What is the recommended treatment for a patient with type III rapidly progressive glomerulonephritis (pauci‑immune, antineutrophil cytoplasmic antibody‑associated)?

Treatment of Type 3 RPGN (Pauci-Immune ANCA-Associated Vasculitis)

Initiate immunosuppression immediately with rituximab or cyclophosphamide plus glucocorticoids when clinical presentation is compatible with ANCA-associated vasculitis and MPO- or PR3-ANCA serology is positive, without waiting for kidney biopsy confirmation. 1

Immediate Treatment Initiation

• Do not delay treatment while waiting for kidney biopsy results if the clinical presentation suggests small-vessel vasculitis and ANCA serology is positive or pending 1
• The only absolute requirement before starting immunosuppression is excluding infection with as much certainty as possible 1, 2
• Obtain kidney biopsy when feasible for diagnosis confirmation and prognosis, but treatment takes priority 1

Induction Therapy Regimen

Choice of Immunosuppressive Agent

Rituximab is preferred for:

• PR3-ANCA positive patients (superior remission rates with OR 2.11 at 6 months, and OR 3.57-4.32 in relapsing disease) 1
• Relapsing disease 1
• Patients where cyclophosphamide toxicity is a concern 2

Cyclophosphamide is preferred for:

• Severe kidney dysfunction (serum creatinine >4 mg/dL [>354 μmol/L]) where limited data exist for rituximab 1
• Combination of two intravenous pulses of cyclophosphamide with rituximab can be considered in severe GN 1

No clear advantage was found between rituximab and cyclophosphamide in MPO-ANCA patients 1

Glucocorticoid Dosing

Standard approach:

• Intravenous methylprednisolone 1-3 g for severe presentations (widely used but not RCT-tested) 1
• Oral prednisone/prednisolone 1.0 mg/kg/day traditionally used in most RCTs 1
• Rapid taper demonstrated in PEXIVAS trial to be as effective but safer than standard tapering for patients with GFR <50 mL/min per 1.73 m² 1

Reduced-dose approach (LoVAS trial):

• Prednisolone 0.5 mg/kg/day was noninferior to 1.0 mg/kg/day when combined with rituximab 1
• Resulted in less severe infections 1
• Caveat: Study excluded patients with eGFR <15 mL/min per 1.73 m² and severe alveolar hemorrhage (oxygen >2 L/min), and was conducted in Japanese population with predominantly MPO-ANCA vasculitis 1

Alternative Glucocorticoid-Sparing Agent

Avacopan (oral C5a receptor antagonist):

• Dosed at 30 mg twice daily 1
• Shown to be noninferior to glucocorticoids in ADVOCATE trial (72.3% vs 70.1% remission at week 26) 1
• Led to earlier reduction in albuminuria and improved kidney function, especially in patients with eGFR <20 mL/min per 1.73 m² 1
• Caveat: Trial excluded patients with eGFR <15 mL/min per 1.73 m² and alveolar hemorrhage requiring mechanical ventilation 1

Plasma Exchange

• Not recommended routinely for ANCA-associated vasculitis based on PEXIVAS trial 1, 2
• Should be used if AAV overlaps with anti-GBM antibody disease 1, 2

Maintenance Therapy

Rituximab is preferred over azathioprine for maintenance therapy 1

Duration:

• Minimum 18 months of maintenance immunosuppression 1
• Up to 4 years for azathioprine has been used 1
• Withdrawal can be considered after factoring in relapse risk 1

Relapse risk factors include:

• Granulomatosis with polyangiitis diagnosis 1
• PR3-ANCA subgroup 1
• History of relapse 1
• ANCA positive at end of induction 1
• Rise in ANCA levels 1
• Lower cyclophosphamide exposure 1
• Glucocorticoid withdrawal 1

Critical Contraindications and Caveats

Withhold immunosuppression when:

• eGFR <30 mL/min per 1.73 m² AND kidney biopsy shows extensive interstitial fibrosis/tubular atrophy, extensive glomerulosclerosis, or absence of active necrotizing/crescentic lesions 2, 3
• The decision must be based on biopsy findings showing overall renal viability, not eGFR alone 2

Treat despite low eGFR when:

• Active necrotizing or crescentic GN is present on biopsy 2
• Preserved renal parenchyma with acute tubular necrosis 2

Common Pitfalls to Avoid

• Delaying treatment while awaiting biopsy results when clinical presentation and positive serology are sufficient 2, 3
• Treating patients with advanced chronic kidney disease and extensive fibrosis on biopsy who will not benefit and face only toxicity risk 2
• Assuming all patients with low eGFR should not be treated—active crescentic disease warrants treatment regardless of eGFR 2
• Failing to exclude infection before initiating immunosuppression, as infection is the most common cause of death in RPGN patients 1, 2

Premedication and Prophylaxis

For rituximab administration:

• Premedicate with acetaminophen and antihistamine before each infusion 4
• Methylprednisolone 100 mg IV or equivalent 30 minutes prior to each infusion 4

Infection prophylaxis:

• PCP prophylaxis during treatment and for at least 6 months following last rituximab infusion 4
• Consider herpes virus prophylaxis 4