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      Peripheral CD19+ B cells are increased in children with active steroid-sensitive nephrotic syndrome

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          Abstract

          Sir, Pathogenesis of steroid-sensitive nephrotic syndrome (SSNS) is thought to be related mainly to T-cell dysfunction [1]. However, the beneficial use of rituximab in cases of frequently relapsing SSNS provided evidence of B cell involvement [2–4]. Our aim was, thus, to investigate prospectively the levels of the circulating CD19+ B cells in children with a first episode of SSNS in sequential stages (presentation, remission on steroids and remission off steroids). Twenty-three children (M/F = 13/10, age = 2.5–14 years, median = 4.32 years) with a first episode of SSNS were studied; 23/23 both at presentation (before steroids initiation) and in remission on steroids (40 mg/m2 on alternate day); 15/23 were tested as well in remission off steroids for at least 6 months. Twenty-five age-matched children who had come to the outpatient haematology clinic in order to be tested for b-thalassaemia trait were found to be negative and served as healthy controls (controls 1). Considering that the presentation of SSNS may be associated with a recent infection, mainly a respiratory tract infection, twenty age-matched children with an upper respiratory tract infection acted as a second control group (controls 2). The percentages of CD3± T cells, as a pan T-cell marker, and the percentages of CD19+ and CD20± B cells were evaluated in all children. The above-mentioned parameters were determined in each sample by flow cytometry using the lysed whole blood method. The duochrome phycoerythrin-cyanin5 (PE-Cy5) conjugated CD3± monoclonal antibody (MoAb) and phycoerythrin (PE) conjugated CD19+ and CD20± MoAbs purchased from Beckman Coulter were used. The samples were analysed with a EPICS-XL flow cytometer. The results were expressed as percentages (%) of fluorescence-positive cells as well as actual numbers (cells/μL) of the circulating CD19+ and CD20+ B cells, based on the white blood cell count. Statistical analysis was performed using the Statistical Package for the Social Sciences for Windows (SPSS version 11.5). The paired t-test and independent-samples t-test were used to compare differences between study groups with and without paired data, respectively. Pearson's coefficient of correlation (r) was used to determine the correlations. A P ≤ 0.05 was considered to be statistically significant. In 5 of 23 children with a first episode of SSNS, there was a recent history of an upper respiratory tract infection. Remission was achieved in all children within 6–15 days after steroid initiation. During remission, all patients presented normoalbuminaemia and were free of proteinuria and albuminuria. Percentages of CD3± T cells were found to be within normal limits in all patients (at presentation of SSNS, in remission still on steroids and in remission off steroids) compared with the two control groups (P ≥ 0.05). As depicted in Figure 1, the circulating CD19+ B cells were significantly higher at presentation of SSNS (mean percentage = 18.13 ± 5.43, mean actual number = 695.34 ± 258.29) compared with remission on steroids (mean percentage = 13.57 ± 4.22 and P < 0.0001, mean actual number = 468.05 ± 164.69 and P < 0.0001), remission off steroids (mean percentage = 13.25 ± 2.32 and P < 0.0001, mean actual number = 414.88 ± 140.76 and P < 0.0001), controls 1 (mean = 13.96 ± 3.29 and P = 0.008, mean actual number = 442.75 ± 99.78 and P = 0.009) and controls 2 (mean percentage = 14.18 ± 3.6 and P = 0.01, mean actual number = 508.05 ± 148.9 and P = 0.015). During remission stages, on and off steroids, CD19+ B cells were comparable with both control groups (P > 0.05). Moreover, circulating CD19+ B cells were inversely correlated with disease activity (r = −0.465, P < 0.0001). CD20+ B cells were similarly significantly higher at presentation of SSNS (mean percentage = 19.31 ± 4.24, mean actual number = 739.85 ± 267.34) compared with remission on steroids (mean percentage = 14.3 ± 3.92 and P < 0.0001, mean actual number = 493.17 ± 157.93 and P < 0.0001), remission off steroids (mean percentage = 13.25 ± 2.32 and P < 0.0001, mean actual number = 413.99 ± 142.64 and P < 0.0001), controls 1 (mean = 13.12 ± 4.01 and P = 0.001, mean actual number = 415.40.75 ± 167.34 and P = 0.002) and controls 2 (mean percentage = 13.5 ± 2.34 and P = 0.001, mean actual number = 483.63 ± 156.84 and P = 0.001). During remission stages, CD20+ B cells were comparable with both control groups (P > 0.05). Fig. 1 Percentage of CD19+ B cells in children with a first episode of SSNS in sequential stages (presentation, remission on steroids, remission off steroids) and in controls 1 and 2. The pathogenesis of SSNS has mainly been focused on T cells dysfunction. The success of rituximab, a chimeric anti-CD20 antibody, in the treatment of cases of frequently relapsing SSNS initiated interest in pathogenic pathways involving B cells [2–4]. There is an interaction between B cells and T cells, and B cells are involved in the presentation of antigens to T cells. However, the effect of B-cell depletion on T-cell function is unknown. Kemper et al. [5] suggested that in children with SSNS, there is a combined T- and B-cell activation. In agreement with our results, recent studies showed that CD19+ B cells may be elevated in relapsing nephrotic children [6,7]. Children with both steroid-sensitive and steroid-resistant nephrotic syndrome were included in this study, and there were no paired data of the circulating CD19+ B cells in remission off steroids. It is worth noting that in our study not all children with SSNS presented elevated CD19+ B cells. We intend to follow up this cohort of 23 nephrotic children in order to identify whether the long-term outcome of the nephrotic syndrome is associated with the up-regulation of CD19+ B cells in these patients taking into account steroid dependency and frequency of relapses. Our findings demonstrated an up-regulation of circulating CD19+ and CD20± B cells in children with a first episode of SSNS. This indicates that B cells may play a role in SSNS and that rituximab may be considered in certain cases. Conflict of interest statement. None declared.

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          Most cited references 7

          • Record: found
          • Abstract: found
          • Article: not found

          T-lymphocyte populations and cytokines in childhood nephrotic syndrome.

          We investigated lymphocyte subpopulations and the production of cytokines by T helper cell subtype 1 (Th1), Th2, and monocytes/macrophages (tumor necrosis factor-alpha [TNF-alpha]) in peripheral-blood mononuclear cells of 18 children with steroid-sensitive (SS) nephrotic syndrome (NS) and 10 children with steroid-resistant (SR) NS. Mean age was 10.9 +/- 5.7 years, with a mean follow-up before the study of 6 +/- 5 years. To evaluate the possible relationship between cytokine levels and response to treatment, patients with SS and SR NS were assessed during relapse/marked proteinuria (group A), total/partial remission (group B), and off treatment (group C). In children with SS and SR NS, we found no significant difference in CD3 counts compared with controls. The proportion of CD4 cells decreased significantly in relapse and off therapy compared with controls in children with SS NS, whereas in those with SR NS, there was a concomitant reduction in all groups. B-Lymphocyte counts were significantly increased in either group versus controls. In SR NS, CD8 and natural killer cell levels increased during relapse versus controls. The CD4+/CD8+ ratio was reduced to the same degree in those with SS and SR NS. In patients with SR NS, we observed increased levels of soluble interleukin-2 (IL-2) receptor (sIL-2R) from corresponding control values (P < 0.01). A significant increase in TNF-alpha levels was found in patients with SS and SR NS versus controls. High levels of IL-2, sIL-2R, and interferon-gamma during relapse in patients with SS NS give further evidence for a Th1 pattern that might be involved in the pathogenesis of NS, and monitoring the Th1/Th2 balance would be useful in evaluating the response to therapy. Copyright 2002 by the National Kidney Foundation, Inc.
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            • Record: found
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            Unexpected efficacy of rituximab in multirelapsing minimal change nephrotic syndrome in the adult: first case report and pathophysiological considerations.

            Nephrotic syndrome secondary to minimal change disease (MCNS) usually is considered to have a good renal prognosis, but frequency of relapses and steroid dependency are therapeutic challenges to physicians. Treatment of patients with multiple relapses remains controversial because few control studies are available. We report the case of a 23-year-old woman of Malian origin who experienced more than 30 relapses of MCNS. Long-term remission was observed only with rituximab (anti-CD20 antibody) treatment after step-by-step use of all currently available medications for MCNS were unsuccessful. Our observation is the first report of efficacy of rituximab during multirelapsing MCNS in an adult patient with a significant follow-up and no adjuvant therapy. This case suggests a role of B cells in MCNS, possibly by regulating T-cell function.
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              • Record: found
              • Abstract: not found
              • Article: not found

              Rituximab: effective treatment for severe steroid-dependent minimal change nephrotic syndrome?

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                Author and article information

                Journal
                NDT Plus
                NDT Plus
                ckj
                ndtplus
                NDT Plus
                Oxford University Press
                1753-0784
                1753-0792
                October 2009
                13 July 2009
                13 July 2009
                : 2
                : 5
                : 435-436
                Affiliations
                1st Department of Pediatrics, Aristotle University , Hippokration General Hospital, ThessalonikiGreece E-mail: nprintza@ 123456in.gr
                Article
                sfp087
                10.1093/ndtplus/sfp087
                4421380
                © The Author [2009]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                Categories
                Letter

                Nephrology

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