Haemolytic uraemic syndrome

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Endothelial injury in small renal vessels exposes prothrombotic surfaces, captures platelets and narrows the lumen. Red cells fragment across these vessels and platelet-rich microthrombi reduce renal perfusion. In STEC-HUS, Shiga toxin absorbed from the intestine binds susceptible endothelium and triggers inflammatory injury. Children are affected most often, but adults—especially older people—can have severe neurological and renal disease. Dehydration may coexist, yet once oliguric kidney injury develops, indiscriminate fluids can cause pulmonary oedema.

Complement-mediated HUS arises when alternative-complement amplification is insufficiently controlled. Pathogenic variants or autoantibodies may be present, but incomplete penetrance and triggering events make family patterns variable. Pregnancy-associated, transplant-associated, malignant-hypertension, drug-related, autoimmune and cancer-associated TMAs can resemble it and may involve complement secondarily. No single low complement level establishes the diagnosis. Specialist teams integrate ADAMTS13, STEC testing, clinical trigger, organ pattern and secondary-cause assessment.

Initial management supports organs while classification proceeds. Measure fluid status and urine output, treat hypertension and electrolytes, and use renal replacement therapy for standard urgent indications. Red-cell transfusion supports symptomatic anaemia; prophylactic platelets are generally avoided unless serious bleeding or an essential procedure exists. Suspected TTP receives exchange immediately. STEC-HUS receives supportive care and public-health management. A high-probability complement-mediated phenotype receives urgent terminal-complement inhibition under the specialised NHS pathway, with vaccines, antimicrobial protection and emergency infection education.

Key points

HUS is a thrombotic microangiopathy characterised by thrombocytopenia, microangiopathic haemolytic anaemia and acute kidney injury, with renal injury often dominating the presentation.
Shiga-toxin-producing Escherichia coli HUS commonly follows abdominal pain and bloody diarrhoea, but diarrhoea may have resolved before kidney and platelet abnormalities appear.
Send stool culture and Shiga-toxin PCR promptly and notify microbiology or UKHSA because infection-control and public-health actions extend beyond the individual patient.
Supportive care with careful fluid assessment, electrolyte control, blood pressure management and dialysis when indicated is central to STEC-HUS.
Avoid antimotility medicines in suspected STEC infection and seek microbiology advice before antibiotics because some antibiotic exposures may increase toxin release and HUS risk.
Complement-mediated HUS results from dysregulated alternative complement and can be triggered by infection, pregnancy, surgery or transplantation in a genetically susceptible person.
An ADAMTS13 activity above the severe TTP range makes TTP less likely but does not itself prove complement-mediated HUS; secondary TMAs must be excluded.
Eculizumab or ravulizumab blocks terminal complement in eligible complement-mediated HUS and should be coordinated urgently through the specialist service with meningococcal protection.
Complement levels can be normal during complement-mediated HUS, and genetic testing may be negative; diagnosis integrates phenotype, exclusions and expert complement assessment.
Long-term follow-up after any HUS includes blood pressure, eGFR, proteinuria and recurrence or family counselling because apparently recovered kidney function may hide later CKD.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Shiga-toxin infection

Toxin-producing E. coli, and less often Shigella, cause gastrointestinal infection followed by systemic endothelial injury and renal thrombotic microangiopathy.

Alternative-complement dysregulation

Pathogenic variants or acquired autoantibodies affecting complement regulators permit uncontrolled amplification, often after an environmental or physiological trigger.

Secondary endothelial injury

Pregnancy, transplantation, severe hypertension, autoimmune disease, cancer and selected medicines can create a TMA phenotype requiring cause-specific treatment and expert classification.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Renal endothelial damage
Toxin or uncontrolled complement activates and injures glomerular and arteriolar endothelium, promoting platelet adhesion and small-vessel thrombi.
2
Microangiopathic haemolysis
Erythrocytes fragment while traversing narrowed renal and systemic microvessels, producing schistocytes, LDH release, depleted haptoglobin and worsening anaemia.
3
Platelet consumption
Platelets are recruited into microthrombi rather than simply destroyed in the spleen, so thrombocytopenia accompanies tissue ischaemia and cannot be treated by routine replacement.
4
Nephron injury
Glomerular thrombosis and tubular ischaemia reduce filtration, causing haematuria, proteinuria, hypertension, oliguria, electrolyte imbalance and potential long-term chronic kidney disease.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Post-diarrhoeal triad

Pallor, reduced urine, bruising and fatigue appear several days after abdominal cramps or bloody diarrhoea with schistocytes and acute kidney injury.

Renal-predominant TMA

Haematuria, proteinuria, hypertension, oliguria and creatinine rise dominate over the fluctuating neurological pattern more typical of TTP.

Complement-mediated recurrence

Recurrent TMA, family cases, pregnancy or transplant trigger and no STEC or severe ADAMTS13 deficiency raise alternative-complement disease.

Dialysis emergencyRed flag

Refractory hyperkalaemia, pulmonary oedema, severe acidosis or uraemic complications requires urgent renal replacement assessment.

Meningococcal warning

Fever, headache, rash or shock during eculizumab or ravulizumab treatment demands immediate antibiotics despite completed vaccines.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Full count, film and haemolysis markersFirst step
Why
Establish evidence of thrombocytopenic microangiopathic haemolysis.
Interpretation and limitations
Schistocytes, raised LDH, low haptoglobin and reticulocytosis support TMA; early films may need expert repeat.
02
Renal profile, urinalysis and urine output
Why
Grade acute kidney injury and dialysis need.
Interpretation and limitations
Trend potassium, bicarbonate, creatinine, haematuria and proteinuria with measured fluid balance; count recovery can precede renal recovery.
03
Stool culture and Shiga-toxin PCR
Why
Identify STEC and trigger public-health action.
Interpretation and limitations
Send promptly even if diarrhoea is resolving; prior antibiotics and sampling delay can reduce yield, so epidemiology still matters.
04
ADAMTS13 activity and inhibitor
Why
Identify severe deficiency supporting TTP.
Interpretation and limitations
Draw before plasma where feasible; activity below 10% strongly favours TTP and demands its established treatment pathway.
05
Coagulation, fibrinogen and D-dimer
Why
Assess DIC and systemic consumption.
Interpretation and limitations
A consumptive pattern supports DIC, while relatively preserved coagulation fits primary TMA; results can overlap in sepsis.
06
Complement and genetic studies
Why
Support classification and recurrence counselling in suspected complement-mediated HUS.
Interpretation and limitations
Normal C3 or C4 and negative genetics do not exclude disease; specialist interpretation considers variants, antibodies and phenotype.
07
Blood pressure, pregnancy and secondary-cause screen
Why
Identify hypertension, obstetric, autoimmune, transplant, cancer or drug-associated TMA.
Interpretation and limitations
Treat dangerous blood pressure and the underlying trigger immediately while complement causality is evaluated.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Immune TTP

TTP often has prominent neurological or cardiac involvement and severe ADAMTS13 deficiency; high clinical probability requires plasma exchange before the assay returns.

Disseminated intravascular coagulation

Sepsis-associated consumption commonly prolongs clotting times, lowers fibrinogen and raises D-dimer more broadly than primary HUS, though mixed illness occurs.

Malignant hypertension

Severe blood pressure elevation can cause retinal, renal and microangiopathic injury; determine whether hypertension drives TMA or reflects renal complement disease.

HELLP syndrome

Pregnancy hypertension, haemolysis, raised liver enzymes and low platelets requires immediate maternity care, while atypical timing or persistence can raise complement-mediated HUS.

Immune haemolysis

Autoimmune haemolytic anaemia can cause anaemia and low platelets in Evans syndrome but produces antiglobulin positivity and spherocytes rather than schistocyte-predominant renal TMA.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Initial TMASupport kidneys while classifying causeFirst stepThrombocytopenia, schistocytes and haemolysis occur with acute kidney injury.

1Call nephrology and haematology, manage fluid, potassium, acidosis, blood pressure, seizures and pulmonary oedema and assess dialysis indications.
2Send stool STEC testing, pre-plasma ADAMTS13, coagulation and complement samples and review pregnancy, drugs, transplant, sepsis and hypertension.
3Treat high-probability TTP immediately with its exchange pathway and avoid prophylactic platelet transfusion while the mechanism remains thrombotic.

02STEC-HUSUse supportive renal and public-health careBloody diarrhoea or outbreak context and positive Shiga-toxin testing support infection-associated HUS.

1Notify infection and public-health teams, apply isolation and contact measures and obtain exposure history without delaying renal support.
2Replace measured early fluid deficits carefully, then restrict or remove fluid as oliguria and overload dictate and dialyse for standard urgent indications.
3Avoid antimotility treatment and discuss any antimicrobial need with microbiology, then follow blood pressure, proteinuria and kidney function after recovery.

03Complement-mediated HUSBlock terminal complement urgentlySevere renal TMA lacks STEC and TTP explanations and specialist assessment supports complement-mediated disease.

1Contact the specialised complement service and preserve complement, autoimmune and genomic samples without waiting for every result before time-critical treatment.
2Start commissioned eculizumab or ravulizumab with meningococcal vaccination, antimicrobial prophylaxis and an emergency infection plan under specialist governance.
3Monitor haematological and renal response, dialysis independence and treatment complications and later review duration, relapse risk, pregnancy and family testing.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Blocks complement C5 to stop terminal-complement endothelial injury in eligible complement-mediated HUS and permits renal recovery.

Eculizumab

The specialised aHUS service gives the licensed intravenous weekly induction followed by weight-appropriate maintenance, with supplemental doses after specified plasma treatments.

Meningococcal infection can be fulminant despite vaccination; provide prophylaxis and fever instructions and monitor infusion reaction, other Neisseria infection and pregnancy needs.

Prevents further cerebral, cardiac and renal endothelial injury while the underlying TMA is treated.

Antihypertensive therapy

Use titratable intravenous treatment for a hypertensive emergency and kidney-appropriate oral agents for ongoing control, with targets set by critical care, renal and pregnancy context.

Avoid precipitous pressure reduction that compromises organ perfusion; AKI, hyperkalaemia and pregnancy limit drug selection and require frequent review.

Restores oxygen carriage while haemolysis and kidney injury recover; it does not treat microvascular platelet thrombosis.

Red-cell transfusion

Use an individual component dose for symptomatic or physiologically important anaemia under transfusion guidance, reassessing haemoglobin and fluid status after each episode.

Volume overload is hazardous in oliguria, while repeated transfusion adds alloimmunisation and iron; avoid routine platelet support without critical bleeding.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Acute kidney failure

Oliguria, hyperkalaemia, acidosis and fluid overload may require dialysis while avoiding vascular access and anticoagulation complications in thrombocytopenia.

Neurological involvement

Seizure, confusion, focal deficit or coma can result from severe hypertension, uraemia or cerebral microangiopathy and needs urgent imaging and critical care.

Chronic kidney disease

Residual proteinuria, hypertension or reduced nephron reserve can develop after apparent haematological recovery, requiring years of renal follow-up.

Complement-inhibitor infection

Terminal-complement blockade markedly increases invasive meningococcal and other Neisseria infection risk despite vaccination, mandating immediate action for compatible fever.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Measure urine output, weight, fluid balance, blood pressure, potassium, bicarbonate and creatinine frequently through acute kidney injury.
Trend platelets, haemoglobin, schistocytes, LDH, haptoglobin and reticulocytes to document TMA activity independently from renal recovery.
Assess neurological status, seizure, vision, cardiac physiology and pulmonary fluid because HUS can extend beyond kidneys.
During complement inhibition review every fever urgently and keep vaccination, antimicrobial prophylaxis and patient-held alerts current.
After discharge follow blood pressure, eGFR, urine albumin or protein and haematuria because chronic injury can appear after count normalisation.
For complement-mediated disease monitor relapse, treatment interval, anti-drug or breakthrough concerns, pregnancy plans and family-genetic implications through the specialist centre.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Diarrhoea may have stopped

Renal TMA often appears after gastrointestinal symptoms improve, so a resolved bowel illness still belongs in the exposure history.

Complement tests can look normal

Serum C3 and C4 are imperfect snapshots and cannot exclude surface-level alternative-pathway dysregulation.

Renal recovery can lag

Platelets and haemolysis may normalise while filtration, proteinuria and blood pressure remain abnormal and require ongoing nephrology.

Hypertension has two directions

Severe pressure can cause secondary TMA, while renal microangiopathy can itself drive severe hypertension; both possibilities require treatment and classification.

11Common pitfallsFrequent interpretation and management errors.

01
Excluding STEC because diarrhoea has resolved.
02
Waiting for genetic results before specialist complement treatment.
03
Using normal C3 to rule out complement-mediated HUS.
04
Giving antimotility medicine during suspected STEC infection.
05
Overloading an oliguric patient with routine fluids.
06
Ending follow-up when the platelet count recovers.