Management of Persistent Membranous Nephropathy After Treatment with Cyclophosphamide, Prednisone, and Rituximab
For patients with persistent membranous nephropathy after treatment with cyclophosphamide, prednisone, and rituximab, the next step should be determined by measuring anti-PLA2R antibody status and evaluating kidney function (eGFR), with consideration for calcineurin inhibitor therapy or additional rituximab depending on these parameters. 1
Evaluation of Treatment Resistance
Before proceeding with additional therapy, it's essential to properly evaluate treatment resistance:
- Check anti-PLA2R antibody status - This is the primary biomarker to guide further management 1
- Evaluate kidney function - Determine if eGFR is stable or declining 1
- Verify treatment compliance and efficacy - Check B-cell response, anti-rituximab antibodies, IgG levels 1
- Consider kidney biopsy - Especially if proteinuria persists despite disappearance of anti-PLA2R antibodies to rule out secondary FSGS 1
Treatment Algorithm Based on Anti-PLA2R Status and Kidney Function
If anti-PLA2R antibodies are present:
- With stable eGFR: Add additional rituximab (1-2 infusions of 1g each, 2 weeks apart) 1
- With declining eGFR: Consider calcineurin inhibitor therapy in combination with rituximab 1
If anti-PLA2R antibodies are absent:
- With stable eGFR: Consider calcineurin inhibitor therapy with tapering schedule 1
- With declining eGFR: Evaluate for other causes of kidney dysfunction; if attributed to MN activity, consultation with an expert center is advised 1
If anti-PLA2R antibodies are present but at low levels (<50 RU/ml):
- Carefully monitor - These patients may still achieve remission with time 1
- Consider calcineurin inhibitor for 6 months with re-evaluation 1
Specific Treatment Options
Calcineurin Inhibitor Therapy:
- Duration: 6-12 months 1
- Caution: Monotherapy has high relapse rate after withdrawal 1
- Monitoring: Regular CNI levels, kidney function, and proteinuria 1
- Combination: In patients with persistent anti-PLA2R antibodies, consider combining with rituximab 1
Additional Rituximab:
- Dosing: Similar to initial treatment (1-2 infusions of 1g each, 2 weeks apart) 1
- Monitoring: Evaluate response of proteinuria and anti-PLA2R antibodies after 3 months 1
- B-cell depletion: Not sufficient to judge efficacy; extra doses may be considered even with absent peripheral B cells 1
Special Considerations
- Cumulative cyclophosphamide exposure: Should not exceed 36g total dose (preferably limit to 25g) due to malignancy risk 1
- Fertility concerns: Maximum 10g cyclophosphamide for patients who wish to conceive 1
- Expert consultation: Recommended for patients who fail to respond to both rituximab and cyclophosphamide 1
- Novel approaches: Combination therapy with rituximab plus calcineurin inhibitors has shown promising results in pilot studies 2
Monitoring Response
- Proteinuria: Regular monitoring of urine protein-to-creatinine ratio 3
- Anti-PLA2R antibodies: Check at 3-month intervals; immunologic remission precedes clinical remission 1
- Kidney function: Regular monitoring of serum creatinine and eGFR 1
- Serum albumin: Improvement indicates therapeutic response even with persistent proteinuria 1
Pitfalls to Avoid
- Defining resistance by proteinuria alone: Persistent proteinuria with improving serum albumin may indicate secondary FSGS rather than active MN 1
- Excessive immunosuppression: Balance efficacy against risk of infections and malignancy 1
- Inadequate monitoring: Anti-PLA2R antibody levels should guide therapy decisions 1
- Premature treatment changes: Response may take time; immunologic remission typically occurs within 3 months, but clinical remission may take longer 1