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?

Question

Accepted Answer

A. Granulomatosis with polyangiitis. ## 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

Answer

B. Microscopic polyangiitis

Answer

C. Goodpasture syndrome

Answer

D. Post-streptococcal glomerulonephritis

Explanation

Clinical Diagnosis Framework

ANCA-Associated Vasculitis (AAV) Classification

Pathophysiology of GPA

Diagnostic Criteria (Chapel Hill Consensus Conference)

Histopathology

Management

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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