Treatment of Vasculitis-Induced Nephropathy
Initiate treatment immediately with glucocorticoids combined with either rituximab or cyclophosphamide without waiting for kidney biopsy confirmation if the clinical presentation and positive MPO- or PR3-ANCA serology are compatible with vasculitis. 1
Immediate Treatment Decision
Do not delay immunosuppressive therapy while awaiting biopsy results, especially in patients who are rapidly deteriorating with clinical presentation compatible with small-vessel vasculitis and positive ANCA serology. 1
Treatment should be initiated at centers with experience in ANCA-associated vasculitis (AAV) management whenever possible. 1
In ANCA-negative patients, perform diagnostic kidney biopsy before starting immunosuppressive therapy to exclude vasculitis mimics from infection, malignancy, or other rheumatologic diseases. 1
Selecting Initial Immunosuppressive Agent
The choice between rituximab and cyclophosphamide depends primarily on severity of renal impairment:
Cyclophosphamide is Preferred When:
- Serum creatinine >4 mg/dL (>354 μmol/L) 1
- Rapidly declining glomerular filtration rate requiring dialysis 1
- Markedly reduced or rapidly declining GFR 1
- A combination of 2 intravenous pulses of cyclophosphamide with rituximab can be considered in severe cases 1
Rituximab is Equally Effective When:
- Serum creatinine <4 mg/dL with less severe renal disease 1
- PR3-ANCA positive disease (rituximab may be preferred) 1
- Concerns about cyclophosphamide toxicity, particularly in younger patients desiring fertility preservation 1
Induction Therapy Regimens
Cyclophosphamide Dosing:
Intravenous route (preferred):
- 15 mg/kg at weeks 0,2,4,7,10, and 13 1
- Dose reduction required for age >60 years or GFR <30 mL/min/1.73 m² 1
- Patients with lower white blood cell counts should receive IV route 1
Oral route:
- 2 mg/kg/day (maximum 200 mg/day) for 3-6 months 1, 2
- More cost-effective for patients without easy access to infusion centers 1
Common pitfall: Pulse cyclophosphamide results in increased risk of relapse (RR 1.79,95% CI 1.11 to 2.87) compared with continuous oral cyclophosphamide, though it reduces total cumulative dose and leukopenia risk. 3, 4
Rituximab Dosing:
Glucocorticoid Regimen:
Initial pulse therapy:
- Intravenous methylprednisolone 500-1000 mg/day for 1-3 days prior to initial immunosuppressive infusion 1, 2
Oral prednisone tapering (weight-based from 2024 KDIGO):
- Week 1: 50 mg (<50 kg), 60 mg (50-75 kg), 75 mg (>75 kg) 1
- Week 2: 25 mg (<50 kg), 30 mg (50-75 kg), 40 mg (>75 kg) 1
- Weeks 3-4: 20 mg (<50 kg), 25 mg (50-75 kg), 30 mg (>75 kg) 1
- Continue tapering to 5 mg daily by weeks 19-20, then maintain through week 52 1
This reduced-dose glucocorticoid regimen from the PEXIVAS trial represents the most current evidence-based approach, minimizing steroid-related toxicity without compromising efficacy. 1
Adjunctive Plasma Exchange
Consider plasma exchange in the following scenarios:
- Serum creatinine >3.4 mg/dL 5, 6
- Patients requiring dialysis at presentation 5, 6, 4
- Diffuse alveolar hemorrhage with hypoxemia 5, 6
Plasma exchange may reduce the need for dialysis at 3 months (RR 0.43,95% CI 0.23 to 0.78) and 12 months (RR 0.45,95% CI 0.29 to 0.72), though it may increase serious infections (RR 1.26,95% CI 1.03 to 1.54). 4
Important caveat: The 2024 KDIGO guidelines note limited evidence supporting routine plasma exchange, and it should be considered on a case-by-case basis rather than used universally. 1
Mandatory Supportive Measures
Pneumocystis Prophylaxis (Critical):
- Trimethoprim-sulfamethoxazole is mandatory for all patients receiving cyclophosphamide or rituximab. 5, 6, 7
- Dosing: 800/160 mg on alternate days OR 400/80 mg daily 5, 6, 7
Cyclophosphamide-Specific Measures:
- Pre-medicate with antihistamine and acetaminophen prior to infusion 2
- Administer antiemetic therapy routinely with IV cyclophosphamide 7
- Ensure high fluid intake or IV fluids on infusion days to prevent hemorrhagic cystitis 6, 7
Maintenance Therapy
After achieving remission (typically at 3-6 months), transition from cyclophosphamide to less toxic maintenance agents:
- Rituximab (preferred for relapsing disease due to lower cumulative toxicity): 500 mg IV every 6 months for 18 months 5, 2
- Azathioprine: 2 mg/kg/day for 12 months, then taper 5, 2
- Methotrexate or Mycophenolate mofetil: alternative options 5, 7
Critical point: Maintenance therapy must continue for at least 18-24 months after achieving remission, as early cessation increases relapse risk. 8
Evidence note: Rituximab demonstrated superior efficacy over azathioprine for maintenance, with major relapse occurring in only 5% versus 29% by month 28. 2
Monitoring Strategy
Regular assessment should include:
- Renal function tests and urinalysis 5, 6
- Inflammatory markers (ESR, CRP) 5, 6
- ANCA levels (though changes are only modestly predictive of relapse and should not solely guide treatment decisions) 1
- Complete blood counts for drug toxicity monitoring 5
- Surveillance for infections given immunosuppression 5
Important nuance: The 2024 KDIGO guidelines updated their position on ANCA monitoring, stating that persistence, increase, or conversion from negative to positive "may be predictive" and "should be considered" in treatment decisions, representing a shift from the 2021 guideline's more dismissive stance. 1 However, ANCA changes should never be the sole determinant of treatment modifications without clinical correlation. 1
Special Considerations
Drug-Induced Vasculitis:
- Suspect with hydralazine, propylthiouracil, levamisole-adulterated cocaine, or minocycline exposure 1
- Characterized by high-titer MPO-ANCA, dual MPO/PR3 positivity, ANA positivity 1
- Discontinuation of the offending agent is critical and may be sufficient without aggressive immunosuppression 1