Question
A 27-year-old man is admitted with abdominal discomfort, repeated vomiting, lethargy, and altered mental status. Investigations show severe acute kidney injury with creatinine 342 µmol/L, anaemia, thrombocytopenia, raised reticulocytes, and markedly elevated LDH. Coagulation times are normal. Testing for Shiga toxin is negative, and ADAMTS13 activity is normal. The haematology team suspects atypical haemolytic-uraemic syndrome (aHUS) and has commenced plasma exchange.
Which additional therapy is most appropriate?
A. Bortezomib
B. Infliximab
C. Azathioprine
D. Mepolizumab
E. Eculizumab
Answer
E. Eculizumab
Explanation
This patient has the characteristic features of a thrombotic microangiopathy (TMA):
- Microangiopathic haemolytic anaemia (MAHA): Hb 85 g/L, raised LDH, raised reticulocytes
- Thrombocytopenia: platelets 93 × 10⁹/L
- Acute kidney injury: creatinine 342 µmol/L
The two particularly important tests help separate the major TMAs:
Shiga toxin negative → argues against typical STEC-associated HUS.
Normal ADAMTS13 activity → argues strongly against TTP, in which severe ADAMTS13 deficiency, usually <10% activity, is characteristic.
This therefore points toward atypical HUS, more accurately described as complement-mediated HUS. It results from inappropriate activation of the alternative complement pathway, often due to inherited or acquired abnormalities in complement regulation.
Why eculizumab?
Eculizumab is a monoclonal antibody against complement component C5.
It prevents cleavage of:
C5 → C5a + C5b
This blocks formation of the C5b-9 membrane attack complex, reducing complement-mediated endothelial injury and therefore the ongoing thrombotic microangiopathy.
Eculizumab is a major treatment for complement-mediated aHUS and can lead to improvement in:
- haemolysis
- thrombocytopenia
- renal function
- overall TMA activity
An important practical point is that terminal complement blockade markedly increases susceptibility to meningococcal infection, so appropriate meningococcal vaccination and infection-prevention measures are required.
Why not the other drugs?
Bortezomib is a proteasome inhibitor mainly used for plasma-cell disorders such as multiple myeloma.
Infliximab is an anti-TNF monoclonal antibody used in conditions such as inflammatory bowel disease and inflammatory arthritis.
Azathioprine is an immunosuppressant used in several autoimmune and inflammatory diseases but is not standard treatment for complement-mediated aHUS.
Mepolizumab targets IL-5 and is used mainly for eosinophilic disorders and severe eosinophilic asthma.
High-yield differentiation
| Disorder | Main mechanism | Key clue |
|---|---|---|
| Typical HUS | Shiga toxin-associated endothelial injury | Often diarrhoeal illness; Shiga toxin positive |
| Atypical HUS | Complement dysregulation | Shiga negative, ADAMTS13 not severely deficient, prominent AKI |
| TTP | Severe ADAMTS13 deficiency | ADAMTS13 <10% |
| DIC | Systemic coagulation activation | Prolonged PT/APTT, low fibrinogen, high D-dimer |
A useful MRCP shortcut is:
MAHA + thrombocytopenia + severe AKI + Shiga negative + normal ADAMTS13 → think atypical HUS → C5 inhibition.
Summary for quick exam revision
Haemolytic-uraemic syndrome is a thrombotic microangiopathy characterised by microangiopathic haemolytic anaemia, thrombocytopenia, and acute kidney injury. Blood film typically shows schistocytes because red cells are mechanically fragmented within damaged small vessels. Haemolysis produces raised LDH, raised reticulocytes, reduced haptoglobin, and usually a negative direct antiglobulin test. Typical HUS is most commonly associated with Shiga toxin-producing E. coli, particularly following a diarrhoeal illness. Stool testing or PCR for Shiga toxin helps identify typical HUS. Atypical HUS is primarily caused by dysregulation of the alternative complement pathway and is therefore also termed complement-mediated HUS. TTP is another important thrombotic microangiopathy but is associated with severe ADAMTS13 deficiency, typically activity below 10%. Thus, a patient with MAHA, thrombocytopenia, severe renal impairment, negative Shiga toxin testing, and normal ADAMTS13 should make you strongly consider atypical HUS. Renal involvement tends to be particularly prominent in HUS compared with classic TTP. Eculizumab is a monoclonal antibody directed against complement C5. It blocks terminal complement activation and prevents formation of the C5b-9 membrane attack complex. Complement inhibition can stop endothelial damage and improve haemolysis, platelet counts, and renal function in complement-mediated aHUS. Plasma exchange was historically used, particularly when the precise diagnosis was initially uncertain, but targeted complement inhibition is central to modern treatment of aHUS. Supportive care may include fluid and electrolyte management, red-cell transfusion, blood-pressure control, and dialysis when necessary. Antibiotics are generally not used simply to treat uncomplicated STEC-HUS and may be harmful with some Shiga toxin-producing organisms. Patients receiving terminal complement inhibitors have an increased risk of invasive meningococcal infection, making meningococcal prevention essential. For exams, remember the key sequence: MAHA + thrombocytopenia + AKI → check Shiga toxin and ADAMTS13 → Shiga negative + ADAMTS13 normal → consider atypical HUS → treat with C5 complement inhibition such as eculizumab.