Rituximab Immunomonitoring Predicts Remission in Membranous Nephropathy

Abstract

Primary membranous nephropathy (pMN) is an autoimmune kidney disease and a common cause of nephrotic syndrome in adults. Rituximab is becoming a first line therapy for patients with persistent nephrotic syndrome with proven safety and efficacy, achieving remission in 60%–80% of cases. For the remaining 20%–40% of patients there is an urgent need to identify early biomarkers of resistance to rituximab to adapt therapeutic management. In nephrotic patients, rituximab is found in the blood more transiently than in other autoimmune diseases without proteinuria, due to rituximab wasting in the urine. However, rituximab immunomonitoring is not routinely performed. We evaluated the predictive value of serum rituximab levels in patients with pMN three months after rituximab injection (month-3) on clinical remission rates six months (month-6) and 12 months (month-12) after injection and investigated predictive factors for serum rituximab levels at month-3. Sixty-eight patients treated with rituximab between July 2015 and January 2020 from two French nephrology centers were included. We identified residual rituximab levels at month-3 as a novel early predictor of remission at month-6 (p <0.0001) and month-12 (p = 0.001). Reduced likelihood of remission in patients with undetectable rituximab at month-3 was associated with lower serum albumin and higher anti-PLA2R1 titers at baseline and with lower serum albumin, higher proteinuria, higher CD19+ counts and higher anti-PLA2R1 titers during follow-up. In multivariate analysis, high baseline proteinuria and undetectable rituximab levels at month-3 were independent risk factors for treatment failure at month-6 and high baseline weight and undetectable rituximab levels at month-3 were independent risk factors for treatment failure at month-12. We identified serum albumin at baseline as a predictive factor for serum rituximab levels at month-3. Patients with serum albumin below 22.5 g/L at baseline had an 8.66-fold higher risk of having undetectable rituximab levels at month-3. Therefore, rituximab immunomonitoring in pMN patients treated with rituximab would allow the detection of patients at risk of treatment failure as early as month-3. Studies are needed to assess whether patients with low residual rituximab levels at month-3 may benefit from an early additional course of rituximab.

Advances in the Management of Primary Membranous Nephropathy and Rituximab-Refractory Membranous Nephropathy

“…Rituximab underdosing is not uncommon in pMN ( 63 , 64 ). Indeed, rituximab bioavailability is significantly decreased in pMN compared to other non-nephrotic autoimmune diseases due to the binding of rituximab to albumin and its wasting in the urine ( 63 , 65 , 66 ).…”

“…Indeed, rituximab bioavailability is significantly decreased in pMN compared to other non-nephrotic autoimmune diseases due to the binding of rituximab to albumin and its wasting in the urine ( 63 , 65 , 66 ). We have shown that rituximab was undetectable three months (month-3) after rituximab infusion (two 1 g infusions two weeks apart) in 56% of nephrotic pMN, these patients were less likely to achieve clinical and immunological remission ( 64 ). Patients with the most severe nephrotic syndrome – with a baseline albumin level of less than 22.5 g/L – were more likely to have an undetectable serum rituximab level at month-3 ( 64 ).…”

“…We have shown that rituximab was undetectable three months (month-3) after rituximab infusion (two 1 g infusions two weeks apart) in 56% of nephrotic pMN, these patients were less likely to achieve clinical and immunological remission ( 64 ). Patients with the most severe nephrotic syndrome – with a baseline albumin level of less than 22.5 g/L – were more likely to have an undetectable serum rituximab level at month-3 ( 64 ). Serum rituximab level can be measured by ELISA (which costs about 40€ in France).…”

“…In nephrotic patients, the bioavailability of rituximab is decreased due to the elimination of rituximab in the urine ( 63 , 64 ). Uncertainty remains regarding the rituximab dosing protocol to be used in nephrotic patients.…”

Therapies for Membranous Nephropathy: A Tale From the Old and New Millennia

“…It is also unclear what the optimal dosing strategy of rituximab is. Importantly, patients with higher proteinuria and lower serum albumin at time of rituximab infusion show lower residual serum rituximab levels at month-3 ( 102 ), and this was associated with subsequent lower response rates ( 103 ). These findings support the idea that rituximab dose can affect the response, especially in patients with higher proteinuria.…”