What are the diagnostic criteria for Hemolytic Uremic Syndrome (HUS)?

Diagnostic Criteria for Hemolytic Uremic Syndrome (HUS)

The diagnosis of Hemolytic Uremic Syndrome requires the presence of microangiopathic hemolytic anemia, acute renal injury, and typically thrombocytopenia, with different criteria applying to typical (post-diarrheal) versus atypical forms of the disease. 1

Core Diagnostic Criteria

Essential Laboratory Findings

• Microangiopathic hemolytic anemia (acute onset) with characteristic morphological changes on peripheral blood smear including schistocytes, burr cells, or helmet cells 1, 2
• Acute renal injury evidenced by either hematuria, proteinuria, or elevated creatinine levels (≥1.0 mg/dL in children <13 years; ≥1.5 mg/dL in individuals ≥13 years; or ≥50% increase over baseline) 1
• Low platelet count (<150,000/mm³) typically detected early in the illness, though this may normalize or even increase later 1, 3

Additional Laboratory Markers

• Elevated lactate dehydrogenase (LDH) levels 1
• Reduced haptoglobin levels 1
• Negative direct and indirect Coombs tests (indicating non-immune hemolysis) 1

Classification of HUS

Typical (Post-diarrheal) HUS

• Onset within 3 weeks after an episode of acute or bloody diarrhea 1, 4
• Usually associated with Shiga toxin-producing Escherichia coli (STEC), particularly O157:H7 4
• Confirmed case: meets laboratory criteria and has clear temporal relationship with preceding diarrheal illness 1

Atypical HUS (aHUS)

• No preceding diarrheal illness or occurs with diarrhea but has evidence of complement dysregulation 1, 5
• Characterized by dysregulation of the alternative complement pathway 6, 7
• May be associated with genetic mutations in complement regulatory proteins (factor H, membrane cofactor protein, factor I) or autoantibodies against complement factors 5, 7

Differential Diagnosis Considerations

Thrombotic Thrombocytopenic Purpura (TTP)

• Distinguished from HUS by ADAMTS13 activity testing (activity >10% in HUS, <10% in TTP) 6, 7
• TTP more commonly presents with neurological abnormalities and fever 2
• Both conditions share features of microangiopathic hemolytic anemia and thrombocytopenia 3

Other Thrombotic Microangiopathies

• Secondary causes including systemic lupus erythematosus, antiphospholipid syndrome 2, 4
• Drug-induced thrombotic microangiopathies 4
• Streptococcus pneumoniae-associated HUS 5, 4

Diagnostic Algorithm

1. Initial Assessment:

   • Identify the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury 1, 3
   • Check for history of preceding diarrheal illness (particularly bloody diarrhea) 1

2. First-line Laboratory Tests:

   • Complete blood count with peripheral blood smear examination for schistocytes 1, 2
   • Renal function tests (creatinine, BUN) 1
   • Urinalysis for hematuria and proteinuria 1
   • LDH, haptoglobin, and direct/indirect Coombs tests 1

3. Differential Diagnosis Testing:

   • Stool culture and PCR for Shiga toxins (to identify STEC-HUS) 5
   • Serology for anti-lipopolysaccharide antibodies 5
   • ADAMTS13 activity (to rule out TTP) 6, 7

4. For Suspected aHUS:

   • Complement system evaluation (C3, C4, factor H, factor I plasma concentrations) 5, 7
   • Membrane cofactor protein (MCP) expression on leukocytes 5
   • Anti-factor H antibodies 5, 7
   • Genetic screening for complement pathway mutations 1, 7

Important Clinical Considerations

• In pediatric patients, both aHUS and STEC-HUS may present with diarrhea; a short period of diarrhea or simultaneous onset of diarrhea and HUS suggests aHUS rather than STEC-HUS 1
• Not all three clinical signs (hemolytic anemia, thrombocytopenia, renal involvement) may be clearly present at disease onset in up to 50% of aHUS cases 1
• If platelet count obtained within 7 days after onset of acute gastrointestinal illness is not below 150,000/mm³, consider alternative diagnoses 1
• Early recognition is crucial as prompt treatment significantly impacts morbidity and mortality outcomes 3

Common Pitfalls to Avoid

• Failing to consider HUS in patients with incomplete presentation (not all elements of the triad may be present initially) 1
• Delaying ADAMTS13 testing, which is critical for distinguishing between TTP and HUS 6
• Administering antibiotics during acute STEC infection, which may increase the risk of developing HUS 4
• Missing atypical HUS due to focus only on diarrheal prodrome; aHUS can occur without preceding gastrointestinal symptoms 5, 7
• Overlooking the need for genetic testing in suspected aHUS cases, which is important for prognosis and treatment decisions 1, 7