What is the treatment for Rapidly Progressive Glomerulonephritis (RPGN) characterized by a rapid decline in Glomerular Filtration Rate (GFR) and extensive glomerular crescent formation?

Treatment of Rapidly Progressive Glomerulonephritis (RPGN)

Patients with rapidly progressive glomerulonephritis should be treated with cyclophosphamide and glucocorticoids according to the ANCA-associated vasculitis treatment protocol, regardless of the underlying cause. 1

Classification and Diagnosis

RPGN is characterized by:

• Rapid decline in GFR (≥50% reduction) over days to weeks
• Extensive glomerular crescent formation on histopathology
• Clinical features including hematuria, proteinuria, oliguria, hypertension, and edema

RPGN can be classified into three major immunopathologic categories:

1. Type I: Anti-GBM antibody disease
2. Type II: Immune complex-mediated
3. Type III: Pauci-immune (ANCA-associated, most common >50% of cases) 2

Diagnostic Approach

Diagnostic workup should include:

• Serum creatinine and eGFR
• Urinalysis with microscopy (look for RBC casts and dysmorphic RBCs)
• 24-hour urine protein or protein-to-creatinine ratio
• Serologic testing:
  • ANCA (anti-MPO and anti-PR3)
  • Anti-GBM antibodies
  • Complement levels (C3, C4)
  • ANA, anti-dsDNA
  • Hepatitis serologies
  • Serum protein electrophoresis 2

Important: Do not delay treatment while waiting for kidney biopsy results if clinical presentation strongly suggests RPGN and serologies are positive for ANCA or anti-GBM antibodies 2

Treatment Algorithm

1. Induction Therapy (First 3-6 months)

For all RPGN with extensive crescents:

• Glucocorticoids:

  • IV pulse methylprednisolone 500-1000 mg daily for 3 days
  • Followed by oral prednisone 1 mg/kg/day (maximum 60-80 mg) with gradual taper 2

• PLUS one of the following:

  • Cyclophosphamide (preferred for severe GN with serum creatinine >4 mg/dL [>354 μmol/L])
    • IV regimen: 15 mg/kg every 2-3 weeks (dose adjustments for age and renal function)
    • OR oral regimen: 2 mg/kg/day (maximum 200 mg/day)
  • Rituximab (alternative to cyclophosphamide)
    • 375 mg/m² weekly for 4 weeks
    • OR 1000 mg on days 0 and 14 1

• Consider combination therapy with both cyclophosphamide and rituximab in severe cases with creatinine >4 mg/dL 1

2. Special Considerations

• Anti-GBM disease: Add plasma exchange (PLEX) to the above regimen 1, 2

• ANCA-associated RPGN with severe kidney failure: Consider PLEX in selected cases, though routine use is not recommended based on the PEXIVAS trial 1

• IgA nephropathy with RPGN: Treat according to the AAV protocol with cyclophosphamide and glucocorticoids 1

3. Maintenance Therapy (After successful induction)

• Duration: At least 18 months 2
• Options:
  • Rituximab: 500 mg every 6 months
  • OR Azathioprine: 2 mg/kg/day (maximum 150-200 mg/day)
  • PLUS low-dose glucocorticoids 1, 2

Monitoring and Prognosis

• Regular assessment of kidney function (serum creatinine, eGFR)
• Urinalysis to monitor disease activity
• Complete blood count to monitor for treatment toxicity
• ANCA titers (though treatment decisions should not be based solely on ANCA titers) 2

Important Caveats

1. Timing is critical: Delay in treatment significantly worsens outcomes. Treatment should be initiated promptly when RPGN is suspected 3

2. Elderly patients (>75 years) are at higher risk of treatment complications but can respond to therapy. Consider dose adjustments and closer monitoring for adverse effects 4

3. Poor prognostic factors include:

   • Dialysis dependence at presentation
   • High percentage of fibrous crescents on biopsy
   • Advanced tubulointerstitial fibrosis
   • Severe kidney dysfunction at presentation 5, 6

4. Post-infectious RPGN in children may have better prognosis and may not require immunosuppression in all cases 5

5. Avoid immunosuppression in patients with advanced CKD, severe tubulointerstitial fibrosis, small kidney size, or other findings consistent with chronic inactive disease 1

By following this treatment algorithm promptly, the likelihood of preserving kidney function and improving patient survival in RPGN is significantly enhanced.