What is the role of Rituximab (rituximab) in treating adult patients with membranous nephropathy who are unresponsive to initial therapies, such as corticosteroids and immunosuppressive agents?

Rituximab in Membranous Nephropathy

Primary Recommendation

Rituximab is a first-line treatment option for primary membranous nephropathy requiring immunosuppression, with equivalent efficacy to cyclophosphamide-based regimens and superior safety profile. 1, 2 For patients unresponsive to initial therapies such as corticosteroids and calcineurin inhibitors, rituximab is the recommended second-line agent when eGFR remains stable. 3, 1

Treatment Algorithm Based on Prior Therapy

For Patients Failing Calcineurin Inhibitors (CNIs)

• Switch to rituximab when eGFR is stable, as this is the guideline-recommended approach for CNI-resistant disease. 3, 1
• If eGFR is declining, cyclophosphamide plus glucocorticoids becomes the preferred option instead. 3, 2

For Patients Failing Cyclophosphamide

• Rituximab is recommended as the alternative second-line therapy. 3
• The 2021 KDIGO guidelines explicitly outline this treatment sequence in their resistant disease algorithm. 3

For Patients Failing Multiple Therapies

• Consultation with an expert center is advised for consideration of experimental therapies (bortezomib, anti-CD38 therapy, belimumab) or higher doses of conventional immunosuppression. 3

Standard Dosing Protocol

Two clinically equivalent rituximab dosing regimens exist: 3, 1

• 1 gram administered on days 1 and 15 (two doses, two weeks apart)
• 375 mg/m² weekly for 4 weeks (four doses total)

Both protocols appear equally effective, though the 1 gram × 2 regimen is increasingly preferred for convenience. 3, 1

Critical Monitoring Parameters

Early Response Assessment (3 Months)

• Evaluate proteinuria and serum albumin levels to determine clinical response trajectory. 3, 1
• Measure anti-PLA2R antibody levels to guide treatment adjustments—antibody depletion predicts remission even before proteinuria improves. 3, 1, 4
• B-cell depletion should be monitored but is insufficient alone to judge treatment efficacy. 3, 1

Common Pitfall to Avoid

• Do not interpret persistent proteinuria alone as treatment failure—response may take 3-6 months, and serum albumin improvement with persistent proteinuria may indicate secondary FSGS rather than active membranous nephropathy. 3, 1
• If proteinuria persists despite normalized albumin or loss of anti-PLA2R antibodies, consider repeat kidney biopsy to document active disease. 3

Compliance and Efficacy Verification

• Check compliance with therapy and monitor B-cell response, anti-rituximab antibodies, and IgG levels when evaluating apparent resistance. 3
• Recent evidence suggests urinary rituximab loss correlates with treatment failure—patients with urinary rituximab ≥2 µg/mL had significantly lower response rates (43% vs 100%) and may benefit from additional dosing. 4

Mandatory Supportive Care

All Patients Must Receive

• RAS blockade (ACE inhibitors or ARBs) with blood pressure target <130/80 mmHg. 1, 2
• Statin therapy for dyslipidemia management. 2
• Diuretics for edema control as needed. 5

Thromboembolism Prophylaxis

• Strongly consider prophylactic anticoagulation when serum albumin <20-25 g/L due to extremely high thromboembolism risk in nephrotic syndrome. 1, 2
• This is a critical safety measure often overlooked in practice. 1

Essential Safety Measures

Infection Prophylaxis

• Administer prophylactic trimethoprim-sulfamethoxazole to prevent Pneumocystis jirovecii pneumonia during rituximab therapy. 1, 2

Pre-Treatment Screening

• Screen for hepatitis B before initiating rituximab due to risk of viral reactivation. 2

Long-Term Monitoring

• Monitor for hypogammaglobulinemia with repeated rituximab cycles, which increases infection risk. 1, 2
• Counsel patients about reduced vaccine efficacy during treatment—ideally vaccinate before starting therapy. 1, 2
• Be aware of rare but serious risk of progressive multifocal leukoencephalopathy (PML). 1, 2

Evidence Quality and Strength

The 2021 KDIGO guidelines (the most recent and authoritative source) provide Grade 1B recommendations for rituximab as first-line therapy, indicating high-quality evidence. 3, 1 This represents a significant evolution from the 2013 KDOQI commentary, which noted rituximab was "not specifically recommended" due to lack of RCTs but acknowledged it as "reasonable" for treatment failures. 3

The key difference: Modern guidelines now position rituximab as equivalent to traditional first-line agents based on accumulated evidence, particularly for patients with stable kidney function. 3, 1, 2 The MENTOR trial and subsequent studies have established rituximab's efficacy, with complete remission rates of 15-20% and partial remission rates of 35-40%. 6

Special Considerations for Kidney Insufficiency

Recent evidence suggests rituximab may be effective even in patients with kidney insufficiency (eGFR <60 mL/min/1.73 m²), though response rates are lower (20% at 6 months). 7 Responders showed significant improvements in anti-PLA2R antibodies, proteinuria, and maintained stable kidney function. 7 This expands rituximab's potential role beyond the traditional stable eGFR indication. 7

Retreatment for Relapse

• Reinstitute rituximab using the same initial dosing protocol (1 gram × 2 doses, two weeks apart) for patients who relapse after achieving remission with rituximab. 3
• The likelihood of response to retreatment is high in patients who initially responded. 3