What diagnostic investigations should be done for a patient suspected of having Hemolytic Uremic Syndrome (HUS)?

Diagnostic Investigations for Hemolytic Uremic Syndrome (HUS)

When HUS is suspected, immediately obtain a complete blood count with peripheral blood smear, LDH, haptoglobin, indirect bilirubin, direct Coombs test, renal function tests (creatinine, urinalysis), and ADAMTS13 activity to confirm thrombotic microangiopathy and distinguish between HUS subtypes. 1, 2

Initial Laboratory Panel (Mandatory for All Suspected Cases)

Any patient presenting with anemia plus thrombocytopenia in the emergency setting must have haptoglobin, indirect bilirubin, and LDH levels determined immediately. 1

Core Diagnostic Triad Confirmation

• Complete blood count with platelet count: Thrombocytopenia is defined as platelets <150,000/mm³ or a 25% reduction from baseline 1, 2
• Peripheral blood smear: Examine for schistocytes, burr cells, or helmet cells indicating microangiopathic hemolysis 1, 2
  • Note: Absence of schistocytes should NOT exclude early diagnosis due to low sensitivity 1, 2
• Hemolysis markers:
  • Elevated LDH levels 1
  • Reduced or absent haptoglobin 1
  • Elevated indirect bilirubin 1
• Direct Coombs test: Must be negative to confirm non-immune hemolytic anemia 1
• Renal function assessment:
  • Serum creatinine (≥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 1

Critical Differential Diagnosis Testing (Urgent)

ADAMTS13 activity must be tested urgently when thrombotic microangiopathy is confirmed, as severely deficient activity (<10 IU/dL) indicates TTP requiring immediate plasmapheresis rather than HUS. 1, 3

Distinguish HUS Subtypes

• Stool culture and Shiga toxin testing: Identify Shiga toxin-producing E. coli (STEC), most commonly O157 serotype 2, 3
  • If stool testing is negative but HUS is present, obtain serologic testing for STEC (CDC-validated testing for serogroups O157 and O111) 2
  • STEC-HUS typically appears 4-5 days after onset of diarrhea; shorter duration or simultaneous onset suggests atypical HUS 1, 3

Additional Testing for Atypical HUS (aHUS)

When STEC is excluded and ADAMTS13 is normal, proceed with complement and genetic evaluation:

Complement Studies

• C3, C4 levels 2, 3
• CH50 (classical pathway) 2
• AP50 (alternative pathway) 2
• Anti-factor H antibodies 3

Genetic Testing

Genetic testing should be performed in all suspected aHUS cases through next-generation sequencing of complement genes: CFH, CFHR1-5, C3, CD46, CFI, THBD, DGKE, and CFB. 1, 2

• Multiplex ligation-dependent probe amplification of genes: CFH, CFHR1, CFHR2, CFHR3, CFHR4, and CFHR5 1
• Results ideally within a few months for prognosis and treatment decisions 2
• Important caveat: aHUS can still be diagnosed when identifiable mutations are not present, as 40-50% of cases have no detectable mutation 1

Special Population Considerations

Pediatric Patients (First Year of Life)

• When aHUS presents in infants <1 year old, test for mutations in complement-unrelated genes (DGKE, WT1) and inborn errors of cobalamin metabolism (MMACHC). 1
• Assess creatinine levels in relation to age, as standard adult cutoffs do not apply 1
• Critical: aHUS may be present even if one of the three parameters (thrombocytopenia, anemia, elevated creatinine) is absent 1, 2

Post-Transplant Patients

• Following renal transplant, absence of marked thrombocytopenia or significant anemia should NOT exclude TMA diagnosis, as 13% of patients lack significant platelet reduction and 38% lack significant anemia or thrombocytopenia. 1

Neurological Involvement (10-20% of aHUS cases)

If neurological symptoms are present (seizures, encephalopathy, motor symptoms, vision changes, generalized weakness):

• Obtain neurological consultation 1
• Electroencephalogram (EEG) 1
• Brain MRI 1

Serial Monitoring Protocol

Daily monitoring of hemoglobin, platelet counts, electrolytes, BUN, and creatinine during the at-risk period (days 1-14) is mandatory for patients with diagnosed or suspected STEC infection. 2

• Monitoring can stop when platelet count begins to increase or stabilize with resolved/resolving symptoms 2
• Serial CBCs are essential as a single CBC is insufficient to define risk 2
• Patients with decreasing platelet trends during diarrheal illness are at higher risk for HUS 2

Common Pitfalls to Avoid

• Do not wait for all three classic features (hemolytic anemia, thrombocytopenia, renal involvement) to be clearly present, as up to 50% of aHUS cases may not show all features at onset 2, 4
• Do not exclude HUS based on absence of schistocytes on initial peripheral smear due to low sensitivity early in disease 1, 2
• Do not delay ADAMTS13 testing, as distinguishing TTP from HUS is critical for immediate management decisions 1, 3
• Near-normal hemoglobin may indicate dehydration rather than absence of anemia 2
• In post-transplant patients, maintain high suspicion even without typical laboratory findings 1