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      Proteinuria and Fusion of Podocyte Foot Processes in Rats after Infusion of Cytokine from Patients with Idiopathic Minimal Lesion Nephrotic Syndrome

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          Abstract

          Background/Aims: We report on the isolation of a factor secreted by peripheral blood mononuclear cells from patients with idiopathic minimal lesion nephrotic syndrome (IMLNS) in relapse and its effect on proteinuria and podocyte morphology in the rat. Methods: Peripheral blood mononuclear cells from patients with IMLNS (in relapse and in remission) and patients with focal segmental glomerulosclerosis were cultured for 72 h. Supernatants from 20 × 10<sup>6</sup> cultured cells were separated by liquid chromatography into three fractions according to markers (bovine serum albumin, β-amylase, and apoferritin). Each supernatant fraction was infused into rats for 5 days using an osmotic pump. Proteinuria, 24-hour albumin excretion or albumin/creatinine ratio in a 24-hour urine collection, was measured daily starting 3 days prior to fraction infusion. Renal tissue was obtained for electron microscopy studies. The β-amylase fraction underwent electrophoresis using isoelectric focusing gel. Results: When protein excretion was compared prior to and during supernatant fraction infusion, a significant increase in proteinuria was observed only when β-amylase fraction from IMLNS patients in relapse was infused (p < 0.05). Protein electrophoresis of the β-amylase fraction showed a single band at pH 6.0 only in samples from IMLNS patients in relapse. The band was composed of two proteins, β-amylase and a 100-kDa glycoprotein. Fusion of foot processes was observed only when the β-amylase fraction from IMLNS patients in relapse was infused. Conclusions: The infusion of the β-amylase fraction containing a 100-kDa glycoprotein from IMLNS patients in relapse induced proteinuria and effacement of foot processes in the rat. This protein may play a role in the pathogenesis of IMLNS.

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          Most cited references 30

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          Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis.

          Heavy proteinuria and progressive renal injury recur after transplantation in up to 40 percent of patients with renal failure caused by idiopathic focal segmental glomerulosclerosis. A circulating factor may be responsible for this recurrence. To determine whether patients with focal segmental glomerulosclerosis have a circulating factor capable of causing glomerular injury, we tested serum samples from 100 patients with the disorder in an in vitro assay of glomerular permeability to albumin. Of the 56 patients who had undergone renal transplantation, 33 had recurrences. Sixty-four patients, many of whom had undergone transplantation, were being treated with dialysis. Thirty-one patients with other renal diseases and nine normal subjects were also studied. The 33 patients with recurrent focal segmental glomerulosclerosis after transplantation had a higher mean (+/-SE) value for permeability to albumin (0.47+/-0.06) than the normal subjects (0.06+/-0.07) or the patients who did not have recurrences (0.14+/-0.06). After plasmapheresis in six patients with recurrences, the permeability was reduced (from 0.79+/-0.06 to 0.10+/-0.05, P = 0.008), and proteinuria was significantly decreased. Patients with corticosteroid-sensitive nephrotic syndrome or with membranous nephropathy after transplantation had low levels of serum activity. The circulating factor bound to protein A and hydrophobic-interaction columns and had an apparent molecular mass of about 50 kd. A circulating factor found in some patients with focal segmental glomerulosclerosis is associated with recurrent disease after renal transplantation and may be responsible for initiating the renal injury.
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            Pathogenesis of lipoid nephrosis: a disorder of T-cell function.

             J Shalhoub (1974)
            Clinical observations suggest that lipoid nephrosis is produced by a systemic abnormality of T-cell function resulting in the secretion of a circulating chemical mediator toxic to an immunologically innocent glomerular basement membrane. The lack of evidence of a humoral antibody response, remission induced by measles which modifies cell-mediated immunity, the therapeutic benefits of steroids and cyclophosphamide which also abate cell-mediated responses, and the occurrence of this syndrome in Hodgkin's disease support this hypothesis. The susceptibility of untreated patients to pneumococcal infections may be of primary or secondary pathogenetic importance. Taken together, the data suggest that this syndrome is a clinical expression of a self-limited primary immune-deficiency disease.
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              The role of podocytes in glomerular pathobiology.

              Podocytes are unique cells with a complex cellular organization. With respect to their cytoarchitecture, podocytes may be divided into three structurally and functionally different segments: cell body, major processes, and foot processes (FPs). The FPs of neighboring podocytes regularly interdigitate, leaving between them the filtration slits that are bridged by an extracellular structure, known as the slit diaphragm (SD). Podocytes cover the outer aspect of the glomerular basement membrane (GBM). They therefore form the final barrier to protein loss, which explains why podocyte injury is typically associated with marked proteinuria. Chronic podocyte injury may lead to podocyte detachment from the GBM. Our knowledge of the molecular structure of the SD has been remarkably improved in the past few years. Several molecules, including nephrin, CD2AP, FAT, ZO-1, P-cadherin, Podocin, and Neph 1-3 have all been shown to be associated with the SD complex, and some of these molecules are critical for its integrity. Podocytes are injured in many forms of human and experimental glomerular disease. The early events are characterized either by alterations in the molecular composition of the SD without visible changes in morphology or, more obviously, by a reorganization of FP structure with the fusion of filtration slits and the apical displacement of the SD. Based on recent insights into the molecular pathology of podocyte injury, at least four major causes have been identified that lead to the uniform reaction of FP effacement and proteinuria: (1) interference with the SD complex and its lipid rafts; (2) direct interference with the actin cytoskeleton; (3) interference with the GBM or with podocyte-GBM interaction; and (4) interference with the negative surface charge of podocytes. There is also evidence, in focal segmental glomerular sclerosis (FSGS) and in idiopathic nephrotic syndrome in humans and rats, that podocyte damage may be caused by circulating albuminuric factors. Ongoing studies in many laboratories are aiming at an understanding of the dynamic relationship between SD proteins, the actin cytoskeleton, and the dynamics of FP structure in nephrotic syndrome and FSGS. These studies should provide us with a better understanding of the biological mechanism underlying the podocyte response to injury. Such studies will potentially translate into more refined treatment and the prevention of proteinuria and progressive glomerular disease.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2006
                February 2006
                05 December 2005
                : 102
                : 3-4
                : e105-e112
                Affiliations
                Departments of aPediatrics and bAnatomy, University of South Florida, Tampa, Fla., USA
                Article
                89689 Nephron Exp Nephrol 2006;102:e105–e112
                10.1159/000089689
                16330882
                © 2006 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 4, Tables: 2, References: 39, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/89689
                Categories
                Original Paper

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