Blackwell Publishing AsiaMelbourne, AustraliaNEPNephrology1320-53582006 Asian Pacific Society of Nephrology200611213218Original ArticleOverview of haemolytic uraemic syndromeI Amirlak and B Amirlak

NEPHROLOGY 2006; 11, 213–218 doi:10.1111/j.1440-1797.2006.00556.x

Review Article

Haemolytic uraemic syndrome: An overview

IRADJ AMIRLAK1 and BARDIA AMIRLAK2

1
Department of Paediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain,
United Arab Emirates; and 2Department of Surgery, Creighton University Medical Center, Omaha, Nebraska, USA

SUMMARY: Haemolytic uraemic syndrome (HUS) is the most common cause of acute renal failure in children.
The syndrome is defined by triad of microangiopathic haemolytic anaemia, thrombocytopenia and acute renal fail-
ure (ARF). Incomplete HUS is ARF with either haemolytic anaemia or thrombocytopenia. HUS is classified into
two subgroups. Typical HUS usually occurs after a prodrome of diarrhoea (D+HUS), and atypical (sporadic) HUS
(aHUS), which is not associated with diarrhoea (D–HUS). The majority of D+HUS worldwide is caused by Shiga
toxin-producing Esherichia coli (STEC), type O157:H7, transmitted to humans via different vehicles. Currently
there are no specific therapies preventing or ameliorating the disease course. Although there are new therapeutic
modalities in the horizon for D+HUS, present recommended therapy is merely symptomatic. Parenteral volume
expansion may counteract the effect of thrombotic process before development of HUS and attenuate renal injury.
Use of antibiotics, antimotility agents, narcotics and non-steroidal anti-inflammatory drugs should be avoided dur-
ing the acute phase. Prevention is best done by preventing primary STEC infection. Underlying aetiology in many
cases of aHUS is unknown. A significant number may result from underlying infectious diseases, namely Strep-
tococcus pneumoniae and human immunedeficiency virus. Variety of genetic forms include HUS due to deficien-
cies of factor H, membrane cofactor protein, Von Willebrand factor-cleaving protease (ADAMTS 13) and
intracellular defect in vitamin B12 metabolism. There are cases of aHUS with autosomal recessive and dominant
modes of inheritance. Drug-induced aHUS in post-transplantation is due to calcineurin-inhibitors. Systemic lupus
erythematosus and catastrophic antiphospholipid syndrome may also present with aHUS. Therapy is directed
mainly towards underlying cause.

KEY WORDS: haemolytic uraemic syndrome, Shiga toxin, Shiga toxin-producing Escherichia coli, Shi-
gella dysenteriae, thrombotic microangiopathy.

Typical haemolytic uraemic syndrome (HUS) is more fre- renal failure (ARF) occurs with either haemolytic anaemia
quent in the summer months1 and occurs most frequently in or thrombocytopenia.5
children younger than 3 years.2 Enterohaemorrhagic Escher- In the present review, clinical manifestation, epidemiol-
ichia coli O157:H7, which produces Shiga toxin 1 and 2, is ogy, pathogenesis, current treatment and prognosis for both
frequently the cause of bloody diarrhoea, which character- types of HUS are discussed.
izes typical HUS.3 Differentiation of HUS into D+HUS
(HUS that occurs after a prodromal episode of diarrhoea)
TYPICAL HAEMOLYTIC URAEMIC SYNDROME
and D–HUS (HUS that is not associated with diarrhoea)
occasionally becomes confusing, as some children having Clinical manifestation
urinary tract infection with Shiga toxin-producing E. coli
(STEC) may develop typical HUS without diarrhoea.4 The Most cases of HUS in children are D+HUS. Almost half of
term incomplete HUS is the terminology used when acute reported cases in the northern hemisphere occur from June
to September. Affected children have prodromal symptom-
atic diarrhoea in 91% of cases and bloody diarrhoea in
Correspondence: Dr Iradj Amirlak, Department of Paediatrics, Fac-
ulty of Medicine and Health Sciences, United Arab Emirates Univer-
57%.6,7 Diarrhoeas due to E. coli O157:H7 infection are usu-
sity, PO Box 17666, Al Ain, United Arab Emirates. Email: ally very painful, mimic ulcerative colitis, and may not be
iradj.amirlak@uaeu.ac.ae or iradj_amirlak@hotmail.com associated with fever.8 Of patients with E. coli O157:H7
Accepted for publication 20 December 2005. infection 6–9% end up developing HUS after 5–10 days.9–11
© 2006 The Authors Acute renal failure may vary from simple haematuria,
Journal compilation © 2006 Asian Pacific Society of Nephrology proteinuria to sever oliguria. ARF with anuria has been
214
reported in 40%, and up to 61% have to undergo dialysis.6
Other systems affected include central nervous system, gas-
trointestinal tract, liver and pancreas.12
In a large study, up to 25% of patients showed neurologic
symptoms, including seizures and stupor, and hypertension
occurring during the acute phase in 15%. Gastrointestinal
tract may show involvement from oesophagus to perianal
area, and may include haemorrhagic colitis, bowl necrosis,
intussusception and intestinal perforation. Hepatomegaly
and/or increased levels of transaminases are frequent indi-
cations of liver involvement. Pancreatic involvement, indi-
cated by glucose intolerance, is usually limited to the acute
phase and occurs in less than 10% of patients. Severe pan-
creatic injury is rare.6
Microbiology
Up to 83% of cases of D+HUS in children occur after an
infection with STEC.6 In USA and Europe 80–86% of these
STEC infections are with E. coli O157:H7.13,14 In Australia,
most cases are due to non-O157 (STEC).15 In Bangladesh,
India and South Africa, gastroenteritis due to Shigella dys-
enteriae type 1 is frequently associated with D+HUS.16–18
Despite the similarity of pathogenesis of post-S dysenteriae
type 1 HUS to that of STEC, the mortality rate is signifi-
cantly higher (7.3%), with more than 40% developing
chronic renal disease.18
Pathogenesis
There is evidence that Shiga toxin is transported by neu-
trophils to the kidneys, where it is transferred and bound to
receptors on target cells, glomerular endothelial and tubular
epithelial cells.19 Toxin is then internalized via receptor-
mediated endocytosis and routed to endoplasmic reticu-
lum,20 leading to glomerular endothelial cell swelling and
detachment from underlying basement membrane with sec-
ondary activation of both platelets and coagulation cascade;
resulting in thrombotic microangiopathy. Although the
major extraintestinal target organ is the kidney, virtually
any organ can be involved.12
Shiga toxin produced by S. dysenteriae type 1 is identical
to Stx1 of E. coli. However, Stx2 is less related to Stx1.
STEC infections producing only Stx2 appears to be associ-
ated with greatest risk of developing HUS.21
Recent investigation suggests that prothrombin abnor-
malities might underlie initial renal injury, and renal insuf-
ficiency is secondary to fibrin thrombi.8
Epidemiology
In a 20-year population-based study of HUS in Utah, in
children younger than 18 years, 89% occurred after a diar-
rhoeal prodrome. Incidence ranged from 0.2 to 3.4 per
100 000 per year.22 Average annual incidences in Germany
were 0.71 per 100 000 in people under 15 years of age and
1.5–1.9 per 100 000 in children younger than 5 years.6 In
Canada, those incidences were 1.44 per 100 000 and 3.1 per
I Amirlak and B Amirlak
100 000, respectively.2,23 Natural reservoir of STEC is the
intestine. Cattle are considered the main source and vector.
Infection in humans follows ingestion of contaminated
undercooked meat, unpasteurized milk or milk products,
fruits and vegetables.24,25E. coli O157:H7 has been recovered
from other food sources, mayonnaise, unpasteurized apple
cider, chicken, seafood, pork, lamb, veal and water.26–28 Sec-
ondary human-to-human transmission is of particular con-
cern in nursing homes and daycare centres.29,30 There are
also reports of nosocomial transmission.31
Laboratory manifestations
Haematology
Microangiopathic haemolytic anaemia is one of the triad
defining HUS and characterized by negative Coombs’ test.
Haemoglobin values range from 5.3 to 6.9 g/dL, Peripheral
blood smear shows up to 10% damaged red blood cells
(schistocytes), including burr or helmet cells, which is
believed to be the result of mechanical trauma to the red
blood cells in the vasculature. Increased lactate dehydroge-
nase is the most sensitive index of ongoing haemolysis.
Additional findings include increased bilirubin level
(mainly indirect), reticulocytosis and sharp decrease in hap-
toglobin levels.32
Thrombocytopenia is another component of the triad.
Platelet counts range form 25 × 109 to 55 × 109 cells/L.
Verotoxin in E. coli O157:H7 decreases prostacyclin synthe-
sis by endothelial cells and promotes platelet aggregation.
Consequently, intravascular thrombi form, mainly in renal
vessels, hence a reduction in platelet count.33
Other laboratory manifestations
Elevated transaminases as well as laboratory findings associ-
ated with renal failure are common.
Serum levels of fibrin degradation product-E have been
reported to be significantly increased in patients with
bloody diarrhoea who ultimately developed HUS. There-
fore, it is suggested that raised serum fibrin degradation
product-E level may be a useful marker of HUS in the clin-
ical setting.34
Pathology
Characteristic renal pathology of HUS comprises arteriolo-
pathies extending to glomerular capillaries, called throm-
botic microangiopathy, and are of the following three
types.35,36
Glomerular thrombotic microangiopathy
Capillary wall thickening with resultant narrowing of lumen
and widening of subendothelial space, with double contour
appearance characterizes glomerular thrombotic microangi-
opathy. Glomeruli appear swollen with reduced caliber,
© 2006 The Authors
Journal compilation © 2006 Asian Pacific Society of Nephrology
Overview of haemolytic uraemic syndrome
resulting in red cell entrapment, interference with blood
flow; with fibrin aggregates plugging. Preglomerular arteri-
oles and glomerular capillaries are mainly affected. Such
lesions are seen in most cases of HUS.
Arterial thrombotic macroangiopathy
Thrombotic microangiopathy involves extraglomerular
arterioles and interlobular arteries, with intimal oedema and
arterial wall necrosis. Affected glomeruli are shrunken and
ischaemic. This is more commonly occurring in atypical
HUS (aHUS) and usually associated with severe
hypertension.
Cortical necrosis
Cortical necrosis is often limited, and may be seen in all
forms of HUS, but more commonly with extraglomerular
arterial involvement. Diffuse forms are rare and observed in
severe cases with prolonged anuria carrying a high risk of
chronic renal failure.
Differential diagnosis
Many disorders share similar clinical and laboratory findings
with HUS. Clinically, severe abdominal pain, bloody diar-
rhoea and leucocytosis, which are common symptoms of
D+HUS, may be observed in other enteric infections, such
as Salmonella, Shigella, Campylobacter and Amebiasis. Ele-
vated blood urea nitrogen (BUN) and serum creatinine lev-
els may also be seen in these enteric infections secondary to
dehydration. Absence of thrombocytopenia and microan-
giopathic anaemia distinguishes these disorders from HUS.
Diagnostic triad of HUS may be seen in severe sepsis, dis-
seminated intravascular coagulation and systemic vasculitis.
Clinical history in most instances will differentiate sepsis
from HUS. Systemic vasculitis has other manifestations,
such as rash, arthralgia, a normal platelet count and periph-
eral rather than central neuropathies. In disseminated intra-
vascular coagulation, intravascular coagulation leads to
thrombocytopenia, low levels of circulating fibrin, factors V
and VIII, prolongation of prothrombin and partial throm-
boplastin time.37
Current and future therapeutic management of typical
haemolytic uraemic syndrome
Proper treatment of HUS is of utmost importance and chal-
lenging for any physician. Mortality rate during the acute
phase is high (3–5%). Of patients 20–30% experience
extrarenal events, and up to 20% of seemingly recovered
children show evidence of renal insult leading to end-stage
renal disease (ESRD). More than 60% show evidence of
renal failure in the acute phase. Parenteral volume expan-
sion with isotonic solutions before development of HUS in
STEC infection, may attenuate renal injury.8,38 Angio-
tensin-converting enzyme inhibitors (ACEI) may compro-
© 2006 The Authors
Journal compilation © 2006 Asian Pacific Society of Nephrology
215
mise renal blood flow further, and therefore is not a drug of
choice in HUS-associated hypertension. However, long-
term study indicates renoprotective effect of ACEI in
patients with proteinuric sequelae after HUS.39 Early peri-
toneal dialysis in the management of HUS has improved
morbidity and mortality. Dialysis needs to be continued
until recovery. Considerable renal function recovery follow-
ing up to 16 months of dialysis has been reported.40
There is no evidence that use of anticoagulants heparins,
prostacyclin, steroids, fibrinolytics streptokinase and intra-
venous immunoglobulins are of value in treating HUS.41,42
Further, antiplatelet factors aspirin and dipyridamole, high-
dose intravenous furosemide, fresh frozen plasma and plas-
mapheresis have no proven therapeutic value.43–45 The only
new drug under investigation is SYNSORB Pk (SYNSORB
Biotech, Calgary, Alberta, Canada), a silicon dioxide parti-
cle covalently linked to a trisaccharide. It mediates binding
of the Shiga toxin to endothelial cell surface and sequesters
toxin in the intestine. However, recent study results are not
promising.46 Monoclonal antibodies against Shiga toxin 2
and endothelial growth factor are being tested on animal
models.47
Although controversial, strong and plausible data sup-
port the association between development of HUS and use
of antibiotics in children with E. coli O157:H7 infections.
Available data support the hypothesis that use of DNA-
damaging antibiotics, fluoroquinolones, and trimethoprim-
sulfamethoxazole increases risk of HUS by inducing greater
Shiga-toxin release as bacteria are killed.48,49
Prevention
Prevention is largely dependent on control of spread of
enterohaemorrhagic E. coli. Steps include proper control of
faecal soiling of meat during slaughter, processing and
proper cooking of food products.50 Internal meat tempera-
ture over 68.3°C (155°F) eradicate enterohaemorrhagic
E. coli contamination.51 Additionally, milk and milk prod-
ucts pasteurization are important measures. More active sur-
veillance system of early identification of cases and removal
of contaminated food items not yet consumed will help pre-
vent the spread of infection.51
Prognosis
Spontaneous resolution usually begins 1–2 weeks after the
onset of the disease. With proper management, most cases
have a favourable recovery, glomerular filtration rate return-
ing to normal. However, there may be persistent decrease in
glomeruli blood flow of 10–20%.52 It is theorized that
D+HUS can lead to a critical reduction in nephron number,
with unsustainable remnant single-nephron hyperfiltration
and progressive renal disease.53 Long-term follow up of these
patients with added proteinuria is advisable, but probably
restricted to those with proteinuria, hypertension, abnormal
ultrasound and/or impaired glomerular infiltration rate
(GFR) at 1 year.54 Permanent renal function losses have
been reported in 5–25% of cases.9,55 Risk of definite HUS
recurrence post transplant is less than 1%.56
216
ATYPICAL HAEMOLYTIC URAEMIC SYNDROME
Characteristic triad of HUS without diarrhoeal prodrome
defines aHUS.57 Approximately 10% of all HUS cases in
children are atypical.57,58 A significant number of HUS cases
may follow an underlying infection.
Clinical manifestations
Many aHUS cases occur either following a non-specific,
non-diarrhoeal prodromal illness or following an insidious
onset with extended protracted course, with no seasonal
predilection. Patients may be markedly hypertensive, and
the outcome is poor compared with D+HUS. Mortality rate
is 25%, with approximately 20% developing ESRD.59,60
In a retrospective review study, the clinical course, lab-
oratory results and outcome variables of atypical and typical
HUS were compared. Atypical HUS patients had a much
lower white blood cell count and serum creatinine concen-
tration (1.2 vs 2.2 mg/dL), less frequent oliguria (28% vs
58%) and anuria (21% vs 47%), and 6% were without
thrombocytopenia. Considerably fewer aHUS patients
required dialysis (21% vs 47%), and disease recurrence was
observed in 18%.57 This study found no significant associa-
tions between chronic renal sequelae and worse outcome, in
contrast with other reports.5
Aetiology
Underlying aetiology in many cases of aHUS is unknown. A
significant number may result from underlying infectious
disease. Streptococcus pneumoniae accounts for nearly 40%
with less favourable short-term course and good recovery on
long-term basis compared with other types of aHUS.3,58 In
another study nine of 11 patients with S. pneumoniae-
related HUS had severe ARF requiring dialysis. Five
patients developed chronic renal failure (CRF), and three
progressed to ESRD after 4–11 years.61 As is the usual prac-
tice, plasma infusion is contraindicated in this condition.
aHUS has also been observed with human immunodefi-
ciency virus infection, most progressing to ESRD.62
A variety of genetic forms of aHUS have been described.
These include HUS due to deficiencies of factor H (FH),
membrane cofactor protein (MCP), Von Willebrand factor-
cleaving protease (ADAMTS 13) and intracellular defect in
vitamin B12 metabolism. There are cases of aHUS that
show autosomal recessive and autosomal dominant modes of
inheritance.
Factor H deficiency-related HUS usually presents during
infancy and early childhood, with some cases reported in
adults. Disease can be sporadic as well as familial.63,64 Gene
linkage analysis in three families with HUS related to FH
deficiency identified the gene locus at chromosome 1q32.63
Further genetic analyses found mutations in the gene for
FH, a serum complement regulatory protease, associated
with both autosomal recessive and dominant forms of the
disease. All homozygous patients have low levels of FH anti-
gen, C3, factor B and CH50, whereas heterozygous muta-
I Amirlak and B Amirlak
tions have low to normal values. Most heterogenous forms
develop HUS; comparatively few of the homozygous have
HUS.63,65 These patients require regular plasma infusions
allowing improvement of renal function and preventing
erythrocyte fragmentation.66 Most kidney transplants are
rejected in these patients consequent upon deficient FH
normally synthesized by the liver. Therefore, liver trans-
plants may cautiously be applied to the affected patients.67
Combined kidney liver transplant may have fatal complica-
tion due to non-functioning of liver graft.68
Membrane cofactor protein deficiency has also been
implicated in familial type of both homozygous and het-
erozygous types of aHUS.69 MCP is synthesized locally by
each cell, therefore MCP produced in transplanted kidney
may protect against HUS recurrance.69 Both FH deficiency
and MCP mutations result in endothelial insult and predis-
pose to thrombotic microangiopathy and HUS.
Factor H and MCP deficiencies are rare, but important
cause of aHUS. It is therefore important to check C3 levels
in children with aHUS; however, normal C3 does not
exclude complement dysfunction.70
Von Willebrand factor-cleaving protease deficiency,
which is related to mutations in the ADAMTS13 gene, has
been reported in children with aHUS. This deficiency is
seen in most adults with thrombotic thrombocytopenic pur-
pura, and may be inherited as autosomal recessive or by an
acquired autoantibody that inhibits protease activity.71
Defects in vitamin B12 metabolism affect transformation
of homocysteine into methionine, and conversion of meth-
ylmalonyl-CoA to succinyl-CoA, resulting in methylma-
lonic acidaemia with homocystinuria. Approximately 25%
of patients with this defect have aHUS.72 Affected children
have non-specific symptoms, such as anorexia, vomiting,
failure to thrive, convulsions and lethargy in the neonatal
period. Symptoms and signs of HUS appear before the age of
3 months.73
Idiopathic autosomal recessive form of HUS has a grad-
ual onset from neonatal period to adulthood. Prognosis is
poor; most patients progress to ESRD.74 Idiopathic autoso-
mal dominant form is less frequent, and affects members of
one family at different ages. This form also carries poor prog-
nosis, with more than 90% progressing to ESRD.75 aHUS
also occurs in children with systemic lupus erythematosus
and catastrophic antiphospholipid syndrome.76 Drug-
induced HUS has been reported with increasing frequency
in transplant patients treated with calcineurin inhibitors,
such as cyclosporin and sirolimus.77
Recurrence of HUS post transplantation is 45% with FH
deficiency, 28% with FH gene mutation with low C3, and
100% with low C3 and normal FH.56
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© 2006 The Authors
Journal compilation © 2006 Asian Pacific Society of Nephrology