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      The Factors That May Predict Response to Rituximab Therapy in Recurrent Focal Segmental Glomerulosclerosis: A Systematic Review

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      Journal: Journal of Transplantation
      Publisher: Hindawi Publishing Corporation

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          Abstract

          Recurrence of FSGS occurs in 30–40% of allografts. Therapies for recurrence are not well established. We retrieved all published reports depicting kidney transplant recipients with focal segmental glomerulosclerosis (FSGS) recurrence, treated with rituximab, to determine factors associated with treatment response. We found 18 reports of 39 transplant recipients who received rituximab. By univariate analysis for two outcomes (no response versus any response), fewer rituximab infusions and normal serum albumin at recurrence were associated with treatment response. For 3 outcomes (no response, partial and complete remission), male gender, fewer rituximab infusions, shorter time to rituximab treatment, and normal serum albumin were associated with remission. Multivariate analysis for both models revealed that normal serum albumin at FSGS recurrence and lower age at transplant were associated with response. Rituximab for recurrence of FSGS may be beneficial for only some patients. A younger age at transplant and normal serum albumin level at recurrence diagnosis may predict response.

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          Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis.

          Thomas Burke, W Seeherunvong, Alessia Fornoni … (2011)
          Focal segmental glomerulosclerosis (FSGS) is a glomerular disease characterized by proteinuria, progression to end-stage renal disease, and recurrence of proteinuria after kidney transplantation in about one-third of patients. It has been suggested that rituximab might treat recurrent FSGS through an unknown mechanism. Rituximab not only recognizes CD20 on B lymphocytes, but might also bind sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) protein and regulate acid sphingomyelinase (ASMase) activity. We hypothesized that rituximab prevents recurrent FSGS and preserves podocyte SMPDL-3b expression. We studied 41 patients at high risk for recurrent FSGS, 27 of whom were treated with rituximab at time of kidney transplant. SMPDL-3b protein, ASMase activity, and cytoskeleton remodeling were studied in cultured normal human podocytes that had been exposed to patient sera with or without rituximab. Rituximab treatment was associated with lower incidence of posttransplant proteinuria and stabilization of glomerular filtration rate. The number of SMPDL-3b(+) podocytes in postreperfusion biopsies was reduced in patients who developed recurrent FSGS. Rituximab partially prevented SMPDL-3b and ASMase down-regulation that was observed in podocytes treated with the sera of patients with recurrent FSGS. Overexpression of SMPDL-3b or treatment with rituximab was able to prevent disruption of the actin cytoskeleton and podocyte apoptosis induced by patient sera. This effect was diminished in cultured podocytes where SMPDL-3b was silenced. Our study suggests that treatment of high-risk patients with rituximab at time of kidney transplant might prevent recurrent FSGS by modulating podocyte function in an SMPDL-3b-dependent manner.
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            Twenty-one-year trend in ESRD due to focal segmental glomerulosclerosis in the United States.

            Chagriya Kitiyakara, Paul Eggers, Jeffrey B Kopp (2004)
            Focal segmental glomerulosclerosis (FSGS) is a clinicopathologic syndrome with a substantial risk for progression to end-stage renal disease (ESRD). Recent studies of renal biopsy archives in the United States suggest that the incidence of FSGS has increased. FSGS has become the leading cause of idiopathic nephrotic syndrome in the United States, with the greatest incidence rates in the black population. In the absence of a population-based estimate of FSGS incidence, we wished to obtain a population-based estimate of incident ESRD cases caused by FSGS (FSGS ESRD) and characterize temporal changes in this group. We examined the incidence of FSGS ESRD during a 21-year period (1980 to 2000) using data from the United States Renal Data System. We excluded patients who were classified as having acquired immunodeficiency syndrome nephropathy. The annual incidence of FSGS ESRD has increased considerably, whether expressed as an absolute number or a fraction of the total incident ESRD population. Thus, the proportion of ESRD attributed to FSGS has increased 11-fold, from 0.2% in 1980 to 2.3% in 2000. The recent increase in incident FSGS ESRD cases likely is multifactorial in origin, with contributions from changes in renal biopsy practices, changes in disease classification, and a real increase in the incidence of FSGS disease. Black individuals have a 4-fold greater risk of FSGS ESRD than white or Asian individuals. The peak decade for FSGS ESRD incidence is 40 to 49 years among black subjects and 70 to 79 years among white and Asian individuals. Males have 1.5- to 2-fold greater risk than females. The incidence of FSGS ESRD has increased considerably in the United States, with black individuals at greatest risk. Idiopathic FSGS now is the most common cause of ESRD caused by primary glomerular disease in the United States in both the black and white populations.
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              Short-term effects of rituximab in children with steroid- and calcineurin-dependent nephrotic syndrome: a randomized controlled trial.

              Alberto Edefonti, Elisa Benetti, Andrea Pasini … (2011)
              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

                Journal
                Journal ID (nlm-ta): J Transplant
                Journal ID (publisher-id): JTRAN
                Title: Journal of Transplantation
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 2090-0007
                ISSN (Electronic): 2090-0015
                Publication date (Print): 2011
                Publication date (Electronic): 24 November 2011
                Volume: 2011
                Electronic Location Identifier: 374213
                Affiliations
                Division of Pediatric Nephrology, University of Florida College of Medicine, 1600 SW Archer Road, Room HD-214, Gainesville, FL 32610-0296, USA
                Author notes

                Academic Editor: Diego Cantarovich

                Article
                DOI: 10.1155/2011/374213
                PMC ID: 3235904
                PubMed ID: 22174985
                SO-VID: e3d917fe-3eec-42d1-8191-47efb8ff9de6
                Copyright © Copyright © 2011 C. E. Araya and V. R. Dharnidharka.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 20 July 2011
                Date accepted : 11 October 2011
                Categories
                Subject: Review Article

                ScienceOpen disciplines: Transplantation
                Data availability:
                ScienceOpen disciplines: Transplantation

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