Key Facts

HUS is a thrombotic microangiopathy (TMA) characterised by the triad of MAHA, thrombocytopenia, and AKI. It is the most common cause of AKI in children in the UK.

Epidemiology

• Typical STEC-HUS: mainly children aged 6 months to 5 years; ~100-150 cases/year in UK
• Atypical HUS: all ages, including adults; rarer (~2 per million/year)
• Seasonal peaks in summer/autumn (STEC infections)
• UK outbreaks linked to undercooked meat, unpasteurised dairy, contaminated water

Aetiology

• Typical HUS (90%): Shiga toxin-producing E. coli (STEC), mainly O157:H7; also O104:H4; rarely Shigella dysenteriae type 1
• Atypical HUS (10%): dysregulation of alternative complement pathway
  • Mutations in complement regulators: CFH, CFI, MCP (CD46), CFB, C3, THBD
  • Anti-factor H autoantibodies (~5-10% of aHUS)
• Secondary HUS: drugs (calcineurin inhibitors, quinine), malignancy, pregnancy (HELLP), bone marrow transplant

Pathophysiology

• Typical HUS: Shiga toxin binds to Gb3 receptors on renal endothelium → endothelial damage → microvascular thrombosis → MAHA and AKI
• Atypical HUS: uncontrolled complement activation on endothelial surfaces → endothelial injury → microvascular thrombosis
• Platelet consumption in microthrombi → thrombocytopenia
• Mechanical shearing of RBCs through damaged vasculature → schistocytes and haemolysis

Typical STEC-HUS

• Prodromal illness: bloody diarrhoea (usually 5-7 days before HUS onset)
• Pallor and jaundice (haemolysis)
• Oliguria/anuria (AKI)
• Oedema and hypertension
• Petechiae/bruising (thrombocytopenia)
• Irritability, lethargy in children

Atypical HUS

• No diarrhoeal prodrome (or non-bloody diarrhoea)
• May present at any age
• Often relapsing course
• Severe AKI
• Hypertension
• Extra-renal involvement: CNS (seizures, stroke), cardiac, hepatic

Red Flags

• Anuria lasting >24 hours → may require dialysis
• Seizures or altered consciousness → CNS involvement
• No improvement after 7-10 days → consider atypical HUS
• Adult presentation without typical diarrhoeal prodrome → atypical HUS or TTP

Bedside

• Blood pressure: hypertension common
• Urine output: oliguria/anuria monitoring
• Stool sample: send for STEC culture and PCR (before antibiotics)

Bloods

• FBC: anaemia, thrombocytopenia
• Blood film: schistocytes (fragmented RBCs)
• LDH: markedly elevated
• Haptoglobin: low/undetectable
• Reticulocytes: elevated
• DAT (Coombs test): negative
• Coagulation screen: normal (distinguishes from DIC)
• U&Es: raised creatinine (often severe in HUS, >300 µmol/L)
• ADAMTS13: >10% (distinguishes from TTP)
• Complement studies (for atypical HUS): C3, C4, factor H, factor I, anti-factor H antibodies

Imaging

• Renal ultrasound: enlarged echogenic kidneys

Special Tests

• STEC PCR/culture: confirms typical HUS
• Complement genetic testing: if aHUS suspected (CFH, CFI, MCP, C3 mutations)
• Renal biopsy: rarely needed acutely; may help distinguish TMA subtypes

Non-pharmacological

• Supportive care is mainstay for typical STEC-HUS
• Fluid and electrolyte management: careful IV fluids, avoid overhydration
• Blood pressure control
• Dialysis (peritoneal or haemodialysis) if severe AKI: indications include hyperkalaemia, fluid overload, uraemia
• Red cell transfusion for symptomatic anaemia
• Avoid platelet transfusion unless life-threatening bleeding

Pharmacological

Typical STEC-HUS:

• Avoid antibiotics during E. coli O157 infection (may increase Shiga toxin release and worsen HUS)
• Supportive management with excellent outcomes

Atypical HUS (complement-mediated):

• Eculizumab (anti-C5 monoclonal antibody): 900mg IV weekly × 4 weeks, then 1200mg every 2 weeks
• Dramatically improves outcomes; prevents complement-mediated endothelial damage
• Ravulizumab (longer-acting anti-C5): 8-weekly dosing
• Meningococcal vaccination required before eculizumab (risk of meningococcal disease) – MenACWY + MenB + prophylactic antibiotics
• Plasma exchange: may be used while awaiting eculizumab or if diagnosis uncertain

Referral Criteria

• All cases of HUS → paediatric/adult nephrology
• Suspected atypical HUS → specialist complement centre
• PHE notification: STEC infection is notifiable

• Typical STEC-HUS: mortality 3-5%; full renal recovery in 70-80% of children
• 15-25% of typical HUS patients develop long-term renal sequelae (proteinuria, hypertension, CKD)
• ~5% progress to ESRD
• Atypical HUS: without treatment, >50% progress to ESRD or death
• With eculizumab, aHUS outcomes dramatically improved (>90% haematological response)
• Recurrence risk in aHUS: 30-50% (depends on mutation type); CFH mutations have highest recurrence risk

Typical vs Atypical HUS

Complement Mutations in aHUS