What is the treatment for Rapidly Progressive Glomerulonephritis (RPGN)?

Treatment of Rapidly Progressive Glomerulonephritis (RPGN)

For patients with RPGN, initiate aggressive immunosuppression immediately with high-dose corticosteroids (pulse IV methylprednisolone followed by oral prednisone) combined with either cyclophosphamide or rituximab, without waiting for biopsy confirmation if clinical suspicion is high. 1

Immediate Diagnostic and Treatment Approach

Do Not Delay Treatment

• Start immunosuppression before biopsy results if clinical presentation is compatible with RPGN and serologies (ANCA, anti-GBM antibodies) are positive or pending. 1
• The only absolute requirement before starting treatment is excluding infection with as much certainty as possible. 1
• Obtain kidney biopsy when feasible for diagnosis confirmation and prognosis, but do not delay treatment waiting for it. 1

Initial Workup While Starting Treatment

• Urinalysis showing proteinuria, hematuria, and glomerular casts 1
• Autoimmune serologies: ANCA (MPO and PR3), anti-GBM antibodies, ANA, complement levels 1
• Evaluate for extrarenal manifestations (pulmonary hemorrhage, skin lesions, systemic symptoms) 1

Treatment Regimens by Etiology

ANCA-Associated Vasculitis (Most Common Cause of RPGN)

Induction therapy consists of either cyclophosphamide OR rituximab plus high-dose corticosteroids. 1

Corticosteroid Regimen

• Pulse IV methylprednisolone 500-1000 mg daily for 3 consecutive days 1, 2
• Followed by oral prednisone starting at 1 mg/kg/day (max 60-80 mg/day) with gradual taper over at least 6 months 1

Choice Between Cyclophosphamide vs. Rituximab

Cyclophosphamide is preferred when: 1

• Severe kidney dysfunction (serum creatinine >4 mg/dL or >354 μmol/L) 1
• In this setting, consider combining two IV pulses of cyclophosphamide with rituximab 1
• Limited data exist for rituximab alone in severely impaired kidney function 1

Rituximab is preferred when: 1

• Less severe kidney dysfunction
• Concerns about cyclophosphamide toxicity (fertility preservation, malignancy risk)
• Patient preference

Cyclophosphamide dosing: Daily oral cyclophosphamide for 3 months, then transition to maintenance therapy 1

Anti-GBM Disease (Goodpasture Syndrome)

Triple therapy is mandatory: cyclophosphamide + corticosteroids + plasmapheresis. 1

Specific Regimen

• Pulse IV methylprednisolone followed by tapering oral prednisone for at least 6 months 1
• Daily oral cyclophosphamide for 3 months 1
• Plasmapheresis daily for 14 days or until anti-GBM antibody is undetectable 1

Critical Exception

• Do NOT treat patients who are dialysis-dependent at presentation with 100% crescents on biopsy and no pulmonary hemorrhage (renal recovery rate only 8%). 1
• However, for functionally young patients with very rapid kidney function loss, consider a limited 4-8 week trial, acknowledging the low likelihood of response. 1
• Always treat any patient with pulmonary hemorrhage regardless of kidney status. 1

Double-Positive Patients (ANCA + Anti-GBM)

• Treat as anti-GBM disease with full triple therapy if not on dialysis 1
• For dialysis-dependent double-positive patients, data are conflicting and limited 1

Crescentic Immune Complex GN (Including MPGN with Crescents)

Treat with regimen similar to ANCA vasculitis: either cyclophosphamide or rituximab plus pulse IV methylprednisolone followed by oral prednisone. 1

• This applies to severe forms with crescents, focal necrosis, and/or RPGN 1
• First identify and treat any underlying cause (infection, autoimmune disease, paraprotein) 1
• For infection-related crescentic GN that persists despite infection control, add immunosuppression 1

Critical Caveats and Contraindications

When NOT to Use Aggressive Immunosuppression

Withhold immunosuppression in patients with: 1

• eGFR <30 mL/min/1.73 m² with chronic changes on biopsy (high degree of interstitial fibrosis, tubular atrophy, glomerular sclerosis) 1
• This does NOT apply if there is active necrotizing or crescentic GN causing the low eGFR 1
• Preserved renal parenchyma with acute tubular necrosis should still be treated 1

Infection-Related RPGN Mimicking Vasculitis

• Infective endocarditis can present identically to ANCA vasculitis (fever, multiorgan involvement, ANCA positivity in 45% of cases) 3
• Treat with antibiotics ± surgery first; immunosuppression only if kidney function does not improve after proper anti-infective therapy 1, 3
• Six of 24 patients in one series were initially misdiagnosed as vasculitis 3

Elderly Patients

• Age is an independent negative risk factor for both death and end-stage renal disease 4
• Elderly patients respond to immunosuppression similarly to younger patients but have higher risk of adverse events 4
• Treatment should still be offered but with heightened monitoring for complications 4

Plasma Exchange Controversy

Plasma exchange is NOT routinely recommended for ANCA vasculitis based on the PEXIVAS trial. 1

Plasma exchange IS recommended for: 1

• Anti-GBM disease (mandatory component of triple therapy) 1
• ANCA vasculitis that overlaps with anti-GBM disease 1

Prognostic Factors for Treatment Response

Favorable response indicators: 5

• Short duration of symptomatic illness 5
• Normal blood pressure at presentation 5
• Minimal glomerular and crescentic sclerosis on biopsy 5
• Mild interstitial fibrosis 5

Poor response indicators: 5

• Long symptomatic illness 5
• Elevated blood pressure 5
• Considerable fibrosis of crescents, glomeruli, and interstitium 5