What is the appropriate management for a patient with perinuclear anti‑neutrophil cytoplasmic antibodies‑positive, myeloperoxidase‑/proteinase‑3‑negative vasculitis with renal involvement and a serum creatinine stabilized at about 2 mg/dL who is on dual antiplatelet therapy?

Management of p-ANCA Positive, MPO/PR3 Negative Vasculitis with Renal Involvement

This patient requires kidney biopsy before initiating immunosuppressive therapy, as the absence of MPO/PR3 antibodies makes the diagnosis uncertain and alternative diagnoses must be excluded. 1

Diagnostic Approach

The 2024 KDIGO guidelines provide clear algorithmic guidance based on ANCA serology status:

• For PR3- and MPO-ANCA negative patients with clinical presentation compatible with small-vessel vasculitis: perform kidney biopsy when feasible before starting treatment 1
• This contrasts with PR3- or MPO-ANCA positive patients, where treatment can commence immediately at experienced centers with rapidly progressive disease 1
• The p-ANCA pattern without MPO/PR3 specificity is insufficient to confirm ANCA-associated vasculitis (AAV), as p-ANCA can occur in other conditions including drug-induced vasculitis, inflammatory bowel disease, and other autoimmune disorders 2, 3

Critical Caveat Regarding Dual Antiplatelet Therapy

The dual antiplatelet therapy presents a significant bleeding risk for kidney biopsy and must be addressed:

• Kidney biopsy carries substantial hemorrhagic risk in patients on dual antiplatelet agents 2
• Weigh the risk-benefit of temporarily holding antiplatelet therapy against cardiovascular risk based on the indication (e.g., recent stent placement versus chronic coronary disease)
• If biopsy cannot be safely performed due to bleeding risk, empiric treatment may be necessary, but this should be a last resort given the diagnostic uncertainty 1

If Biopsy Confirms Pauci-Immune Glomerulonephritis

Should biopsy demonstrate pauci-immune necrotizing glomerulonephritis consistent with AAV despite negative MPO/PR3:

Induction Therapy Selection

Given the stabilized creatinine at 2 mg/dL (not >4 mg/dL), either rituximab or cyclophosphamide combined with glucocorticoids is appropriate 1:

• Rituximab 375 mg/m² weekly for 4 weeks OR 1 g at weeks 0 and 2 1, 3, 4
• Cyclophosphamide is NOT mandatory at this creatinine level since the threshold for preferring cyclophosphamide is SCr >4 mg/dL (>354 μmol/L) 1
• The RAVE trial demonstrated equivalent efficacy of rituximab versus cyclophosphamide in patients with renal involvement and mean eGFR of 41-50 mL/min 5

Glucocorticoid Regimen

Use the reduced-dose PEXIVAS protocol 1:

• Week 1: 50-75 mg daily (weight-based: <50 kg = 50 mg; 50-75 kg = 60 mg; >75 kg = 75 mg)
• Week 2: 25-40 mg daily (weight-based)
• Weeks 3-4: 20-30 mg daily
• Continue tapering to 5 mg daily by weeks 19-20
• Maintain 5 mg daily through week 52 1

Mandatory Supportive Care

Pneumocystis jirovecii prophylaxis is required 2, 3, 6:

• Trimethoprim-sulfamethoxazole 800/160 mg on alternate days OR 400/80 mg daily 3, 6
• Continue during treatment and for at least 6 months following the last rituximab or cyclophosphamide dose 4

Plasma Exchange Consideration

Plasma exchange is NOT indicated at this creatinine level 1, 2:

• Consider only if creatinine >3.4 mg/dL, requiring dialysis, or with diffuse alveolar hemorrhage 2, 6
• Current creatinine of 2 mg/dL does not meet these thresholds

Monitoring Strategy

Serial monitoring must include 2, 6:

• Renal function (creatinine, eGFR) and urinalysis every 2-4 weeks initially
• ANCA levels (p-ANCA titer) - persistence or rising levels may predict relapse even without MPO/PR3 positivity 1
• Complete blood counts for cytopenias
• Infection surveillance given immunosuppression 2, 6

Maintenance Therapy Planning

After achieving remission (typically 3-6 months), transition to maintenance therapy 2, 3, 6:

• Rituximab 500 mg every 6 months, OR
• Azathioprine 2 mg/kg/day, OR
• Mycophenolate mofetil 2, 3
• Continue low-dose glucocorticoids (5 mg daily) 1
• Rituximab may be preferred for maintenance given lower relapse rates 7

Key Clinical Pitfall

The absence of MPO/PR3 antibodies despite p-ANCA positivity creates diagnostic uncertainty that cannot be ignored. Approximately 10-20% of patients with clinical AAV are ANCA-negative, but p-ANCA without MPO/PR3 specificity requires histologic confirmation before committing to potentially toxic immunosuppression 1. The stabilized creatinine suggests this is not an immediately life-threatening situation where empiric therapy would be justified without tissue diagnosis.