A 35-year-old man from Bangalore with a 5-year history of recurrent sinusitis, otitis media, and pneumonia (4 episodes in the past year) presents with fatigue and mild jaundice. Serum creatinine is 1.8 mg/dL (baseline 0.9). Urinalysis shows 2+ proteinuria and dysmorphic RBCs. Serum C3 is 45 mg/dL (normal 90–180). C4 is normal. What is the most appropriate immediate next step in management?

Explanation

## Clinical Presentation Analysis **Key Point:** This patient has two distinct but related pathologies: 1. **Recurrent infections** (sinusitis, otitis, pneumonia) → suggests complement deficiency 2. **Glomerulonephritis** (elevated creatinine, proteinuria, dysmorphic RBCs, low C3) → suggests complement-mediated kidney disease The combination of **low C3 with normal C4** is the critical clue: this pattern indicates **alternative pathway (AP) complement activation**, not classical pathway deficiency. ## Pathophysiology: C3 Glomerulopathy **High-Yield:** C3 glomerulopathy (C3GN) is characterized by: - Isolated or dominant C3 deposition on immunofluorescence (minimal or no immunoglobulin) - Dysregulation of the alternative pathway (mutations in Factor H, Factor I, or C3; or presence of C3 nephritic factor) - Low serum C3 (consumed by continuous AP activation) - Normal C4 (classical pathway intact) - Progressive renal failure if untreated **Mnemonic for low C3 + normal C4:** **APAC** — **A**lternative **P**athway **A**ctivation **C**auses isolated C3 depression ## Why Option 1 Is Correct 1. **C3 Nephritic Factor (C3NF):** An IgG autoantibody that stabilizes C3 convertase (C3bBb), preventing its degradation. Present in ~40% of C3GN cases. Drives relentless AP activation. 2. **Anti-PLA2R:** While classically associated with membranous nephropathy, it is tested here to exclude secondary causes of proteinuria. 3. **Nephrology referral:** C3GN requires specialist management (immunosuppression, complement-targeted therapy like eculizumab in severe cases, genetic counseling). 4. **Timing:** These serologies and specialist evaluation are the immediate next step before empiric treatment. ## Complement Pathway Interpretation | Pathway | C3 | C4 | Classic Cause | |---------|----|----|---------------| | **Classical** | ↓ | ↓ | SLE, IC disease, C1q deficiency | | **Alternative** | ↓ | Normal | C3GN, post-infectious GN, Factor H/I deficiency | | **Terminal (MAC)** | Normal | Normal | Recurrent Neisseria (no renal disease) | ## Why Each Distractor Is Wrong | Option | Reason | |--------|--------| | **0: Renal biopsy + empiric corticosteroids** | While renal biopsy is eventually needed to confirm C3GN, it is not the *immediate* next step. Empiric corticosteroids without diagnosis are inappropriate and may worsen outcomes in some complement-mediated diseases. Serology must guide the biopsy interpretation and treatment plan. | | **2: Penicillin V + pneumococcal vaccine** | This addresses recurrent infections but ignores the acute renal failure and glomerulonephritis. The low C3 with normal C4 pattern is NOT typical of classical complement deficiency (which would show low C3 and C4). Prophylaxis alone will not prevent progressive renal damage. | | **3: Immunofixation for light-chain disease** | Light-chain disease (multiple myeloma, AL amyloidosis) can cause proteinuria and renal failure, but does NOT explain the low C3, recurrent infections, or dysmorphic RBCs. This is a distractor for patients who focus only on the renal findings. | ## Clinical Pearl **C3GN is increasingly recognized as a cause of progressive renal failure in young adults, especially those with recurrent infections.** The combination of AP dysregulation (low C3, normal C4) + glomerulonephritis + infection susceptibility should immediately trigger C3NF testing and nephrology referral. Early diagnosis and complement-targeted therapy (eculizumab, pegcetacoplan) can halt progression.