Haemolytic Uraemic Syndrome
Thrombotic microangiopathy characterised by the triad of microangiopathic haemolytic anaemia (MAHA), thrombocytopenia, and acute kidney injury. Typical (Shiga toxin-associated) HUS is most common in children following E. coli O157:H7 gastroenteritis. Atypical HUS is complement-mediated and requires eculizumab.
Key Facts
HUS is defined by the triad of MAHA (fragmented RBCs), thrombocytopenia, and AKI Typical HUS (90% of childhood cases): caused by Shiga toxin-producing E. coli (STEC), most commonly O157:H7; follows bloody diarrhoea Atypical HUS (aHUS): complement-mediated (Factor H, Factor I, MCP mutations, anti-Factor H antibodies); not preceded by diarrhoea Blood film: schistocytes (fragmented red blood cells) are characteristic of MAHA Typical HUS: supportive management only – IV fluids, dialysis if needed; do NOT give antibiotics (may increase toxin release) Atypical HUS: eculizumab (anti-C5 monoclonal antibody) is first-line – dramatically improves outcomes (NICE TA694) Typical HUS prognosis: 90-95% recover renal function; mortality <5% in children Do NOT transfuse platelets unless active life-threatening bleeding (worsens thrombotic process)
Overview
Key Facts
HUS is a medical emergency requiring urgent recognition. The distinction between typical (STEC) and atypical (complement-mediated) HUS is critical as management differs fundamentally.
Epidemiology
- Typical HUS: peak age 6 months to 5 years; incidence ~1.5 per 100,000 children/year in the UK
- aHUS: much rarer; ~0.5 per million/year; any age
- Leading cause of AKI in children
Aetiology
Typical HUS:
- STEC (Shiga toxin-producing E. coli) O157:H7 (most common), O104:H4
- Source: undercooked beef, unpasteurised milk, contaminated water/produce
- 5-15% of STEC infections develop HUS
Atypical HUS:
- Complement dysregulation: mutations in Factor H (25%), Factor I, MCP (CD46), C3, Factor B
- Anti-Factor H antibodies (especially children)
- Acquired: pregnancy, drugs (ciclosporin, tacrolimus, quinine), transplant
Pathophysiology
- Typical: Shiga toxin binds Gb3 receptors on renal endothelium → endothelial damage → platelet activation → microthrombi in glomerular capillaries → MAHA + thrombocytopenia + AKI
- Atypical: uncontrolled alternative complement pathway activation → C5b-9 (MAC) formation on endothelial surfaces → thrombotic microangiopathy
- Red blood cells fragment as they pass through occluded microcirculation → schistocytes
Clinical Presentation
Typical HUS
- Prodromal illness: bloody diarrhoea (3-10 days before HUS onset)
- Pallor and jaundice (MAHA)
- Oliguria/anuria (AKI)
- Petechiae/purpura (thrombocytopenia)
- Oedema and hypertension
- Lethargy, irritability
Atypical HUS
- No preceding diarrhoeal illness
- May present at any age
- Similar triad: MAHA, thrombocytopenia, AKI
- Can be triggered by pregnancy, infection, drugs
- Relapsing-remitting course
Red Flags
- Anuria → urgent dialysis
- Seizures, altered consciousness → cerebral involvement (10%)
- Severe hypertension → encephalopathy risk
- No diarrhoeal prodrome → think aHUS → urgent complement studies and eculizumab
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| TTP | ADAMTS13 <10%, neurological predominance | ADAMTS13 activity |
| DIC | Prolonged PT/APTT, low fibrinogen, multi-organ | Coagulation screen |
| Pre-eclampsia/HELLP | Pregnancy, hypertension, liver dysfunction | Pregnancy test, LFTs |
| Malignant hypertension | Very high BP, papilloedema, MAHA | BP, fundoscopy |
| SLE with TMA | ANA positive, multi-system | Immunology |
Diagnosis / Investigation
Bloods
- FBC: anaemia (Hb often <80 g/L), thrombocytopenia (often <50 × 10⁹/L)
- Blood film: schistocytes (fragmented RBCs) – diagnostic of MAHA
- Reticulocyte count: raised (haemolysis)
- LDH: markedly elevated (haemolysis and tissue damage)
- Haptoglobin: low/absent (consumed in haemolysis)
- Direct Coombs test: NEGATIVE (distinguishes from AIHA)
- U&Es: raised creatinine, often severe AKI
- Coagulation: PT and APTT usually NORMAL (distinguishes from DIC)
- ADAMTS13 activity: >10% (excludes TTP; <10% = TTP)
Microbiology
- Stool culture: for STEC (E. coli O157); PCR for Shiga toxin genes
- Serology: for STEC if stool negative
Special Tests
- Complement studies (if aHUS suspected): C3, C4, Factor H, Factor I, MCP
- Anti-Factor H antibodies: especially in children
- Genetic testing: complement gene mutations
- Renal biopsy: shows TMA; not routinely needed for diagnosis
Management
Typical (STEC-HUS)
- Supportive care: IV fluids, monitor fluid balance, electrolytes, BP
- Dialysis: if severe AKI (indications as per standard)
- Red cell transfusion: if Hb <60-70 g/L
- DO NOT give antibiotics: may increase Shiga toxin release and worsen HUS
- DO NOT transfuse platelets: unless life-threatening bleeding (worsens microthrombosis)
- Antihypertensives: as needed
- Monitoring: daily FBC, U&Es, LDH, reticulocytes
- Notification: STEC is notifiable to public health
Atypical HUS
- Eculizumab (anti-C5 monoclonal antibody): first-line (NICE TA694)
- Induction: 900mg IV weekly × 4 weeks, then 1200mg every 2 weeks
- Dramatic improvement in outcomes
- Must vaccinate against meningococcus (serogroups ACWY and B) before starting; prophylactic antibiotics if urgent
- Plasma exchange: bridge while awaiting eculizumab; effective for anti-Factor H antibody-mediated aHUS
- Immunosuppression: for anti-Factor H antibodies (rituximab, mycophenolate)
Referral
- All HUS → paediatric/adult nephrology
- aHUS → tertiary centre with complement expertise
- Public health notification for STEC
Prognosis
- Typical HUS in children: mortality <5%; 90-95% recover renal function; 5-10% develop CKD
- Typical HUS in adults: higher mortality (10-25%) and greater CKD risk
- Atypical HUS without eculizumab: >50% progress to ESRD or die within first episode
- Atypical HUS with eculizumab: >80% achieve haematological remission; significant renal recovery
- Transplant: aHUS recurs in 50-80% of transplants without eculizumab prophylaxis
Other Relevant Information
HUS vs TTP
| Feature | HUS | TTP |
|---|---|---|
| Age | Children (typical) | Adults |
| ADAMTS13 | >10% | <10% |
| Renal involvement | Predominant | Variable |
| Neurological | Less common | Predominant |
| Diarrhoeal prodrome | Yes (typical) | No |
| Treatment | Supportive (typical) / Eculizumab (atypical) | Plasma exchange + caplacizumab |
Complement Mutations in aHUS
| Gene | Frequency | Recurrence Risk |
|---|---|---|
| Factor H | 25% | High (75%) |
| MCP (CD46) | 10% | Low (20%) |
| Factor I | 5-10% | High (70%) |
| C3 | 5-10% | High (50%) |
| Factor B | 1-2% | High |