What are the diagnostic steps and management for Hemolytic Uremic Syndrome (HUS)?

Diagnostic Steps and Management for Hemolytic Uremic Syndrome (HUS)

The diagnosis of HUS requires identification of the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, with immediate testing for ADAMTS13 activity and Shiga toxin-producing E. coli to differentiate between TTP, typical HUS, and atypical HUS. 1, 2

Diagnostic Approach

Initial Laboratory Evaluation

• First-line testing when anemia plus thrombocytopenia is present:
  • Haptoglobin, indirect bilirubin, and LDH levels 1, 2
  • Complete blood count with peripheral blood smear (looking for schistocytes)
  • Renal function tests (creatinine, BUN)
  • Urinalysis (for hematuria and/or proteinuria)

Diagnostic Criteria for HUS

• Microangiopathic hemolytic anemia:
  • Non-immune hemolytic anemia (negative direct Coombs test)
  • Elevated LDH levels
  • Reduced haptoglobin levels
  • Presence of schistocytes in peripheral blood smear
• Thrombocytopenia:
  • Platelets <150,000/mmc or 25% reduction from baseline
• Renal involvement:
  • Elevated creatinine
  • Presence of hematuria and/or proteinuria 1

Note: In almost 50% of cases, not all three clinical signs may be clearly present at onset 1

Differential Diagnosis Testing

1. ADAMTS13 activity testing:

   • Must be performed urgently (within hours)
   • <10% indicates TTP rather than HUS 2

2. Stool testing:

   • Test for verocytotoxin-producing E. coli (VTEC)
   • Positive indicates typical/STEC-HUS 2

3. Complement testing:

   • C3, C4, CH50 levels
   • Genetic testing for complement pathway mutations
   • Anti-complement factor H antibodies 2

Special Considerations

• In children: Short period of diarrhea or simultaneous appearance of diarrhea and HUS suggests atypical HUS, as STEC-HUS typically appears 4-5 days after diarrhea onset 1
• In first year of life: Consider mutations in complement-unrelated genes (DGKE, WT1) 1
• Post-renal transplant: Absence of marked thrombocytopenia or significant anemia should not exclude TMA diagnosis 1

Management Algorithm

1. Initial Management

• Immediate hospitalization
• Supportive care:
  • IV fluids
  • Blood pressure control
  • Monitor renal function
  • Dialysis if needed

2. Determine HUS Type

• Typical HUS (STEC-HUS):

  • Positive stool culture for STEC
  • Recent history of bloody diarrhea (4-5 days prior)
  • Management: Supportive care and monitoring renal function 2

• Atypical HUS (aHUS):

  • Normal ADAMTS13 activity
  • Negative STEC testing
  • Possible complement abnormalities
  • Management: Immediate complement inhibition therapy 1, 2, 3

3. Specific Treatment for aHUS

• Complement inhibition:

  • Eculizumab or ravulizumab should be initiated within 4-8 hours of diagnosis 1, 3
  • Adult dosing for eculizumab: 900 mg weekly for 4 weeks, then 1200 mg for fifth dose, followed by 1200 mg every 2 weeks 3
  • Pediatric dosing: Weight-based according to FDA guidelines 3

• Prophylaxis requirements:

  • Meningococcal vaccination (quadrivalent A, C, W, Y and B) prior to treatment
  • Long-term antimicrobial prophylaxis with penicillin (or macrolides for penicillin-allergic patients) 1, 3

• Alternative therapy:

  • Plasma exchange if complement inhibitors unavailable or in cases with anti-CFH antibodies 4

4. Monitoring and Follow-up

• Regular assessment of:
  • Platelet count
  • Hemoglobin
  • LDH
  • Renal function 2
• Genetic counseling for confirmed genetic mutations 1, 2

Important Caveats

1. Diagnostic pitfalls:

   • Not all patients present with the complete triad of symptoms
   • Renal dysfunction may be minimal in some cases 5
   • Schistocytes may not be present in early disease 2

2. Treatment urgency:

   • Delayed treatment increases risk of progression to renal failure 6
   • Mortality rate for first aHUS attack is ~25% without treatment 6
   • ~50% of untreated cases progress to end-stage renal disease 6

3. Genetic implications:

   • 60% of aHUS cases have detectable mutations in complement proteins
   • Genetic background strongly influences prognosis, especially in children 1
   • Genetic testing results should inform renal transplantation decisions 4, 7

4. Transplantation considerations:

   • Renal transplantation may trigger aHUS recurrence
   • Complement inhibition therapy may be needed before and after transplantation 7, 8

By following this diagnostic and management approach, clinicians can rapidly identify and appropriately treat HUS, significantly improving patient outcomes and reducing mortality and progression to end-stage renal disease.