What is the likely diagnosis and treatment plan for a patient with Rapidly Progressive Glomerulonephritis (RPGN) who was started on Cyclophosphamide, suggesting an aggressive immune-mediated cause, likely Type 2 or Type 3?

Likely Diagnosis and Treatment for RPGN Started on Cyclophosphamide

The initiation of cyclophosphamide strongly suggests either ANCA-associated vasculitis (Type 3 pauci-immune) or severe immune complex-mediated RPGN (Type 2), with ANCA-associated vasculitis being the most common cause of rapidly progressive kidney failure requiring this aggressive therapy. 1

Diagnostic Classification

The use of cyclophosphamide narrows the differential significantly:

• ANCA-associated vasculitis (Type 3 pauci-immune) is the most common cause of RPGN requiring cyclophosphamide, accounting for the majority of rapidly progressive kidney failure cases 1
• Immune complex-mediated RPGN (Type 2) from lupus nephritis or post-infectious causes also warrants cyclophosphamide when presenting with crescentic disease and rapid progression 2, 3
• Anti-GBM disease (Type 1) would typically include plasma exchange in addition to cyclophosphamide, so its absence makes this less likely unless plasma exchange was contraindicated 1, 2

Confirming the Specific Diagnosis

The diagnostic workup should have included or will include:

• ANCA serology (MPO-ANCA or PR3-ANCA) - positive results with compatible clinical presentation justify immediate treatment without waiting for biopsy 1, 2
• Anti-GBM antibodies - to exclude Type 1 disease, which would require plasma exchange 1, 2
• ANA, complement levels (C3, C4), anti-dsDNA - to evaluate for lupus nephritis as the immune complex cause 1, 2
• Kidney biopsy - should be performed when feasible to confirm necrotizing and crescentic glomerulonephritis, but treatment should not be delayed waiting for results 1, 2
• Infection exclusion - the only absolute requirement before starting immunosuppression is ruling out infection with as much certainty as possible 1, 2

Standard Treatment Regimen

The complete induction therapy protocol includes:

Corticosteroids (Essential Component)

• IV methylprednisolone 500-1000 mg daily for 3 consecutive days as initial pulse therapy 2
• Oral prednisone 1 mg/kg/day following IV pulses, with gradual taper over at least 6 months 2, 4
• Recent evidence from the PEXIVAS trial demonstrates that glucocorticoid dosing can be safely reduced from traditional high-dose regimens 1

Cyclophosphamide Dosing

• Intravenous: 40-50 mg/kg divided over 2-5 days for initial course in patients without hematologic deficiency 4
• Alternative regimens: 10-15 mg/kg every 7-10 days or 3-5 mg/kg twice weekly 4
• Oral cyclophosphamide combined with low-dose corticosteroids for duration <6 months initial therapy 3
• Treatment duration typically 3-6 months for induction phase 2, 3

When Cyclophosphamide is Specifically Preferred Over Rituximab

Cyclophosphamide was chosen over rituximab in this case likely because:

• Severe kidney dysfunction (serum creatinine >4 mg/dl [>354 μmol/L]) - cyclophosphamide remains the preferred immunosuppressive for such patients 1
• Limited data for rituximab in severely impaired kidney function - rituximab has only limited evidence in this setting 1
• Combination therapy option - for very severe cases, two intravenous pulses of cyclophosphamide combined with rituximab can be considered 1

Maintenance Therapy Planning

After induction with cyclophosphamide, the maintenance phase includes:

• Rituximab or azathioprine plus low-dose glucocorticoids for maintenance, with rituximab preferred 1
• Minimum duration of 18 months for maintenance immunosuppression, with some protocols extending to 4 years for azathioprine 1
• Withdrawal can occur after 18 months if disease remains controlled 1

Critical Caveats and Monitoring

Absolute Contraindications to Treatment

• Do NOT treat if kidney biopsy shows extensive interstitial fibrosis and tubular atrophy, extensive glomerulosclerosis, or absence of active necrotizing/crescentic lesions, even with low eGFR 2
• Withhold immunosuppression in patients with eGFR <30 mL/min/1.73 m² ONLY if chronic changes dominate the biopsy without active disease 2
• The decision is based on biopsy findings showing renal viability, not eGFR alone 2

Common Pitfalls to Avoid

• Delaying treatment while waiting for biopsy - compatible clinical presentation plus positive serology is sufficient to begin therapy 2
• Assuming all dialysis-dependent patients should not be treated - active crescentic disease warrants treatment regardless of dialysis status, unless biopsy shows irreversible chronic changes 2
• Using calcineurin inhibitors (tacrolimus, cyclosporine) - these cause immune complex-negative angiopathy and thrombotic microangiopathy in RPGN 2, 3

Monitoring for Complications

• Close hematological monitoring required due to severe myelosuppression and immunosuppression risk 4
• Monitor for hemorrhagic cystitis, pyelitis, ureteritis, and hematuria - exclude or correct urinary tract obstructions prior to treatment 4
• Cardiotoxicity monitoring - myocarditis, pericardial effusion, arrhythmias, and congestive heart failure can occur 4
• Pulmonary toxicity surveillance - pneumonitis, pulmonary fibrosis, and pulmonary veno-occlusive disease may develop 4
• Infection risk - severe immunosuppression may lead to serious and sometimes fatal infections 4

Plasma Exchange Consideration

• Plasma exchange is NOT routinely recommended for ANCA vasculitis based on the PEXIVAS trial 1, 2
• Plasma exchange SHOULD be used if AAV overlaps with anti-GBM antibody disease 1, 2
• For pure anti-GBM disease, plasma exchange is essential in addition to cyclophosphamide and glucocorticoids 2

Prognosis and Relapse Risk

• 50% of patients maintain stable renal function for at least 2 years with aggressive treatment 5
• Relapse occurs in approximately 44% of patients followed longer than 2 years, but most respond again to therapy 5
• Risk factors for relapse include: diagnosis of granulomatosis with polyangiitis, ANCA positivity at end of induction, PR3-ANCA subgroup, history of prior relapse, and rise in ANCA titers 1
• Long remissions are achievable in most patients with RPGN treated aggressively, though complications of therapy are frequent 5