Haemolytic uraemic syndrome
Description
- Thrombotic microangiopathy triad: microangiopathic haemolytic anaemia + thrombocytopenia + acute kidney injury
- Renal-predominant - the discriminator from TTP, which is neurological-predominant
| STEC-HUS ("typical") | Complement-mediated (atypical) HUS | Secondary TMA | |
|---|---|---|---|
| Share | ~90% of childhood HUS | ~5-10% | Common in adults |
| Trigger | *Shiga toxin - E. coli O157:H7 (and O104:H4), Shigella dysenteriae*** | Complement regulatory defect + a trigger | Drugs, pregnancy, malignancy, transplant, infection, autoimmune |
| Prodrome | Bloody diarrhoea | Often none | Underlying condition |
| Age | Children <5 | Any; ~60% before adulthood | Adults |
| Treatment | Supportive | Complement inhibition | Treat the cause |
| Outcome | Mostly recovers | Relapsing, progressive CKD | Variable |
- *Never a diagnosis of exclusion made slowly* - the immediate task is to separate it from TTP, because TTP needs plasma exchange within hours
Epidemiology
- STEC-HUS: ~1-2 per 100,000/yr; peak age 6 months to 5 years, summer months; outbreaks from undercooked mince, unpasteurised milk and dairy, contaminated produce, petting zoos, contaminated water
- ~5-15% of children with STEC gastroenteritis develop HUS
- Complement-mediated (atypical) HUS: ~0.5-2 per million/yr, any age; F>M in adults, often pregnancy-associated
- Secondary TMA is the commonest form seen in adult practice
- In Australia, STEC-HUS is notifiable and outbreaks are investigated by public health
Aetiopathogenesis
The common final pathway
- Endothelial injury -> platelet-rich microthrombi in arterioles and capillaries
- -> mechanical red cell fragmentation (schistocytes) as cells traverse the fibrin/platelet meshwork
- -> platelet consumption -> thrombocytopenia
- -> glomerular capillary and arteriolar occlusion -> AKI
- *Coagulation screen is NORMAL - this is a platelet/endothelial process, not consumptive coagulopathy (the discriminator from DIC*)
STEC-HUS
- Shiga toxin (Stx1, Stx2) absorbed from the colon
- Binds globotriaosylceramide (Gb3) receptors, expressed most densely on renal glomerular endothelium (and cerebral endothelium)
- -> internalised -> inhibits the 60S ribosomal subunit -> arrests protein synthesis -> endothelial apoptosis
- -> local complement activation and thrombosis
- Stx2 is more nephrotoxic than Stx1
Complement-mediated (atypical) HUS
- Loss of regulation of the alternative complement pathway on endothelial surfaces
- Genetic abnormality in ~60%
| Type | Genes |
|---|---|
| Loss of function (regulators) | CFH (~25%, the commonest), CD46/MCP, CFI, THBD |
| Gain of function (activators) | C3, CFB |
| Acquired | Anti-factor H autoantibodies - often with CFHR1/CFHR3 deletion; commonest in children, and treatable with immunosuppression |
- *Penetrance is incomplete (~50%) - a trigger is almost always required*: infection, pregnancy/postpartum, surgery, transplant, drugs
- Pregnancy-associated aHUS is characteristically postpartum
Secondary TMA - the adult differential
- Drugs: quinine (classic), gemcitabine, mitomycin C, calcineurin inhibitors (ciclosporin, tacrolimus), VEGF inhibitors (bevacizumab), oxaliplatin, interferon, ticlopidine/clopidogrel
- Pregnancy: HELLP, pre-eclampsia, postpartum aHUS
- Malignancy (especially disseminated adenocarcinoma), haematopoietic stem cell transplant-associated TMA
- Malignant hypertension, scleroderma renal crisis, antiphospholipid syndrome (catastrophic APS), SLE
- Infection: *invasive Streptococcus pneumoniae** (neuraminidase exposes the Thomsen-Friedenreich antigen -> polyagglutination; DAT may be positive and plasma-containing products are relatively contraindicated*), HIV, influenza
- Cobalamin C deficiency in infants (methylmalonic aciduria + homocystinuria)
Diagnosis
Confirm a thrombotic microangiopathy
- FBE: anaemia, thrombocytopenia
- Film: schistocytes/fragments (>1% is significant)
- LDH very high, haptoglobin undetectable, unconjugated bilirubin high, reticulocytes high
- DAT negative (except pneumococcal HUS)
- *Coagulation screen and fibrinogen NORMAL* - separates from DIC
- UEC, urinalysis (haematuria, proteinuria), urine output
Then separate the causes - this is the whole diagnostic task
| TTP | HUS | DIC | |
|---|---|---|---|
| Dominant organ | CNS | Kidney | Multi-organ + bleeding |
| Platelets | Often <30 | 30-100 | Low |
| Creatinine | Mildly raised | Markedly raised | Variable |
| Coagulation screen | Normal | Normal | Deranged, low fibrinogen |
| ADAMTS13 | <10% | Normal or mildly reduced | Normal |
- *Send ADAMTS13 activity BEFORE plasma exchange, but never wait for the result to start it if TTP is possible*
- PLASMIC score stratifies the probability of severe ADAMTS13 deficiency while awaiting the assay
Cause-specific tests
- Stool culture for STEC and PCR for Shiga toxin genes; serology for O157 LPS (stool culture is often negative by the time HUS appears)
- Complement studies: C3 (low in ~50% of aHUS - a normal C3 does not exclude it), C4, factor H, factor I, factor B levels, anti-factor H antibodies, CD46 expression on leucocytes
- Genetic panel: CFH, CFI, CD46, C3, CFB, THBD, DGKE, plus CFHR1/3 copy number
- Takes weeks - do not delay treatment
- Pregnancy test; blood pressure; ANA, ENA, antiphospholipid antibodies; HIV; blood cultures; drug history
- Renal biopsy if the diagnosis is unclear and the platelet count permits
Key clinical clue
- *A child with bloody diarrhoea, oliguria, pallor and a low platelet count is STEC-HUS until proven otherwise*
- *An adult with a TMA and no diarrhoeal prodrome needs ADAMTS13 and complement work-up, and a search for a secondary cause*
Management
A. STEC-HUS - supportive, and the details matter
- *Careful IV volume expansion early in STEC infection reduces the severity of HUS and the need for dialysis* - do not dehydrate these children
- Electrolyte management, early dialysis for oliguria, hyperkalaemia, acidosis or fluid overload (~50% need it)
- Red cell transfusion for symptomatic anaemia; *platelets only for active bleeding or before surgery* (may fuel microthrombosis)
- Nutritional support; antihypertensives
- *Contraindicated / not indicated*
- Antibiotics - increase toxin release and the risk of HUS in STEC infection
- Anti-motility agents
- Plasma exchange - no benefit in typical STEC-HUS
- Eculizumab - not routine; considered only in severe neurological involvement
- Public health notification and contact tracing
B. Complement-mediated (atypical) HUS
- *Start eculizumab (or ravulizumab) as early as possible* - renal recovery falls sharply with delay
- Eculizumab - anti-C5, 2-weekly maintenance
- Ravulizumab - engineered longer half-life (~52 days), 8-weekly maintenance
- Crovalimab - binds a different C5 epitope; effective in patients with the C5 R885H polymorphism that prevents eculizumab binding (relevant in East Asian populations)
- Factor B (iptacopan) and other alternative-pathway inhibitors are in trials
- *Meningococcal vaccination (ACWY and B) plus antibiotic prophylaxis before or at the time of the first dose - complement blockade causes a several-hundred-fold increase in meningococcal risk*
- If treatment cannot wait, give the first dose with antibiotic cover and vaccinate as soon as possible
- Anti-factor H antibody disease: plasma exchange + immunosuppression (steroid, rituximab, cyclophosphamide) in addition
- Plasma exchange if complement inhibition is not immediately available, or while the diagnosis is uncertain
- Duration: increasingly individualised - discontinuation may be considered in patients without a high-risk variant, with close monitoring for relapse
- Renal transplantation: high recurrence without prophylaxis (especially CFH variants) -> peri-transplant eculizumab; CD46 variants rarely recur, as CD46 is membrane-bound and replaced by the graft
C. Secondary TMA
- *Treat or remove the cause* - stop the drug, deliver the fetus, control the blood pressure, treat the malignancy or infection
- Pneumococcal HUS: treat the pneumococcal infection; avoid plasma-containing products (adult plasma contains anti-T antibodies)
- Complement inhibition in selected refractory cases
D. When TTP cannot be excluded
- *Start plasma exchange immediately* - the harm of delay in TTP far exceeds the harm of unnecessary exchange
- De-escalate once ADAMTS13 returns
Associations
- **E. coli O157:H7 and other Shiga toxin-producing E. coli; Shigella dysenteriae type 1**
- *Invasive Streptococcus pneumoniae*** (neuraminidase-mediated)
- Pregnancy and the postpartum period; HELLP and pre-eclampsia
- Drugs - quinine, gemcitabine, mitomycin C, calcineurin inhibitors, VEGF inhibitors, ticlopidine
- Haematopoietic stem cell and solid organ transplantation
- Malignant hypertension, scleroderma renal crisis, SLE, catastrophic antiphospholipid syndrome
- TTP and DIC - the differentials
- Cobalamin C deficiency and DGKE nephropathy (infantile TMA)
- HIV, influenza, COVID-19
- Paroxysmal nocturnal haemoglobinuria - the other complement-driven disease treated with C5 inhibition
Natural history & complications
STEC-HUS
- Acute mortality ~3-5%
- ~70-85% recover renal function
- *But long-term follow-up is mandatory - ~25-30% have proteinuria, hypertension or reduced GFR at 5-10 years*, and a minority progress to ESKD decades later
- Adverse markers: prolonged anuria (>10 days), need for dialysis, WCC >20 at presentation, CNS involvement, age <2
Complement-mediated (atypical) HUS
- *Historically: ~50% progressed to ESKD or death within a year*
- Eculizumab transformed this - most patients now achieve haematological remission and preserve or recover renal function if treated early
- Relapsing course - triggered by infection, pregnancy, surgery
- Prognosis by genotype: CFH variants worst; CD46 best (frequent relapses but good renal outcome)
Complications
- ESKD requiring dialysis or transplantation
- CNS involvement (~20% in severe STEC-HUS) - seizures, stroke, encephalopathy
- Colonic necrosis, intussusception, perforation, pancreatitis and transient or permanent diabetes mellitus (STEC-HUS)
- Cardiac involvement, hypertension
- Meningococcal sepsis on complement inhibition
- Transplant recurrence
Follow-up
- Lifelong blood pressure, urinalysis for proteinuria, and eGFR monitoring in every survivor
🔒
6 more sections, plus exam facts
Premium unlocks every note across every specialty, and the full exam fact library behind it.
Get premium access