A 28-year-old Indian male with known hepatitis B surface antigen (HBsAg) positivity presents with nephrotic syndrome: 24-hour urine protein 6.5 g, serum albumin 2.4 g/dL, and ankle edema. Serum creatinine is 1.1 mg/dL. Urinalysis shows 4+ proteinuria with no RBCs or casts. Complement C3 and C4 are normal. Kidney biopsy light microscopy shows capillary wall thickening without proliferation. Immunofluorescence reveals IgG, IgM, and C3 in a granular pattern along the capillary walls. Electron microscopy shows subepithelial electron-dense deposits. What is the most likely diagnosis?

Explanation

## Diagnosis: Hepatitis B-Associated Membranous Nephropathy ### Clinical Context **High-Yield:** Hepatitis B virus (HBV) is a well-established cause of **secondary membranous nephropathy**, particularly in endemic regions (Southeast Asia, Africa, India). HBsAg-positive patients with nephrotic syndrome and membranous pattern on biopsy should be presumed to have HBV-associated disease until proven otherwise. ### Pathological Features | Finding | This Case | Interpretation | |---------|-----------|----------------| | **Light microscopy** | Capillary wall thickening, no proliferation | Membranous pattern (Stage 1–2) | | **Immunofluorescence** | IgG, IgM, C3 granular | Immune complex deposition; IgM suggests HBV (hepatitis B core antigen, HBcAg) | | **Electron microscopy** | Subepithelial electron-dense deposits | Pathognomonic for membranous nephropathy | | **Serum complement** | Normal C3, C4 | Excludes MPGN; consistent with in situ immune complex formation | ### Mechanism of HBV-Associated Membranous Nephropathy **Key Point:** HBV immune complexes (HBsAg, HBcAg, anti-HBc) deposit in the glomerular basement membrane, triggering in situ complement activation and proteinuria. Unlike MPGN, systemic complement is not consumed, so C3/C4 remain normal. ### Clinical Features of HBV-Associated GN | Type | Prevalence | Complement | EM Deposits | Clinical Presentation | |------|-----------|-----------|-------------|----------------------| | **Membranous** | 50–60% | Normal | Subepithelial | Nephrotic syndrome | | **MPGN** | 30–40% | Low C3 | Subendothelial | Nephrotic + hematuria | | **FSGS** | 5–10% | Normal | Foot process effacement | Variable | **Clinical Pearl:** HBV-associated membranous nephropathy is more common in **children and young adults** from endemic areas. The presence of IgM on immunofluorescence (reflecting HBcAg) is a clue to HBV etiology. ### Management Implications **High-Yield:** Treatment of HBV-associated membranous nephropathy includes: 1. **Antiviral therapy** (tenofovir, entecavir) — can induce remission of proteinuria 2. **ACE inhibitors/ARBs** — reduce proteinuria and slow progression 3. **Immunosuppression** — reserved for steroid-resistant cases (avoid in HBV reactivation risk) **Warning:** Immunosuppressive therapy without concurrent antiviral coverage risks HBV reactivation and fulminant hepatitis. ### Why Not MPGN? **Key Point:** MPGN would show **low C3 and C4** (complement consumption), **subendothelial deposits** (not subepithelial), and often **hypercellularity** on light microscopy. This patient has normal complement and a pure membranous pattern.