What is the optimal management for a patient with vasculitis and nephropathy?

Management of Vasculitis with Nephropathy

For patients with vasculitis and nephropathy, initiate combination therapy with glucocorticoids plus either cyclophosphamide or rituximab immediately, with the choice depending on disease severity and specific clinical features. 1

Initial Assessment and Diagnostic Confirmation

• Obtain renal biopsy to confirm pauci-immune glomerulonephritis - this provides both diagnostic confirmation (91.5% yield in GPA with renal involvement) and prognostic information through assessment of glomerular sclerosis 1

• Test for ANCA using antigen-specific immunoassays (MPO-ANCA and PR3-ANCA ELISA) rather than indirect immunofluorescence, as these have higher diagnostic accuracy 2

• Assess disease severity immediately using serum creatinine, urinalysis for hematuria and red cell casts, and evaluation for extrarenal manifestations 1

• Do not delay treatment while awaiting biopsy results if the patient has positive ANCA serology and clinical presentation compatible with rapidly progressive glomerulonephritis 2

Remission Induction Therapy: Treatment Algorithm

For Severe Renal Disease (Creatinine >4.0 mg/dL or Rapidly Progressive Renal Failure)

• Initiate cyclophosphamide (2 mg/kg/day oral or IV pulse 0.6 g/m² every 2-4 weeks) plus high-dose glucocorticoids (1 mg/kg/day, maximum 80 mg/day) 1

• Consider adding rituximab to cyclophosphamide in this severe phenotype, as observational data shows excellent remission and survival rates with triple therapy (glucocorticoids + cyclophosphamide + rituximab) 1

• Consider plasma exchange as adjunctive therapy - it reduces the risk of end-stage kidney disease at 12 months (RR 0.47,95% CI 0.30-0.75) and reduces dialysis need at 3 months (RR 0.43,95% CI 0.23-0.78) 1, 3, 4

• Administer 1,000 mg IV methylprednisolone daily for 1-3 days prior to initial immunosuppressive infusion 5

For Moderate Renal Disease (Creatinine <4.0 mg/dL, Organ-Threatening but Not Life-Threatening)

• Choose either rituximab (375 mg/m² weekly for 4 weeks) or cyclophosphamide - both are equally effective for remission induction 1, 5

• Prefer rituximab in the following situations: 1

  • Younger patients with fertility concerns
  • Relapsing disease
  • PR3-ANCA positive disease
  • Patient preference to avoid cyclophosphamide toxicity

• Prefer cyclophosphamide when: 1

  • Severe glomerulonephritis with rapidly declining kidney function
  • Need for rapid onset of action
  • Limited access to rituximab infusion facilities

• Combine with glucocorticoids (1 mg/kg/day, not exceeding 80 mg/day) with pre-specified tapering protocol 1, 5

Critical Dosing Details

• Cyclophosphamide dosing: Oral 2 mg/kg/day (maximum 200 mg/day) for 3-6 months, OR IV pulse 0.6 g/m² every 2 weeks initially, then every 4 weeks 1

• Adjust cyclophosphamide dose in elderly patients and monitor closely for bone marrow suppression 1

• Rituximab dosing: 375 mg/m² IV weekly for 4 weeks during induction 5

• Premedicate before rituximab with antihistamine and acetaminophen; patients should already be on background oral corticosteroids 5

Maintenance Therapy After Remission

First-Line Maintenance Options

• Switch to azathioprine (2 mg/kg/day) after achieving remission at 3-6 months if cyclophosphamide was used for induction - azathioprine has equivalent efficacy to continued cyclophosphamide with fewer episodes of leukopenia 1, 3, 4

• If rituximab was used for induction, continue rituximab 500 mg IV every 6 months for 18 months as maintenance therapy - this results in only 5% major relapse rate compared to 29% with azathioprine 5

Alternative Maintenance Agents

• Methotrexate or leflunomide are potential alternatives for maintenance therapy, though leflunomide causes more serious adverse events than methotrexate 4

• Avoid mycophenolate mofetil for maintenance - it results in higher relapse rates compared to azathioprine despite being effective for induction 3, 4

Duration of Maintenance Therapy

• Continue azathioprine or methotrexate for 2-4 years with gradual tapering 1

• Continue rituximab maintenance for 18 months (500 mg every 6 months), then discontinue 5

• Taper glucocorticoids gradually to low-dose maintenance (approximately 5 mg/day) for at least 18 months 5

Infection Prophylaxis (Mandatory)

• Prescribe trimethoprim-sulfamethoxazole 800/160 mg on alternate days (or 400/80 mg daily) for Pneumocystis jiroveci prophylaxis throughout immunosuppressive therapy 6

• Administer pneumococcal vaccine, influenza vaccine annually, and ensure household contacts receive influenza vaccination 6

• Screen for tuberculosis, hepatitis B, hepatitis C, HIV, and syphilis before initiating immunosuppression 6

Critical Monitoring Parameters

• Monitor urinalysis at every clinic visit to screen for infection, renal relapse, or bladder complications from cyclophosphamide 2

• Check complete blood count and liver function tests every 1-3 months to monitor for drug toxicity - acute fall in white cell count requires dose reduction or discontinuation 2

• Monitor inflammatory markers (ESR, CRP) and renal function every 1-3 months, though recognize these are nonspecific and cannot distinguish vasculitis activity from infection 2

• Assess for hypogammaglobulinemia - at 6 months, 27% of rituximab-treated patients develop low IgA, 58% low IgG, and 51% low IgM 5

Management at Centers of Expertise

• Refer all patients to centers with vasculitis expertise - this is a unanimous recommendation (100% strength of vote) given the unpredictable nature of AAV, need for long-term follow-up, and risk of late complications 1, 2

• For refractory disease, consider referral to centers participating in clinical trials as alternative therapeutic options may be available 1

Common Pitfalls to Avoid

• Do not wait for biopsy confirmation if ANCA-positive with rapidly progressive glomerulonephritis - immediate treatment initiation is critical to prevent irreversible kidney damage 2, 7

• Do not use pulse cyclophosphamide if you want to minimize relapse risk - pulse regimens cause 79% increased relapse risk (RR 1.79,95% CI 1.11-2.87) compared to continuous oral cyclophosphamide, though they reduce total cumulative dose 3, 4

• Recognize that 10% of patients with clinical AAV are ANCA-negative - tissue biopsy is essential for definitive diagnosis in these cases 2

• Be aware that persistent hematuria does not necessarily indicate active disease - more than 40% of patients in clinical remission have persistent hematuria 1

• Infection is the leading cause of death in the first year - maintain high vigilance for infectious complications, as infection-related mortality may be substantial 5, 7, 8

• Plasma exchange increases bleeding risk during renal biopsy - consider timing of procedures carefully, especially in elderly patients with hypertension and worse renal function 1