A 35-year-old woman from Delhi presents with sudden-onset haematuria, proteinuria (3.2 g/day), and hypertension (160/100 mmHg) for 5 days. She denies recent infection or systemic symptoms. Serum creatinine 2.8 mg/dL (baseline unknown). Urinalysis shows RBC casts, WBC casts, and dysmorphic RBCs. Complement levels (C3, C4) are normal. ANCA serology is negative. Renal biopsy shows crescent formation in >50% of glomeruli with fibrinoid necrosis and minimal immune deposits on immunofluorescence (pauci-immune pattern). What is the most likely diagnosis?

Explanation

## Rapidly Progressive Glomerulonephritis (RPGN) — Pauci-Immune Type ### Classification of RPGN RPGN is defined by **crescent formation in >50% of glomeruli** and rapid loss of renal function (days to weeks). It is classified by immunofluorescence pattern and aetiology: | Type | IF Pattern | Serology | Prevalence | |------|-----------|----------|------------| | **ANCA-associated** | Pauci-immune | ANCA+ (MPO or PR3) | ~50% of RPGN | | **Anti-GBM** | Linear IgG along GBM | Anti-GBM antibodies | ~10–15% of RPGN | | **Immune-complex** | Granular deposits (IgG, C3) | ANA, anti-dsDNA, ASO titre | ~30–35% of RPGN | | **ANCA-negative, pauci-immune** | Minimal/no deposits | ANCA negative | ~5–10% of RPGN | **Key Point:** The **pauci-immune pattern (minimal or no immune deposits on IF) + negative ANCA + crescent formation** defines ANCA-negative, pauci-immune RPGN — a distinct entity from ANCA-associated vasculitis. ### Diagnostic Reasoning 1. **Crescent formation in >50% of glomeruli** → Defines RPGN 2. **Fibrinoid necrosis** → Indicates acute, severe glomerular injury 3. **Pauci-immune IF pattern** → Rules out immune-complex and anti-GBM disease 4. **Negative ANCA serology** → Rules out ANCA-associated RPGN (GPA, MPA, EGPA) 5. **Normal complement levels** → Rules out post-infectious and lupus RPGN (which show low C3/C4) 6. **No systemic symptoms or SLE serology** → Rules out lupus nephritis **High-Yield:** ANCA-negative, pauci-immune RPGN is a diagnosis of **exclusion** — all other causes of RPGN must be ruled out first. It accounts for 5–10% of RPGN cases. ### Clinical Pearl ANCA-negative, pauci-immune RPGN has a **worse prognosis** than ANCA-associated RPGN, with higher rates of progression to end-stage renal disease (ESRD) despite immunosuppressive therapy. Some cases may be associated with **anti-GBM antibodies that are not detected by standard serology** (low titre or epitope variation). ### Management ```mermaid flowchart TD A[RPGN diagnosed on biopsy]:::outcome --> B{Creatinine level?}:::decision B -->|Cr > 5 mg/dL or oliguria| C[Plasmapheresis + high-dose corticosteroids + cyclophosphamide]:::action B -->|Cr < 5 mg/dL| D[High-dose corticosteroids + cyclophosphamide/rituximab]:::action C --> E[Monitor renal function & ANCA]:::action D --> E E --> F{Response at 3-6 months?}:::decision F -->|Yes| G[Maintenance therapy: azathioprine or rituximab]:::action F -->|No| H[Consider rescue therapy or dialysis]:::urgent ``` [cite:Harrison 21e Ch 279]