What are the recommended rituximab dosing regimens, screening, monitoring, contraindications, and alternative therapies for adult immune‑mediated kidney diseases such as ANCA‑associated vasculitis, primary membranous nephropathy, and refractory lupus nephritis?

Rituximab in Kidney Diseases: Evidence-Based Management

Rituximab is a first-line therapy for ANCA-associated vasculitis and an important option for refractory membranous nephropathy and lupus nephritis, with specific dosing protocols, mandatory screening requirements, and clear alternatives when contraindicated.

ANCA-Associated Vasculitis (AAV)

Induction Therapy

Rituximab is equivalent to cyclophosphamide for remission induction in AAV and is the preferred agent for relapsing disease. 1

Dosing for induction:

• 375 mg/m² weekly for 4 weeks, combined with glucocorticoids 1, 2
• Achieves remission in 70-90% of patients by 6 months 3, 4

When to choose rituximab over cyclophosphamide: 1

• Relapsing disease (rituximab strongly preferred)
• PR3-ANCA positive patients
• Younger patients concerned about fertility
• Patients with prior cyclophosphamide exposure >36g cumulative dose

When cyclophosphamide is preferred: 1

• Severe renal impairment (serum creatinine >4 mg/dL [354 μmol/L])
• Life-threatening pulmonary hemorrhage with hypoxemia
• In severe cases, consider combining two pulses of cyclophosphamide with rituximab 1

Maintenance Therapy

Rituximab is the preferred maintenance agent for AAV, particularly for relapsing disease and PR3-ANCA patients. 1, 5

Two validated dosing protocols: 1

1. MAINRITSAN scheme: 500 mg × 2 at complete remission, then 500 mg at months 6,12, and 18
2. RITAZAREM scheme: 1000 mg at complete remission, then at months 4,8,12, and 16 (validated specifically for relapsing AAV)

Duration: Minimum 18 months, up to 4 years after achieving remission 1, 5

Glucocorticoid tapering during maintenance: Continue 5-7.5 mg/day for 2 years, then reduce by 1 mg every 2 months 1

When azathioprine is preferred over rituximab: 1

• Baseline IgG <300 mg/dL
• Limited rituximab availability
• Cost considerations

Refractory Disease

For treatment-refractory AAV, switch from cyclophosphamide to rituximab or vice versa. 1

• Increase glucocorticoids (IV or oral) 1
• Add plasma exchange only if diffuse alveolar hemorrhage with hypoxemia is present 1
• Reassess diagnosis to exclude infection, malignancy, or chronic damage 1

Primary Membranous Nephropathy

Rituximab is reserved for patients who fail initial therapy with MMF/MPA or CNIs, though emerging evidence suggests potential first-line use. 1

Dosing considerations:

• Standard lymphoma dosing (375 mg/m² weekly × 4) or modified protocols
• Pharmacokinetics are significantly altered in nephrotic syndrome with heavy proteinuria 6
• May require higher or more frequent dosing due to urinary losses 6

Key caveat: Rituximab clearance increases dramatically with non-selective proteinuria, potentially requiring therapeutic drug monitoring to ensure adequate B-cell depletion 6

Lupus Nephritis

Rituximab is reserved for refractory lupus nephritis after failure of standard therapy (MMF/MPA or cyclophosphamide). 1

Important limitations in lupus nephritis: 1, 6

• Hypocomplementemia (common in SLE) may reduce rituximab efficacy through impaired complement-mediated cytotoxicity
• Not recommended as first-line therapy
• Standard induction regimens (MMF/MPA or cyclophosphamide) remain preferred

Mandatory Pre-Treatment Screening

Before initiating rituximab, screen for: 2

• Hepatitis B: HBsAg, anti-HBc, anti-HBs (reactivation risk is significant)
• Hepatitis C: Anti-HCV antibodies
• HIV: Per institutional protocols
• Baseline immunoglobulins: IgG, IgA, IgM levels 2
• Pregnancy test: In women of childbearing potential

Monitoring During Therapy

Required monitoring parameters: 5, 2

• Serum immunoglobulins: Every 6 months during treatment 5
• Complete blood count: Before each infusion
• Renal function and urinalysis: Monthly initially, then every 3 months
• ANCA titers: Do NOT use to guide rituximab re-dosing; use scheduled protocols instead 1, 5, 7
• CD19+ B-cell counts: Do NOT use to guide re-dosing, as relapses can occur despite B-cell depletion 5, 7

Infection Prophylaxis

Mandatory prophylaxis: 8, 2

• Pneumocystis jirovecii: Trimethoprim-sulfamethoxazole throughout rituximab therapy 5, 8
• Consider antiviral prophylaxis if hepatitis B core antibody positive
• Avoid live vaccines during and for 12 months after rituximab

Contraindications

Absolute contraindications: 2

• Active, severe infections
• Known hypersensitivity to rituximab or murine proteins
• Active hepatitis B infection (relative; requires antiviral coverage)

Relative contraindications requiring careful consideration:

• Severe hypogammaglobulinemia (IgG <300 mg/dL) 1
• History of recurrent severe infections
• Live virus vaccination within 4 weeks

Infusion-Related Reactions

Premedication protocol: 2

• Acetaminophen 650-1000 mg PO
• Diphenhydramine 50 mg PO or IV
• Consider methylprednisolone 100 mg IV for first infusion

Incidence: 12% experience infusion reactions with first dose, decreasing to 1-4% with subsequent infusions 2

Common symptoms: Cytokine release syndrome, flushing, throat irritation, tremor 2

Alternative Therapies When Rituximab Fails or Is Contraindicated

For AAV:

Induction alternatives: 1

• Cyclophosphamide (2 mg/kg/day oral or IV pulses)
• Consider plasma exchange for severe renal disease or pulmonary hemorrhage with hypoxemia

Maintenance alternatives: 1

• Azathioprine 1.5-2 mg/kg/day (first-line alternative)
• Mycophenolate mofetil 2000 mg/day in divided doses (second-line)
• Methotrexate (only if GFR >60 mL/min/1.73 m²) 1

For Membranous Nephropathy:

Standard first-line options: 1

• MMF/MPA at doses used for class III/IV lupus nephritis
• Calcineurin inhibitors (tacrolimus or cyclosporine)
• Cyclophosphamide (older regimen)

For Lupus Nephritis:

Standard first-line regimens: 1

• MMF/MPA 2-3 g/day (preferred)
• Cyclophosphamide (Euro-Lupus or NIH protocols)
• Tacrolimus + MMF combination (especially for nephrotic-range proteinuria)

Critical Pitfalls to Avoid

Do not combine rituximab with MMF for AAV maintenance therapy - these are alternative monotherapy options, not meant to be used together 7

Do not use ANCA titers or B-cell counts to guide rituximab re-dosing - use scheduled protocols instead, as disease flares can occur despite negative ANCA or complete B-cell depletion 1, 5, 7

Do not discontinue immunosuppression before 18 months - significantly increases relapse risk 5

Account for altered pharmacokinetics in nephrotic syndrome - rituximab clearance increases dramatically with heavy proteinuria, potentially requiring dose adjustments 6

Hold plasma exchange 48-72 hours after rituximab infusion - to avoid removing the antibody 7

Monitor for hypogammaglobulinemia - occurs in 27-58% of patients by 6 months and increases infection risk 2