Mycophenolate Mofetil after Rituximab for Childhood-onset Complicated Frequently-relapsing or Steroid-dependent Nephrotic Syndrome

Background. Rituximab is the standard therapy for childhood-onset complicated frequently-relapsing or steroid-dependent nephrotic syndrome (FRNS/SDNS). However, most patients redevelop FRNS/SDNS following peripheral B cell recovery. Methods. We conducted a multicenter, randomized, double-blind, placebo-controlled trial to examine whether mycophenolate mofetil (MMF) administration after rituximab can prevent treatment failure (FRNS, SDNS, steroid resistance, or use of immunosuppressive agents or rituximab). Thirty-nine patients (per group) were treated with rituximab, followed by either MMF or placebo until Day 505 (treatment period). The primary outcome was time to treatment failure (TTF) throughout the treatment and follow-up periods (until Day 505 for the last enrolled patient). Results. TTFs were clinically but not statistically significantly longer among patients given MMF after rituximab than among patients receiving rituximab monotherapy (median: 784.0 vs. 472.5 days, hazard ratio (HR): 0.593, 95% confidence interval (CI): 0.336-1.049, log-rank test: P=0.0694). Because most patients in the MMF group presented with treatment failure after MMF discontinuation, we performed a post-hoc analysis limited to the treatment period and found that MMF after rituximab prolonged the TTF and decreased the risk of treatment failure by 80% (HR: 0.202, 95% CI: 0.081-0.503). Moreover, MMF after rituximab reduced the relapse rate and daily steroid dose during the treatment period by 74% and 57%, respectively. The frequency and severity of adverse events were similar in both groups. Conclusions. Administration of MMF after rituximab may sufficiently prevent the development of treatment failure and is well tolerated, although the relapse-preventing effect disappears after MMF discontinuation.

Population Pharmacokinetics of Rituximab in Pediatric Patients With Frequent-Relapsing or Steroid-Dependent Nephrotic Syndrome

Objectives: Rituximab is frequently used off-label for the treatment of frequent-relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS), but the relapse rate remained high and the dosing regimen varied widely. The objective of this study was to characterize rituximab pharmacokinetics (PK) in pediatric patients with FRNS/SDNS, and to investigate the differences in rituximab PK between patients with FRNS/SDNS and other disease populations.Methods: Fourteen pediatric patients received rituximab for FRNS/SDNS treatment were enrolled in a prospective, open-label, single-center PK study. A population PK model of rituximab was developed and validated, and PK parameters were derived for quantitative evaluation.Results: A two-compartment PK model best described the data. Body surface area was the most significant covariate for both central clearance (CL) and apparent central volume of distribution (V1). Patients with FRNS/SDNS exhibited a clinically relevant increase in rituximab CL compared to patient population with non-Hodgkin’s lymphoma (NHL).Conclusion: This pilot study indicated that higher doses or more frequent regimens of rituximab may be required for optimal therapeutic effects in patients with FRNS/SDNS. Further clinical studies with more patients are warranted to confirm this result.

Corticosteroid Sparing Agents in Frequent Relapsing and Steroid Dependent Nephrotic Syndrome in Children: A Single Center Retrospective Study

Background: Children with frequently relapsing nephrotic syndrome (FRNS) or Steroid-dependent nephrotic syndrome (SDNS) may be prescribed non-corticosteroid immunosuppressive agents whenever there is a failure to maintain remission with low-dose alternate-day prednisone and/or significant adverse effects of prednisone develop. A wide variety of immunosuppressive agents have been used in these patients to reduce the number of relapses and maintain remission. Objective: to evaluate the outcome of Steroid sparing agents in the management of FRNS and SDNS in children with nephrotic syndrome. Patients and methods: A retrospective study was conducted on all steroid-sensitive nephrotic syndrome (SSNS) children (1-11 years) who received any type of second line agents (e.g. CNI, MMF, cyclophosphamide, and Rituximab) over a period of 9 years from January 2010 to January 2019 in pediatric nephrology unit in Prince Sultan Military Medical City, Riyadh. Results: The study included 24 patients. Their age at diagnosis ranged between 1 and 11 years with a mean of 3.8 years and standard deviation of (±) 2.6 years. During the first year of steroid therapy, relapse occurred among 87% of patients; of them, the number of relapses being 4 or more in 21.7%. Regarding indication for the second line of treatment, SDNS was the most frequent reported (60.9%), followed by FRNS (30.4%). Concerning agents used in the second line, MMF ranked first (58.4%), followed by Cyclophosphamide (33.3%). Number of relapses after starting steroid sparing agent was more than once among 41.7% of patients. Duration of remission after starting steroid sparing agent ranged between 2 and 72 months (14±14.1). Overall response to the second line of treatment was observed among majority of patients (91.7%). Renal biopsy was performed in 45.8% of patients. Concerning side effects of steroid sparing agents, electrolytes disturbances and hypertension were reported by two (8.3%) and one (4.2%) patients respectively. Duration of remission was significantly longer among patients treated with cyclosporine (48±33.9 months) compared to other lines of treatment, p<0.001. On the other hand, hypertension was only reported among patients treated with cyclosporine, p=0.003. Conclusion: The overall response of children with SDNS and FRNS to the second line agents was significant, with favorable longer remission free period with Cyclosporine use with no major side effects. Our results affected by the retrospective design of the study, as well as the small sample size. Therefore larger scale study with prospective design is highly encouraged.

The Efficacy and Safety of Rituximab for Childhood Steroid-Dependent Nephrotic Syndrome: A Systematic Review and Meta-Analysis

Objectives: Rituximab (RTX), a possible alternative treatment option, is recognized as a new therapeutic hope for the treatment of steroid-dependent nephrotic syndrome (SDNS) in children. However, the efficacy and safety of RTX in the treatment of childhood SDNS are still controversial. The objective of this study was to evaluate the efficacy and safety of RTX treatment in children with SDNS.Study Design: Six randomized controlled trials (RCTs) and one retrospective comparative control study data from studies, performed before January 2021 were collected, from PubMed, Cochrane Library, Embase, and Web of Science. The studies evaluating the efficacy and safety of RTX in childhood SDNS were included.Results: Six RCTs and one retrospective comparative control study were included in our analysis. Compared with the control group, the RTX treatment group achieved a higher complete remission rate (OR = 5.21; 95% CI, 3.18–8.54; p &lt; 0.00001), and we found significant differences between the two groups on serum albumin level (MD = 0.88; 95% CI, 0.43–1.33; p = 0.0001) and estimated glomerular filtration rate (MD = 6.43; 95% CI, 2.68–10.19; p = 0.0008). However, RTX treatment did not significantly lower serum creatinine levels nor did it significantly reduce the occurrence of proteinuria. In addition, we found no advantages with RTX on treatment safety.Conclusions: RTX has shown satisfactory characteristics in terms of efficacy and may be a promising treatment method for SDNS in children. However, the long-term effects have not been fully evaluated and should be further studied through randomized clinical trials.

MO291RITUXIMAB IS EFFECTIVE AND SAFE IN ADULTS WITH STEROID-DEPENDENT NEPHROTIC SYNDROME: A LONG-TERM, SINGLE-CENTER EXPERIENCE

Background and Aims Steroid-dependent nephrotic syndrome (SDNS) may require a prolonged multi-drug therapy with risk of drug toxicity and renal failure. Rituximab (RTX) treatment has been found to be helpful in reducing the steroid dosage and the need for immunosuppressants (ISs), but little data are currently available regarding very long-term outcomes in adults. We herein describe a long-term, single-center experience of RTX use in a large series of adults with SDNS. Method We studied 23 adult patients with SDNS (mean age 54.2±17.1 y; 65% male; BMI 28.5±4.7), mostly consequent to membranous (47.8%) or focal glomerulonephritis (30.2 %) who were eligible to start a RTX regimen. Before entering the RTX protocol, proteinuria and eGFR were 7.06±3.87 g/24h and 65.9±28.2 ml/min/1.73 m2, respectively; albumin and CD19/CD20 ratio were 2.9±0.9 g/L and 0.99±0.01 respectively; the mean number of ISs was 2.39±0.89 and the mean annual rate of relapses was 2.2±0.9. Results Patients were followed over a mean follow-up of 64 months (range: 12-144). After RTX (mean dose: 1202.1±372.4 mg) the rate of relapses was virtually nullified (p&lt;0.001). eGFR remained roughly stable (62.1±19.8 ml/min/1.73 m2, p=NS), while proteinuria, albumin, CD19/CD20 and BMI all significantly improved (p ranging from 0.01 to 0.001). The mean number of additional ISs was also reduced (0.44±0.12; p&lt;0.001) and RTX enabled discontinuation of steroids in 13/23 (56.5%) patients. No major adverse events related to therapy were recorded. Conclusion Findings from this large case-series with a remarkable very long follow-up reinforce the role of RTX as an efficient and safe weapon to improve outcomes in adult patients suffering from SDNS.