What is the initial treatment for membranous nephropathy associated with Phospholipase A2 Receptor (PLA2R)?

Initial Treatment for PLA2R-Associated Membranous Nephropathy

For patients with PLA2R-associated membranous nephropathy and at least one risk factor for disease progression, rituximab or cyclophosphamide with alternate month glucocorticoids for 6 months, or tacrolimus-based therapy for ≥6 months should be used as initial treatment, depending on the estimate of risk and eGFR status. 1

Risk Assessment and Treatment Decision Algorithm

Step 1: Determine Need for Immunosuppression

• Immunosuppressive therapy is NOT required if ALL of the following are present:

  • Proteinuria <3.5 g/day
  • Serum albumin >30 g/L (by bromocresol purple or immunometric assay)
  • eGFR >60 mL/min/1.73m² 1

• Immunosuppressive therapy IS indicated if ANY of the following are present:

  • Risk factors for disease progression
  • Serious complications of nephrotic syndrome (AKI, infections, thromboembolic events)

Step 2: Select Initial Treatment Based on eGFR Status

For Patients with Stable eGFR:

• First choice: Rituximab (especially in younger patients or those concerned about fertility) 1, 2
  • Dosing: Either 2 weekly infusions of 375 mg/m² or 2 infusions of 1 g each given 2 weeks apart
  • Monitor anti-PLA2R antibody levels at 3 months to evaluate response

For Patients with Decreasing eGFR:

• First choice: Cyclophosphamide with glucocorticoids 1
  • Cyclophosphamide: Important dosing limitations:
    • Maximum cumulative dose: 36g (to limit malignancy risk)
    • Maximum 10g if preservation of fertility is required
  • Alternate month glucocorticoids for 6 months

Alternative Option (Regardless of eGFR):

• Tacrolimus-based therapy for ≥6 months 1, 2
  • Consider especially when rapid remission is needed or when rituximab/cyclophosphamide are contraindicated

Monitoring Response to Treatment

1. Monitor anti-PLA2R antibody levels every 3 months 1, 2

   • Immunological remission (disappearance of antibodies) typically precedes clinical remission
   • Response usually occurs within 3 months after starting therapy

2. Evaluate proteinuria and serum albumin regularly

   • Clinical remission may take 12-18 months to achieve
   • Consider treatment failure if no substantial reduction in proteinuria (30-50%) after 4-6 months 2

Special Considerations

For Patients with Severe CKD (eGFR <30 mL/min/1.73m²):

• Rituximab may still be effective in selected patients with stage 4-5 CKD 3
• Urinary albumin-to-protein ratio before treatment may predict renal response
• Higher risk of adverse events in this population

Thromboprophylaxis

• Consider prophylactic anticoagulation in patients with:
  • Serum albumin <25 g/L (by bromocresol purple) or <20 g/L (by bromocresol green) 1
  • Additional risk factors for thrombosis

Treatment Resistance Management

If initial therapy fails:

• For patients initially treated with calcineurin inhibitors: Switch to rituximab
• For patients initially treated with rituximab with stable eGFR: Consider cyclophosphamide with glucocorticoids
• For patients initially treated with cyclophosphamide with decreasing eGFR: Consider consultation with an expert center 1

Emerging Approaches

For truly resistant cases:

• Monthly mini-dose rituximab (100 mg) may be effective, especially in patients with lower anti-PLA2R titers 4
• Obinutuzumab (a type II anti-CD20 antibody) has shown promise in rituximab-resistant cases 5
• Therapeutic plasmapheresis combined with rituximab may be beneficial in selected cases 6

Remember that treatment decisions should prioritize preventing mortality, morbidity, and preserving quality of life, with careful consideration of the individual patient's risk factors and disease severity.