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      Mesothelial Dysplastic Changes and Lipid Peroxidation Induced by 7.5% Icodextrin

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      Nephron

      S. Karger AG

      Ixudative stress, Apoptosis, Glucose polymer

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          Abstract

          Background: The issue of icodextrin biocompatibility is somehow ambiguous. Whereas some experimental data point at better bicompatibility of icodextrin compared with high glucose concentration fluid, other reports showed substantial cytotoxic effects upon monocytes and cultured mesothelial cells. The present investigation exposes the first attempt to investigate the biocompatibility issue in an in vivo and in situ setup. Methods: Mice were intraperitoneally injected once a day with the 7.5% icodextrin solution, during 30 consecutive days. Imprints of the mesothelial monolayer covering the anterior liver surface were taken after 2 h, 15 and 30 injections, as well as after recovery periods of 7, 30 and 60 days. Changes on the cell population were evaluated as a function of: density, cell surface area, cell radius, nuclear surface area, number of nucleoli per nucleus, nuclear cytoplasmic index, as well as for prevalence of multinucleation, mitosis, non-viable cells and apoptotic bodies. Additionally, peritoneal dialysis was performed in 3 groups of rats exposed to 4.25% glucose dialysis fluid, 1.1% amino acids solution, or to 7.5% icodextrin. Samples were taken for thiobarbituric acid reactive substances (TBARS) from each group. Results: Mesothelial cell populations of mice exposed to 7.5% icodextrin displayed significantly reduced density, increased cell size, higher increased nuclear/cytoplasmic index, increased numbers of heterogeneous nucleoli, extremely low prevalence of mitosis, atypical mitosis, micronuclei, reduced cell viability as well as a significantly higher prevalence of apoptosis. Rats exposed to the same experimental solution showed significantly higher levels of TBARS (basically malondialdehyde), testifying for an undergoing process of lipid peroxidation. Conclusions: Overall, these results suggest that the 7.5% icodextrin dialysis solution induced, through a mechanism of lipid peroxidation, substantial DNA injury, leading the exposed monolayer to commit protective cellular suicide. Consequently, this information raises some doubts about the safety of 7.5% icodextrin solution in peritoneal dialysis patients.

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          Most cited references 5

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          Methods for determination of aldehydic lipid peroxidation products

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            Transient Adaptation to Oxidative Stress in Mammalian Cells

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              High Glucose Induces a Hypertrophic, Senescent Mesothelial Cell Phenotype after Long in vivo Exposure

              Previous studies, done using our mouse model for population analysis of the mesothelium, showed evidence indicating that in vivo, long-term exposure (up to 30 days) of the peritoneum to high-glucose (4.25% D -glucose) concentration dialysis solutions resulted in a hypertrophic mesothelial phenotype characterized by increased cell surface area, multinucleation, low proliferative capabilities, reduced cell viability, and enhanced enzymatic activity. These elements that define a senescent population of cells were not related to the pH of the fluid and its osmolality, or to the presence of buffer lactate. The present study was designed to explore the adverse effects of a lactate-free, filter-sterilized, high- D -glucose concentration solution (4.25%) at normal pH and prepared in Hanks’ buffered salt solution after 2 h, 15 and 30 days of once a day intraperitoneal injection. Analysis of our observations indicate that in vivo exposure of the mesothelium to a high-glucose concentration induced a decreased density of the cell population, made up by larger and multinucleated cells, the viability of which was significantly lower than that observed in intact unexposed mice. The prevalence of mitosis showed an early and short-lived acceleration (up to 3 days), followed by values near zero during the rest of the follow-up period. So far, the main effect of the high-glucose concentration appears to result not from a mechanism of cytotoxicity, but from a substantial change in the life cycle of the exposed cell population, leading to their premature senescence and death in apoptosis. We hypothesize that this outcome may well be mediated by sustained oxidative stress derived from both a reduced production of scavengers, as well as the increased generation of oxygen-reactive species.
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                Author and article information

                Journal
                NEF
                Nephron
                10.1159/issn.1660-8151
                Nephron
                S. Karger AG
                1660-8151
                2235-3186
                2002
                September 2002
                14 August 2002
                : 92
                : 1
                : 142-155
                Affiliations
                Department of Nephrology and Hypertension and the Research Center for Experimental Nephrology, ‘Ha’Emek Medical Center’, Afula, Israel
                Article
                64482 Nephron 2002;92:142–155
                10.1159/000064482
                12187097
                © 2002 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: 13, References: 67, Pages: 14
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/64482
                Categories
                Original Paper

                Cardiovascular Medicine, Nephrology

                Apoptosis, Ixudative stress, Glucose polymer

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