A 32-year-old Indian woman presents with progressive facial puffiness and leg swelling for 3 weeks. She reports foamy urine and denies recent infections or drug use. On examination: BP 128/82 mmHg, bilateral pitting ankle edema, no rash. Labs: serum albumin 2.1 g/dL, total protein 4.8 g/dL, 24-hour urine protein 8.2 g, serum creatinine 0.9 mg/dL, urinalysis shows 3+ proteinuria with occasional RBCs, no casts. Complement C3 and C4 are normal. Kidney biopsy shows capillary wall thickening with subepithelial "spike and dome" deposits on electron microscopy. What is the most likely diagnosis?

Explanation

## Diagnosis: Membranous Nephropathy ### Clinical Presentation **Key Point:** This patient presents with the classic nephrotic syndrome triad: nephrotic-range proteinuria (>3.5 g/day), hypoalbuminemia with edema, and preserved renal function. ### Pathological Hallmark **High-Yield:** The pathognomonic finding is **subepithelial "spike and dome" electron-dense deposits** on electron microscopy (EM). These represent immune complex deposition along the glomerular basement membrane (GBM) with GBM projections creating the characteristic appearance. ### Diagnostic Criteria for Membranous Nephropathy | Feature | Membranous Nephropathy | MPGN | FSGS | IgA Nephropathy | |---------|------------------------|------|------|------------------| | **EM deposits** | Subepithelial "spike and dome" | Subendothelial | Foot process effacement | Mesangial | | **IF pattern** | IgG, IgM, C3 (granular) | C3 dominant | Negative/minimal | IgA dominant | | **LM appearance** | Thickened capillary walls | Hypercellularity, double contours | Sclerosis in some glomeruli | Mesangial proliferation | | **Complement** | Normal (primary) | Low C3 | Normal | Normal | | **Hematuria** | Mild, occasional RBCs | Often present | Variable | Prominent | ### Pathogenesis **Clinical Pearl:** Primary membranous nephropathy (85% of adult cases) is associated with **phospholipase A2 receptor (PLA2R) antibodies** in ~70% of cases. Secondary forms are linked to malignancy (lung, gastric, breast), SLE, hepatitis B, and drugs (NSAIDs, gold). ### Why Normal Complement? **Key Point:** Unlike MPGN (which shows low C3 from complement activation), membranous nephropathy typically preserves normal complement levels because immune complex deposition occurs *in situ* without systemic complement consumption. ### Natural History - ~25% spontaneous remission - ~25% progressive renal failure - ~50% persistent nephrotic syndrome with stable renal function - Risk of thromboembolism (hypercoagulability from urinary loss of anticoagulants) **Warning:** Do not confuse the "spike and dome" appearance with the "double contour" (tram-track) of MPGN on light microscopy.