Timing of Rituximab Addition to CNI Therapy in Membranous Nephropathy
In high-risk membranous nephropathy patients, rituximab should be added after 6 months of calcineurin inhibitor (CNI) treatment if the patient has not achieved adequate response, rather than starting both agents simultaneously. 1
Risk-Based Treatment Strategy
The approach depends critically on the patient's risk stratification at baseline:
High-Risk Patients (eGFR <60 ml/min/1.73 m² and/or proteinuria >8 g/d for >6 months)
- Start with CNI monotherapy (with glucocorticoids) and reassess at 6 months 1
- Add rituximab after 6 months of CNI treatment if adequate response has not been achieved 1
- The key exception: if anti-PLA2R antibodies have disappeared during the 6-month CNI treatment period, additional rituximab may not be necessary 1
Moderate-Risk Patients (Normal eGFR, proteinuria >3.5 g/d without 50% decrease after 6 months conservative therapy)
- CNI monotherapy may be considered, though it is less efficient and associated with high relapse rates upon withdrawal 1
- These patients may develop spontaneous remission, so CNI can shorten the period of proteinuria while monitoring 1
Rationale for Sequential Rather Than Simultaneous Therapy
CNI monotherapy for 6-12 months with rapid withdrawal is associated with high relapse rates, which is why the sequential addition of rituximab is recommended for high-risk patients. 1
The guideline explicitly states that in patients with high risk of progression, addition of rituximab after 6 months of CNI treatment is advised, indicating a sequential rather than simultaneous approach. 1
Monitoring During the 6-Month CNI Period
Anti-PLA2R Antibody Monitoring
- Check anti-PLA2R antibodies at 3-6 month intervals (shorter intervals for patients with high baseline levels) 1
- If anti-PLA2R antibodies disappear during CNI treatment, refrain from adding rituximab 1
- Disappearance of anti-PLA2R antibodies precedes clinical remission and indicates immunologic response 1
Clinical Parameters
- Monitor proteinuria, serum albumin, and kidney function (eGFR/serum creatinine) regularly 2
- Assess for CNI-related nephrotoxicity (unexplained rise in creatinine >20%) 3
- Monitor CNI blood levels throughout treatment 3
Decision Algorithm at 6 Months
If Anti-PLA2R Antibodies Are Present:
- With stable eGFR: Add rituximab (1-2 infusions of 1g each, 2 weeks apart) 2
- With declining eGFR: Add rituximab AND continue CNI in combination 2
If Anti-PLA2R Antibodies Are Absent:
- Taper the CNI rather than adding rituximab 1
- Continue CNI for total duration of 12-24 months after achieving remission 3
If Anti-PLA2R Antibodies Decreased to Low Levels (<50 RU/ml):
- Continue CNI for another few months and re-evaluate at 6 months before deciding on rituximab 1
Evidence for Combination Therapy
While one small pilot study (n=13) showed promising results with simultaneous rituximab plus cyclosporine from the start, achieving 92% combined remission by 9 months 4, this approach is not reflected in the KDIGO 2021 guidelines, which represent the highest quality evidence and recommend sequential therapy. 1
Critical Pitfalls to Avoid
- Do not start both agents simultaneously in routine practice - the guideline-recommended approach is sequential addition after 6 months 1
- Do not add rituximab if anti-PLA2R antibodies have disappeared during CNI treatment, as this indicates immunologic remission 1
- Do not rely solely on proteinuria to judge response - persistent proteinuria with improving serum albumin may indicate secondary FSGS rather than active disease 2
- Do not continue CNI indefinitely without rituximab in high-risk patients who fail to respond at 6 months, as this leads to high relapse rates 1