How do I diagnose atypical hemolytic‑uremic syndrome (aHUS)?

How to Diagnose Atypical Hemolytic-Uremic Syndrome (aHUS)

Diagnose aHUS by confirming the simultaneous presence of three laboratory findings—microangiopathic hemolytic anemia (elevated LDH, reduced/absent haptoglobin, schistocytes on smear), thrombocytopenia (platelets <150,000/mm³), and acute kidney injury (elevated creatinine, hematuria, or proteinuria)—while urgently excluding TTP with ADAMTS13 activity testing and typical STEC-HUS with stool testing. 1, 2

Initial Emergency Laboratory Panel

When you suspect aHUS based on anemia plus thrombocytopenia, immediately order this comprehensive panel:

• Complete blood count with peripheral blood smear to identify schistocytes, burr cells, or helmet cells indicating microangiopathic hemolysis 1, 2
• Hemolysis markers: elevated LDH, reduced or absent haptoglobin, and elevated indirect bilirubin 1, 2
• Direct Coombs test must be negative to confirm non-immune hemolytic anemia 1, 2
• Comprehensive metabolic panel with creatinine to assess acute kidney injury (≥1.0 mg/dL in children <13 years; ≥1.5 mg/dL in individuals ≥13 years; or ≥50% increase over baseline) 2
• Urinalysis for hematuria and/or proteinuria to confirm renal involvement 1, 2

Critical pitfall: Up to 50% of aHUS cases lack one component of the triad at initial presentation, but at least one laboratory abnormality is always detectable—complete normalization of all parameters argues against active aHUS. 2

Urgent Differential Diagnosis Testing

Exclude TTP First

• ADAMTS13 activity must be ordered immediately and simultaneously with other testing 1
• ADAMTS13 <10 IU/dL confirms TTP, which requires urgent plasma exchange rather than complement inhibition 1, 3
• Do not wait for ADAMTS13 results to start plasma exchange if TTP is clinically suspected, as mortality is too high without immediate treatment 1

Exclude Typical STEC-HUS

• Stool culture and Shiga toxin testing (both O157 culture AND Shiga toxin/genes) must be performed urgently 1, 3
• Positive STEC with diarrhea 4-5 days before symptom onset indicates typical HUS requiring supportive care only, not complement inhibition 1, 3
• If stool testing is negative but HUS is present, serologic testing for STEC (serogroups O157 and O111) may aid diagnosis 1, 3

Key clinical distinction: A short period of diarrhea or simultaneous onset of diarrhea and HUS suggests aHUS rather than STEC-HUS. 2

Complement and Genetic Testing for aHUS

Once you have excluded TTP and typical STEC-HUS, proceed with aHUS-specific workup:

Complement Assessment

• Measure C3, C4, CH50 (classical pathway), and AP50 (alternative pathway) to assess complement activation 2
• These levels are typically normal regardless of disease activity but are useful for future monitoring during treatment 2

Genetic Testing

• Next-generation sequencing of complement genes: CFH, CFHR1-5, C3, CD46, CFI, THBD, DGKE, and CFB 2, 3
• Multiplex ligation-dependent probe amplification of genes: CFH, CFHR1, CFHR2, CFHR3, CFHR4, and CFHR5 2
• Results ideally within a few months for prognosis and treatment decisions 2

Important caveat: 40-50% of aHUS patients have no identifiable genetic mutation, yet can still be diagnosed with aHUS based on clinical and laboratory criteria. 2 A negative genetic panel does not exclude aHUS, and a pathogenic mutation alone without active TMA does not justify treatment. 2

Special Population Considerations

• Infants <1 year old: Test for complement-unrelated genes (DGKE, WT1) and inborn errors of cobalamin metabolism (MMACHC) 2
• Post-transplant patients: 13% lack significant platelet reduction and 38% lack significant anemia or thrombocytopenia despite active TMA 2

Monitoring Protocol During Acute Phase

• Daily monitoring of hemoglobin, platelet counts, electrolytes, BUN, and creatinine during days 1-14 1, 2
• Monitoring can stop when platelet count begins to increase or stabilize with resolved/resolving symptoms 2

Additional Testing for Complications

Neurological Involvement

• Obtain neurology consultation immediately if neurological symptoms present 1
• Perform EEG and brain MRI with FLAIR and T2-weighted sequences 1
• Bilateral symmetric hyperintensities in basal ganglia on MRI suggest TMA 1

Biomarkers for Differential Diagnosis

• Urinary NGAL with cutoff value of 220-244 μg/g creatinine can differentiate acute tubular necrosis from aHUS 2
• Urinary NGAL levels in aHUS are always much lower than in ATN, even when aHUS has not responded to treatment 2

Critical Diagnostic Pitfalls to Avoid

• Do not assume absence of all three classic findings excludes aHUS, as up to 50% of cases lack one component at onset 1, 2
• Absence of schistocytes should not exclude early diagnosis due to low sensitivity, though other hemolysis markers must still be present 2
• Do not start complement inhibition without laboratory-confirmed active TMA, as eculizumab and ravulizumab carry serious meningococcal infection risks 2
• A pathogenic complement mutation alone does not indicate active aHUS requiring therapy—treatment depends on active disease evidence 2
• Near-normal hemoglobin may indicate dehydration rather than absence of anemia 2