Haemolytic uraemic syndrome

What is haemolytic uraemic syndrome?

Haemolytic uraemic syndrome (HUS), a form of thrombotic microangiopathy, is defined by the clinical triad of thrombocytopenia, anaemia, and acute kidney damage.

Who gets haemolytic uraemic syndrome?

Haemolytic uraemic syndrome is one of the leading causes of acute kidney damage in children and is becoming increasingly common in adults.

• Typical HUS:
  • Mainly affects children (under five years of age) and the elderly
  • Estimated overall annual incidence 2 cases/100000 and up to 6/100000 in young children
  • Most common in summer months and rural areas
  • Can be sporadic or in outbreaks large or small
  • Increased risk of HUS developing if antibiotics and antimotility agents are used during the diarrhoeal phase.

• Atypical HUS (aHUS):
  • Rare
  • Affects children under 2 years of age and adults
  • Annual incidence 0.5–2 per million
  • Can be isolated or familial.

What causes haemolytic uraemic syndrome?

The pathophysiology of HUS involves vascular endothelial cell damage which increases the risk of thrombosis and organ damage, particularly of the kidneys. Disorders of the complement system may predispose to the development of HUS in response to specific triggers, with the resultant dysregulation of the complement cascade.

Haemolytic uraemic syndrome can be classified as:

• Typical infection-related HUS (90%) is usually due to Shiga toxin-producing bacteria such as enterohaemorrhagic E. coli (STEC), Shigella dysenteriae, or non-Shiga toxin-associated diarrhoeal infections. Less commonly other infections can be implicated such as pneumococcal pneumonia and HIV/AIDS.
• Atypical HUS (10%) results from many different diseases producing the HUS clinical pattern — 
  • Inherited disorders
    • Defect in control of complement activation
    • Mutations in diacylglycerol kinase ε
  • Acquired conditions
    • Pregnancy — 20% of aHUS cases
    • Severe/uncontrolled hypertension
    • Malignancy — including stomach, breast, bowel, haematological
    • Autoimmune disease — such as systemic lupus erythematosus, antiphospholipid syndrome, scleroderma
    • Transplantation — solid organ (mainly kidney) or allogeneic bone marrow
  • Medications
    • Immunosuppressants — for example, ciclosporin, tacrolimus, sirolimus
    • Antibiotics — such as penicillins, ciprofloxacin
    • Others — including chemotherapy drugs, oral contraceptive pill

What are the clinical features of haemolytic uraemic syndrome?

Haemolytic uraemic syndrome presents with:

• Pallor
• Acute kidney failure — oedema, nausea and vomiting, reduced urine output, high blood pressure
• Extrarenal manifestations such as shortness of breath and neurological symptoms and signs (irritability, confusion, seizures, decreased level of consciousness).

Skin signs are nonspecific and may include jaundice, bleeding and bruising, petechiae, livedo reticularis, and purpura.

Shiga toxin-related HUS

• Onset of abdominal pain and bloody diarrhoea, which can be severe, 4–7 days after ingestion of contaminated food or water
• Abrupt onset of HUS symptoms and signs 2–10 days later

Atypical HUS

• Usually triggered by a respiratory or gastrointestinal febrile illness
• Onset of HUS manifestations usually less abrupt than in typical HUS
• Recurrent episodes not associated with one specific trigger

What are the complications of haemolytic uraemic syndrome?

Diarrhoea-associated haemolytic uraemic syndrome may be complicated by:

• Rectal prolapse
• Colonic gangrene
• Bowel perforation.

Neurological complications of HUS include stroke and coma.

How is haemolytic uraemic syndrome diagnosed?

Haemolytic uraemic syndrome is diagnosed on the following findings:

• Haematology
  • Anaemia — haemoglobin < 80g/L
  • Fragmented red cells (schistocytes, helmet cells) and reticulocytes
  • Thrombocytopenia — platelet count <140000/mm³
  • Haemolysis — negative Coombs test, high lactate dehydrogenase, high bilirubin, low haptoglobin
• Kidney
  • Peripheral blood — elevated creatinine and urea
  • Urinalysis — haematuria, proteinuria, red cell casts.

The cause and complications of HUS should be investigated.

• Stool sample
• Autoimmune panel
• Complement studies
• Other specific tests as clinically indicated including for complications

What is the differential diagnosis for haemolytic uraemic syndrome?

• Disseminated intravascular coagulation (DIC)
• Thrombotic thrombocytopenic purpura (TTP)
• Systemic vasculitis

What is the treatment for haemolytic uraemic syndrome?

General measures

• Management of fluids, electrolytes, pH, and nutrition
• Blood pressure control
• Transfusion — if haemoglobulin <60g/L or platelets <10000/mm³

Specific measures

• Typical HUS — supportive care including dialysis if required
• Atypical HUS — depends on the cause and severity but may include:
  • Plasma exchange
  • Eculizumab
  • Specific treatment if required for the underlying cause.

What is the outcome for haemolytic uraemic syndrome?

Haemolytic uraemic syndrome can cause acute and/or end-stage renal failure. Most patients with Shiga toxin-related HUS recover fully. Poor prognostic signs include neurological symptoms, low neutrophil count, low platelet count, and prolonged anuria.

The prognosis for atypical HUS depends on the associated trigger. Eculizumab, if available, has improved outcomes.