What is the management of Anti-Neutrophil Cytoplasmic Antibody (ANCA) nephritis?

Management of ANCA-Associated Nephritis

The management of ANCA-associated nephritis requires glucocorticoids in combination with either rituximab or cyclophosphamide for induction therapy, followed by maintenance therapy with rituximab or azathioprine to prevent disease relapse. 1

Diagnosis and Initial Assessment

• In patients with clinical presentation compatible with small-vessel vasculitis and positive MPO or PR3-ANCA serology, immunosuppressive therapy should be initiated without delay, especially in rapidly deteriorating patients 1
• Patients with ANCA-associated vasculitis (AAV) should be treated at centers with experience in AAV management, equipped with adequate facilities for rapid diagnosis and management 1
• Kidney biopsy remains the gold standard for diagnosis but should not delay treatment initiation in clear cases 1

Induction Therapy

First-Line Treatment Options

• Glucocorticoids combined with either rituximab or cyclophosphamide are recommended as initial treatment for new-onset AAV 1
• For patients with severe glomerulonephritis (serum creatinine >4 mg/dl or >354 μmol/l), consider:
  • Cyclophosphamide with glucocorticoids, OR
  • Combination of rituximab and cyclophosphamide 1

Cyclophosphamide Dosing

• Oral cyclophosphamide: 2 mg/kg/day for 3 months, continue for ongoing activity to maximum of 6 months 1
  • Reduce dose for age: 60 years (1.5 mg/kg/day), 70 years (1.0 mg/kg/day)
  • Reduce by 0.5 mg/kg/day for GFR <30 ml/min/1.73 m² 1
• Intravenous cyclophosphamide: 15 mg/kg at weeks 0,2,4,7,10,13 (16,19,21,24 if required) 1
  • Reduce dose for age: 60 years (12.5 mg/kg), 70 years (10 mg/kg)
  • Reduce by 2.5 mg/kg for GFR <30 ml/min/1.73 m² 1

Rituximab Dosing

• 375 mg/m² weekly for 4 weeks 1
• May be combined with IV cyclophosphamide (15 mg/kg at weeks 0 and 2) in severe disease 1

Plasma Exchange Consideration

• Consider plasma exchange for patients with serum creatinine >3.4 mg/dl (>300 mmol/l), patients requiring dialysis or with rapidly increasing serum creatinine, or patients with diffuse alveolar hemorrhage who have hypoxemia 1

Maintenance Therapy

Recommended Options

• Maintenance therapy is recommended with either rituximab or azathioprine with low-dose glucocorticoids after induction of remission 1
• Rituximab is preferred for maintenance therapy, particularly for patients with:
  • Known relapsing disease
  • PR3-ANCA positivity
  • Azathioprine allergy
  • After rituximab induction 1

Maintenance Dosing Protocols

• Rituximab maintenance options:
  • 500 mg × 2 at complete remission, and 500 mg at months 6,12, and 18 thereafter (MAINRITSAN scheme), OR
  • 1000 mg infusion after induction of remission, and at months 4,8,12, and 16 after the first infusion (RITAZAREM scheme) 1
• Azathioprine maintenance:
  • 1.5–2 mg/kg/day at complete remission until 1 year after diagnosis
  • Then decrease by 25 mg every 3 months
  • For extended therapy: continue at 1 mg/kg/day until 4 years after diagnosis, then taper 1
• Glucocorticoids:
  • Continue at 5–7.5 mg/day for 2 years
  • Then slowly reduce by 1 mg every 2 months 1

Duration of Maintenance Therapy

• The optimal duration of maintenance therapy is between 18 months and 4 years after induction of remission 1
• Extended immunosuppressive therapy should be associated with a minimum of adverse events, and relapse risk may influence maintenance duration 1

Special Considerations

Relapse Risk Assessment

• Several AAV relapse risk factors have been identified:
  • Prior history of relapse
  • PR3-ANCA positivity (versus MPO-ANCA)
  • Persistence of ANCA positivity, increase in ANCA levels, or change from negative to positive 1

Patients with End-Stage Kidney Disease

• Even in patients on kidney replacement therapy, extrarenal AAV can relapse, and remission should be consolidated with maintenance therapy 1
• In patients with kidney failure, anti-MPO positivity, and no extrarenal symptoms, long-term maintenance may not be necessary 1
• The need for and length of maintenance treatment should be assessed at an individual level in these cases 1

Monitoring and Follow-up

• Remission is defined as absence of disease activity (BVAS=0) with stable or improved glomerular filtration rate 1
• Relapse is defined as increased disease activity after a period of partial or complete remission 1
• Regular monitoring of ANCA serologies is important, especially if maintenance therapy is not used 1

Potential Complications and Management

• Long-term morbidity with damage accumulating partly due to adverse events of treatment (gonadal toxicity, malignancy, bone disease, cataracts, diabetes, thromboembolic and cardiovascular disease) 2
• Hypogammaglobulinemia may occur with rituximab treatment 3
• Infusion-related reactions with rituximab (most common with first infusion) 3
• Infections are common adverse events (47-62% of patients) 3

Pitfalls to Avoid

• Do not delay immunosuppressive treatment in rapidly deteriorating cases while waiting for biopsy results 1
• Do not withhold induction treatment based on unfavorable histologic findings, as kidney recovery can be seen even in the face of advanced kidney damage 1
• Do not discontinue maintenance therapy too early, as this is associated with increased risk of relapse 4
• Do not underestimate the importance of monitoring for long-term complications of immunosuppressive therapy 2