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      Low-dose rituximab is no less effective for nephrotic syndrome measured by 12-month outcome

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          Abstract

          Objective

          Rituximab is an effective treatment for children with steroid dependent or frequently relapsing nephrotic syndrome. The optimum dosing schedule for rituximab has not been established. We hypothesized that a single low dose of 375 mg/m 2 would have comparable outcomes to higher doses in reducing the frequency of relapse and time to B cell reconstitution.

          Methods

          We conducted a multicenter retrospective observational cohort study of children with steroid-sensitive frequently relapsing nephrotic syndrome. Data were extracted from clinical records including the dates of diagnosis, treatment, relapses, the use of concomitant immunosuppression, and lymphocyte subset profiling. Patients treated earlier received variable doses of rituximab, although typically two doses of 750 mg/m 2. Later, patients received the current regimen of a single dose of 375 mg/m 2. The primary outcome was an absence of clinically confirmed relapse 12 months following rituximab administration. Secondary outcomes were median time to relapse, probability of being relapse-free at 6 and 24 months and time to reconstitution of CD19 + B cells.

          Results

          Sixty patients received 143 courses of rituximab. Seven different dosing regimen strategies were used, ranging between 375 and 750 mg/m 2 per dose, with administration of 1–4 doses. There was no significant difference in event-free survival at 12 months between dosing strategies. The median time to reconstitution of B cells was not significantly different between groups.

          Conclusions

          Use of a single low-dose regimen of rituximab in the management of frequently relapsing nephrotic syndrome does not affect the probability of relapse at 12 months or time to B cell reconstitution compared to a conventional higher dose.

          Electronic supplementary material

          The online version of this article (10.1007/s00467-018-4172-3) contains supplementary material, which is available to authorized users.

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          Most cited references 26

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          Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial.

          Rituximab could be an effective treatment for childhood-onset, complicated, frequently relapsing nephrotic syndrome (FRNS) and steroid-dependent nephrotic syndrome (SDNS). We investigated the efficacy and safety of rituximab in patients with high disease activity.
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            Treatment of steroid-sensitive nephrotic syndrome: new guidelines from KDIGO.

            The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on glomerulonephritis (GN) is intended to assist the practitioner caring for patients with GN. Two chapters of this guideline focus specifically on nephrotic syndrome in children. Guideline development followed a thorough evidence review, and management recommendations and suggestions were based on the best available evidence. Critical appraisal of the quality of evidence and strength of recommendations followed the Grades of Recommendation Assessment, Development and Evaluation (GRADE) approach. Chapters 3 and 4 of the guideline focus on the management of nephrotic syndrome in children aged 1-18 years. Guideline recommendations for children who have steroid-sensitive nephrotic syndrome (SNSS), defined by their response to corticosteroid therapy with complete remission, are addressed here. Recommendations for those with steroid-resistant nephrotic syndrome (SRNS) (i.e., do not achieve complete remission) are discussed in the companion article. Limitations of the evidence, including the paucity of large-scale randomized controlled trials, are discussed. This article provides a short description of the KDIGO process, the guideline recommendations for treatment of SSNS in children and a brief review of relevant treatment trials related to each recommendation.
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              Short-term effects of rituximab in children with steroid- and calcineurin-dependent nephrotic syndrome: a randomized controlled trial.

              Prednisone and calcineurin inhibitors are the mainstay therapy of idiopathic nephrotic syndrome (INS) in children. However, drug dependence and toxicity associated with protracted use are common. Case series suggest that the anti-CD20 monoclonal antibody rituximab (RTX) may maintain disease remission. This open-label randomized controlled trial was powered to show that a strategy based on RTX and lower doses of prednisone and calcineurin inhibitors was noninferior to standard doses of these agents in maintaining 3-month proteinuria as low as baseline or up to 1 g/d greater (noninferiority margin). Participants were stratified by the presence of toxicity to prednisone/calcineurin inhibitors and centrally assigned to add RTX (Mabthera, 375 mg/m(2) intravenously) to lower doses of standard agents or to continue with current therapy alone. The risk of relapse was a secondary outcome. Fifty-four children (mean age 11 ± 4 years) with INS dependent on prednisone and calcineurin inhibitors for >12 months were randomized. Three-month proteinuria was 70% lower in the RTX arm (95% confidence interval 35% to 86%) as compared with standard therapy arm (intention-to-treat); relapse rates were 18.5% (intervention) and 48.1% (standard arm) (P = 0.029). Probabilities of being drug-free at 3 months were 62.9% and 3.7%, respectively (P < 0.001); 50% of RTX cases were in stable remission without drugs after 9 months. Rituximab and lower doses of prednisone and calcineurin inhibitors are noninferior to standard therapy in maintaining short-term remission in children with INS dependent on both drugs and allow their temporary withdrawal.
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                Author and article information

                Contributors
                +44(0)1414516563 , ben.reynolds@ggc.scot.nhs.uk
                Journal
                Pediatr Nephrol
                Pediatr. Nephrol
                Pediatric Nephrology (Berlin, Germany)
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0931-041X
                1432-198X
                18 December 2018
                18 December 2018
                2019
                : 34
                : 5
                : 855-863
                Affiliations
                [1 ]Nottingham Children’s Hospital Renal and Urology Unit, Nottingham, UK
                [2 ]Department of Paediatric Nephrology, Royal Hospital for Children, 1345 Govan Road, Glasgow, G51 4TF UK
                [3 ]ISNI 0000 0004 4904 7256, GRID grid.459561.a, Great North Children’s Hospital, ; Newcastle Upon Tyne, UK
                [4 ]ISNI 0000 0001 2193 314X, GRID grid.8756.c, School of Mathematics and Statistics, , University of Glasgow, ; Glasgow, UK
                Article
                4172
                10.1007/s00467-018-4172-3
                6424916
                30564878
                © The Author(s) 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                Funding
                Funded by: University of Glasgow
                Categories
                Original Article
                Custom metadata
                © IPNA 2019

                Nephrology

                rituximab, nephrotic syndrome, dosing

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