What is the best management approach for Hemolytic Uremic Syndrome (HUS)?

Management of Hemolytic Uremic Syndrome

For atypical HUS (aHUS), immediately initiate complement inhibitor therapy with eculizumab or ravulizumab as the standard of care, while for typical Shiga-toxin-associated HUS (STEC-HUS), provide supportive care only without specific pharmacologic intervention. 1, 2

Immediate Diagnostic Differentiation

The first critical step is distinguishing between typical and atypical HUS, as management differs fundamentally:

• Typical (STEC-HUS): Preceded by bloody diarrhea, caused by Shiga toxin-producing E. coli (most commonly O157:H7), accounts for 90-95% of pediatric cases 3, 4
• Atypical (aHUS): No diarrheal prodrome, caused by complement dysregulation (genetic mutations or anti-CFH antibodies), represents 5% of cases but carries significantly worse prognosis 5, 3

Essential first-line laboratory tests include: complete blood count with peripheral blood smear (looking for schistocytes >1%), ADAMTS13 activity, and stool testing for verocytotoxin-producing E. coli 1

Critical Diagnostic Caveat

• Schistocytes >1% favor thrombotic microangiopathy diagnosis, but their absence should not exclude early TMA due to low test sensitivity 1
• In pediatric patients, especially newborns, HUS may be present even if one component of the triad (thrombocytopenia, anemia, or elevated creatinine) is absent 1
• Evaluate creatinine levels relative to age in children, not absolute values 1

Management of Atypical HUS (aHUS)

Treat aHUS as a medical emergency requiring immediate complement inhibition 1

Pharmacologic Treatment

• Eculizumab (Soliris) is FDA-approved and represents the standard of care for aHUS 2
• Dosing per FDA label: Initiate immediately upon diagnosis to inhibit complement-mediated thrombotic microangiopathy 2
• Pregnancy-triggered aHUS: C5 inhibitors have been instrumental in resolving TMA in pregnant women 1

Mandatory Infection Prophylaxis

All patients receiving complement inhibitors must receive:

• Meningococcal vaccination (serogroups A, C, W, Y, and B) before initiating therapy when possible 1
• Long-term antimicrobial prophylaxis due to increased meningococcal infection risk 1

Treatment Duration and Discontinuation Risk

• Discontinuing complement inhibitors carries 10-20% risk of disease recurrence and renal failure 1
• Requires thorough assessment of genetic risk factors before considering discontinuation 1
• Monitor for relapse signs: clinical presentation changes, laboratory abnormalities, and glomerular proteinuria appearance 1

Special Population Considerations

• Patients of Chinese/Japanese descent may not respond to C5 inhibitors due to polymorphic C5 gene variants 1
• Renal transplant recipients: aHUS may recur in the graft or present as de novo disease; maintain complement inhibition perioperatively 1
• Genetic counseling should be offered to all confirmed aHUS patients due to possible genetic transmission 1

Management of Typical STEC-HUS

No specific pharmacologic therapy exists for STEC-HUS; management is entirely supportive 1, 6, 7

Supportive Care Measures

• Fluid and electrolyte management: Maintain optimal hydration for nephroprotection 4
• Renal replacement therapy: Approximately two-thirds of children require dialysis; peritoneal dialysis should be first-choice modality 6, 4
• Antihypertensive therapy when indicated 6
• Blood transfusions only for symptomatic anemia or hemodynamic instability 6

Critical Medications to AVOID in STEC-HUS

• No antibiotics: May increase Shiga toxin release and worsen outcomes 4
• No antimotility agents (e.g., loperamide) 4
• No narcotics for pain control 4
• No non-steroidal anti-inflammatory drugs 4

Monitoring for Complications

• Neurological involvement is the most frequent non-renal complication and leading cause of death (mortality 3-5%) 6, 4
• Monitor for severe CNS disease, which is associated with nearly all HUS-related deaths 6
• Extrarenal manifestations require close surveillance 6

Multidisciplinary Team Approach

Management requires coordination between multiple specialists 5, 1:

• Nephrology (adult or pediatric depending on patient age)
• Hematology
• Intensive care when indicated
• Referral to rare disease reference centers for aHUS cases 5

Long-Term Follow-Up

For STEC-HUS Survivors

• One-third develop long-term renal sequelae: proteinuria, hypertension, decreased GFR 4, 7
• Duration of anuria correlates with sequelae risk—longer anuria predicts worse outcomes 4
• Lifelong renal monitoring required for all HUS survivors 4

For aHUS Patients

• Regular monitoring of complement parameters (C3, C4, CH50, AP50) if extending C5 inhibitor dosing intervals 1
• Continuous assessment for relapse indicators 1
• Permanent clinical referral to treatment centers 5

Prognosis

• STEC-HUS: Generally favorable immediate outcome with supportive care; 95-97% survival 6, 4
• aHUS without complement inhibition: More than 50% progress to death or end-stage renal disease; frequent recurrence after transplantation 7
• aHUS with complement inhibition: Dramatically improved outcomes with eculizumab/ravulizumab therapy 1, 2

Common Pitfalls to Avoid

• Do not delay complement inhibitor therapy in suspected aHUS while awaiting genetic testing results—treat empirically given high morbidity/mortality 5, 1
• Do not use antibiotics in suspected STEC-HUS even with positive stool cultures 4
• Do not assume absence of diarrhea rules out STEC-HUS—some cases present atypically 3
• Do not discontinue complement inhibitors without comprehensive risk assessment due to high relapse rates 1