What is the role of Rituximab (rituximab) in the treatment of membranous nephropathy?

Rituximab in Membranous Nephropathy

Rituximab is now a first-line treatment option for primary membranous nephropathy with nephrotic syndrome and risk factors for disease progression, with equivalent efficacy to cyclophosphamide-based regimens and a more favorable safety profile. 1

First-Line Treatment Indications

For patients with primary membranous nephropathy requiring immunosuppression, rituximab should be considered as initial therapy alongside cyclophosphamide/glucocorticoids or calcineurin inhibitors, particularly when eGFR is stable. 1

Immunosuppressive therapy is indicated when patients have: 1, 2

• Proteinuria ≥3.5 g/day with serum albumin <30 g/L (by bromocresol purple) or <25 g/L (by bromocresol green)
• eGFR >60 ml/min per 1.73 m² with at least one risk factor for progression
• Serious complications of nephrotic syndrome (AKI, infections, thromboembolic events)

Standard Dosing Protocol

The recommended rituximab dosing is either 1 gram administered on days 1 and 15 (two weeks apart), or 375 mg/m² weekly for 4 weeks—both regimens appear clinically equivalent. 1, 2

Treatment Response and Monitoring

Clinical response to rituximab typically occurs within 3-6 months, though proteinuria may persist for months after immunologic remission. 2

Key monitoring parameters include: 1, 2

• Proteinuria and serum albumin at 3 months to assess clinical response
• Anti-PLA2R antibody levels (if initially positive) to guide treatment adjustments
• B-cell depletion, though this alone is insufficient to judge efficacy

Complete remission is defined as proteinuria <0.3 g/day, while partial remission requires proteinuria <3.5 g/day with ≥50% reduction from baseline. 3

The overall response rate with rituximab is approximately 60-70%, with complete remission in 15-20% and partial remission in 35-40% of patients. 4, 5

Second-Line Use After Treatment Failure

For patients who fail calcineurin inhibitor-based therapy with stable eGFR, rituximab is the recommended next treatment option. 1, 2

Rituximab as second-line therapy achieves similar remission rates to first-line use, though first-line therapy may produce slightly higher cumulative remission rates. 5, 6

In patients previously treated with steroids, alkylating agents, or cyclosporine, rituximab reduced proteinuria by approximately 50-70% at 1-2 years, with 8 of 11 patients achieving full or partial remission in one matched-cohort study. 6

Management of Rituximab Resistance

Approximately 30% of patients fail to respond to rituximab, potentially due to urinary drug loss in severe nephrotic syndrome. 3, 7

For rituximab-resistant patients: 1

• Verify compliance and check B-cell response, anti-rituximab antibodies, and IgG levels
• Consider repeat dosing if urinary rituximab loss is significant (≥2 µg/mL)
• Switch to cyclophosphamide/glucocorticoids if eGFR is declining
• Consider ofatumumab (a second-generation anti-CD20 antibody) as an alternative

In rituximab-intolerant patients with hypersensitivity reactions, ofatumumab (50-300 mg single infusion) achieved complete or partial remission in all 7 patients in one case series. 3

Comparative Efficacy

A 2022 meta-analysis of 11 trials (723 participants) demonstrated that rituximab significantly improved cumulative remission compared to other treatments (OR=3.06,95% CI 1.35-6.94, P=0.007). 5

Rituximab also significantly reduced: 5

• Relapse rates (OR=0.06,95% CI 0.02-0.19, P<0.00001)
• Anti-PLA2R antibody levels (SMD=-0.52,95% CI -0.83 to -0.21, P=0.0009)
• Proportion of anti-PLA2R antibody-positive patients (OR=6.11,95% CI 1.85-20.24, P=0.003)

Safety Profile

Rituximab is generally well-tolerated with minimal adverse events, primarily self-limited infusion-related reactions. 4, 6

Important safety considerations include: 1, 2

• Prophylactic trimethoprim-sulfamethoxazole to prevent Pneumocystis jirovecii pneumonia
• Risk of hypogammaglobulinemia with repeated cycles
• Rare but serious complications: hepatitis B reactivation, progressive multifocal leukoencephalopathy
• Reduced vaccine efficacy during treatment

Supportive Care Requirements

All patients receiving rituximab must continue optimal supportive care, including RAS blockade, blood pressure control to <130/80 mmHg, and management of nephrotic complications. 1, 8, 2

Prophylactic anticoagulation should be strongly considered when serum albumin is <20 g/L (by bromocresol purple) or <25 g/L (by bromocresol green) due to high thromboembolism risk. 1, 2

Common Pitfalls to Avoid

Do not interpret persistent proteinuria alone as treatment failure—proteinuria may lag behind immunologic remission by several months. 8, 2

Do not rely solely on B-cell depletion to assess treatment efficacy; anti-PLA2R antibody levels and clinical parameters are more reliable indicators. 1, 2

Do not discontinue rituximab prematurely—response may take 3-6 months, and some patients benefit from additional dosing even with peripheral B-cell depletion. 1

In patients with severe proteinuria and low serum rituximab levels, consider measuring urinary rituximab loss to identify those who may benefit from higher or repeated dosing. 7