Management of Persistent Proteinuria >1g/day in Primary Membranous Nephropathy
In patients with primary membranous nephropathy who have proteinuria persistently greater than 1 g/day despite 3-6 months of optimized supportive care (ACE inhibitors/ARBs and blood pressure control), immunosuppressive therapy should be initiated with either rituximab or cyclophosphamide plus alternate-month glucocorticoids, with rituximab preferred as first-line therapy based on the most recent high-quality evidence. 1
Risk Stratification and Treatment Threshold
Immunosuppressive therapy is specifically indicated when proteinuria remains ≥1 g/day after 3-6 months of optimized supportive care, particularly if the patient has elevated anti-PLA2R antibody levels, eGFR >50 ml/min per 1.73 m², or complications of nephrotic syndrome. 1
The 2021 KDIGO guidelines establish that patients with at least one risk factor for disease progression—including persistent proteinuria >3.5 g/day, serum albumin <30 g/l, or declining eGFR—should receive immunosuppressive therapy rather than continued observation. 1
Approximately 40-60% of untreated patients with nephrotic-range proteinuria will progress to end-stage renal disease within 10 years, making early intervention critical for those who fail conservative management. 2, 3
First-Line Immunosuppressive Options
Rituximab (Preferred First-Line)
Rituximab is the preferred initial immunosuppressive agent based on the MENTOR trial, which demonstrated superiority over cyclosporine for inducing proteinuria remission with a more favorable safety profile. 1, 4
The standard rituximab regimen consists of 1000 mg IV on days 1 and 15, or 375 mg/m² weekly for 4 weeks, with response evaluated at 3 months by monitoring anti-PLA2R antibody levels and proteinuria. 1
Rituximab achieves immunologic remission (disappearance of anti-PLA2R antibodies) before clinical remission (reduction in proteinuria), with antibody levels declining within weeks while proteinuria may persist for months. 2, 5
Cyclophosphamide Plus Glucocorticoids (Alternative First-Line)
The modified Ponticelli regimen—alternating monthly cycles of IV methylprednisolone (1g for 3 days) followed by oral prednisone (0.4 mg/kg/day) with oral cyclophosphamide (2 mg/kg/day) for 6 months—represents the only therapy proven to preserve kidney function over long-term follow-up. 1
This regimen should be considered for patients with rapidly declining eGFR or those at highest risk for progression, though it carries greater toxicity including infection risk, bone marrow suppression, and gonadal toxicity. 1, 4
The cumulative cyclophosphamide dose should not exceed 10 g if fertility preservation is required, and should not exceed 36 g to limit malignancy risk. 1
Monitoring Treatment Response
Longitudinal monitoring of anti-PLA2R antibody levels at 6 months after starting therapy is essential for evaluating treatment response and guiding adjustments, as immunologic remission precedes clinical remission by several months. 1
If anti-PLA2R antibodies disappear by 6 months but proteinuria persists with improving serum albumin, consider secondary focal segmental glomerulosclerosis rather than treatment failure, and a repeat kidney biopsy may be warranted. 1
Persistent anti-PLA2R antibodies at 6 months despite treatment indicates inadequate immunosuppression and should prompt either continuation of current therapy or switching to an alternative agent. 1
Management of Treatment-Resistant Disease
For patients who fail to respond to initial rituximab therapy (defined as persistent proteinuria with stable or rising anti-PLA2R antibodies at 6 months), switch to cyclophosphamide plus glucocorticoids if eGFR is declining, or consider a second rituximab cycle if eGFR remains stable. 1
Patients who fail cyclophosphamide should be switched to rituximab, as cross-resistance between these mechanistically distinct agents is uncommon. 1
Consultation with an expert center is recommended for patients who fail both rituximab and cyclophosphamide, as experimental therapies (bortezomib, anti-CD38 therapy, belimumab) may be considered. 1
Calcineurin Inhibitors (Third-Line)
Tacrolimus-based therapy for ≥6 months can be used as an alternative when rituximab and cyclophosphamide are contraindicated, but should be considered third-line due to high relapse rates after discontinuation and lack of sustained immunologic remission. 1, 4
Calcineurin inhibitors reduce proteinuria through hemodynamic effects rather than immunologic mechanisms, resulting in frequent rebound of both proteinuria and anti-PLA2R antibodies after drug withdrawal. 1
Critical Contraindications and Safety Monitoring
Do not initiate immunosuppressive therapy in patients with eGFR <30 ml/min per 1.73 m² unless there is crescentic disease with rapidly deteriorating kidney function, as outcomes are poor and toxicity risk is substantially elevated. 1
Monitor serum creatinine and potassium within 1-2 weeks of starting or intensifying ACE inhibitor/ARB therapy to detect hyperkalemia or acute kidney injury. 1
Check compliance and treatment efficacy markers (B-cell response for rituximab, leukocyte counts for cyclophosphamide, drug levels for calcineurin inhibitors) when evaluating apparent treatment resistance. 1
Common Pitfalls to Avoid
Do not interpret persistent proteinuria alone as treatment failure—immunologic remission (disappearance of anti-PLA2R antibodies) is the primary endpoint, and proteinuria may lag by 6-12 months. 1, 2
Avoid sequential tacrolimus-rituximab regimens, as the STARMEN trial demonstrated this approach is inferior to other rituximab protocols and offers no advantage over rituximab monotherapy. 4
Do not delay immunosuppressive therapy beyond 6 months of optimized supportive care in patients with persistent nephrotic-range proteinuria and elevated anti-PLA2R antibodies, as prolonged nephrotic syndrome increases risks of thromboembolism, infection, and irreversible kidney damage. 1, 2