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

Diagnosis and Management of Hemolytic Uremic Syndrome (HUS)

Hemolytic Uremic Syndrome (HUS) is definitively diagnosed by the presence of microangiopathic hemolytic anemia, acute kidney injury, and thrombocytopenia, with the typical form occurring after an episode of bloody diarrhea within the preceding 3 weeks.

Diagnostic Criteria

Essential Laboratory Criteria for HUS Diagnosis 1

Both of the following must be present at some time during the illness:

1. Microangiopathic hemolytic anemia

   • Acute onset anemia with microangiopathic changes (schistocytes, burr cells, or helmet cells) on peripheral blood smear
   • Note: The presence of schistocytes on smear is critical for diagnosis 2

2. Acute kidney injury evidenced by either:

   • Hematuria
   • Proteinuria
   • Elevated creatinine level (≥1.0 mg/dL in children <13 years or ≥1.5 mg/dL in persons ≥13 years, or ≥50% increase over baseline)

3. Thrombocytopenia is typically present but may normalize:

   • If platelet count obtained within 7 days after onset of acute gastrointestinal illness is not <150,000/mm³, consider other diagnoses

Case Classification 1

• Confirmed HUS: Acute illness that meets laboratory criteria AND began within 3 weeks after onset of an episode of acute or bloody diarrhea
• Probable HUS:
  • Meets laboratory criteria but no clear history of acute/bloody diarrhea in preceding 3 weeks, OR
  • Onset within 3 weeks of acute/bloody diarrhea and meets laboratory criteria except microangiopathic changes not confirmed

Differential Diagnosis

Critical Distinction: HUS vs. TTP

• TTP (Thrombotic Thrombocytopenic Purpura):
  • Test ADAMTS13 activity (normal in HUS, severely decreased in TTP) 1, 3
  • TTP more commonly presents with CNS involvement and fever 1
  • TTP may have more gradual onset 1

Types of HUS

1. Typical/Diarrhea-associated HUS (STEC-HUS):

   • Most common in children
   • Preceded by bloody diarrhea (usually within 3 weeks)
   • Associated with Shiga toxin-producing E. coli (especially O157) 1

2. Atypical HUS (aHUS):

   • Associated with complement dysregulation
   • No preceding diarrhea or negative Shiga toxin testing
   • Poorer prognosis with higher rates of ESRD 4, 3

Diagnostic Workup Algorithm

Initial Laboratory Testing

1. Complete blood count with peripheral smear

   • Look specifically for schistocytes, burr cells, helmet cells 1, 2
   • Check hemoglobin and platelet count

2. Renal function tests

   • Serum creatinine
   • Urinalysis for hematuria and proteinuria

3. Hemolysis markers

   • LDH
   • Haptoglobin
   • Reticulocyte count
   • Direct antiglobulin test (Coombs) to rule out immune-mediated hemolysis 1

Specific Diagnostic Tests

1. For STEC-HUS:

   • Stool culture for E. coli O157:H7
   • Shiga toxin testing of stool 1
   • Serologic tests may be considered if stool culture negative but HUS present 1

2. For atypical HUS:

   • ADAMTS13 activity (normal in aHUS, <5-10% in TTP) 3
   • Complement testing (C3, C4, CH50) 1
   • Genetic testing for complement regulatory mutations 3

Management Strategies

Monitoring

• Frequent monitoring of hemoglobin, platelet counts, electrolytes, BUN, and creatinine is essential for patients with diagnosed E. coli O157 or other STEC infections 1
• Examine peripheral blood smear regularly for red blood cell fragmentation when HUS is suspected 1

Treatment Based on HUS Type

STEC-HUS (Typical)

• Supportive care is the mainstay of treatment 5, 6
• Fluid and electrolyte management
• Renal replacement therapy if indicated for acute kidney injury
• Avoid antimicrobials for STEC infections as they may increase risk of HUS development 1

Atypical HUS

• Eculizumab (anti-C5 monoclonal antibody) is the first-line therapy 7, 3

  • Dosing: 900 mg weekly for four doses, 1,200 mg week 5, then 1,200 mg every 2 weeks 7
  • Effectively prevents recurrences before and after renal transplantation 6

• Plasma exchange may be considered when:

  • Complement inhibitor is unavailable
  • Autoantibodies to complement factors are present 3

Management Based on Severity 1

• Grade 1-2: Evidence of RBC destruction without clinical consequences - supportive care
• Grade 3: Laboratory findings with clinical consequences (renal insufficiency, petechiae) - consider eculizumab
• Grade 4: Life-threatening consequences (CNS thrombosis/embolism or renal failure) - eculizumab and supportive measures

Important Caveats

1. Eculizumab is NOT indicated for STEC-HUS (typical HUS) 7

2. Early recognition is critical - delay in identification is associated with increased mortality/morbidity 1

3. Meningococcal vaccination is required before starting eculizumab due to increased risk of meningococcal infections 7

4. TTP is a medical emergency requiring prompt plasmapheresis and must be ruled out quickly 5

5. Long-term follow-up is essential, especially for atypical HUS patients, due to risk of recurrence and progression to end-stage renal disease