What is the initial treatment approach for membranous nephropathy according to the latest KDIGO (Kidney Disease: Improving Global Outcomes) guideline?

Initial Treatment Approach for Membranous Nephropathy According to Latest KDIGO Guidelines

For patients with membranous nephropathy (MN) 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, with the choice depending on the risk estimate and eGFR status. 1, 2

Risk Stratification and Indications for Immunosuppression

• Immunosuppressive therapy is NOT required in patients with:

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

• Immunosuppression should be considered when at least ONE risk factor for disease progression is present:

  • Persistent proteinuria >4 g/day despite 6 months of supportive care
  • Severe, disabling, or life-threatening symptoms related to nephrotic syndrome
  • Serum creatinine rise ≥30% within 6-12 months (with eGFR >30 mL/min/1.73m²) 2

• Immunosuppression is NOT recommended in patients with:

  • Serum creatinine persistently ≥3.5 mg/dL or eGFR ≤30 mL/min/1.73m²
  • Reduced kidney size on ultrasound
  • Severe or potentially life-threatening infections 2

Initial Treatment Algorithm Based on KDIGO 2021 Guidelines

1. For patients with stable eGFR:

   • First choice: Rituximab
   • Dosing: Two weekly infusions of 375 mg/m² or two infusions of 1g each given 2 weeks apart 1, 2

2. For patients with declining eGFR:

   • First choice: Cyclophosphamide with glucocorticoids
   • Cyclophosphamide limitations:
     • Maximum cumulative dose: 36g
     • If fertility preservation needed: Maximum 10g 1, 2

3. Alternative option (for both stable or declining eGFR):

   • Tacrolimus-based therapy for ≥6 months 1
   • Monitor blood levels regularly
   • Watch for nephrotoxicity
   • Note: Higher relapse rate after discontinuation 2

Monitoring Treatment Response

• Anti-PLA2R antibody levels should be monitored every 3 months 2
• Immunological remission (disappearance of antibodies) typically precedes clinical remission 2
• Response usually occurs within 3 months after starting therapy 1
• Clinical remission may take 12-18 months to achieve 2
• Persistence of proteinuria for 12-24 months after disappearance of anti-PLA2R antibodies is expected and does not constitute resistant disease 2

Management of Treatment-Resistant Disease

If initial therapy fails, the KDIGO guidelines recommend:

1. For patients initially treated with calcineurin inhibitors:

   • Switch to rituximab 1, 2

2. For patients initially treated with rituximab:

   • With stable eGFR: Consider calcineurin inhibitor 1
   • With declining eGFR: Switch to cyclophosphamide with glucocorticoids 1

3. For patients initially treated with cyclophosphamide:

   • Consider rituximab 1

4. For patients who fail both rituximab and cyclophosphamide:

   • Referral to specialized glomerulonephritis centers is recommended 2
   • Experimental therapies may be considered (second-generation anti-CD20 agents, anti-CD38 therapy, proteasome inhibitors, belimumab) 2, 3

Supportive Care and Thromboprophylaxis

• All patients with primary MN and proteinuria should receive optimal supportive care 1
• Consider prophylactic anticoagulation in patients with:
  • Serum albumin <25 g/L (by bromocresol purple) or <20 g/L (by bromocresol green)
  • Additional risk factors for thrombosis 2

Caveats and Pitfalls

• Before declaring treatment resistance, check:

  • Patient compliance
  • B-cell response (for rituximab)
  • Anti-rituximab antibodies
  • IgG levels
  • Leukocytopenia during cyclophosphamide
  • CNI blood levels 1, 2

• Consider secondary focal segmental glomerulosclerosis (FSGS) if anti-PLA2R antibodies have disappeared but proteinuria persists 1, 2

• Approximately 20%-40% of MN patients experience rituximab resistance and failure, which may be due to reduced bioavailability, RTX internalization, anti-RTX antibody production, autoreactive B-cell reservoirs, or chronic renal damage 3