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Hemolytic Uremic Syndrome (HUS)

Definition

1. Microangiopathic hemolytic anemia (MAHA)
2. Thrombocytopenia
3. Acute kidney injury (AKI)

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Classification

Typical HUS (Epidemic, Diarrhea-Positive, STEC-HUS)

• ~90% of pediatric cases
• Caused by Shiga toxin-producing E. coli (STEC), most commonly O157:H7
• Preceded by a prodrome of bloody diarrhea
• Source: undercooked meat, unpasteurized milk, contaminated produce
• 10–15% of children with STEC infection develop HUS

Atypical HUS (aHUS, Diarrhea-Negative, Nonepidemic)

• Complement dysregulation is the dominant mechanism
• Triggers include: S. pneumoniae infection (~5%), pregnancy/postpartum, OCP use, antiphospholipid syndrome, systemic sclerosis, genetic mutations
• Worse prognosis than typical HUS

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Pathophysiology

Typical HUS (Shiga Toxin-Mediated)

• Activate endothelial cells → increased leukocyte adhesion molecules and endothelin, decreased nitric oxide
• Cause endothelial apoptosis (facilitated by cytokines such as TNF)
• Inhibit Factor H (a complement regulatory protein) → possible complement hyperactivation
• Net result: platelet activation, vasoconstriction, microthrombus formation in renal vessels → glomerular ischemia, oliguria, AKI

Atypical HUS (Complement-Mediated)

S. pneumoniae-Associated HUS

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Renal Pathology (Morphology)

• Patchy or diffuse cortical necrosis and subcapsular hemorrhages (grossly)
• Glomeruli: thickened capillary walls, mesangiolysis, microthrombi (fibrin/platelet) in capillary loops
• Arterioles and small arteries: endothelial swelling and detachment, subendothelial accumulation of fluffy material, RBC fragmentation ("onion-skin" lesions in chronic/recurrent disease)
• Renal vessels are especially vulnerable because the exposed subendothelial membrane is susceptible to complement-mediated damage

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Clinical Features

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Laboratory Evaluation

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HUS vs. TTP

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Treatment

Typical HUS (STEC-HUS)

• Supportive care is the primary approach
• IV fluids (early aggressive volume expansion, 10–20 mL/kg NS) may improve outcomes in the absence of fluid overload
• Correct electrolyte disturbances (hyperkalemia, hyponatremia)
• Blood transfusion for severe anemia
• Platelet transfusion: contraindicated — worsens thrombotic process
• Antibiotics: contraindicated in diarrheal illness — increase risk of HUS (possibly by releasing more toxin)
• Antiperistaltic agents: contraindicated
• Renal replacement therapy required in ~50% of acute cases
• Eculizumab or plasma exchange may be helpful (evidence remains limited for STEC-HUS)
• ~95% of children survive the acute phase; most regain normal renal function

Atypical HUS (aHUS)

• Eculizumab (humanized anti-C5 monoclonal antibody): FDA-approved for complement-mediated aHUS; proven effective for CFH and CFI mutations — removes terminal complement activation
  • Cost: ~$400,000/year (a practical consideration)
• Plasma exchange: removes autoantibodies and provides functional complement factors, but less effective than in TTP
• Immunosuppressants (corticosteroids, azathioprine, MMF, rituximab, vincristine): used in atypical/autoimmune HUS
• Kidney transplantation: role is unclear — high recurrence risk; success depends on mutation type (MCP mutations have best outcomes post-transplant)
• OCP use should be avoided — can trigger aHUS in patients with CFH (8%) and CFI (20%) mutations

Disposition

• All HUS patients require hospitalization
• Neurologic symptoms + oliguric renal failure → ICU admission

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Prognosis