What is the next treatment option for a patient with membranous nephropathy (MN) who has persistent proteinuria and hypoalbuminemia after completing 5 cycles of the Ponticelli regimen?

Next Treatment Option for Membranous Nephropathy After Failed Ponticelli Regimen

For a patient with membranous nephropathy who has persistent proteinuria and hypoalbuminemia after completing 5 cycles of the Ponticelli regimen, rituximab is the recommended next treatment option.

Assessment of Treatment Failure

• The patient has completed 5 cycles of the Ponticelli regimen (cyclophosphamide/glucocorticoids) but still has persistent proteinuria and hypoalbuminemia, indicating treatment resistance 1
• Before initiating alternative therapy, it's important to wait at least 6 months after completing the initial regimen to confirm treatment failure, unless kidney function is deteriorating or severe symptoms related to nephrotic syndrome are present 1
• Persistent proteinuria alone is not sufficient to define resistance - evaluation of anti-PLA2R antibody status (if initially positive) should be performed to assess for immunological remission 1

Recommended Next Treatment: Rituximab

• For patients with membranous nephropathy who have failed initial therapy with cyclophosphamide (Ponticelli regimen) and have stable eGFR, rituximab is the recommended next treatment option 1, 2
• The KDIGO management algorithm specifically indicates that when initial treatment with cyclophosphamide fails, the next step is rituximab 1
• The standard rituximab dosing protocol is 1g every 2 weeks for 2 doses 2
• Rituximab has been shown to be effective as second-line therapy in patients who failed to respond to previous immunosuppressive treatment, including alkylating agents 3

Evidence Supporting Rituximab Use

• Rituximab has demonstrated efficacy in membranous nephropathy by targeting B-cell lineages to prevent antibody production, particularly anti-PLA2R antibodies 4
• The MENTOR trial showed rituximab was superior to cyclosporine in maintaining proteinuria remission up to 24 months, with 60% of patients achieving complete or partial remission at 24 months 5
• In patients with PLA2R-related disease, remission can be predicted by anti-PLA2R antibody depletion 4
• Rituximab is effective in reducing proteinuria in membranous nephropathy patients with no or only transient response to previous immunosuppression 3

Monitoring Treatment Response

• Anti-PLA2R antibody levels (if initially positive) should be monitored at 3 months after starting rituximab to evaluate treatment response 2
• Proteinuria and serum albumin should be evaluated after 3 months of treatment to assess clinical response 2
• B-cell depletion should be monitored, though it is not sufficient alone to judge efficacy 2
• Immunologic remission (disappearance of anti-PLA2R antibodies) typically precedes clinical remission (reduction in proteinuria) by several months 1

Alternative Options if Rituximab Fails

• If rituximab fails, calcineurin inhibitors (CNIs) could be considered as an alternative therapy 1
• CNIs can reduce proteinuria through multiple mechanisms but are often less effective at reducing autoantibodies and may lead to rebound of proteinuria after discontinuation 1
• For patients who develop anti-rituximab antibodies (which occurs in approximately 23% of patients), alternative humanized anti-CD20 antibodies like ofatumumab may be effective 6

Important Considerations and Potential Pitfalls

• Patients should continue to receive optimal supportive care, including RAS blockade and blood pressure control 2, 7
• If there is no response to rituximab after 3-6 months, additional evaluation should be performed, including checking anti-PLA2R antibody status 2
• Persistent proteinuria with normal or increasing serum albumin may indicate secondary FSGS rather than active membranous nephropathy 1
• In patients with persistent proteinuria despite disappearance of anti-PLA2R antibodies, a kidney biopsy should be considered to document active disease 1
• Expert consultation is recommended for patients who fail to respond to both rituximab and cyclophosphamide 2