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

Management of Hemolytic Uremic Syndrome (HUS)

Immediate Diagnostic Differentiation is Critical

The first priority in managing HUS is to immediately distinguish between Shiga toxin-associated HUS (STEC-HUS) and atypical HUS (aHUS), as this determines whether complement inhibitor therapy should be initiated emergently—STEC-HUS requires supportive care only, while aHUS is a medical emergency requiring immediate eculizumab or ravulizumab. 1, 2

Emergency Laboratory Workup

When any patient presents with the HUS triad (microangiopathic hemolytic anemia, thrombocytopenia, acute renal failure), immediately order: 1, 2

• Complete blood count with peripheral smear for schistocytes (>1% supports diagnosis, but absence does not exclude early disease) 1, 2
• ADAMTS13 activity to exclude thrombotic thrombocytopenic purpura (TTP)—if <10 IU/dL, this is TTP, not HUS 1, 2
• Stool testing for verocytotoxin-producing E. coli (VTEC/STEC) 1, 2
• Hemolysis markers: LDH (elevated), haptoglobin (reduced), indirect bilirubin (elevated), direct Coombs test (negative) 1, 2
• Renal function: creatinine, urinalysis for hematuria and proteinuria 1, 2

The Critical Timing Distinction

STEC-HUS typically appears 4-5 days AFTER diarrhea onset; if diarrhea and HUS appear simultaneously or with a shorter interval, suspect aHUS and initiate complement inhibitor therapy immediately. 1, 2, 3

• STEC-HUS: Positive stool VTEC testing AND diarrhea onset 4-5 days before HUS symptoms 1, 2
• aHUS: Negative VTEC testing OR short diarrhea period OR simultaneous onset 1, 2

Management Algorithm by HUS Type

For STEC-HUS (Typical HUS)

STEC-HUS is managed with supportive care ONLY—do NOT use complement inhibitors, as eculizumab is specifically NOT indicated for STEC-HUS. 4, 5

Supportive management includes: 3, 6, 7

• Maintain optimal hydration for nephroprotection 3
• Initiate dialysis when indicated (required in approximately 46-66% of cases)—peritoneal dialysis should be first-choice when both modalities are available 3, 7
• Manage hypertension aggressively with antihypertensive therapy 8, 7
• Transfuse red blood cells for symptomatic anemia per standard guidelines 1
• AVOID platelet transfusions unless life-threatening bleeding occurs, as they may worsen thrombotic microangiopathy 1

Critical medications to AVOID in STEC-HUS: 3, 7

• Antibiotics (may increase Shiga toxin release)
• Antimotility agents
• Narcotics
• Non-steroidal anti-inflammatory drugs

Prognosis: Mortality 3-5%, with approximately one-third developing long-term renal sequelae (proteinuria, hypertension, decreased GFR). 3, 7

For Atypical HUS (aHUS)

aHUS is a medical emergency requiring IMMEDIATE initiation of complement inhibitor therapy with eculizumab or ravulizumab—do NOT delay treatment while awaiting genetic testing results, as mutations are found in only 50-60% of cases. 1, 4

Pre-Treatment Requirements (Do NOT Delay Therapy)

Before initiating eculizumab/ravulizumab: 1, 4

• Vaccinate against meningococcal infection (serogroups A, C, W, Y, and B) at least 2 weeks prior to first dose if possible 1, 4
• If urgent therapy cannot be delayed for vaccination: Administer vaccines as soon as possible AND provide antibacterial prophylaxis (ciprofloxacin) immediately 1, 4
• Enroll in the ULTOMIRIS and SOLIRIS REMS program (required for prescribing) 4

Eculizumab Dosing for aHUS

For adults (≥18 years and ≥40 kg): 4

• Induction: 900 mg IV weekly × 4 weeks
• Fifth dose: 1200 mg at week 5
• Maintenance: 1200 mg every 2 weeks thereafter

For pediatric patients (weight-based dosing): 4

• 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

Concurrent Supportive Care for aHUS

While initiating complement inhibitor therapy: 1

• Obtain immediate hematology consultation 1
• Stabilize critical organ dysfunction 1
• Transfuse red blood cells for symptomatic anemia per standard guidelines 1
• AVOID platelet transfusions unless life-threatening bleeding 1
• Initiate dialysis when indicated 6

Monitoring Response to Therapy

Assess treatment response by monitoring: 1

• Platelet count normalization (target >150,000/mm³) 1
• Resolution of hemolysis (LDH normalization, disappearance of schistocytes) 1
• Stabilization or improvement in renal function (serum creatinine) 1
• Complete blood count every 2-4 weeks until doses stabilized 1

Critical Warning About Treatment Discontinuation

Discontinuing complement inhibitor therapy in aHUS carries a 10-20% risk of disease recurrence with potential renal failure—thorough assessment of risk factors is required before any consideration of stopping therapy. 1

Special Clinical Contexts

Pregnancy-Triggered aHUS

For pregnancy-associated aHUS, initiate C5 inhibitors (eculizumab/ravulizumab) immediately, as these have been instrumental in resolving thrombotic microangiopathy in this population. 1

Neurological Involvement

If neurological symptoms develop (occurs in 10-20% of aHUS cases): 1, 2

• Obtain neurology consultation immediately 2
• Perform electroencephalogram (EEG) 2
• Obtain brain MRI with FLAIR and T2-weighted sequences looking for bilateral symmetric hyperintensities in basal ganglia, cerebral peduncles, caudate nuclei, putamen, thalami, hippocampi, insulae, or brainstem 2
• Consider early plasmapheresis, which may improve prognosis 3

Renal Transplantation Considerations

Maintain complement inhibitor therapy in aHUS patients being evaluated for kidney transplantation to prevent recurrence in the transplanted kidney. 1

Genetic Counseling

Offer genetic counseling to all patients with confirmed aHUS diagnosis due to possible genetic transmission. 1

Common Pitfalls to Avoid

• Never delay eculizumab/ravulizumab in suspected aHUS while awaiting genetic testing—only 50-60% have identifiable mutations 1
• Never use antibiotics in suspected STEC-HUS—they may increase Shiga toxin release 3
• Never assume schistocyte absence excludes HUS—sensitivity is low in early disease 1, 2
• Never discontinue complement inhibitors prematurely in aHUS—10-20% relapse risk 1
• Never forget meningococcal vaccination and prophylaxis when using complement inhibitors—life-threatening meningococcal infections are the primary risk 4

Long-Term Follow-Up

All patients with a history of HUS require long-term renal monitoring for: 3

• Proteinuria
• Arterial hypertension
• Decreased glomerular filtration rate
• The longer the duration of anuria during acute phase, the greater the risk of sequelae 3