What is the recommended diagnostic work‑up and initial management for rapid progressive glomerulonephritis (RPGN)?

Rapidly Progressive Glomerulonephritis: Diagnostic Work-Up and Initial Management

Immediate Diagnostic Evaluation

Begin immunosuppressive therapy immediately when clinical presentation suggests RPGN (rapid creatinine rise over days to weeks, active urinary sediment with glomerular hematuria and proteinuria) and serologies are positive or pending—do not wait for kidney biopsy results. 1

Essential Laboratory Work-Up

• Urinalysis and sediment examination: Confirm urine dipstick positive for protein and blood; examine sediment for glomerular hematuria (dysmorphic red blood cells, red cell casts) and/or pyuria without infection 2
• Autoimmune serologies (send immediately): ANCA (MPO and PR3), anti-GBM antibodies, ANA, complement levels (C3, C4) 3, 2
• Infection screening (mandatory before immunosuppression): Hepatitis B and C serologies, HIV, tuberculosis screening, urine culture, chest imaging 1, 2
• Kidney biopsy: Obtain when feasible to confirm diagnosis and assess disease activity versus chronicity, but prioritize treatment initiation over waiting for biopsy 3, 1

Critical Caveat on Biopsy Timing

The only absolute requirement before starting treatment is excluding active infection with the highest possible certainty—biopsy confirmation is not required if clinical syndrome is compatible with RPGN and serologies are positive. 1 Anti-GBM antibodies can be falsely negative in approximately 10% of cases, making tissue diagnosis crucial when safe and feasible. 3

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Initial Immunosuppressive Management by Etiology

ANCA-Associated Vasculitis (Most Common, ~50-60% of RPGN)

Induction Regimen:

• Glucocorticoids: IV methylprednisolone 500-1000 mg daily for 3 consecutive days, followed by oral prednisone 1 mg/kg/day (maximum 60-80 mg/day) with gradual taper over at least 6 months 1
• Choice of immunosuppressive agent:
  • Rituximab preferred for PR3-ANCA positive patients (odds ratio ~2.1 for remission at 6 months), relapsing disease regardless of ANCA subtype, or when cyclophosphamide toxicity is a concern 1
  • Cyclophosphamide preferred when severe renal dysfunction is present (serum creatinine >4 mg/dL or eGFR <15 mL/min/1.73 m²) because data for rituximab are limited in this setting 1
  • For MPO-ANCA patients, no clear superiority of rituximab over cyclophosphamide has been demonstrated 1

Reduced-Dose Glucocorticoid Option:

• Prednisolone 0.5 mg/kg/day combined with rituximab was non-inferior to standard dose and resulted in fewer severe infections in the LoVAS trial 1
• Caveat: This trial excluded patients with eGFR <15 mL/min/1.73 m², severe alveolar hemorrhage, and was conducted predominantly in Japanese patients with MPO-ANCA disease 1

Glucocorticoid-Sparing Alternative:

• Avacopan 30 mg twice daily was non-inferior to standard glucocorticoid regimens (72.3% vs 70.1% remission at week 26) and accelerated reduction of albuminuria, especially in patients with eGFR <20 mL/min/1.73 m² 1
• Caveat: ADVOCATE trial excluded patients with eGFR <15 mL/min/1.73 m² and severe alveolar hemorrhage requiring mechanical ventilation 1

Anti-GBM Antibody Disease (~20% of RPGN)

Initiate immediately: Cyclophosphamide + high-dose glucocorticoids + plasmapheresis for all patients except those who are dialysis-dependent at presentation with 100% crescents or >50% global glomerulosclerosis on adequate biopsy sample and no pulmonary hemorrhage 3

Key Decision Point:

• Patients presenting on dialysis have >90% chance of remaining dialysis-dependent, so treatment should be reserved for those with pulmonary hemorrhage or very recent dialysis initiation 1
• Treat aggressively even without alveolar hemorrhage if there is potential renal viability based on clinical and pathologic features 3

Immune Complex-Mediated RPGN (~20-25% of RPGN)

Treatment approach: High-dose glucocorticoids + cyclophosphamide (similar to ANCA-associated vasculitis regimen) for crescentic presentation with rapidly progressive disease 1

• Consider rituximab as alternative to cyclophosphamide 1
• Pulse IV methylprednisolone followed by oral prednisone with gradual taper 1

Common causes: IgA nephropathy with extensive crescent formation, lupus nephritis with crescentic changes, cryoglobulinemic vasculitis 2

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Critical Contraindications to Immunosuppression

Withhold immunosuppression ONLY if ALL of the following are present:

• eGFR <30 mL/min/1.73 m² AND
• Kidney biopsy shows high degree of interstitial fibrosis and tubular atrophy, extensive glomerulosclerosis, or absence of active necrotizing or crescentic lesions 1

Do NOT withhold treatment based on eGFR alone—active crescentic disease warrants treatment regardless of eGFR if there is preserved renal parenchyma with acute tubular necrosis. 1

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Plasma Exchange Indications

• Routine plasma exchange is NOT recommended for ANCA-associated vasculitis based on the PEXIVAS trial 1
• Plasma exchange IS recommended for:
  • Anti-GBM antibody disease 3, 1
  • ANCA-associated vasculitis that overlaps with anti-GBM disease 1
  • Severe pulmonary hemorrhage in exceptional situations 1

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Maintenance Therapy (After Induction)

• Rituximab preferred over azathioprine for long-term maintenance 1
• Minimum duration: 18 months of maintenance immunosuppression; up to 4 years of azathioprine has been used in practice 1
• Discontinuation can be considered after individualized assessment of relapse risk factors 1

High relapse risk factors: Granulomatosis with polyangiitis diagnosis, PR3-ANCA serology, prior relapse history, persistent ANCA positivity at end of induction, rising ANCA titers during follow-up, lower cumulative cyclophosphamide exposure, early glucocorticoid withdrawal 1

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Common Pitfalls to Avoid

• Delaying treatment while waiting for biopsy results: The combination of compatible clinical presentation and positive serology is sufficient to begin therapy 1
• Treating patients with advanced chronic kidney disease and extensive fibrosis on biopsy: These patients will not benefit and face only toxicity risk 1
• Assuming all patients with low eGFR should not be treated: Active crescentic disease warrants treatment regardless of eGFR if biopsy shows active inflammation 1
• Starting immunosuppression without excluding infection: Infection is the leading cause of death in RPGN patients and the only absolute contraindication to immediate therapy 1
• Using calcineurin inhibitors (tacrolimus, cyclosporine) for immune complex RPGN: These cause immune complex-negative angiopathy and thrombotic microangiopathy 1