A 32-year-old woman from Tamil Nadu presents with a 3-day history of haematuria, mild proteinuria (1.2 g/day), and hypertension (BP 155/95 mmHg). Serum creatinine is 2.1 mg/dL. Urinalysis shows dysmorphic RBCs and RBC casts. Serological workup reveals positive ANCA (cytoplasmic pattern, anti-PR3 antibody). Complement levels (C3, C4) are normal. Chest X-ray shows bilateral pulmonary infiltrates. What is the most likely diagnosis?

Explanation

## Clinical Diagnosis Framework **Key Point:** The combination of **c-ANCA/anti-PR3 positivity, necrotizing glomerulonephritis, and pulmonary infiltrates** is diagnostic of **granulomatosis with polyangiitis (GPA)**, formerly known as Wegener granulomatosis. ### ANCA-Associated Vasculitis (AAV) Classification | Feature | GPA (c-ANCA/PR3) | MPA (p-ANCA/MPO) | Goodpasture (ANCA−) | |---------|------------------|-------------------|---------------------| | **ANCA pattern** | Cytoplasmic (c-ANCA) | Perinuclear (p-ANCA) | Negative | | **Antigen specificity** | Anti-PR3 | Anti-MPO | Anti-GBM | | **Upper respiratory involvement** | Yes (sinusitis, granulomas) | Rare | No | | **Pulmonary infiltrates** | Yes (cavitary, nodular) | Yes (alveolar haemorrhage) | Yes (alveolar haemorrhage) | | **Kidney involvement** | Necrotizing GN (crescentic) | Necrotizing GN (crescentic) | Linear IgG on GBM | | **Systemic manifestations** | Granulomatous inflammation | Vasculitis only | Pulmonary-renal syndrome | | **Prognosis untreated** | Poor (median survival ~5 months) | Poor | Poor | **High-Yield:** **c-ANCA/anti-PR3 = GPA** is the most frequently tested ANCA pattern in NEET PG. GPA is the only ANCA-associated vasculitis with granulomatous inflammation. ### Pathophysiology of GPA ```mermaid flowchart TD A[Genetic predisposition + Environmental trigger]:::outcome --> B[Activation of PR3-specific T cells and B cells]:::action B --> C[Production of anti-PR3 ANCA]:::action C --> D[Neutrophil activation and degranulation]:::action D --> E[Necrotizing vasculitis of small/medium vessels]:::action E --> F[Granulomatous inflammation in upper respiratory tract]:::action E --> G[Necrotizing crescentic glomerulonephritis]:::action E --> H[Pulmonary alveolar haemorrhage]:::action F --> I[Sinusitis, nasal granulomas, subglottic stenosis]:::outcome G --> J[Acute kidney injury, haematuria, RBC casts]:::outcome H --> K[Haemoptysis, pulmonary infiltrates]:::outcome ``` ### Diagnostic Criteria (Chapel Hill Consensus Conference) **GPA is defined by:** 1. Necrotizing vasculitis of small and medium vessels. 2. Granulomatous inflammation of the respiratory tract (upper or lower). 3. Necrotizing glomerulonephritis (pauci-immune, ANCA-associated). 4. **c-ANCA/anti-PR3 positivity** (present in >90% of generalized GPA). **Clinical Pearl:** The **triad of upper respiratory, pulmonary, and renal involvement** with **c-ANCA/anti-PR3 positivity** is pathognomonic for GPA. ### Histopathology - **Kidney:** Necrotizing crescentic glomerulonephritis with minimal or absent immune deposits (pauci-immune pattern). - **Lung:** Granulomatous inflammation with necrotizing vasculitis. - **Upper respiratory tract:** Granulomatous inflammation, necrosis, and vasculitis. ### Management 1. **Induction therapy:** Corticosteroids + cyclophosphamide or rituximab. 2. **Maintenance therapy:** Azathioprine or rituximab. 3. **Monitoring:** ANCA titers (rising titers may predict relapse), renal function, pulmonary function. **Mnemonic:** **GPA = Granulomatosis with Polyangiitis** - **G**ranulomatous inflammation (upper respiratory tract) - **P**ulmonary infiltrates (cavitary, nodular) - **A**ANCA-positive (c-ANCA/anti-PR3) - **A**cute necrotizing glomerulonephritis