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      Dialyzable Uremic Solutes Contribute to Enhanced Oxidation of Serum Albumin in Regular Hemodialysis Patients

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          Abstract

          Background: Oxidative stress (OS) is reportedly enhanced in patients receiving regular hemodialysis (HD). However, the in vivo redox state of HD patients, particularly after HD sessions, remains unclear. This study aimed to clarify the influence of HD on OS using the albumin redox state as a marker. Method: Blood samples of 8 regular HD patients were obtained during the course of study. The redox state of albumin was determined using high-performance liquid chromatography. Results: The mean fraction of reversibly oxidized albumin [f(HNA-1)] declined significantly over the course of the session and reached a minimum 4 h after the session had ended (pre-HD, 36.16 ± 7.50%; 4 h after HD, 25.71 ± 6.41%), then gradually rose to predialytic levels. The proportion of irreversibly oxidized albumin did not change significantly over time. Positive correlations were demonstrated between f(HNA-1) and uremic small solutes in each case. Conclusion: Accumulation of dialyzable uremic solutes may contribute to OS in HD patients.

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          The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia.

          Cardiovascular disease is the leading cause of mortality in uremic patients. In large cross-sectional studies of dialysis patients, traditional cardiovascular risk factors such as hypertension and hypercholesterolemia have been found to have low predictive power, while markers of inflammation and malnutrition are highly correlated with cardiovascular mortality. However, the pathophysiology of the disease process that links uremia, inflammation, and malnutrition with increased cardiovascular complications is not well understood. We hereby propose the hypothesis that increased oxidative stress and its sequalae is a major contributor to increased atherosclerosis and cardiovascular morbidity and mortality found in uremia. This hypothesis is based on studies that conclusively demonstrate an increased oxidative burden in uremic patients, before and particularly after renal replacement therapies, as evidenced by higher concentrations of multiple biomarkers of oxidative stress. This hypothesis also provides a framework to explain the link that activated phagocytes provide between oxidative stress and inflammation (from infectious and non-infections causes) and the synergistic role that malnutrition (as reflected by low concentrations of albumin and/or antioxidants) contributes to the increased burden of cardiovascular disease in uremia. We further propose that retained uremic solutes such as beta-2 microglobulin, advanced glycosylated end products (AGE), cysteine, and homocysteine, which are substrates for oxidative injury, further contribute to the pro-atherogenic milieu of uremia. Dialytic therapy, which acts to reduce the concentration of oxidized substrates, improves the redox balance. However, processes related to dialytic therapy, such as the prolonged use of catheters for vascular access and the use of bioincompatible dialysis membranes, can contribute to a pro-inflammatory and pro-oxidative state and thus to a pro-atherogenic state. Anti-oxidative therapeutic strategies for patients with uremia are in their very early stages; nonetheless, early studies demonstrate the potential for significant efficacy in reducing cardiovascular complications.
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            Oxidative stress is enhanced in correlation with renal dysfunction: examination with the redox state of albumin.

            Cardiovascular disease is known to be the most important complication among patients with renal failure, and oxidative stress has been proposed to play a major role as the source of such complications. Human serum albumin (HSA) is composed of human mercaptoalbumin (HMA) with cysteine residues having reducing powers, of reversibly oxidized human non-mercaptoalbumin-1 (HNA-1), and strongly oxidized human non-mercaptoalbumin-2 (HNA-2). We used the "redox state of HSA" as a marker to investigate the current status of oxidative stress in predialysis patients with renal failure. The subjects were 55 nondialysis patients (31 males and 24 females) with chronic renal diseases, and having various degrees of renal function. The subjects' redox state of HSA was determined by a high-performance liquid chromatographic (HPLC) procedure, and the results presented in terms of the ratios between HNA-total(HNA-1 + HNA-2) and HNA-2. The values for each fraction of HNA-total (f(HNA-total)) and f(HNA-2) were increased with a decrease of renal functions, and a significant positive correlation with serum creatinine (R= 0.529, P < 0.0001 and R= 0.618, P < 0.0001) was detected. Multiple (forward stepwise) regression analysis using f(HNA-total) and f(HNA-2) as the criterion variables was performed, and creatinine was adopted as significant explanatory variable in both equations. We found that even before dialysis, oxidative stress was enhanced in correlation with the level of renal dysfunction among patients with chronic renal failure. In the future, antioxidant strategies should become part of treatment for predialysis renal failure.
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              Overproduction of reactive oxygen species in end-stage renal disease patients: a potential component of hemodialysis-associated inflammation.

              During the past decade, hemodialysis (HD)-induced inflammation has been linked to the development of long-term morbidity in end-stage renal disease (ESRD) patients on regular renal replacement therapy. Because interleukins and anaphylatoxins produced during HD sessions are potent activators for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, an example of an enzyme that is responsible for overproduction of reactive oxygen species (ROS), this may constitute a link between leukocyte activation and cell or organ toxicity. Oxidative stress, which results from an imbalance between oxidant production and antioxidant defense mechanisms, has been documented in ESRD patients using lipid and/or protein oxidative markers. Characterization of HD-induced oxidative stress has included identification of potential activators for NADPH oxidase. Uremia per se could prime phagocyte oxidative burst. HD, far from improving the oxidative status, results in an enhancement of ROS owing to hemoincompatibility of the dialysis system, hemoreactivity of the membrane, and trace amounts of endotoxins in the dialysate. In addition, the HD process is associated with an impairment in antioxidant mechanisms. The resulting oxidative stress has been implicated in long-term complications including anemia, amyloidosis, accelerated atherosclerosis, and malnutrition. Prevention of oxidative stress in HD might focus on improving the hemocompatibility of the dialysis system, supplementation of deficient patients with antioxidants, and modulation of NADPH oxidase by pharmacologic approaches.
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                Author and article information

                Journal
                BPU
                Blood Purif
                10.1159/issn.0253-5068
                Blood Purification
                S. Karger AG
                0253-5068
                1421-9735
                2007
                July 2007
                25 April 2007
                : 25
                : 3
                : 274-279
                Affiliations
                aResearch Division of Dialysis and Chronic Kidney Disease and bDepartment of Blood Purification, Tohoku University Graduate School of Medicine, Sendai, cDepartment of Physiology and Biophysics, Gifu University Graduate School of Medicine, Gifu, and dDepartment of Nephrology and Hypertension, Jikei University School of Medicine, Tokyo, Japan
                Article
                101986 Blood Purif 2007;25:274–279
                10.1159/000101986
                17460395
                c0a9c02e-5ff7-4cc4-96d5-1a5ad33fd418
                © 2007 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.

                History
                : 15 December 2006
                : 01 March 2007
                Page count
                Figures: 4, Tables: 2, References: 22, Pages: 6
                Categories
                Original Paper

                Cardiovascular Medicine,Nephrology
                Hemodialysis,Oxidative stress,Albumin redox state,Dialyzable solute

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