What is the approach to treating Rapidly Progressive Glomerulonephritis (RPGN)?

Treatment Approach for Rapidly Progressive Glomerulonephritis (RPGN)

For patients with rapidly progressive glomerulonephritis, immediate treatment with high-dose glucocorticoids and cyclophosphamide plus plasmapheresis is recommended, except in patients who are dialysis-dependent at presentation with 100% crescents on biopsy and no pulmonary hemorrhage. 1

Diagnostic Evaluation

• Obtain urinalysis (looking for protein and blood)
• Check urine sediment for glomerular hematuria and/or pyuria
• Evaluate for extrarenal manifestations
• Order autoimmune serologies:
  • ANCA (MPO and PR3)
  • Anti-GBM antibodies
  • ANA
  • Complement levels
• Obtain kidney biopsy if feasible
• Exclude infection before starting immunosuppression

Treatment Algorithm Based on RPGN Etiology

1. Anti-GBM Disease (Goodpasture's Syndrome)

• Start treatment without delay once diagnosis is confirmed or highly suspected 1, 2
• Treatment regimen:
  • Plasmapheresis (continue until anti-GBM antibodies undetectable on two consecutive tests)
  • IV pulse methylprednisolone (1g daily for 3 days) followed by oral prednisone
  • Oral cyclophosphamide (2-3 mg/kg daily for 2-3 months)
• Special considerations:
  • If pulmonary hemorrhage present: Treat regardless of renal status
  • If 100% crescents and dialysis-dependent without pulmonary hemorrhage: Poor prognosis with <5-8% renal recovery, consider withholding immunosuppression 2
  • No maintenance therapy needed for isolated anti-GBM disease 1, 2
  • Defer kidney transplantation until anti-GBM antibodies undetectable for ≥6 months 2

2. ANCA-Associated Vasculitis

• Induction therapy:

  • High-dose glucocorticoids (IV pulse methylprednisolone followed by oral prednisone)
  • Cyclophosphamide OR rituximab 1
  • Consider plasma exchange if overlapping with anti-GBM disease 1

• Cyclophosphamide preferred when:

  • Severe GN with serum creatinine >4 mg/dl (354 μmol/l)
  • For severe cases, combination of cyclophosphamide with rituximab can be considered 1

• Maintenance therapy:

  • Required for at least 18 months 1
  • Options: Rituximab (preferred) or azathioprine plus low-dose glucocorticoids 1
  • Do not use maintenance therapy in dialysis-dependent patients with no extrarenal manifestations 1

3. Immune Complex-Mediated RPGN

• For rapidly progressive crescentic idiopathic immune complex GN:

  • High-dose glucocorticoids and cyclophosphamide 1
  • Treatment similar to ANCA-associated vasculitis

• For patients with abnormal kidney function (without crescents):

  • Add glucocorticoids and immunosuppressive therapy to supportive care 1

Treatment Considerations

Glucocorticoid Regimen

• IV pulse methylprednisolone 1g daily for 3 days
• Follow with oral prednisone, tapering over approximately 6 months 2
• Recent evidence suggests reduced glucocorticoid dosing can be safely used in ANCA vasculitis 1

Cyclophosphamide Dosing

• Oral: 2-3 mg/kg daily for 2-3 months
• Adjust dose for reduced GFR and older age
• Provide Pneumocystis prophylaxis with trimethoprim-sulfamethoxazole until cyclophosphamide is complete and prednisone <20 mg daily 2

Plasmapheresis

• Use albumin replacement generally
• Use fresh frozen plasma if pulmonary hemorrhage or recent kidney biopsy 2
• Continue until antibodies undetectable (typically within 8 weeks) 2

Special Situations

Double-Positive Patients (Anti-GBM + ANCA)

• Approximately 30% of anti-GBM patients are also ANCA positive 2
• Require maintenance immunosuppression as for ANCA-associated vasculitis 2
• Higher relapse rates compared to isolated anti-GBM disease 2

Refractory Disease

• Consider:
  • Rituximab
  • Mycophenolate mofetil
  • IV immunoglobulin 3
  • Clinical trial enrollment 2

Poor Prognostic Factors

• Dialysis dependency at presentation
• 100% crescents on kidney biopsy
• High chronicity index on biopsy 4
• Delayed treatment initiation 2

Monitoring

• Continue monitoring for at least 2 years after diagnosis, even for anti-GBM disease which rarely relapses 2
• Do not change immunosuppression based on ANCA titer changes alone 1
• Monitor for treatment complications, particularly infections

Common Pitfalls to Avoid

• Delaying treatment while awaiting biopsy results when clinical suspicion is high
• Inadequate duration of plasma exchange leading to persistent antibodies
• Overtreatment of end-stage cases increasing complication risk
• Missing pulmonary involvement in anti-GBM disease
• Overlooking double-positivity (ANCA + anti-GBM)
• Failure to provide Pneumocystis prophylaxis

The most critical factor in treating RPGN is early diagnosis and prompt initiation of appropriate therapy, as delays can lead to irreversible kidney damage and increased mortality.