A 32-year-old Indian woman presents with progressive ankle and facial swelling for 3 weeks. She reports foamy urine and weight gain of 4 kg. On examination: BP 128/82 mmHg, bilateral pitting ankle edema, mild ascites. Serum albumin 2.1 g/dL, total protein 4.8 g/dL, serum creatinine 0.9 mg/dL, 24-hour urine protein 8.2 g. Lipid profile shows total cholesterol 320 mg/dL, triglycerides 280 mg/dL. Urinalysis: 3+ proteinuria, no RBCs, no casts. Renal biopsy shows diffuse thickening of the glomerular basement membrane with a characteristic "spike and dome" appearance on electron microscopy. What is the most likely diagnosis?

Explanation

## Diagnosis: Membranous Nephropathy ### Clinical Presentation **Key Point:** Membranous nephropathy is the most common cause of nephrotic syndrome in adults worldwide and the second most common in India after FSGS. This patient presents with the classic tetrad of nephrotic syndrome: - Heavy proteinuria (8.2 g/24 h, well above 3.5 g threshold) - Hypoalbuminemia (2.1 g/dL) - Edema (ankle and facial) - Hyperlipidemia (cholesterol 320, triglycerides 280) ### Pathological Features | Feature | Membranous Nephropathy | FSGS | MPGN | MCD | |---------|------------------------|------|------|-----| | **Light Microscopy** | Normal glomeruli initially | Segmental sclerosis | Proliferation + crescent | Normal | | **Electron Microscopy** | Spike and dome | Foot process fusion | Electron-dense deposits | Foot process fusion | | **Immunofluorescence** | Granular IgG/C3 along GBM | Negative or IgM | C3 dominant | Negative | | **GFR at presentation** | Usually preserved | Often reduced | Variable | Preserved | **High-Yield:** The pathognomonic "spike and dome" appearance on electron microscopy is virtually diagnostic of membranous nephropathy. Spikes are subepithelial immune deposits with intervening GBM projections resembling a railroad track. ### Mechanism of Proteinuria 1. Subepithelial immune complex deposition (IgG + C3) 2. Complement activation (C5b-9) → podocyte injury 3. Disruption of glomerular filtration barrier 4. Massive proteinuria (often >10 g/day) ### Clinical Pearls - **Primary (idiopathic):** Most common in developed countries; associated with anti-PLA2R antibodies in ~70% of cases - **Secondary:** Associated with malignancy (20–30% in adults >60 years), SLE, hepatitis B, NSAIDs, gold - **Prognosis:** 30–40% progress to ESRD over 10 years; 30% remit spontaneously - **Normal renal function at presentation** is typical (unlike MPGN or FSGS) ### Why This Patient Has Membranous Nephropathy - Preserved serum creatinine (0.9 mg/dL) despite heavy proteinuria - Absence of hematuria or RBC casts (rules out proliferative GN) - Pathognomonic electron microscopy finding (spike and dome) - Granular IgG deposition pattern on immunofluorescence (expected) [cite:Robbins 10e Ch 20]