Potential Role of Soluble ST2 Protein in Idiopathic Nephrotic Syndrome Recurrence Following Kidney Transplantation (original) (raw)
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After transplantation, corticosteroid-resistant Idiopathic Nephrotic Syndrome (INS) rapidly recurs in 30-50% of recipients, suggesting the presence of (a) circulating factor(s) which alter(s) the glomerular filtration barrier. In this paper, we investigated the possible implication of the soluble ST2 protein (sST2), a product of the c-maf pathway and a marker of Th2 cells, in the development of INS recurrence, as an association between INS relapse and an atypical Th2 polarization involving activation of c-maf has recently been reported. We analyzed sST2 levels in the serum of kidney recipients with INS as their primary kidney disease but with (n=31) and without (n=40) recurrence after transplantation and of recipients with primary glomerular diseases different from INS (n=34). We found a significant increase of sST2 levels in the sera of patients suffering INS recurrence, but not in those of nonrecurrent INS and non-INS patients. No differences were detected in these sera before transplantation. Moreover, recurrent patients displayed the same sST2 isoform as the two control groups. In vitro, a mouse podocyte cell line was profoundly altered by incubation with sera of recurrent patients. However, purified sST2 from these patients was not able to reproduce these damages. In addition, induction of high sST2 levels in rats did not trigger proteinuria. Collectively, these data suggest that sST2 is a marker of INS recurrence that could be of interest for its diagnosis in ambiguous clinical situations. Nonetheless, sST2 does not seem to be directly implicated in INS development.
Immunopathogenesis of idiopathic nephrotic syndrome with relapse
Idiopathic change nephrotic syndrome (INS), the most frequent glomerular disease in children and young adults, is characterized by heavy proteinuria and a relapsing remitting course. Although the mechanisms underlying the pathophysiology of proteinuria remain unclear, clinical and experimental observations suggest that lymphocyte and podocyte disturbances are two sides of the disease. The current hypothesis suggests that immune cells release a putative factor, which alters podocyte function resulting in nephrotic proteinuria. Besides T-cell abnormalities, recent evidence of B-cell depletion efficacy in sustained remissions added a new challenge in understanding the immunological mechanisms of INS. In this review, we discuss recent insights related to podocyte disorders occurring in INS and their relevance in human diseases.
Recent Progress in the Pathophysiology and Treatment of FSGS Recurrence
American Journal of Transplantation, 2013
Focal segmental glomerulosclerosis (FSGS) is a glomerular disease characterized by proteinuria, frequent progression to end-stage renal disease, and recurrence after kidney transplantation in ∼25% of patients, which negatively impacts long-term allograft survival. Experimental studies suggest that abnormalities in T and, possibly, B cells may represent one initial pathogenic trigger, leading to podocyte injury and progressive loss. New data also support the existence of circulating permeability factors able to damage the podocytes, but no single molecule has been consistently identified as the causal pathogenic element in FSGS recurrence. Unfortunately, major progress from mechanistic studies has not translated into substantial advancements in patient treatment, with plasmapheresis (PP) and high doses of cyclosporine (CsA) remaining the mainstays of therapy. Despite consistent experimental and clinical evidence that treatment of proteinuria slows renal function decline in proteinuric nephropathies, maximal use of antiproteinuric agents such as renin angiotensin system antagonists is not routine in the management of FSGS recurrence. More recently, encouraging results have been reported with anti-CD20 depleting antibody rituximab, but further studies are needed to establish its safety/efficacy profile.
Dominant T cells in idiopathic nephrotic syndrome of childhood
Kidney International, 2000
Dominant T cells in idiopathic nephrotic syndrome of childless frequently focal global sclerosis (FGS) may be seen hood. [2]. Therapy of INS was well elaborated in several clinical Background. Because of several studies, idiopathic nestudies and mainly consists of steroids. In case of frephrotic syndrome (INS) of childhood is suspected to have an quent relapsing INS, additional immunosuppression with immunologic pathogenesis with T cells playing a major role. cyclophosphamide or cyclosporine A has been approved To investigate this hypothesis further, we studied the diversity of the CDR3 region of the T-cell receptor (TCR) -chain from [3-5]. peripheral T cells isolated from patients with INS. An association of INS with certain human leukocyte Methods. The study was performed over a three-year period antigens (HLA) has been repeatedly reported. The to obtain longitudinal data on the repertoire of peripheral T HLA-B8-DR3 haplotype,-DR7 and-DQ2 are significells. mRNA from peripheral mononuclear cells (PBMCs) of cantly associated with disease susceptibility [6-10]. In seven INS patients and two healthy controls (NHD) was prepared and analyzed for CDR3 length polymorphism of TCR 1974, Shalhoub suggested INS to be a disorder of T-cell -chain by spectratyping. function [11]. Since then, a number of studies have shown Results. All INS patients presented individually skewed immunologic abnormalities in this disease. Activated spectratype histograms in at least one V-family. Patients suf-CD4-positive (CD4ϩ) T cells were found to be up-regufering from a frequent relapsing course of INS or a focal global sclerosis showed some alterations to persist in all samples isolated during active stages of disease, producing increased lated in the observation period (up to 3 years). In addition, levels of interleukin-2 (IL-2) [12, 13]. Moreover, the sequence analyses of the -chain of the TCR CDR3 region CD4ϩ/CD8ϩ ratio was observed to be inversed, pointconfirmed clonal expansion of peripheral T cells in those paing to an increased cytotoxic T-cell recruitment during tients who had displayed spectratype alterations. active stages of disease [14]. Conclusions. The data give strong evidence for an direct involvement of CD8ϩ T cells in the complicated course of Human leukocyte antigen molecules, the presented INS.
2013
Background In our study, diagnostic and demographic characteristics of patients diagnosed with RPGN by biopsy, clinical and laboratory findings in our country were investigated. Methods Data were obtained from the Turkish Society of Nephrology Glomerular Diseases (TSN-GOLD) Working Group database. Demographic characteristics, indications for biopsy, diagnosis of the glomerular diseases, comorbidities, laboratory and biopsy findings of all patients were recorded. According to their types, RPGN patients were classified as type 1 (anti-GBM related), type 2 (immuncomplex related) and type 3 (pauci-immune). Results Of 3875 patients, 200 patients with RPGN (mean age 47.9 ± 16.7 years) were included in the study which constitutes 5.2% of the total glomerulonephritis database. Renal biopsy was performed in 147 (73.5%) patients due to nephritic syndrome. ANCA positivity was found in 121 (60.5%) patients. Type 1 RPGN was detected in 11 (5.5%), type 2 RPGN in 42 (21%) and type 3 RPGN in 147 (73.5%) patients. Median serum creatinine was 3.4 (1.9-5.7) mg/dl, glomerular filtration rate was 18 (10-37) ml/min/1.73m 2 and proteinuria 2100 (1229-3526) mg/day. The number of crescentic glomeruli ratio was ratio 52.7%. It was observed that urea and creatinine increased and calcium and hemoglobin decreased with increasing crescentic glomerular ratio. Conclusions Our data are generally compatible with the literature. Advanced chronic histopathological findings were prominent in the biopsy of 21 patients. Early biopsy should be performed to confirm the diagnosis of RPGN and to avoid unnecessary intensive immunosuppressive therapy. In addition to the treatments applied, detailed data, including patient and renal survival, are needed.
Induction of T Regulatory Cells Attenuates Idiopathic Nephrotic Syndrome
Journal of the American Society of Nephrology, 2009
Buffalo/Mna rats spontaneously develop FSGS and nephrotic syndrome as a result of an immune disorder. Similar to some humans with FSGS, the disease recurs after renal transplantation, suggesting the involvement of a circulating factor. Here, we tested the effect of several immunosuppressive treatments on these rats. Although corticosteroids, cyclosporin A, and anti-T cell receptor treatment reduced proteinuria, only the deoxyspergualin derivative LF15-0195 led to a rapid and complete normalization of proteinuria. Furthermore, this compound led to the regression of renal lesions during both the initial disease and posttransplantation recurrence. The frequency of splenic and peripheral CD4 ϩ CD25 ϩ FoxP3 ϩ T lymphocytes significantly increased with remission. Moreover, the transfer of purified LF15-0195-induced CD4 ϩ CD25 ϩ T cells to irradiated Buff/Mna rats significantly reduced their proteinuria compared with the transfer of untreated control cells, suggesting that LF15-0195 induces regulatory T cells that are able to induce regression of rat nephropathy. These data suggest that idiopathic nephrotic syndrome/FSGS disease can be regulated by cellular transfer, but how this regulation leads to the reorganization of the podocyte cytoskeleton remains to be determined.
Pediatric Research, 2008
The pathogenesis of idiopathic nephrotic syndrome (INS) remains unknown. Several findings suggest a role for the immune system. This study aimed to evaluate immune mediators in INS by measuring plasma and urinary levels of transforming growth factor  1 (TGF- 1 ), monocyte chemoattractant protein-1 (MCP-1/ CCL2), regulated on activation normal T-cell expressed and secreted (RANTES/CCL5) and IL-8 (IL-8/CXCL8) in pediatric patients with INS and in age-matched healthy controls. Patients were divided according to their response to corticosteroids: steroid-sensitive (SS, n ϭ 8), or steroid-resistant (SR, n ϭ 24). Immune mediators were also compared in regard with disease activity (relapse and remission). Immune mediators were measured by ELISA. Plasma TGF- 1 levels in SR patients were approximately 2.8-fold higher than control values (p Ͻ 0.05). Urinary IL-8/CXCL8 was 2.9-fold higher in INS patients in relapse (proteinuria Ͼ100 mg/m 2 /24 h) when compared with patients in remission (p Ͻ 0.05), and levels had a positive correlation with individual proteinuria values (p Ͻ 0.05). Urinary IL-8/CXCL8 was significantly higher in relapsed SR than in SS patients in remission. No changes in MCP-1/CCL2 and RANTES/CCL5 levels were detected. Our findings suggest that IL-8/CXCL8 and TGF- 1 are involved in the pathogenesis of INS: IL-8/CXCL8 associated with local changes in glomerular permeability and TGF- 1 could be related to worse response to corticosteroids.