A 28-year-old Indian male presents with nephrotic syndrome (proteinuria 12 g/day, serum albumin 2.0 g/dL, edema) and hematuria. Serum creatinine is 1.8 mg/dL with progressive decline in renal function over 2 months. Blood pressure is 148/94 mmHg. Renal biopsy shows mesangial proliferation with IgA-dominant deposits on immunofluorescence. Electron microscopy reveals electron-dense deposits in the mesangium and subendothelial space. What is the most likely diagnosis?

Explanation

## Diagnosis: IgA Nephropathy ### Clinical Presentation **Key Point:** IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and the most common cause of glomerulonephritis in Asia, including India. This patient presents with: - Nephrotic syndrome (proteinuria >3.5 g/day, hypoalbuminemia, edema) - Hematuria (RBC casts or dysmorphic RBCs) - Progressive renal dysfunction (creatinine rising from baseline to 1.8 mg/dL) - Hypertension ### Pathological Hallmark **High-Yield:** IgA-dominant deposits on immunofluorescence microscopy are diagnostic for IgA nephropathy. This is the defining feature that distinguishes it from all other glomerulonephritides. ### Light Microscopy Features - Mesangial proliferation (expansion of mesangial matrix and cellularity) - Segmental involvement (not all glomeruli affected) - Crescent formation in severe cases - Glomerular sclerosis in advanced disease - Tubular atrophy and interstitial fibrosis correlate with prognosis ### Immunofluorescence Pattern **Clinical Pearl:** IgA is the predominant immunoglobulin deposit (IgA > IgG, IgM). C3 is also typically present. The pattern is mesangial and occasionally capillary wall distribution. ### Electron Microscopy Findings | Feature | IgAN | Membranous | MPGN | PIGN | |---------|------|-----------|------|------| | Mesangial deposits | Electron-dense | Absent/minimal | Subendothelial | Subepithelial "humps" | | GBM thickness | Normal/thin | Markedly increased | Normal/thick | Normal | | Mesangial proliferation | Yes | No | Yes | No | | Foot process fusion | Diffuse | Diffuse | Diffuse | Diffuse | ### Clinical Variants 1. **Asymptomatic hematuria** — most common presentation 2. **Episodic gross hematuria** — often following URI (Berger's disease) 3. **Nephrotic presentation** — as in this case (poor prognosis) 4. **Rapidly progressive** — with crescent formation ### Risk Factors for Progression **Mnemonic:** "CHOP-P" — Creatinine elevation, Hypertension, Older age, Proteinuria >1 g/day, Persistent hematuria. ### Prognostic Indicators in This Case **Warning:** This patient has multiple poor prognostic features: - Nephrotic-range proteinuria (12 g/day) - Elevated serum creatinine (1.8 mg/dL) - Progressive renal dysfunction over 2 months - Hypertension (148/94 mmHg) - Mesangial proliferation on biopsy These suggest advanced disease with higher risk of progression to ESRD. ### Management Approach ```mermaid flowchart TD A[IgA Nephropathy Diagnosed]:::outcome --> B{Risk Stratification}:::decision B -->|Low risk: eGFR >60, proteinuria <1 g/day| C[Supportive therapy: ACE-I/ARB]:::action B -->|High risk: eGFR <60 or proteinuria >1 g/day| D[Intensive therapy]:::action C --> E[Monitor renal function & proteinuria]:::action D --> F[ACE-I/ARB + Corticosteroids ± Immunosuppression]:::action F --> G{Renal function stable?}:::decision G -->|Yes| H[Continue current regimen]:::action G -->|No| I[Consider additional agents: mycophenolate, cyclophosphamide]:::urgent ``` ### Differential Considerations **High-Yield:** IgA nephropathy must be distinguished from other causes of mesangial proliferation: - IgM nephropathy: IgM-dominant deposits - IgG nephropathy: IgG-dominant deposits - C3 glomerulopathy: C3-dominant, IgA-negative [cite:Robbins 10e Ch 20]