C-HUS (Atypical HUS)

Question 1

🧬 Pathophysiology of C-HUS (Complement-mediated HUS / aHUS)

• Etiology
• Trigger

Answer 1

Excessive complement activation–>

• Core mechanism: Dysregulation(hyperactivity) of the alternative complement pathway

	Endothelial injury → microvascular thrombosis → TMA
*	Release of C3a/C5a → interstitial edema (via histamine)

• Etiologies:
  
  • Genetic deficiency of inhibitory proteins
    (although deficiency genetic, HUS usually presents in adulthood)
  • Acquired: Autoantibodies against complement factor H or I
    -Trigger: Infection, pregnancy, autoimmune disease, drugs, etc.

Question 2

Clinical Features of C-HUS

Answer 2

⚠️ Clinical Presentation of C-HUS

[1] Triggers (often present)
* Infections (GI, viral, sepsis) – ~50% of adult cases
* Pregnancy (especially postpartum)
* Drugs: Bleomycin, cisplatin, mitomycin-C, quinine, cocaine
* Surgery
* Autoimmune diseases (SLE)
* Malignancy

[2] TMA Features
* Renal failure (hallmark):
* May require dialysis
* Hematuria, proteinuria (may reach nephrotic range)
* Hypertension:
* Labile and severe due to renin release from arteriolar obstruction
* Neurologic (most common extrarenal):
* Headache, confusion, seizures, coma
* PRES, edema, or herniation on imaging
* Visual: Exudative or ischemic retinopathy
* Cardiac (~10%): Ischemia, arrhythmia, myocarditis, pericardial effusion, ↓EF
* Pulmonary: Alveolar edema, pleural effusion, pulmonary hemorrhage
* GI: Pancreatitis, hepatitis, ascites, colitis
* Soft tissue: Anasarca (facial/body/extremity edema)

Question 3

Diagnostic strategy

Limitations of Lab testing in
C-HUS

Answer 3

🔬 Evaluation of C-HUS

Lab Testing Limitations
* No rapid, definitive complement test available in most hospitals
* C3, C4, CH50: Often measured but not sensitive/specific
* Advanced tests (e.g., sC5b-9, C-HUS panels): May take >2–3 weeks
* Genetic testing: Slow, often yields inconclusive or nonspecific results

Diagnostic Strategy
* Clinical diagnosis based on:
* TMA with renal involvement
* No better alternative diagnosis
* Suggestive scenario (e.g., postpartum, renal-dominant TMA)
* Empiric diagnosis + treatment may be warranted while awaiting labs

Question 4

Treatment

Answer 4

💊 Treatment of C-HUS

General Supportive Care
* Treat underlying triggers if present
* Avoid platelet transfusion unless life-threatening bleeding

Anti-C5 Monoclonal Antibody Therapy
* Eculizumab (first-line):
* Inhibits terminal complement activation (C5)
* Dose: 900 mg IV weekly × 4 weeks
* Can reverse renal failure, even post-dialysis initiation
* Ravulizumab: Longer half-life alternative

*	Infection risk:
   -	↑ risk of encapsulated organisms (e.g., meningococcus)
   -	Vaccinate before/after starting + empiric penicillin prophylaxis
*	Safe in pregnancy

Plasma Exchange: Not Recommended
* Ineffective in most
* May worsen C-HUS or remove eculizumab
* May be considered in:
* Life-threatening organ injury
* Patients with known anti-complement antibodies

Question 5

When do you consider empirical Eculizumab?

Answer 5

💉 Empiric Eculizumab for C-HUS

*	Severe renal dysfunction ± hypertension
*	Postpartum TMA without another explanation
*	Lack of clinical improvement despite treating the trigger
*	Family history of C-HUS