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?

Question

Accepted Answer

D. Membranous nephropathy. ## 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.

Answer

A. IgA nephropathy

Answer

B. Membranoproliferative glomerulonephritis

Answer

C. Focal segmental glomerulosclerosis

Explanation

Diagnosis: Membranous Nephropathy

Clinical Presentation

Pathological Hallmark

Diagnostic Criteria for Membranous Nephropathy

Pathogenesis

Why Normal Complement?

Natural History

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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