How should atypical hemolytic uremic syndrome be treated?

Treatment of Atypical Hemolytic Uremic Syndrome (aHUS)

Initiate complement inhibitor therapy with eculizumab or ravulizumab immediately upon clinical suspicion of aHUS—within 4-8 hours of diagnosis—without waiting for genetic test results, as treatment delays directly increase morbidity and mortality. 1, 2

Immediate First-Line Treatment

Complement Inhibition (Standard of Care)

• Eculizumab and ravulizumab have equivalent efficacy and are FDA-approved for aHUS treatment 1, 3
• Ravulizumab offers longer duration of action with less frequent infusions (every 8 weeks vs every 2 weeks), which may improve adherence 2

Eculizumab dosing for adults (≥18 years): 3

• 900 mg IV weekly × 4 weeks
• 1200 mg IV at week 5
• 1200 mg IV every 2 weeks thereafter

Eculizumab dosing for pediatrics (<18 years) is weight-based: 3

• ≥40 kg: 900 mg weekly × 4 doses, then 1200 mg at week 5, then 1200 mg every 2 weeks
• 30-40 kg: 600 mg weekly × 2 doses, then 900 mg at week 3, then 900 mg every 2 weeks
• 20-30 kg: 600 mg weekly × 2 doses, then 600 mg at week 3, then 600 mg every 2 weeks
• 10-20 kg: 600 mg weekly × 1 dose, then 300 mg at week 2, then 300 mg every 2 weeks
• 5-10 kg: 300 mg weekly × 1 dose, then 300 mg at week 2, then 300 mg every 3 weeks

Critical Meningococcal Prophylaxis (Non-Negotiable)

• Administer both quadrivalent meningococcal conjugate vaccine (serogroups A, C, W, Y) AND meningococcal B vaccine at least 2 weeks before starting complement inhibition 2, 3
• If urgent therapy cannot be delayed for vaccination, start antibacterial prophylaxis immediately and vaccinate as soon as possible 1, 3
• Provide continuous antimicrobial prophylaxis with penicillin (or macrolide if penicillin-allergic) for the entire duration of complement inhibitor therapy 2
• Monitor continuously for signs/symptoms of meningococcal infection (fever, headache, neck stiffness)—this is a life-threatening risk 3

Concurrent Supportive Management

Blood Product Administration

• Transfuse red blood cells only for symptomatic anemia or to achieve hemoglobin 7-8 g/dL in stable patients 1, 2
• Use minimum number of RBC units necessary to relieve symptoms 2
• Avoid platelet transfusions unless life-threatening bleeding occurs—they worsen thrombotic microangiopathy 1, 2
• Notify blood bank that patient has complement-mediated TMA before any transfusions 2

Additional Supportive Care

• Provide folic acid 1 mg daily to support erythropoiesis 2
• Obtain urgent hematology consultation—delays increase mortality 2
• Stabilize critical organ dysfunction while initiating complement inhibitor 1

Diagnostic Confirmation (Do Not Delay Treatment)

Obtain these tests immediately but do NOT wait for results before starting eculizumab/ravulizumab: 1, 2

• ADAMTS13 activity level to exclude thrombotic thrombocytopenic purpura (TTP)
• Stool testing for Shiga toxin/E. coli O157 to exclude STEC-HUS
• Complete blood count with peripheral smear demonstrating schistocytes >1%
• Complement testing: C3, C4, CH50, and anti-complement antibodies
• Genetic testing (next-generation sequencing of CFH, CFHR1-5, C3, CD46, CFI, THBD, DGKE, CFB) after treatment initiation—mutations found in only 50-60% of cases 1, 2

Monitoring Treatment Response

Target Parameters

• Platelet count normalization to >150,000/mm³ (or avoid >25% reduction from baseline) 1, 2
• Resolution of hemolysis: LDH normalization, disappearance of schistocytes 1
• Stabilization or improvement in renal function (serum creatinine) 1

Monitoring Schedule

• Complete blood count every 2-4 weeks until doses stabilized 1
• Regular serum creatinine measurement and urinalysis for hematuria/proteinuria 2
• Monitor for signs of relapse: clinical presentation, laboratory data, proteinuria 1

Duration of Treatment and Discontinuation

• Minimum treatment duration is 6 months 2
• Discontinuing complement inhibitors carries 10-20% risk of disease recurrence and renal failure 1, 2
• Use genetic risk stratification to guide discontinuation decisions—absence of identified mutations does NOT guarantee low recurrence risk 2
• Thorough assessment of risk factors required before any discontinuation attempt 1

Special Clinical Contexts

Pregnancy-Triggered aHUS

• Initiate C5 inhibitors immediately—they have been instrumental in resolving TMA in pregnancy 1

Transplant Patients

• Maintain complement inhibitor therapy in patients being evaluated for or receiving kidney transplantation to prevent aHUS recurrence in the transplanted kidney 1
• Renal transplantation may trigger aHUS as recurrent or de novo disease 1

Patients of Asian Descent

• Patients of Chinese and/or Japanese descent may not respond to C5 inhibitors due to polymorphic variants of the C5 gene 1

Plasmapheresis/Plasma Exchange

• Supplemental dosing of eculizumab required during concomitant plasmapheresis, plasma exchange, or fresh frozen plasma infusion 3

Critical Pitfalls to Avoid

• Never delay eculizumab/ravulizumab while awaiting genetic testing—only 50-60% have identifiable mutations 1, 2
• Never discontinue complement inhibitor prematurely—carries 10-20% relapse risk with potential renal failure 1, 2
• Never administer platelet transfusions except for life-threatening bleeding—worsens microangiopathic thrombosis 1, 2
• Never start complement inhibition without meningococcal vaccination and antimicrobial prophylaxis plan 2, 3

Long-Term Outcomes

• Clinical studies demonstrate 73% complete TMA response rate at 26 weeks 4
• 79% of dialysis-dependent patients discontinued dialysis during eculizumab treatment 4
• Quality of life measures significantly improved with treatment 4
• Early treatment prevents irreversible renal damage—delays result in permanent kidney injury 5

Genetic Counseling

• Offer genetic counseling to all patients with confirmed aHUS diagnosis due to possible genetic transmission 1, 2