What is the treatment approach for treatment-resistant membranous nephropathy?

Treatment Approach for Treatment-Resistant Membranous Nephropathy

For patients with treatment-resistant membranous nephropathy, switching to a different class of immunosuppressive agent is recommended, with rituximab being the preferred second-line therapy for patients who failed calcineurin inhibitor treatment, and calcineurin inhibitors for those who failed rituximab. 1

Definition of Treatment Resistance

Treatment resistance in membranous nephropathy (MN) is characterized by:

• Persistent anti-PLA2R antibodies after initial immunosuppressive therapy
• No substantial reduction in proteinuria (30-50%) after 4-6 months of therapy
• Persistent nephrotic syndrome without improvement in serum albumin

It's important to note that persistence of proteinuria for 12-24 months after disappearance of anti-PLA2R antibodies is expected and does not constitute resistant disease 1.

Management Algorithm for Treatment-Resistant MN

The approach depends on the initial treatment and kidney function status:

If Initial Treatment was Calcineurin Inhibitor (CNI):

• Switch to rituximab (preferred option)
• Dosing options:
  • Two weekly infusions of 375 mg/m²
  • Two infusions of 1 g each given 2 weeks apart 1, 2

If Initial Treatment was Rituximab:

• With stable eGFR: Consider cyclophosphamide with glucocorticoids
• With declining eGFR: Cyclophosphamide with glucocorticoids is strongly recommended 1

If Initial Treatment was Cyclophosphamide:

• With stable eGFR: Consider rituximab
• With declining eGFR: Consultation with an expert center is recommended 1

Monitoring Treatment Response

1. Anti-PLA2R antibody levels: Monitor every 3 months

   • Immunological remission typically precedes clinical remission
   • Response usually occurs within 3 months after starting therapy 2
   • Negative immunofluorescence test indicates immunologic remission
   • If measured by ELISA, a cutoff value of 2 RU/ml defines complete immunologic remission 1

2. Clinical parameters:

   • Proteinuria and serum albumin should be evaluated regularly
   • Clinical remission may take 12-18 months to achieve 2
   • eGFR should be monitored for stability

Special Considerations for Resistant Cases

Compliance and Efficacy Monitoring

Before declaring resistance, check:

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

Persistent Proteinuria Despite Normal Serum Albumin

Consider secondary focal segmental glomerulosclerosis (FSGS), especially if anti-PLA2R antibodies have disappeared 1.

Highly Resistant Cases

For patients who fail both rituximab and cyclophosphamide:

• Referral to specialized glomerulonephritis centers is recommended
• Experimental therapies may be considered:
  • Second-generation anti-CD20 agents (e.g., ofatumumab)
  • Anti-CD38 therapy
  • Proteasome inhibitors (e.g., bortezomib)
  • Belimumab 1, 3

Evidence for Second-Generation Anti-CD20 Antibodies

Ofatumumab has shown promise in rituximab-resistant and rituximab-intolerant patients:

• All rituximab-intolerant patients achieved complete or partial remission
• 30% of rituximab-resistant patients achieved remission
• Significant reduction in proteinuria and increase in serum albumin were observed
• Measured GFR increased by an average of 13.4% at 24 months 3

Cautions and Limitations

1. Cyclophosphamide dosing limitations:

   • Maximum cumulative dose should not exceed 36g
   • Maximum 10g if preservation of fertility is required 1, 2

2. CNI considerations:

   • Monitor blood levels regularly
   • Watch for nephrotoxicity
   • Less effective at reducing autoantibodies
   • High relapse rate after discontinuation 1

3. Mycophenolate mofetil (MMF):

   • Not recommended as monotherapy for initial treatment of MN 1
   • Limited evidence for resistant cases 4

By following this structured approach to treatment-resistant membranous nephropathy, clinicians can optimize outcomes while minimizing unnecessary medication exposure and toxicity.