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

Diagnostic Criteria for Hemolytic Uremic Syndrome (HUS)

The diagnosis of Hemolytic Uremic Syndrome (HUS) is based on the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, with differentiation between typical and atypical forms requiring specific laboratory testing. 1

Core Diagnostic Criteria

HUS diagnosis requires the presence of:

1. Microangiopathic hemolytic anemia:

   • Presence of schistocytes (fragmented RBCs) in peripheral blood smear
   • Elevated LDH levels
   • Reduced haptoglobin levels
   • Negative direct and indirect Coombs tests (to exclude immune-mediated hemolysis)

2. Thrombocytopenia:

   • Platelet count <150,000/μL or a 25% reduction from baseline

3. Acute kidney injury:

   • Elevated serum creatinine
   • Presence of hematuria and/or proteinuria 2, 1

Important Clinical Consideration

It's crucial to recognize that not all three clinical signs may be present at disease onset. In approximately 50% of cases, particularly in atypical HUS, the complete triad may not be evident initially, which can delay diagnosis and treatment 2. In pediatric patients, creatinine levels should be assessed in relation to age 2.

Differential Diagnosis Algorithm

1. First, determine if it's HUS vs. other thrombotic microangiopathies:

   • Test ADAMTS13 activity (>10% in HUS, <10% in TTP) 1, 3
   • Rule out DIC (normal coagulation studies in HUS)
   • Rule out HELLP syndrome in pregnant women
   • Exclude vasculitis and malignancies 1

2. Then, differentiate between typical and atypical HUS:

   • Typical HUS (STEC-HUS):

     • Positive stool culture for Shiga toxin-producing E. coli
     • PCR for Shiga toxins
     • Serology for anti-lipopolysaccharide antibodies
     • Usually preceded by bloody diarrhea 4-5 days before HUS onset 2, 1

   • Atypical HUS (aHUS):

     • Negative tests for STEC
     • Complement evaluation (C3, C4, factor H, factor I)
     • Genetic testing for complement regulatory proteins
     • Testing for anti-factor H antibodies 2, 3

Special Diagnostic Considerations

In Pediatric Patients

• Both aHUS and STEC-HUS may present with diarrhea
• Short duration of diarrhea or simultaneous appearance of diarrhea and HUS suggests aHUS rather than STEC-HUS 2
• Typical HUS represents 90-95% of cases in children 1

In Adult Patients

• Atypical HUS is more common in adults than in children 3
• Genetic factors play a significant role (mutations in complement regulatory proteins) 2

In Transplant Recipients

• Diagnosis is more challenging due to:
  • Need for in-depth knowledge of the pathology
  • Potential absence of typical laboratory findings (13% may not show significant platelet reduction) 2

Laboratory Evaluation

First-line Tests

• Complete blood count with peripheral smear (specifically looking for schistocytes)
• Renal function tests (serum creatinine, BUN)
• Urinalysis for hematuria and proteinuria
• Hemolysis markers (LDH, haptoglobin, reticulocyte count)
• Direct Coombs test
• Stool culture and PCR for Shiga toxins 1

Second-line Tests

• ADAMTS13 activity
• Complement evaluation (C3, C4, factor H, factor I)
• Anti-factor H antibodies
• Genetic testing for complement regulatory proteins 2, 1, 3

Red Flags for Early Recognition

Early recognition of HUS is critical as delays in diagnosis are associated with increased morbidity and mortality. Key red flags include:

• Bloody diarrhea followed by unexplained anemia and thrombocytopenia
• Acute kidney injury following a gastrointestinal illness
• Fragmented red blood cells on peripheral smear with negative Coombs test
• Family history of HUS or unexplained kidney disease 2, 1

Common Pitfalls in Diagnosis

• Failure to recognize HUS when the complete triad is not present
• Misdiagnosis as immune thrombocytopenia or other causes of anemia
• Delayed testing for STEC in patients with diarrhea
• Inappropriate use of antibiotics in suspected STEC infections, which may increase the risk of developing HUS 1
• Failure to consider atypical HUS in the absence of diarrhea 4

Early diagnosis and prompt initiation of appropriate treatment are essential, as delays can lead to increased morbidity, mortality, and progression to end-stage renal disease 2, 5.