What is Rapidly Progressive Glomerulonephritis (RPGN)?

What is Rapidly Progressive Glomerulonephritis (RPGN)?

Rapidly progressive glomerulonephritis (RPGN) is a nephrological emergency characterized by rapid decline in kidney function over days to weeks, typically with extensive crescent formation (usually >50% of glomeruli) on kidney biopsy, that leads to irreversible kidney damage if not promptly diagnosed and treated. 1

Clinical Definition and Pathology

RPGN represents a severe form of glomerular disease with distinct histopathologic features:

• Crescentic glomerulonephritis with crescents present in at least 50-75% of glomeruli, often accompanied by glomerular necrosis 1, 2
• The rapid tempo of kidney function decline occurs over days to weeks, distinguishing it from other forms of glomerulonephritis 3, 1
• Without treatment, approximately 90% of cases progress to renal failure or death 4

Major Etiologic Categories

RPGN encompasses three main pathogenic mechanisms:

1. ANCA-Associated Vasculitis (Most Common)

• AAV is the most common cause of rapidly progressive kidney failure, accounting for the majority of RPGN cases 3, 1
• Includes granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis 3
• Characterized by pauci-immune crescentic glomerulonephritis with positive MPO-ANCA or PR3-ANCA serology 3

2. Anti-GBM Antibody Disease

• Second major cause of RPGN, often presenting with pulmonary-renal syndrome 3, 1
• Requires plasma exchange in addition to immunosuppression 3

3. Immune Complex-Mediated Disease

• Includes lupus nephritis, post-infectious glomerulonephritis, and IgA nephropathy with crescentic features 3, 2
• Lupus nephritis is associated with poor prognosis, with ESKD developing in more than 30% of cases 2

Clinical Presentation

The key warning sign is "flu-like syndrome" associated with glomerular hematuria, which appears before obvious renal functional deterioration 4:

• Tea-colored or cola-colored urine (gross hematuria) 5
• Significant proteinuria 5, 2
• Oliguria (reduced urine output) 2
• Hypertension and edema 2
• Acute kidney injury with rising creatinine over days to weeks 1, 5

Critical Pitfall

Do not wait for obvious renal failure to consider RPGN—early nonspecific symptoms like malaise with abnormal urinalysis should trigger immediate evaluation 4, 6. Delayed diagnosis is common because patients present with nonspecific symptoms across multiple encounters before the correct diagnosis is made 6.

Diagnostic Approach

The diagnostic workup must proceed simultaneously with treatment initiation when clinical suspicion is high 3:

Immediate Laboratory Evaluation

• Urinalysis with microscopy: Look for urine dipstick positive for protein and blood, with sediment showing glomerular hematuria (dysmorphic RBCs, RBC casts) and/or pyuria without infection 3, 1
• Autoimmune serologies: ANCA (MPO and PR3), ANA, anti-GBM antibodies, complement levels (C3, C4) 3, 1
• Renal function tests: BUN, creatinine, electrolytes to assess severity 5
• Complete blood count: Assess for anemia or thrombocytopenia 5

Kidney Biopsy Strategy

• Kidney biopsy confirms diagnosis and provides prognostic information about disease activity versus chronicity 1, 3
• However, if clinical presentation is compatible with ANCA vasculitis and MPO- or PR3-ANCA serology is positive, do not delay starting immunosuppressive therapy while waiting for biopsy 3
• The same principle applies for suspected anti-GBM disease or lupus nephritis with RPGN 3
• Biopsy should be performed soon after starting treatment when feasible 3

Critical Safety Consideration

Infection must be excluded with as much certainty as possible before initiating significant immunosuppression 3, 1. This is non-negotiable given the aggressive immunosuppression required.

Treatment Principles

Induction Therapy for ANCA-Associated Vasculitis

Initial therapy includes cyclophosphamide or rituximab plus glucocorticoids 3, 1:

• For severe GN (serum creatinine >4 mg/dL or 354 μmol/L), consider combination of two intravenous pulses of cyclophosphamide with rituximab 3
• Plasma exchange is not routinely recommended for AAV alone, but must be used if AAV overlaps with anti-GBM antibody disease 3

Maintenance Therapy

• Rituximab or azathioprine plus low-dose glucocorticoids, with rituximab preferred 3
• Minimum duration of maintenance therapy is 18 months, with consideration for withdrawal after factoring relapse risk 3

Prognostic Factors

Poor renal survival is predicted by:

• Nephrotic-range proteinuria 2
• Severe acute kidney injury requiring dialysis 2
• Presence of fibrous crescents and chronicity on biopsy 2
• Serum creatinine >3 mg/dL severely limits drug efficacy 5
• Serum creatinine >5 mg/dL may require hemofiltration or dialysis 5

When to Send to Emergency Department

RPGN with rapid decline in kidney function over days to weeks constitutes a medical emergency that must not be missed 5:

• Creatinine rising over days to weeks requires immediate ER referral 5
• Acute nephritic syndrome with full presentation (tea-colored urine, significant proteinuria, RBC casts, hypertension, edema, acute renal dysfunction) requires urgent evaluation 5
• Early recognition and prompt immunosuppressive therapy are critical for favorable outcomes 1, 3