubule effects. Most
likely, multiple factors participate in various combinations
to produce ARF in both experimental animals and humans.
Fig.2
Fig 2 : Mechanisms of
GFR in ARF
Acute Renal Injury
ACUTE INTERSTITIAL NEPHRITIS
Acute interstitial nephritis (AIN) leading to ARF may be
caused by a variety of agents (Table 7). An increasing
number of drugs have been incriminated in the genesis of
ARF due to AIN and the mechanism is usually immunologi
cally mediated. Fever, rash, arthralgia, lymphadenopathy
and Eosinophilia with ARF are suggestive of AIN but are
.neither sensitive nor specific markers13. The same is true
of nephritic urinary sediment, eosinophiluria and positive
gallium scan. Because of the potential benefit from
glucocorticoid treatment, a kidney biopsy is indicated when
the diagnosis is in doubt. It is interesting to note that NSAID’s
cause a type of AIN, associated with nephrotic syndrome and
the biopsy resembles minimal change disease.
Sarcoidosis
Idiopathic
Diagnosed by exclusion
Vascular effects
Tubular effects
TUBULE EFFECTS
Increased Permiability (back leak)
The tubules may contribute to diminished renal function
through increased reabsorption. Of tubular fluid through
- damaged epithelium. In human ARF, using different clear
ance of dextrans, Myers and colleagues have recently
estimated backleak in severe ARF as about 20-50 percent,
whereas there was no backleak in less severe forms of
azotaemia14. Hence this mechanism is probably not
31 —
St. John’s Medical College Journal of Medicine
The humoral mediators which may have a possible role in
tubulo glomerular feedback include, renin, adenosine,
prostaglandins intracellular calcium and endothelin.
important in mild to moderate ARF.
Tubular Obstruction
The tubule may contribute to diminished renal function by
obstruction with casts, cellular debris or cellular swelling.
Tubule obstruction in humans has been inferred from luminal
casts and tubule dilatations in some severe forms of toxic or
ischaemic ARF15. The exact role played by obstruction re
mains uncertain.
To explain these various tubular effects observed in the
experimental setting, it has been proposed that there may
a heterogenicity of tubular damage in ARF. Some tubules
may be obstructed, some may manifest back leak and
others may be normal.
Vascular Effects
A reduction by more than 50 percent of RBF with a rise in
renal vascular resistance has been extensively documented
during the initial phase of many models of experimental
ARF16. During this initial phase restoration of RBF by volume
expansion restores GFR to normal. Later 1 to 2 days after the
insult, restoration of RBF, either spontaneous or induced
does not improve GFR. During this established phase of
ARF, the fall in GFR is disproportionately greated than the
reduction in RBF.
In human ARF, evidence for decreased RBF, and
particularly decreased cortical perfusion, has been devel
oped, corroborating a common observation of cortical pallor
at autopsy. The mechanism of impairment of RBF is
controversial. The involvement of vasoconstrictive -humoral
factors such as increased intra renal renin activity, adeno
sine, thromboxanes or endothelins have been considered.
ROLE OF TUBULO GLOMERULAR FEED BACK
How does ‘tubular necrosis' lead to diminised GFR needs an
explanation. A regulatory mechanism which lowers GFR
whenever the solute delivery or solute concentration at the
macula densa is. raised has been well documented and
termed tubulo glomerular feedback. Fig. 3.
Fig 3 : Tubuloglomerular Feed Back
f Macula densa flowrate
| Chloride ion transport
Mesangial
Contraction
f Renal arteriolar resistances
Kf
4JSNGFR<<
----
32 -------------------------------------------------------------------- --------------------
Susceptibility of Kidney
A few points on why the kidney is susceptible to injury is in
order. The reason for this susceptibility is not readily apparent
as the RBF and oxygen supply are usually high and above
requirements. Several studies has suggested, however, that
this overall
balance conceals remarkable regional
hypoxia, predominently in the outer medulla. This may
explain why the brunt of the damage is borne by the thick
ascending limb of the loop of Henle and the S3 portion of the
proximal tubule.
Multiple factors predispose the kidney to injury from drugs
or toxins; high blood flow, vast electrically charged surfaces
for glomerular filtration and tubular reabsorption, active trans
portsystems for ions, organic acids and bases, an efficient
concentrating mechanism and a distal tubule system of
acidification. Also it is appropriate to emphasise that
simultaneous renal hypoperfusion and toxic insult are syner
gistic in increasing the probability of ARF.
CLINICAL EVALUATION OF THE PATIENT WITH ARF
It is important to exclude the syndromes discussed in (Table
-1) before concluding that the given patient has intrinsic
renal failure.
Estimate of renal hyperfusion and nephrotoxic exposure
An important part of the history in patients with ARF is the
sequence of deterioration in renal function in relation to
chronology of the potential etiologies of ARF. An estimate of
the adequency of renal perfusion prior to the onset of ARF
is of paramount importance. The clinical estimate of the
patient's volume status requires a detailed history and
physical examination. Table 8 and Table 9.
TABLE 8
Check list in the evaluation of a patient with ARF
1) Evidence of genuine and recent decrease in GFR
2) Sequence of deterioration of renal function and its relation
to possible causative factors in the history
3) Estimate of the adequacy of renal perfusion prior to and
during the decrease in renal function.
Volume status
Cardiac function
Renovascular status
4) Record of potential nephrotoxins (exogenous, endoge
nous)
5) Search for extrarenal manifestations of disease
6) Urine examination
Volume, Sediment and composition
---------- —------------------------------------------------------------ VOL IV No. 2 —
St. John's Medical College Journal of Medicine
Fig 4 : Interpretation of urine sediment in ARF
7) Renal imaging
8) Consideration of need for kidney biopsy.
1.
Bland or scant findings
a) Vasculitides
Preglomerular vasculitis
Haemolytic uraemic syndrome
scleroderma
b) Renovascular diseases
Arterial thrombosis or emboli
c) Prerenal azotaemia
d) Postrenal azotaemia
2.
Granular casts
ATN - Pigmented, coarsely granular casts common
3.
Red blood cells and RBC casts
a) Glomerulonephritis highly likely
b) Interstitial nephritis rarely seen
c) ATN rarely seen
4.
Epithelial and white blood cells
white blood cell casts
a) Eosinophiluria present
Acute interstitial nephritis likely
b) Eosinophiluria absent
Acute interstitial nephritis possible
c) Pyelonephritis
Severe with abscesses
5.
Crystalluria
a) Uric acid
tumour lysis syndrome
b) Calcium oxalte
Glycol toxicity
TABLE 9
Clinical estimate of volume status
HISTORY
1)
History of fluid losses
Gastrointestinal (vomiting, diarrhoea,
biliary drinage)
Drainage of fluids (Third space)
Renal (osmotic or non osmotic diuresis)
Skin (excessive sweating or burns)
2) Thirst, dryness of mucosae, oliguria
3) Fluid balance records, weights charts
nasogastric,
PHYSICAL EXAMINATION
Signs of volume depletion
Poor skin turgor
Dry skin axillae and mucosa
•PTemperature of extremities
Postural signs IBP (10mm Hg),TPR (10/min)
Signs of volume excess
Gallop (S3), cardiomegaly
Jugular vein distention
Pulmonary congestion
Liver congestion
Periferal edema
Third spacing (ascitis, pleural effusion)
Accurate analysis of the timing and dosage of all drugs
administered is basic to a comprehensive evaluation.
Specific emphasis should be placed on antibiotics, contrast
agents, anaesthetics, NSAID and Cimitidine. Note should
also be taken of all potential endogenous toxins (hypercalcaemia, hyper uricemia, myoglobinuria, haemoglobinuria,
etc).
Search for extra renal cause
Frequently, the cause of ARF appears obvious when an
overt ischaemic or toxic insult can be identified. At other
times, however, a clearcausal link between an insult and the
ARF is missing. A careful search for extra renal manifes
tations is rewarding.
Special attention should be given to the urogenital system
since obstructive uropathy must be promptly excluded. Care
ful review of systems may provide a due to the involvement
of the kidney (glomerulonephritis, vasculitis, intersitial ne
phritis) or reveal an over looked cause for renal hypoperfusion
or toxic exposure.
Examination of urine sediment and volume :
This can give a clue to the cause of ARF (Fig.4)
June 1991
Evaluation of urine output may reveal anuria ( < 100 ml/day)
oliguria (< 400 ml/day) or non oliguria or polyuria (> 400 ml/
day). Anuria suggests bilateral cortical necrosis, vascular
occlusion, severe proliferative glomerulonephritis or com
plete obstruction, but it occurs in ATN as well. Non oliguric
ARF is increasingly recognised in nephrotoxin-induced as
well as hypoperfusion-induced disease usually associated
with a less severe insult to the kidney and with lower
morbidity and mortality than oliguric ARF.
RENAL IMAGING
Visualisation of the kidneys in ARF has the following
purposes.
1.
Differentiation from chronic renal failure where one finds
small contracted kidneys in contrast to ARF where the
kidneys are usually normal.
2.
Diagnosis of obstructive uropathy as evidenced
dilatation of the pelvi-calyceal system.
3.
Estimate of patency of the renal vessels.
by
33 —
St. John’s Medical College Journal of Medicine
6. Infectious
Neurologic
Pneumonia
Arterexis
Septicaemia
Neuromuscular
irritability
Urinary tract infection
Mental status changes
Wound infection
Somnolence
Coma
Seizures
To evaluate for kidney size and cortical thickness and to rule
out obstruction, the most effective and noninvasive method
available is ultrasonography. If obstruction is suggested by
this method, further evaluation may be needed with
retrograde and antegrade pyelography. To see the patency
of the renal vessels, radionuclide studies usually give
suggestive evidence and renal angiography is needed for
confirmation.
3.
Renal biopsy
MANAGEMENT
Renal biopsy to confirm the course of ARF is required in the
following settings.
Prevention
1.
Equivocal history and no definite proof of hypoperfusion
or toxic insult.
2.
Renal signs suggestive of glomerular vascular or inter
stitial lesions.
3.
Extra renal manifestations suggesting a systemic cause
of disease.
4.
Prolonged ARF (3 weeks since oliguria) where the
consideration are causes other than tubular necrosis.
Also, cortical necrosis has to be ruled out in this situation.
Complications
The complications of ARF recapitulate the uraemic syn
drome and differ mainly because of their rapid onset. The
degree of derangement depends on the catabolic state of the
patient and on account of residual renal function. Thus
nonoliguric patients, with better preserved excretary func
tion, generally have fewer uraemic symptoms than oliguric
patients. Hypercatabolic patients with high fever, sepsis and
trauma are at greater risk for life threatening hyperkalaemia
or acidosis. Table 10.
TABLE 10
Complications of Acute Renal Failure
Cardiovascular
4. Gastrointestinal
Pulmonary edema
Nausea
Arrhythmias
Vomiting
Hypertension
Gastritis
Pericardial effusion
Gastroduodenal ulcers
Myocardial infarction
Gastrointestinal
Pulmonary embolism
bleeding
Malnutrition
2. Metabolic
5. Hematologic
Hyponatraemia
Anaemia
Hyperkalaemia
Haemorrhagic diathesis
Acidosis
Hypocalcaemia
Hyperphophataemia
Hyper uricaemia
1.
34
Early identification of patients of risk with prompt elimination
of potential insults is the golden rule that has saved many
lives. The importance of rapid and adequate restitution of
circulating plasma and extracellular volume in preventing
progression from prerenal azotaemia to ATN has been
demonstrated by several observations.
As a corollary to the apparent synergism between ischaemic
and nephrotoxic insults, adequate hydration and volume
repletion (as evidenced by the establishment of diuresis)
are recommended whenever possible before and during
exposure to potential toxins, dosage of aminoglycosides.
should be reduced appropriately in the elderly and debilitated
patients in whom a misleadingly low serum creatinine may
suggest an over estimate of true GFR17. Serum levels of the
drug as well as the renal function should be closely
monitored. Combination of multiple insults such as
myeloma, dehydration and contrast agents or Jaundice,
and aminoglycosides, carry special risk and should be
avoided if possible.
Controversial or experimental Modalities (Table 11)
TABLE 11
Potential Therapeutic Modalities for ATN
Agents that may prevent ATN if administered before or
during the initiation phase
Diuretic (mannitol, loop diuretics)
Atrial natriuretic peptide*
Calcium channel blockers*
Oxygen radical scavengers*
Prostanoids*
Agents that may alter the coarse of the maintenance phase
of ATN by increasing GFR and/or urine output
Diuretics
Dopamine
Atrial natriuretic peptide*
Calcium channel blockers*
Prostanoids*
Intraventions that may hasten recovery by promoting
VOL IV No. 2 -----
St. John's Medical College Journal of Medicine
4.
tubular epithelial regeneration and repair
Parenteral nutrition
Adenine nucleotides’
Thyroxine’
Growth hormones’
*
Denotes therepeutic interventions that have not yet
been extensively evaluated in humans.
A variety of pharmacologic agents have been proposed to
prevent ARF in the high risk setting to attenuate its severity
or to hasten recovery. Because of the lack of sufficient
controlled information, the use of these modalities has
remained controversial.
TREATMENT OF ESTABLISHED ARF
Conservative measures
Conservative therapy is capable of controlling many of the
complications of ARF Table 12
TABLE 12
Checklist of conservative measures in the manage
ment of ARF
1.
Fluid Balance
Careful monitoring of intake/output and weight
Fluid restriction (usually to less than 1L/day in
oliguric ARF)
Total intake = urine output + extra renal losses
Clinical examination for fluid overload/dehydration
2. Electrolytes and acid-base
Prevent/treat hyperkalaemia
Avoid hypernatraemia
Keep serum bicarbonate >15 meq/L
Minimise hyperphosphataemia with AI(oH)3
Treat hypocalcaemia if symptomatic only.
3. Uraemia-nutrition
Restrict protein (0.6 g/Kg/day) but maintain
caloric intake:
Carbohydrate intake atleast 100gm/day to minimise
Ketosis and endogenous protein catabolism
Drugs
Review all medications
Stop magnesium containing medications
Adjust-dose for renal failure, readjust with improve
ment in GFR.
DIALYSIS MEASURES
If conservative measures fail to prevent symptomatic
uraemia, manifested by confusion or coma, nausea and
vomiting, increasing hyperkalaemia, severe acidaemia,
fluid overload, platelet dysfunction or pericarditis, dialysis
should be insituted.
Among the modes of dialysis available, the choice depends
on the clinical situation (Table 13).
I would like to highlight continuous arterio-venous
haemofiltration/haemodialysis. This is a new therapeutic
modality which is useful in patients who are haemodynami
cally unstable. A haemofilter is used to remove fluid as well
as do continous dialysis, at the bedside and without the need
for high blood flow with its attendant complications. World
wide the experience with its procedure is rapidly accumulat
ing and in our center we have carried out this procedure on
more than 30 patients in the last one year.
Course and Recovery
Course :
The clinical course of ARF is conveniently divided into an
oliguric phase, a diuretic phase and a recovery phase. This
does not apply to the now widely recognised nonoliguric renal
failure.
The duration of oliguria may be as short as a few hours or
as long as several weeks or even months with an average of
10 to 14 days. The longer the oliguria the slower and less
complete the recovery. If oliguria persists for more than 3
weeks, the diagnosis of ATN has to be reconsidered and a
renal biopsy is needed to evaluate the course.
The onset of the diuretic phase is heralded by progressive
TABLE 13 : Dialytic therapy of Acute renal failure
Favour haemodialysis
Favour peritoneal dialysis
Favour continuous haemofiltration
Haemodynamically stable
non-hypotensive patient
Catabolic patient
Haemodynamically unstable
patient
Non-catabolic patient
Haemodynamically unstable
Undiagnosed intra-abdominal
disease
Recent abdominal or
retroperitoneal surgery
Poor vascular access
June 1991
Active haemorrhage
(avoids anticoagulation)
Hypotensive patient with
volume overload
Partial preservation of
renal function
Intra-abdominal disease or
recent surgery
35 —
St. John’s Medical College Journal of Medicine
increments in urine output. During this phase it is vital to
monitor the fluid state and the electrolytes in order to pre-empt
complications. Typically the BUN and creatinine continue to
rise during the diuretic phase, then reach a plateau and begin
their descent only after several days of urine output > 1000
ml.day.
In non-oliguric patients, a marked diuretis is usually not
observed and the recovery phase commences with a fall in
BUN and creatinine. Although the major improvement in
GFR occurs within the first 2 weeks of the recovery phase,
renal function continues to improve for 3 to 12 months after
the episode of ATN.
REFERENCES
1. Anderson, R.J. and Schrier, R.W : Clinical spectrum of oliguric and nonoliguric acute renal failure. In Brenner, B.M., and Stein. J.H. (eds): Acute renal
failure (contemporary issues in Nephrology, Vol .6). Churchill Livingstone.
New York, 1980.
2. Schrier, R.W.: Acute renal failure: Pathogenesis, diagnosis and manage
ment. Hosp. Practice 1981;16:93
3. Hou, S.H.. Bushrnsky, D.A., Wish J.B., et al : Hospital acquired renal
insufficiency : A prospective study. Am. J.Med. 1983,74 243.
4 Walshl, J.J. and venuto. R.C : Acute oliguric renal failure induced by
indomethacin : Possible mechanisms. Ann Intern. Med. 1979:91 47.
Prognosis of recovery and survival
5. Boyer, T.D.. Zia, P , and Reynolds, T.B. : Effect of indomethacin and
prostaglandin A1 on renal function and plasma renin activity in alcoholic liver
disease. Gastroenterology 1979,77:215.
Repeated surveys of mortality in large series of patients with
ATN indicate that the major determinent of survival is the
nature of the condition that precipitated the renal insuffi
ciency.
6. Arisz, Donker, A.J.M. Brentjens, J.R.H.,and Vander Hem, G.K. : The
effect of indomethacin on proteinuria and kidney function in the nephrotic
syndrome. Acta Med. Scand. 1976:199.121.
Despite the regular use of dialysis and other improvements in
the management technique over the past decades, a
decrease in mortality seems to have been achieved in
certain populations associated with surgery or trauma but
not in the medical or obstetric setting. This lack of
improvement has been attributed to two factors : 1) the
increase in the age of the patient population 2) the larger
proportion of cases complicated by multiple organ failure,
in which life is more efficiently maintained in intensive care
units but with a smaller chance of survival18. ARF compli
cated by multiple organ failure is associated with increased
mortality, rising toward 100 percent when three or more
systems have failed19.
The increasing recognition of milder forms of ARF by multiphasicscreeing may infact artificially improve its prognosis
by extending the definition of ARF to relatively mild renal
insufficiency.
The causes of death are primarily infectious, cardiovascular
and respiratory complications.
Late prognosis of renal function
Irreversible loss of kidney function is essentially the rule in
complete bilateral cortical necrosis but is variable in the
incomplete type, where fewer than 50 percent of nephrons
are necrotic20. A small proportion of patients with ATN
never recover kidney function, especially when the insults
have been severe or multiple.
The vast majority of patients who survive an episode of ATN
achieve clinically normal renal function despite the frequent
sub clinical functional and histologic defects like impaired
concentrating ability and impaired acidification.
7. Wagoner, R.D.: Renal effects of the newer non-steroidal anti-inflamma
tory agents. Mayo-Clin. Proc. 1981:56:525.
8. Hricik, D.E., Browning, P.J., Kopelman. R., et al : Captopril-induced
functional renal insufficiency in patients with bilateral renal-artery stenosis or
renal-artery stenosis in a solitary kidney. N Engl.J.Med. 1983,308:373.
9. Smith, C R. Lipsky. J.J. Lakshmi, O.L., et al.: Double blind comparison
Of the nephrotoxicity and auditory toxicity of gentamycin and Tobramycin.
N.Engl. J Med. 1980:302:1106.
10. Moore, RD., Smith, C.R., Lipsky, J.J. etal: Risk factorsof nephrotoxicity
in patients treated with aminoglycosides. Ann.Intern.Med. 1984;100:352.
11. Lipsky, J.J. and Lietman, P S. : Aminoglycoside inhibition of renal
phosphotidyl ionisitol phospholipase. C.J. Pharmacol,
Exp. Ther.
1982,220.287.
12. Wilkins, R.G. and Faragher. E.B. Acute renal failure in an intensive care
unit : Incidence, prediction and outcome. Anaesthesia 1983,38.628.
13. Steinman, T.l. and Silva, P.. Acute renal failure, skin rash and Eosinophilia
associated with captopril therapy. Am. J. Med. 1983:75:154.
14. Myers, B.D. Chui, F., Hilberman, M., and Michaels, A.S.: Transtubular
leakage of glomerular filtrate in human acute renal failure. Am.J.Physiol.
1979;237:F319.
15. Oliver, J., Mac Dowell, M., and Tracy A: The pathogenesis of acute renal
failure associated with traumatic and toxic injury : Renal ischaemia, nephro
toxic damage and the ischaemic episode. J.Clin. Invest. 1951;1307.30.
16. Daugharty, T.M., Ueki, I.F., Merar, P.F., and Brenner, B. : Dynamics of
glomerular ultrafiltration in the rat. I. Response to ischaemic injury. J.CIin.
invest. 1974:53:105.
17. Rowe, J.W. Andres; R., Tobin J.D. et al: The effect of age on creatinine
clearance in man : A cross-sectional and longitudinal study: J.Gerontol.
1976:31:155.
1.8. McMurry, S.D Luft, F.C. Maxwell, DM etal : Prevailing Patterns and
predictor variables in patients with acute tubular necrosis. Arch. Intern. Med.
1978:138:950.
19. Cameron, J.S.: Acute renal failure - the continuing challenge. Q.J.Med.
. 1986:59:337.
20. Matlin, R A., and Gr^y.^ty.E : Acute cortical necrosis case report and
review of the riter.ature. Am, J. Med. 1974:56:110.
36
VOL IV No. 2 -----
ESSAY
St. John's Medical College Journal of Medicine
THE LEPROSY VACCINE - AN EXERCISE IN FUTILITY
ANNE REGO
INTRODUCTION
The M.leprae bacillus despite its promising origins as one of
the first human pathogenic bacteria to be discovered has lived
in the shadow of its cousin M. tuberculosis discovered a
decade later. The latter has an accurate skin conversion test
(Mantoux 1901) its very own vaccine (B.C.G. first used in
Europe in 1926) and an effective therapeutic armamentar
ium. Leprosy in the 1990’s continues to be an "orphan dis
ease" receiving only the hand-me-downs of Tuberculosis
research.
But M.leprae has not been an easy bacillus to live with. It still
defies attempts to cultivate it in artificial media, it has turned
out to be a “Janus faced" enigma with gross differences
existing between organisms isolated from tissues and those
grown in vitro.1 It took a century before an animal model
was developed. Even now the data on the precise etiopathogenesis remains hopelessly inadequate.
This essay reviews the evolution of the vaccine and examines
the candidates developed so far. It concludes with a discus
sion which seeks to answer the question put forth in the title
of this article.
THE VACCINE ERA
Ever since J.M. Fernandez wrote his now famous treatise in
1939 on “Estudio comparative de la reaccione de Mitsuda
con las reaccione tuberculinas" in the Argentinian review of
Dermatology- the quest for the elusive Leprosy vaccine
began.2 In essence he reported on “The possibility of
awakening in healthy people a resistance against Hansens
bacilli by B.C.G. vaccination”. He found that 92% of 123
Lepromin negative children converted to Lepromin positivity
following B.C.G.
The possibility of a close relationship between the two dis
eases was extended in the late 1950s by Chaussin and when
he suggested that the decline in Leprosy throughout Europe
was due to the rising incidence of Tuberculosis.3Shepard
later provided the first experimental evidence of the protec
tive effect of B.C.G. in M.leprae infection in the mouse foot
pad model.4The 1950s and the 1960s brought on the “Age
DR. ANNE REGO
.
EMMAUS - SWISS LEPROSY PROJECT
PALAMANER, AP
SOUTH INDIA
COMMUNITY HEALTH
_____________________________ 3.2g. V Main, I Block.
Koram^ngala
—
June 1991
----------------- Bang»lore-bb(JU34---India
of the B.C.G. trials”. The results are depicted in figure one
and are puzzling in their variation. The differences could be
due to :-
Different exposure of the population to Leprosy.
Differences in immuno-genetic characteristics of the
population
3. Different strains of M.leprae.
4. Varying protective effect of B.C.G.
A major shot in the arm, literally, was the establishment by
Eleanor Storrs and W.F. Kircheimer in 1971 of the ninebanded armadillo as a model for the in-vivo cultivation of
M.leprae.8 When fully infected it can yield as many as 10
organisms per gram of tissue.
1.
2.
Philip Draper in his “Purification of M.leprae protocol 1/79"
perfected the technique to separate the bacilli from its host
components and make it safe for human administration.9
Almost a ton of infected livers, spleens, and leproma masses
are now stored in an “Armadillo bank” in London.
Cultivable mycobacteria and second generation vaccines
using recombinant D.N.A. technology has ensured an
almost limitless supply of M.leprae for vaccine research.
1. The “IMMLEP initiative” formed by the Scientific Work
ing Group of Immunology of Leprosy arose after it was
realised that B.C.G. was not the solution. This body is
responsible for sustaining progress in vaccine research.
Killed M.leprae was first considered after it was found that it
induces protective immunity in mice and armadillos against
a challenge with live M.leprae. This vaccine is yet to
undergo clinical trials.
2. Convit et al elegantly demonstrated how B.C.G. sensi
tised lymphocytes induced macrophage activation resulting
in digestion of M.leprae.10 They injected a concentrated
suspension of Lepromin in LL and TT patients. In the former
they were unable to eliminate the bacilli but the later formed
typical immune granulomas. This test for the capacity to
eliminate M.leprae is known as the G.C.B. test (competency
in clearing baccili). Then the LL patients were injected
subcutaneously a mixture of B.C.G. and M.leprae and after
a month granulomas were formed. This proves an M.leprae
specific defect in macrophages i.e. an inability to present
M.leprae antigens for the sensitization of T cells.
The
M.leprae- B.C.G. combination is unique from conventional
vaccines. The latter protects a virgin population which
develops a normal immuno response to a non-pathogenic
Specific antigen. But here there are two micro organisms (a)
the specific heat killed M.leprae and (b) a living non-patho
__________————————
37 —
St. John’s Medical College Journal of Medicine
B.C.G. which acts as a macrophage activator to correct the
defect in the primary presentation of the specific antigen.
This vaccine besides immuno-prophylaxis has additional
immuno-therapeutic potential. Immuno-prophylaxis entails
protection of the population at risk against developing
clinical leprosy while immuno-therapeutics converts anergic
LL to a state of enhanced C.M.I. thus pushing it towards the
Tuberculoid pole.
3. Talwar et al have proposed the use of hapten or carrier
modified M.leprae to break the immuno-tolerance/anergy
seen in LL patients to M.leprae.
congenital athymic nude mouse and Grey Mangabey mon
key are not suitable alternatives either.
2. WHY VACCINATE?
That 2.5% living in endemic areas are already being
vaccinated daily by droplet infection, scratches and dust.
How is it they are still Lepromin negative after daily highly
natural vaccination with live and dead bacilli? What evidence
is there that "our vaccine” will provide better immunity?
3.
IS THE VACCINE ETHICALLY JUSTIFIED?
4. M.vaccae is an environmental mycobacteria isolated by
Stanford and is currently undergoing trials in Nepal.
The maximal dose required for sensitization and for deter
mining patient acceptability has yet to be established.
5. The I.C.R.C. (Indian Cancer Research Institute) vaccine
belongs to the M .avium intracellulare group.13 It shows exten
sive cross reactivity with M.leprae with respect to both B and
T cell antigens. The I.C.R.C. is now under a large scale trial
in Maharashtra.
4.
6. Mycobacteria w is a saprophytic non-pathogenic fast
growing soil mycobacteria similar to Runyons Group IV
classification.11 Trials for this vaccine started in 1986 in two
Delhi hospitals.
Criteria for the ideal vaccine are1. Should cross react with M.leprae.
2. Should activate T cells.
3. Should not have suppressor epitopes responsible for
energy seen in LL patients.
None of the vaccines have fulfilled all criteria in both in-vivo
and vitro tests. In the global contest the I.C.R.C. and the
Convit vaccine have been elected "the most promising candi
dates”.
CAN THE VACCINE CAUSE LEPROSY?
Possibly, in an endemic area patients with sub-clinical,
indeterminate or borderline disease can show signs of tuber
culoid leprosy after vaccination. Patients who harbour bacilli
around the nerves may develop serious nerve damage as
their C.M.I. increases. Besides M.leprae shares its immuno
dominant antigen with many other bacilli which may lead to
a disturbed immuno response to them. A cross reactivity
between M.leprae antigen and host tissue has been reported
which can lead to the induction of auto-immunity.
5.
HOW LONG IS THE DURATION OF SENSITIZATION?
Since the duration of sensitization is not known we cannot
determine the necessity or timing of the boosters.
6. CAN WE OVERCOME THE PROBLEM OF VACCINE
DELIVERY?
Is all the hype in the mass media and among the scientific
community justified?
Administering the primary and booster injections within the
existing frame work of our health system will prove
extremely difficult. Consider Tetanus where an effective
vaccine has been available for over fifty years and the
disease continues to be a major killer in India.
1. IS IT FEASIBLE?
7.
Even in the most highly endemic areas HD rarely affects
greater than 5% of the population of which in India only 20%
develop LL. So 95% of the worlds population does not need
vaccination and half of the remaining 5% live in non-endemic
areas and would never expect to encounter the bacilli. How
do you detect that 2.5% ? Do you Lepromin test all 100%
and read the result one month later? And here again only
10-15% of Lepromin negative patients are at risk for
developing the disease.
Skin test conversion is the only method inspite of reports
stating that delayed type hyper-sensitivity and protection are
not synonymous. This may result in selection of vaccines that
are not protective but may actually exacerbate an even
stronger hypersensitivity reaction in Tuberculoid patients.
Besides the responses to the 48-hour soluble protein antigen
(SPA) used by Convit and the Mitsuda reaction used in the
ICRC to assess efficacy cannot be compared.
DISCUSSION
Where do you find the armadillos especially since the clever
beasts do not breed in captivity? So when HD is finally in
control armadillos will be extinct. Other animal models like the
38
HOW DO WE ASSESS EFFICACY?
8. WHEN WILL RESULTS OF THE TRIALS BECOME
AVAILABLE?
Approximately 10 years are needed to determine whether
VOL IV No. 2 —
St. John's Medical College Journal of Medicine
Lepromin conversion has any protective value. Add another
10 years for consistent results from global multicentric trials
to come in. The vaccine is obviously not destined to play
a role in the Eradication of Leprosy by 2000 A.D.I!
9. IS THE EXPENSE ON VACCINE RESEARCH
JUSTIFIED?
Considering all the limitations discussed so far it is fair to
conlcude that a higher cost benefit ratio would be realised if
the money were spent on improving case detection and
drug research and ensuring regularity of treatment. The
emphasis should be shifted from high tech laboratory
experimentation to field based operational research.
10. CAN WE HOPETO ANSWER ALL QUESTIONS ON
THE LEPROSY VACCINE WHEN ALL THE BASIC ONES
ON THE DISEASE ITSELF REMAIN UNANSWERED?
4. Shepard CC: Vaccination against human leprosy bacilli in infection of
mice. Protection by B.C.G. given during the incubation period. J. Immunol
1966;96:229-229.
5. Stone MM. Brown JA: The trial of BCG against Leprosy in Uganda. Int.
J. Leprosy 1973,41:616.
6. Bechelli CM etal: BCG vaccination of children against leprosy - 9 year
findings of the WHO. Controlled programme in Burma. Bull. WHO
1974;51:93-99.
7. Russel DA. Scot GG and Wigley SC: BCG and prophylaxis. The Karimui
trial. Int J. Lep 1968;36:618.
8. Kircheimer WF and Storrs EE : Attempts to establish the armadillo
(Dasypus novemcinctus) as a model for study of leprosy. Int. J. L.
1971;39:692.
9. Draper P : Purification of M.leprae protocol 1/79. Report of the fifth
meeting of the Scientific working group on the immunology. Geneva June
80.
10. Convit et al: Immuno changes observed in indeterminate patients, LL
and Lepromin negative contacts after vaccination with M.leprae and BCG.
Clin Exp. Immunol 36(193) 159-167.
REFERENCES
1. Kato L : The Janus face* of Mycobacteria leprae Characteristics of
invitro growth are not predictable. Int. J. of Lepr. 1977;45:175.
2. Fernandez JM: Estudio comparative de la reaccione de Mitsuda con las
reaccione Tuberculinas. Rev. Argent. Dermatosif. 1939;23:45.
3. Chaussinand R : Tuberculose et Leprae - Maladies antagoniques. Int J
Lepr 1948;431-438.
June 1991
11. Talwar GP : Lepromin conversion after immunisation with autoclaved
M.W. Int. J. Lep51(193):159-169.
12.
Stanford JL: A vaccine for Leprosy. Lepr. Rev. 1977;48:87-91.
13. Deo MG, Bapat CV : Potential anti-leprosy vaccines from killed ICRC
bacilli.
14. Ridley DS : The dissociation of hyper sensitivity and immunity in the
spectrum of leprosy. Int. J. Lepr. 1982;50:363-364.
39 —
St. John’s Medical College Journal of Medicine
SELECTED SUMMARIES
Weber TR, Connor HR, Tracy TF
Congenital Tracheal Stenosis with Unilateral pulmo
nary agensis Ann.Surg. 1991;243:70-74
A combination of congenital tracheal stenosis and
unilateral pulmonary agensis is a rare and often fatal anom
aly. This series consists of 5 infants (ages 2-6 months)
treated over a 8 year period. The symptoms and signs at
presentation consisted of wheezing, stridor and tachypnea.
some present with frank respiratory failure. The surgical
therapy of this difficult anomaly is discussed. Two types of
surgical techniques were used. When the stenosis is over
a short segment resection and anastomosis of trachea is
carried out. In long segment stenosis rib cartilage tracheo
plasty was carried out. Most patients require cardiopulmon
ary bypass or ECMO during the tracheal repair.
Considering the rarity of this lesion this series represents
a substantial experience.
Blyth B and Duckett JW Jr.
Gonadal Differentiation : A review of the physiological
process and influencing factors based on Recent ex
perimental evidence. J.Urol. 1991;145:689-694.
This recent review is a complete update on the current
research in the field of gonadal differentiation. Sexual
differentiation is a sequential, ordered and relatively straight
forward process. Though the main steps and outcomes of
these have been clearly elucidated the molecular and genetic
basis of these processes are being unravelled only recently.
Of particular interest is the Y-chromosome and the various
gene loci controlling the complex process of male gonadal
differentiation. The exact genetic code has only recently
been cracked with isolation of a 35kb segment of DNA close
to the X/Y meiotic paring zone. This gene has been desig
nated SRY and is believed to be what was previously
described as the TDF(testis determining factor) gene. The
molecular biology of Y chromosome and its importance in the
male gonadal differentiation with particular reference to
disease conditions is discussed. Of particular note is the
value of these findings in true hermaphroditism.
With the use of more and more sophisticated equipment
and with increasing experience most obvious malforamtions
are easily diagnosed. Also, definition of certain findings in the
cranium which are very subtle but certainly point to the
presence of the spinal lesion have increased the ‘pickup’ rate.
Against this back ground it is essential for a doctor caring
for these mothers and these children born with neruattube
defects, to prognosticate on the outcome when faced with
an antenatal ultrasound which indicates the presence of the
anomaly.
This paper is a 10 year retrospective study of 200 cases
of uncomplicated meningomyelocele in the state of Washing
ton. The outcomes of 47 infants delivered by cesarean
section before labor began, 35 delivered by cesarean section
after the onset of labor and 78 who were delivered vaginally
are compared. The results revealed that infants exposed to
labor were 2.2 times more likely to have severe paralysis
than those delivered by cesarean section without labor.
Infants delivered by cesarean section before the labor had
begun had a mean (± S.D) level of paralysis 3.3 + 3.0
segments below the anatomical level of the spinal lesion at
2 years of age as compared with 1.1 + 2.3 for infants
delivered vaginally and 0.9 + 4.1 for infants delivered by
cesarean section after labor began (p < 0.001 for both
comparisons). Exposure to labor did not affect the frequency
of neonatal complications or later intellectual performance.
The results of this study are remarkable. But certain objec
tions have been raised. Firstly, this study is retrospective
and the results need to be confirmed in a prospective
controlled trial. Secondly, the numberof cases is small and
therefore a larger multicenter trial is warranted. Thirdly
the statistical significance achieved in several categoris with
a wide variation around the means also brings to
doubt
the results reported. Considering all these short comings
this is still an important contribution, if the results are
confirmed in a larger controlled trial with better prenatal
diagnostic screening. The efforts in this direction may well be
worth it as a two segment difference in this location will mean
whether or not a child will walk!
Luthy DA, Wardinsky T, Shurtleff DB, Hollenback KA, Hickok DE,
Nyberg DA et al.
Cesarean section before the onset of labour and
sybsequent motor function in infants with Meningo
myelocele diagnosed
antenatally N.Engl J.Med
1991;324:662-666.
The exact of incidence of neural tube defects in our country
is not known. It is seen in 10 of every 10,000 live births in the
U.S.A. Myelomeningocele and other varieties of neural tube
defects are most often diagnosed antenatally. This is due to
routine use of antenatal ultrasound in most major centers.
40
C. RAMACHANDRA
Thierry Poynard et al.
Beta - Adrenergic antagonist in the prevention of
gastrointestinal bleeding in patients with cirrhosis
and esophageal varices - An analysis of data and
prognostic factors in 589 patients from four ran
domised clinical trials, N Engl J Med 1991 ;324:1532-38.
The value of B-adrenergic-antagonist drug therapy for the
prevention of initial episodes of gastrointestinal bleeding in
VOL IV No. 2 -----
St. John’s Medical College Journal of Medicine
patients with cirrhosis and esophageal varices is uncertain,
both positive and negative study results having been
reported.
The authors have analysed data on individual patients from
four randomized, controlled trials to assess the efficacy of
this treatment. Of the 589 patients studied, 286 received
a B-adrenergic antagonist drug (porpanolol in 203 and
nadolol in 83) and 303 received placebo. The patients were
blinded to the treatment. A standard questionaire was sent
to the physcians and data analysed after a 2 year follow up.
and adjusted analyses.
The conclusions were:
*
*
*
*
The significant results were as follows :
Study
Control
P Value
Prevention of
primary bleeding
78±3
65±3
0.002
Prevention of
fatal bleeding
90±2
82±3
0.01
The efficacy was greatest in patients with good compliance
who did not have ascites and in patients in good condition.
The two drugs were also effective in patients with ascites or
severe cirrhosis as demonstrated by the multi dimensional
B blockers are effective in preventing the first bleed.
(primary prevention).
Reduce mortality associated with gastrointestinal bleed
in patients with cirrhosis regardless of severity.
Patients with cirrhosis with large or moderate size varices
should be treated with one of the B - adrenergic antogonist
drugs.
All patients with cirrhosis should be screened for large or
moderate size varices.
Though the various studies have used different criteria for
selection of patients the combined data have been evenly
matched for control as well as treatment groups when differ
ent variables were studied. The conclusion that has emerged
from the study is that B blockers as a class prevent episodes
of bleeding. The independent prognostic factors did not differ
from treatment and control group. The presence of ascites
and severe cirrhosis indicated a poor prognosis in both the
treatment and control group.
A study of this nature involves a lot of work and effort but it
is valuable, as prognostic factors have been identified and
the results showed that B blockers prevent the first episode
of bleeding. It also reduced the mortality after a bleed.
G.D. RAVINDRAN
Unsolicited contributions to this column are welcome
June 1991
41 —
CASE REPORT
St. John’s Medical College Journal of Medicine
AN UNUSUAL CASE OF ACUTE PANCREATITIS
RAVISHANKAR H.R, K.BADRINATH, TITUS AUGUSTINE, H.R.RAVI, NANDAKUMAR JAIRAM
INTRODUCTION
Post-operative pancreatitis following major surgery is a
potentially fatal complication. Itsoccurence after total colec
tomy is not reported. This report presents a case of acute
pancreatitis following total colectomy and ileostomy, briefly
discusses the possible etiology and the benign course of the
disease inrthis patient.
With conservative treatment for 7 days the clinical picture
improved and patient was started on oral feeds. Predniso
lone which was discontinued during the acute illness was
restarted and tapered. A week later the patient was
discharged and serial ultrasound scans done during follow up
showed complete resolution of the disease. The steroid was
stopped and the patient is totally asymptomatic.
DISCUSSION
CASE REPORT
Miss P. a 17 year old girl had ulcerative colitis of 8 years*
duration and was on treatment with high doses of steroids.
Due to failure of medical treatment and the development of
features of subacute intestinal obstruction, she was referred
to surgery. Pre-operatively she received total parenteral
nutrition for 10 days in addition to the steroids.
She underwent a total colectomy and ileostomy after due
preparation. The condition at operation was stable through
out with no hypotension, hypoxia or hypovolemia. The initial
post operative period was uneventful and the patient was
started on oral feeds on the fourth post-operative day. The
next day the patient developed nausea, vomiting and
abdominal distension. On examination there was fever
(101 ’F), tachypnea, tachycardia, epigastric fullness, tender
ness and absent bowel sounds. There was no cyanosis,
icterus, palpable mass or free fluid.
After ruling out other post-operative complications a diagno
sis of acute pancreatitis was considered. Investigations done
at that time revealed, hematocrit 31.5, total leucocyte
count 18,400/cu.mm, blood sugar 102 mg%, blood urea 21
mg%, serum amylase 338 units, urinary amylase 3,380 units,
serum calcium < 8 mg%. Blood cultures showed no growth of
organisms. The abdominal ultrasound scan showed fea
tures of acute pancreatitis with peripancreatic fluid collec
tion.
She received conservative treatment; keeping her nil per
oral I.V. ranitidine, I.V. fluids and antibiotics. Due to the
persistence of fever and other clinical signs, an abdominal
CT scan was done which revealed pancreatic necrosis
and peripancreatic fluid collection tracking down to the left
para renal space and into the lesser sac.
DR. RAVISHANKAR H.R
DR. K.BADRINATH
DR. TITUS AUGUSTINE
DR. H.R.RAVI
DR. NANDAKUMAR JAIRAM
DEPARTMENT OF GENERAL SURGERY
ST.JOHN'S MEDICAL COLLEGE AND HOSPITAL
BANGALORE - 560 034
42
Pancreatitis is known to occur following any type of major
surgery. It is rarely seen after colonic surgery and there are
no case reports of pancreatitis after total colectomy and
ileostomy. This patient had a combination of precipitating
factors, pre-operativeTPN including lipid infusions, long term
high dose steroid1 therapy and major intra-abdominal sur
gery. Any or all of these factors could cause post-operative
pancreatitis.
The unusual feature in her presentation was the painless
nature of the disease. The patient was comfortable although
she had not received any analgesics in the immediate post
operative period. The CT scan showed extensive pancre
atic necrosis and large peripancreatic fluid collection
suggesting severe disease. However, with conservative
management of keeping the patient nil per oral and use of H2
- receptor blockers and antibiotics, she showed signs of.
clinical improvement. The nausea and vomiting subsided,
abdominal distension decreased and she was afrebrile. Post
operative pancreatitis is known to be severe with a fatal
outcome in 25-50% of cases this patient however had a
relatively benign course. Complications associated with
pancreatic necrosis locally and systemically, are usually
serious2. Early recognition of' the disease, careful monitor
ing and prevention of known aggravating factors are
probably responsible for the benign course in our patient.
Prednisolone was restarted after the acute features
regressed and the patient continued with her steady
recovery.
CONCLUSION
This case report highlights the “silent" nature of presentation
and should alert the clinician to the possibility of post-opera
tive pancreatitis, especially when a combination of precipi
tating factors exist. Finally, the disease process may be
benign despite extensive pancreatic necrosis, contrary to
the fulminant course it is known to follow.
REFERENCES
1. Studley JGN etal. Pathophysiology of acute pancreatic, evaluation of
the effect and mode of action of steroids in experimental pancreatitis Am J.
Surg 1982;143:761.
2. Henry L.G. London RE, Ablative Surgery for necrotizing pancreatitis
Am J Surg 1976;131:125.
VOL IV No. 2 -----
Position: 2634 (5 views)