What is the recommended treatment for a patient with ANCA (Antineutrophil Cytoplasmic Antibody)-associated vasculitis, interstitial lung disease (ILD), and impaired renal function?

Treatment of ANCA-Associated Vasculitis with ILD and Renal Failure

For ANCA-associated vasculitis presenting with interstitial lung disease and renal failure, initiate treatment immediately with glucocorticoids combined with cyclophosphamide, without waiting for kidney biopsy confirmation. 1, 2

Immediate Treatment Initiation

• Do not delay treatment while awaiting biopsy results if the clinical presentation and positive MPO- or PR3-ANCA serology are compatible with vasculitis, especially in rapidly deteriorating patients 1, 2, 3
• Begin immunosuppressive therapy based on clinical presentation and positive ANCA serology alone 1, 3
• Patients should ideally be managed at centers with experience in AAV management 1, 2

Choice of Induction Agent: Cyclophosphamide Preferred

For severe renal impairment with renal failure, cyclophosphamide is strongly preferred over rituximab. 1, 2, 4

Rationale for Cyclophosphamide Selection:

• The 2024 KDIGO guidelines specifically recommend cyclophosphamide for patients with serum creatinine >4 mg/dL (>354 μmol/L) or rapidly declining GFR 1, 2, 3
• Limited data support rituximab monotherapy in markedly reduced or rapidly declining GFR 1
• A combination approach using rituximab plus two intravenous cyclophosphamide pulses can be considered for severe renal disease 1
• Rituximab is equally effective only for less severe renal disease (serum creatinine <4 mg/dL) 3

Evidence Quality Note:

While rituximab demonstrated non-inferiority to cyclophosphamide in the RAVE trial, this study excluded patients with severe renal impairment (median eGFR was 18 ml/min in the RITUXVAS trial, but patients with more severe disease were underrepresented) 5, 6. The most recent 2024 KDIGO guidelines reflect this limitation by recommending cyclophosphamide for severe renal involvement 1.

Cyclophosphamide Dosing Regimens

Intravenous Route (Preferred):

• 15 mg/kg at weeks 0,2,4,7,10, and 13 1, 2, 3
• Dose reduction required for age >60 years or GFR <30 ml/min/1.73 m² 2

Oral Route (Alternative):

• 2 mg/kg/day (maximum 200 mg/day) for 3-6 months 1, 3, 4

Glucocorticoid Regimen

Initial High-Dose Therapy:

• Intravenous methylprednisolone 500-1000 mg/day for 1-3 days 4, 7
• All patients should receive 1,000 mg of pulse intravenous methylprednisolone per day for 1 to 3 days within 14 days prior to initial infusion 7

Oral Prednisone Tapering:

• Start at 1 mg/kg/day (maximum 60-75 mg/day) 4
• Weight-based tapering per 2024 KDIGO: Week 1: 50-75 mg depending on body weight; Week 2: 25-40 mg; Weeks 3-4: 20-30 mg 3
• Continue tapering to 5 mg daily by weeks 19-20, then maintain 5 mg through week 52 3

Adjunctive Plasma Exchange

Consider adding plasma exchange for patients with renal failure, particularly those requiring dialysis or with serum creatinine >3.4 mg/dL. 1, 2, 3

Evidence for Plasma Exchange:

• The 2021 ACR guidelines conditionally recommend against routine plasma exchange but acknowledge it can be considered for patients at higher risk of ESRD 1
• Combined data from two major trials show decreased risk of ESRD (hazard ratio 0.72,95% CI 0.53-0.98) 1
• For diffuse alveolar hemorrhage with hypoxemia (relevant for ILD presentation), plasma exchange should be strongly considered 2, 3
• Minimum of seven plasma exchanges recommended when used 8

Critical Caveat:

The PEXIVAS trial showed plasma exchange decreased ESRD risk but did not improve the composite outcome of ESRD or death, and was associated with increased infection risk 1. Balance this against the severity of renal failure when deciding.

Mandatory Supportive Measures

Pneumocystis Prophylaxis:

• Trimethoprim-sulfamethoxazole (800/160 mg on alternate days or 400/80 mg daily) is mandatory for all patients receiving cyclophosphamide or rituximab 1, 2, 3

Hemorrhagic Cystitis Prevention:

• High fluid intake or intravenous fluids on cyclophosphamide infusion days 3
• Antiemetic therapy routinely with intravenous cyclophosphamide 3

Osteoporosis Prophylaxis:

• Calcium, vitamin D, and bisphosphonates given high-dose glucocorticoid exposure 4

Alternative Combination Approach for Severe Disease

For life-threatening disease with both ILD and renal failure, a combination regimen of rituximab plus low-dose cyclophosphamide plus plasma exchange may provide rapid disease control. 8

Combination Regimen Details:

• This approach achieved 94% remission rates at 6 months in patients with median eGFR of 9 ml/min 8
• 67% of dialysis-requiring patients recovered independent kidney function 8
• Median cumulative doses: rituximab 2g, cyclophosphamide 3g, glucocorticoid 2.6g at 6 months 8
• Serious infection rate was 0.28 infections/patient/year, suggesting acceptable safety 8

When to Consider Combination Therapy:

• Diffuse alveolar hemorrhage (52% of patients in the combination study had this) 8
• Dialysis requirement (47% required dialysis in the combination study) 8
• Life-threatening multi-organ involvement 8

Monitoring Strategy

Disease Activity Monitoring:

• Regular assessment of renal function, urinalysis, inflammatory markers, and ANCA levels 2, 4
• Persistent hematuria indicates ongoing disease activity; resolution followed by recurrence suggests relapse 4
• ANCA positivity, increasing ANCA levels, or conversion from negative to positive may predict future relapse 1, 4

Drug Toxicity Monitoring:

• Complete blood counts and renal function tests regularly 2, 4
• Monitor for infections given profound immunosuppression 2

Transition to Maintenance Therapy

After achieving remission (typically 3-6 months), transition from cyclophosphamide to a less toxic maintenance agent. 4

Maintenance Options:

• Rituximab (preferred for relapsing disease due to lower cumulative toxicity) 2
• Azathioprine 1, 7
• Methotrexate 2
• Mycophenolate mofetil 2
• Low-dose glucocorticoids should continue with any maintenance agent 2

Common Pitfalls to Avoid

• Do not withhold treatment based solely on unfavorable histologic findings - kidney recovery can occur even with advanced damage 4
• Do not dose immunosuppressive therapy based on ANCA titer results alone 1
• Do not underestimate infection risk - infection was the most common adverse event category (47-62%) in clinical trials 7
• Do not forget that rituximab monotherapy has limited data in severe renal failure - the evidence base is strongest for cyclophosphamide in this population 1, 5