How is atypical hemolytic‑uremic syndrome (aHUS) diagnosed?

How to Diagnose Atypical Hemolytic-Uremic Syndrome (aHUS)

Diagnose aHUS by confirming the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, then immediately ordering ADAMTS13 activity and stool testing for Shiga toxin-producing E. coli to exclude TTP and typical HUS—the two critical differential diagnoses that require completely different management. 1

Step 1: Confirm Thrombotic Microangiopathy (TMA)

Essential Laboratory Tests to Order Immediately

• Complete blood count with peripheral blood smear to identify schistocytes (>1% threshold), though their absence does not exclude early disease due to low sensitivity 1, 2
• Platelet count must be <150,000/mm³ or show ≥25% reduction from baseline to confirm thrombocytopenia 3, 2
• Hemolysis markers including 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
• Serum creatinine and urinalysis for hematuria and/or proteinuria to document renal involvement 1, 3

Critical Diagnostic Pitfall

Up to 50% of aHUS cases lack one component of the triad at initial presentation, but some laboratory abnormality is always detectable—completely normal labs between episodes argues against aHUS 2

Step 2: Exclude TTP and Typical HUS (The Two Must-Not-Miss Diagnoses)

Order These Tests Urgently and Simultaneously

• ADAMTS13 activity level: Activity <10 IU/dL confirms TTP, which requires immediate plasma exchange rather than complement inhibition 1, 4
• Stool testing for Shiga toxin-producing E. coli (STEC): Positive STEC with diarrhea 4-5 days before symptoms indicates typical HUS, which requires supportive care only—no complement inhibitors 1
• Do not wait for ADAMTS13 results if TTP is suspected clinically, as mortality is too high without immediate plasma exchange 1

Key Clinical Distinctions

• Typical HUS: Onset within 3 weeks after bloody diarrhea, positive STEC testing 2
• aHUS: No preceding diarrheal illness, or if diarrhea present, it is brief with simultaneous onset of HUS symptoms rather than the typical 4-5 day lag 2

Step 3: Confirm aHUS Diagnosis

Once TTP and Typical HUS Are Excluded

aHUS is a clinical diagnosis requiring all three elements present simultaneously: microangiopathic hemolytic anemia (elevated LDH, low haptoglobin, schistocytes), thrombocytopenia, and acute renal injury 2, 5, 4

Complement Testing (For Monitoring, Not Diagnosis)

• Measure C3, C4, CH50, and AP50 as part of comprehensive complement assessment 3, 2
• Important limitation: Complement levels are typically normal regardless of disease activity and cannot confirm or exclude aHUS 2
• These levels are useful for future monitoring during treatment but not for acute diagnosis 2

Step 4: Genetic Testing (After Treatment Initiation)

Order Next-Generation Sequencing

• Test complement-regulatory genes: CFH, CFHR1-5, C3, CD46, CFI, THBD, DGKE, and CFB 3, 2
• Critical understanding: 40-50% of aHUS patients have no identifiable mutation, so negative genetic testing does not exclude aHUS 3, 2
• Do not delay treatment while waiting for genetic results—initiate complement inhibition immediately upon clinical diagnosis 3

Special Population Considerations

• Infants <1 year old: Also test 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

Step 5: Additional Diagnostic Considerations

Neurological Involvement

• If neurological symptoms present: Obtain immediate neurology consultation, EEG, and brain MRI with FLAIR and T2-weighted sequences 1
• Bilateral symmetric hyperintensities in basal ganglia suggest TMA 1

Biomarkers for Differential Diagnosis

• Urinary NGAL (cutoff 220-244 μg/g creatinine) can differentiate acute tubular necrosis from aHUS, with better performance when measured 2 days after fluid challenge 2
• NGAL levels in aHUS are always much lower than in ATN, even when treatment has not yet responded 2

Common 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
• Do not rely on a single CBC to define risk—serial monitoring of hemoglobin and platelets is mandatory 2
• Do not exclude aHUS based on negative genetic testing alone, as mutations are identified in only 50-60% of cases 3, 5
• Do not start complement inhibition without laboratory-confirmed active TMA, as eculizumab carries serious meningococcal infection risk and requires lifelong vaccination 2
• Recognize that carrying a pathogenic complement mutation alone does not indicate active aHUS requiring therapy—treatment depends on active disease evidence 2