Haemolytic uraemic syndrome

SYMPOSIUM: NEPHROLOGY

Haemolytic uraemicsyndromeAmrit Kaur

Larissa Kerecuk

AbstractHaemolytic uraemic syndrome (HUS) the commonest cause of acute renal

failure (ARF) in children. It is categorized by a triad of clinical features,

haemolytic anaemia, thrombocytopenia and ARF. HUS is subdivided in to

two broad categories, typical, usually diarrhoea positive D þ HUS (more

than 90% of cases) most commonly caused by Shiga toxin (Stx)-producing

Escherichia coli (STEC; also called verotoxin, VTEC). Atypical, usually

diarrhoea negative D � HUS or aHUS (approximately 5% of cases).

Clinical spectrum of HUS is initiated by intestinal colonization of STEC.

Histological appearance of HUS shows widespread thrombotic microangi-

opathy (TMA) in renal glomeruli, the gastrointestinal tract, the brain, and

the pancreas. Intraluminal thrombosis occurs leading to partial or

complete obstruction of the vessel lumen.

The aim of this review is to summaries the latest development and

understanding of this condition. Focussing on epidemiology, pathophys-

iology and disease course. An emphasis on the diagnosis, management

and follow-up of HUS has also been taken.

Keywords acute renal failure; haemolytic uraemic syndrome;

pneumococcal haemolytic uraemic syndrome; shigatoxin; thrombotic

microangiopathy

How common? UK and worldwide

The overall incidence of haemolytic uraemic syndrome (HUS) in

UK and Ireland is 0.71 per 100,000 children under 16 years of

age. Prospective surveillance study of childhood HUS from 1997

to 2001 in UK and Ireland showed the highest incidence rates

were in Scotland (1.56 per 100,000). This difference could be

secondary to the relative population densities of livestock and

humans and reliance on private water supplies in rural areas.

The prevalence of HUS has remained unchanged since 1985.

The incidence is similar across Europe, Australia and North

America. A large outbreak occurred in Germany this year with

the strain E. Coli 0104:H4. Argentina is reported to have the

highest incidence worldwide, 22 per 100,000.

Amrit Kaur MB ChB MRCPCH BSc Hons is a Nephrology Specialist Registrar in

Birmingham Children’s Hospital, Steelhouse Lane, Birmingham UK.

Conflict of interest: none declared.

Larissa Kerecuk MBBS BSc MRCPCH FRCPCH is a Consultant Paediatric

Nephrologist at Birmingham Children’s Hospital, Steelhouse Lane,

Birmingham, UK. Conflict of interest: none declared.

PAEDIATRICS AND CHILD HEALTH 22:8 332

Definition

Swiss haematologist Conrad von Gasser first described HUS in

1955. He used the term to describe the combined symptoms of

diarrhoea, haemolytic anaemia, thrombocytopenia and acute

renal failure (ARF), which he observed in five children. This

description is still valid today however HUS is further subdivided

into two broad categories:

� Typical, usually diarrhoea positive D þ HUS (more than

90% of cases)

� Atypical, usually diarrhoea negative D � HUS or aHUS

(approximately 5% of cases)

Please refer to Table 1 for common causes of each category.

The D þ HUS is the most common cause of ARF in childhood.

Haemolytic anaemia is defined as a haemoglobin level <10

g/dlitre and fragmented erythrocytes on blood film, thrombocy-

topenia with a platelet count <150 � 109/litre, and ARF with

serum creatinine greater than the age-related range (more than

97th percentile) or glomerular filtration rate (GFR) <80 mlitre/

min/1.73 m2 by the Schwartz formula.

Epidemiology

The incidence of HUS is greatest in children under 5 years old

and then peaks again in the elderly. Studies suggest greatest risk

of developing HUS is in areas with high density of cattle. There is

a seasonal variation with majority of cases occurring in the

summer months.

Infections with Shiga toxin (Stx)-producing Escherichia coli

(STEC; also called verotoxin, VTEC) is the greatest risk factor.

E. coli 0157:H7 is the most prevalent serotype of STEC associated

with human disease worldwide. STEC colonizes animals without

causing disease. STEC are not part of the normal human gut flora

and transmission occurs mainly through ingestion of infected

food or water, person to person spread and animal contact.

Contaminated ground beef, unpasteurized milk products, vege-

tables, drinking water and petting of farm animals have been the

source of infection in previous outbreaks. Isolated cases can also

occur. Inoculation with 100 organisms is sufficient enough to

cause disease. The incubation period is 1e8 days, although

asymptomatic infection may occur. Shedding of the bacterium

may persist for more than 3 weeks after infection.

Approximately 10% of children exposed to STEC will develop

gastrointestinal symptoms. Of these children, 3e7% (isolated

cases) or up to 20% in outbreaks will develop HUS.

Pathology, pathogenesis and applied physiology

Understanding of the pathogenesis of HUS allows the clinician

a logical approach and explanation of the presenting symptoms

and complications seen in severe HUS.

Histological appearance of HUS shows widespread thrombotic

microangiopathy (TMA) in renal glomeruli, the gastrointestinal

tract, the brain, and the pancreas. TMA describes the process of

vessel wall thickening, namely at arteriolar-capillary junction,

with swelling or detachment from the basement membrane.

Intraluminal thrombosis occurs leading to partial or complete

obstruction of the vessel lumen. Thrombosis can also be seen in

the hilum of the glomeruli and interlobular arteries. Cortical

necrosis can occur in extreme cases.

� 2012 Elsevier Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.paed.2012.01.002

Some causes of HUS depending on category type

Typical HUS Atypical HUS

Infectious causes

C Escherichia coli

C Shigella dystenteriae

C Citrobacter freundii

Infectious causes

C Streptococcus pneumoniae

Inherited forms

C Complement abnormalities

C Von Willebrand factor-cleaving

protease constitutional deficiency

C Cobalamin metabolism defect

Autoimmune

C Systemic lupus erythematosus

C Scleroderma

C Antiphospholipid syndrome

Drugs

C Cyclosporine A, tacrolimus

C Cytotoxic drugs

C Quinine

C Oral contraceptives

Other

C Autosomal dominant and

recessive types

C Cancer associated

C Pregnancy

C Post renal transplant

C HIV associated

Table 1


Clinical spectrum of HUS is initiated by intestinal colonization

of STEC. Attachment of STEC to host intestinal enterocytes is

aided by bacterial proteins. This causes destruction of microvilli

and the symptom of watery diarrhoea. Further translocation of

bacterial proteins from STEC into host enterocytes causes

disturbance of cell structure and function.

The role of Stx is vital in the virulence of STEC. The toxin has

two subunits, designated A and B. The A subunit has enzyme

activity whilst the pentamer B subunit binds specifically to

glycosphingolipid receptor (Gb3) on host cells. STEC have

bacteriophages that encode Stx, strains can encode for more

than one Stx if they process the specific bacteriophage. The

recent E. coli 0104:H4 in Germany was caused by an enter-

oaggressive E. coli that has acquired Shiga-toxin producing

bacteriophages. Antibiotics can cause the release of these toxins

hence the use of antibiotics is relatively contraindicated in the

treatment of HUS.

Binding of the toxin to Gb3 causes internalization of the A

subunit, this is then cleaved into two parts. The A1 binds to

ribosomes and disrupts protein synthesis causing cell death. The

Gb3 receptor is found on glomerular endothelium, brain and

pancreatic cells. The distribution helps to explain some of the

clinical symptoms found in HUS. The presence of Stx in the

intestinal lumen is also thought to trigger presence of inflam-

matory mediators (cytokines, interleukins) that cause endothelial


damage and further promote platelet adhesion to the sub-

endothelium. Damage to the intestinal epithelium allows Stx to

enter the circulation in addition to causing local damage. Stx

circulates bound to platelets, monocytes, neutrophils, as well as

leucocyte complexes. The leucocytes used for transport are

resistant to Stx associated cell damage therefore promote the

spread of the toxin to distant sites. The finding of leucocytosis is

a poor prognostic factor in HUS.

During the illness, platelets adhere to injured endothelium

resulting in TMA. Multiple microthrombi lead to thrombocyto-

penia. Studies on animal models have shown coagulation factors

are not involved in this process and adherence is a result of Stx,

inflammatory proteins and factors released by the damaged cell

surface. Stx induces tissue factor expression on endothelial cells,

which is a receptor for coagulation factor VII. Via the extrinsic

coagulation pathway, factor X is converted to Xa, which in turn

promotes clot formation and further platelet activation. Hae-

molysis of erythrocytes is less well understood and is assumed as

a result of mechanical damage secondary to movement through

occluded blood vessels.

Once transported from the intestines the main target organ is

the kidney. Kidney cells express Gb3 receptor. Stx causes

a cytotoxic and apoptotic effect on glomerular endothelial and

epithelial cells. Glomerular and tubular cells are damaged during

the acute infection. Presence of the toxin in the kidney results in

similar expression of cytokine release, tissue factor expression

and inhibition of protein synthesis as seen in the intestines.

Pathophysiology of atypical HUS is dependant on the aeti-

ology. Endothelial cell insult and damage is the histopathological

manifestation regardless of cause. This may be caused by drugs,

autoimmune or genetic mechanisms. In pneumococcal HUS,

neuraminidase produced by pneumococcus exposes the T

Antigen on erythrocytes which is then bound by pre-existing IgM

antibodies and haemolysis.

Course of the disease

After the initial incubation period D þ HUS is usually preceded

by gastroenteritis with bloody or watery diarrhoea (90% of

cases), abdominal cramps, nausea and vomiting (50% of cases).

The intestinal symptoms can lead to haemorrhagic colitis,

colonic gangrene or perforation. Within 2 weeks of the intestinal

symptoms the child develops pallor and jaundice secondary to

haemolysis. Thrombocytopenia is found on full blood count and

clinically may manifest itself as petechiae or bleeding from

mucosal surfaces. Renal involvement leads to oligouria/anuria,

hypertension (20e30% of cases) and oedema. Renal involve-

ment is typically seen between days 4 and 7 after the onset of

diarrhoea. Fever is not usually a presenting symptom but the

child may have a history of low grade pyrexia prior to presenting.

Central nervous involvement can occur in up to 20% of children.

Symptoms range can from irritability, seizures to cerebral

encephalopathy. A French study of 52 patients with severe

neurological involvement that occurred during the illness, coma,

seizures, pyramidal and extrapyramidal signs were found to be

the most frequent clinical features. Neurological complications

led to death in 17% of these children and 23% had severe

neurological sequelae. Complete neurological recovery was seen

in 50% of patient. In a small percentage of children




cardiomyopathy and pancreatitis may also be a feature. Please

refer to Table 2 for a list of clinical features associated with each

system involved.

Duration of symptoms to recovery is variable, usually 1e3

weeks after onset. Onset of improvement is depicted by a rise in

platelet count. Haematological improvement is followed by renal

function recovery.

Diagnosis, history and physical examination

In order to make the diagnosis a standard paediatric history

together with emphasis on fluid balance is essential. Specifically

ask about gastrointestinal symptoms and losses. Toleration of

oral fluids and micturition should be documented. Exploration of

ingestion of infected food products, farm animal contact and

person to person spread is essential.

Examination should include height, weight and body surface

area calculation. Vital signs including blood pressure must be

measured. In view of potential complications of HUS, the

cardiovascular, respiratory, abdominal, and central nervous

systems should be examined, paying particular attention to

hydration status and acute abdominal signs. Regular examina-

tion during hospital admission is essential to allude to clinical

List of clinical features associated with HUS

System involvement Clinical features

Gastrointestinal Bloody or watery diarrhoea

Abdominal cramps

Nausea and/or vomiting

Rectal prolapse

Intussusception

Toxic dilatation of colon

Bowel perforation

Haematology Petechaie

Mucosal bleeding

Jaundice

Renal Oligouria or anuria

Hypo or hypervolaemia

Hypovolaemic shock

Hypertension

Oedema

Central nervous Lethargy

Irritability

Seizures

Cranial nerve palsy

Cerebral oedema

Encephalopathy

Abnormal posturing

Coma

Cardiac Cardiomyopathy

Arrhythmias secondary to electrolyte

disturbances

Myocarditis and tamponade

Pancreas Diabetes mellitus

Pancreatitis

Table 2


deterioration in abdominal signs and changes in central nervous

system.

Investigations

Initial inpatient investigations should include the following:

� FBC and film, assessment of anaemia, thrombocytopenia

and erythrocyte fragmentation

� Urea and electrolytes

� Liver and bone function

� Bicarbonate, assessment of acid-base status

� Blood glucose and amylase, assess pancreatic involvement

� Lactate dehydrogenase, index of degree of haemolysis

� Clotting screen

� Group and save, blood transfusion may be required

� Urine dipstick for blood and protein

� Urine microscopy and culture

� Urine albumin and creatinine ratio, assessment of

glomerular leak

� Stool microscopy and culture

� STEC/VTEC serology

If patient presents with severe abdominal signs, chest and

abdominal radiographs especially erect films looking for signs of

perforation must be performed. Abdominal ultrasound to exclude

preceding renal structural abnormalities, pancreatitis and liver

involvement. Further imaging including CT abdomen and MRI

brain may be required depending on clinical status and

neurology. Renal biopsy is very rarely indicated in typical HUS. If

performed TMA in more than 50% of glomeruli has the worst

prognosis. Renal cortical necrosis is seen if arterial thrombosis is

severe.

In aHUS, the investigations are slightly more complex and

early involvement of local paediatric nephrology services is

advised. Specialist investigations will include, complement

levels/activity, Factor H concentrations, plasma vWF protease

activity, metabolic disease investigations and autoimmune anti-

body screen.

Differential diagnosis

Thrombotic thrombocytopenic purpura (TTP) is a condition

classified by microangiopathic haemolytic anaemia, thrombocy-

topenia, nephropathy, fever and neurological symptoms associ-

ated with mutations in the von Willebrand cleaving protease.

Other differentials include disseminated intravascular coagula-

tion, sepsis, systemic lupus erythematosus and vasculitis.

Management

There is no specific treatment for D þ HUS. Early diagnosis and

supportive care is fundamental to clinical recovery. Early

involvement of specialist paediatric nephrology advice is also

beneficial. These children should be nursed in isolation to

prevent secondary transmission. HUS is a notifiable disease and

local procedures for contacting Health Protection Agency should

be adhered too.

Treatment in atypical HUS may include plasmaphaeresis for

complement dysregulation causes and intravenous antibiotics in

Steptococcus pneumonia-associated HUS, which in comparison to

D þ HUS is not routinely recommended.




General considerations

The majority of all children with D þ HUS develop some degree

of renal impairment. Approximately two thirds will require renal

replacement therapy (RRT). Those children who do not require

dialysis, fluid management is key to a successful outcome.

Regular assessment of hydration status, twice daily weight, strict

fluid balance and regular electrolyte measurements including

blood sugar must be routine. Daily fluid replacement regimen

should include insensible losses (400 mlitres/m2/day) plus total

24 h urine output, emphasis is on maintaining euvolaemia in the

acute phase. Choice of intravascular fluid replacement should be

governed by plasma electrolytes.

Packed red cell transfusion may be required in those with

a haemoglobin less than 7 g/dlitre or symptomatic anaemia.

Careful monitoring is required in view of potential fluid overload

and hyperkalaemia secondary to blood transfusion.

Platelet transfusions are generally not required. If count is

particularly low (less than 10 � 109/litre), episodes of active

bleeding or pre-operative correction, transfusions may be given.

Careful monitoring and treatment of hypertension should not

be overlooked in the management of these children. In the acute

phase, if hypertension persists after fluid overload has been dealt

with, antihypertensive therapy should be started with calcium-

channel blockers. Once, renal function has improved and if

hypertension is persistent, angiotensin converting enzyme

inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) are

particularly useful especially if there is also proteinuria. Seizures

in central nervous disease should be managed in accordance

with advance paediatric life support (APLS) algorithms ensuring

that electrolyte, metabolic abnormalities and intracranial lesions

have been excluded.

Renal replacement therapy

RRT is required in those children who are fluid overloaded in

presence of oliguria, correction of electrolyte or acid-base

disturbances and symptomatic uraemia. Common electrolyte

disturbance include hyperkalaemia and hyponatraemia. Fluid

overload can lead on to pulmonary oedema and myocardial

insufficiency. The type of RRT offered is governed by clinical and

logistic factors. Peritoneal dialysis (PD) has the advantage of

avoiding large volume imbalances. Disadvantages include the

need for surgical placement of PD catheter. This may not be

possible in view of acute abdominal signs or impede ultrafiltra-

tion during acute enterocolitis. Haemodialysis (HD) has the

advantages of potentially being available without the need for

abdominal surgery however central venous catheters must be

placed in order to perform HD. Disadvantages include the need

for anticoagulation, haemodynamic instability and additional

loss of blood and platelets in the extracorporeal circulation.

Continuous haemofiltration can be instituted in cases of hae-

modynamic instability.

Renal transplant in D þ HUS is rare. If transplant is required

recurrence of the disease in the transplanted kidney is again rare

(approximately 1%) and transplantation can be performed

without increased risk of failure.

Other treatments

Nutritional support and early involvement of dietetic support is

particularly important to prevent a catabolic state during


protracted illnesses. Antimotility agents and nonsteroidal anti-

inflammatory analgesics (NSAIDs) are not recommended in the

management of D þ HUS. Antimotility agents have been asso-

ciated with higher rates of HUS and NSAIDs increase the risk of

gastrointestinal bleeding and reduce renal perfusion thereby

affecting GFR.

Antibiotics are not recommended as part of the treatment.

Experimental data has shown certain classes of antibiotics,

trimethoprim, sulfamethoxazole, and quinolones stimulate the

bacterial Shiga toxin expression and release. Other studies have

shown antibiotic administration does not increase the risk of HUS.

In view of the disparity between studies the general consensus is

not to administer antibiotics as part of routine management.

Plasma infusions and therapeutic plasma exchange have no

proven beneficial role in D þ HUS although there are limited

studies to support the use of plasma exchange in D þ HUS with

central nervous system involvement.

Future treatment options

Anti-Shiga toxin antibodies have been shown to prevent HUS in

animals. The monoclonal antibodies are intended to neutralize

the circulating Stx. Healthy adults have been exposed to mono-

clonal antibodies, no serious adverse events were reported. In

2003 a randomized, double blind, placebo-controlled study was

initiated in Canada and Argentina. Children with STEC positive

stools were randomized. Children were treated within 72 h of the

onset of bloody diarrhoea and then followed up for 4 months.

The study concentrated on the safety and pharmokinetics of the

humanized monoclonal antibody (Urtoazumab) as a therapy

against paediatric patients infected with Shiga toxin. The study

showed no serious adverse effects of administering the mono-

clonal antibody and there was no evidence of human antibodies

against the monoclonal antibody after treatment. No comment

was made on the clinical benefit of administering Urtoazumab in

paediatric patients with D þ HUS.

Eculizimab is a monoclonal antibody against complement

factor 5 and has been used in the recent DþHUS outbreak in

Germany with anedoctal beneficial reports. However, a RCT is

required to establish its usefulness in this setting.

Prognosis and explanation to patient

D þ HUS generally has a good prognosis. Early recognition and

treatment including dialysis has improved disease outcomes.

Acute mortality rate is 5e10% in D þ HUS. Long term complica-

tions after initial disease are seen in approximately 25% of

patients. Complications include persistent proteinuria, arterial

hypertension, neurological impairment, diabetes mellitus, and

chronic renal failure. End stage renal failure occurs in 1.8% of

these children.

Poor prognostic factors for long term renal complications

include;

� leucocytosis gt; 20 � 109/litre with neutrophilia

� shock during acute illness

� anuria for more than 2 weeks

� dialysis for more than 4 weeks is unlikely to lead to full

renal recovery

� hypertension

� persistent proteinuria



Practice points

C HUS is the combined symptoms of diarrhoea, haemolytic

anaemia, thrombocytopenia and acute renal failure (ARF).

Typical HUS, usually diarrhoea positive DþHUS (more than 90%

of cases), atypical HUS, usually diarrhoea negative D � HUS or

aHUS (approximately 5% of cases)

C The D þ HUS is the most common cause of ARF in childhood

C E. coli 0157:H7 is the most prevalent serotype of STEC asso-

ciated with human disease worldwide

C Approximately 10% of children exposed to STEC will develop

gastrointestinal symptoms. Of these children, 3e7% (isolated

cases) or up to 20% in outbreaks will develop HUS

C Histological appearance of HUS shows widespread thrombotic

microangiopathy (TMA) in renal glomeruli, the gastrointestinal

tract, the brain, and the pancreas

C Duration of symptoms to recovery is variable, usually 1e3

weeks after onset. Onset of improvement is depicted by a rise

in platelet count

C There is no specific treatment for Dþ HUS. RRT is required in those

childrenwhoarefluidoverloaded inpresenceofoliguria, correction

of electrolyte or acid-base disturbances and symptomatic uraemia

C Long term complications after initial disease are seen in

approximately 25% of patients


� central nervous involvement

� severe colitis and/or rectal prolapse

� cortical necrosis and TMA (more than 50% glomeruli

involved) on renal biopsy

� atypical HUS

It is important to follow up cases of even mild HUS. In a study

in which 130 children with D þ HUS not requiring dialysis during

the acute illness, 3.8% and 11.5% had proteinuria or hyperten-

sion, respectively. Nearly one fifth had microalbuminuria after

12 years from the onset of disease.

In D � HUS, renal prognosis is significantly worse, with

nearly half of children developing end-stage renal failure (ESRF)

and a quarter dying in the acute period. Renal transplantation in

D þ HUS children has low recurrence risk of original illness. In

D � HUS depending on the aetiology, recurrence of illness in

transplanted organ may be extremely high especially in factor

deficiencies.

Follow up

Subsequent medical follow up after the initial admission will

depend on the severity of the disease. Those who have had

a milder form of HUS should be seen soon after discharge and

then annually to monitor for hypertension and proteinuria. This

service can be offered by the local paediatrician or general

practioner. Early referral to paediatric nephrologist is recom-

mended should the annual review highlight a concern.

Of those children that have had a more protracted illness, they

will remain under the care of the paediatric renal services and

other specialists depending on the complications of their illness.

Prevention

Hygienic measures are themost important factor in preventing the

disease. Avoiding ingestion of contaminated food by assuring

thorough cooking ofmeat products, correct pasteurization of dairy

products, and vegetables/fruit to be washed thoroughly. Young

children should avoid consumption of unpasturized food prod-

ucts. It seems extreme to prohibit the petting of farm animals,

however hand washing should be encouraged afterwards.

Person to person spread amongst children who attend nursery

again can be limited by ensuring adequate hand hygiene during

toileting.

Early involvement of the Health Protection Agency once a case

has been diagnosed is paramount in ascertaining the epidemiology

of the current case and prevent spread amongst the public. A

FURTHER READING

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hemolytic uremic syndrome. Seminars in Thrombosis & Hemostasis

September 2010; 36: 594e610.


Garg AX, Suri RS, Barrowman N, et al. Long-term renal prognosis of

diarrhea-associated haemolytic uremic syndrome. JAMA September

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Gianviti A, Tozzi AE, De Petris L. Risk factors for poor renal prognosis in

children with hemolytic uremic syndrome. Pediatric Nephrology

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Karpman D. Haemolytic uraemic syndrome and thrombotic thrombocy-

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Shiga-toxin-associated hemolytic uremic syndrome (HUS). Pediatric

Nephrology 2008; 23: 1749e60.

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