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      Erythropoietin Therapy Decreased Tissue Factor, Its Pathway Inhibitor, and Oxidative Stress in Peritoneal Dialysis Patients with Diabetes

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          Abstract

          Aims: We designed a study to evaluate whether erythropoietin (EPO), given to patients on continuousambulatory peritoneal dialysis (CAPD) both with and without diabetes mellitus (DM), influences tissue factor (TF), tissue factor pathway inhibitor (TFPI) and oxidative stress (SOX). Methods: We assessed TF, TFPI and a marker of SOX, Cu/Zn superoxide dismutase (Cu/Zn SOD) in 16 diabetic CAPD patients (8 with EPO therapy), 39 non-diabetic CAPD patients (23 with EPO therapy) and 18 healthy controls. Results: Patients on CAPD showed a significant increase in plasma concentrations of TF, TFPI and Cu/Zn SOD as compared to controls. EPO therapy was related to a decrease in these parameters in diabetic patients, whereas in non-diabetic patients EPO did not affect their levels. In diabetics, TF was positively correlated with TFPI and Cu/Zn SOD levels. There was a positive relationship between TFPI and Cu/Zn SOD, whereas inverse relationships existed between TFPI and haemoglobin, haematocrit (Ht), EPO dose and triglycerides. Multivariate analysis showed that independent variables linked to TFPI levels in diabetic patients were Cu/Zn SOD, Ht and EPO dose. Conclusion: Our data suggest that correction of anaemia with EPO therapy is associated with a significant decrease in TF, TFPI and SOX in diabetic CAPD patients.

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          Most cited references 14

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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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            New aspects in the pathogenesis of diabetic atherothrombosis.

            Diabetes mellitus is increasing worldwide, resulting from the interaction of obesity, inflammation, and hyperglycemia. Activated immunity and cytokine production lead to insulin resistance and other components of the metabolic syndrome, establishing the link between diabetes and atherosclerosis. Hyperglycemia-induced endothelial dysfunction is mediated by increased oxidative stress, a promoter of adventitial inflammation and vasa vasorum neovascularization in experimental models of diabetic atherosclerosis. Recent studies have documented increased inflammation, neovascularization, and intraplaque hemorrhage in human diabetic atherosclerosis. This inflammatory microangiopathic process is independently associated with plaque rupture, leading to coronary thrombosis. Tissue factor, the most potent trigger of the coagulation cascade, is increased in diabetic patients with poor glycemic control. Circulating tissue factor microparticles are also associated with apoptosis of plaque macrophages, closing the link among inflammation, plaque rupture, and blood thrombogenicity. High-density lipoproteins, responsible for free cholesterol removal, are reduced in patients with insulin resistance and diabetes. High-density lipoprotein therapy leads to a significant decrease in plaque macrophages and increase in smooth-muscle cells. These beneficial effects may be responsible for coronary plaque stabilization in patients treated with recombinant Apolipoprotein A-I Milano/phospholipid complex. Finally, peroxisomal proliferator-activated receptors (PPARs) are now considered the nuclear transcriptional regulators of atherosclerosis. Three subfamilies, including PPAR-alpha, -delta, and -gamma, have been identified with crucial roles in lipid metabolism, plaque inflammation, expression of adhesion molecules and cytokines, and regulation of matrix metalloproteinases. Multiple experimental studies have documented plaque stabilization with PPAR-gamma agonists, a group of medications holding great promise in the treatment of diabetes atherosclerosis.
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              Does long-term treatment of renal anaemia with recombinant erythropoietin influence oxidative stress in haemodialysed patients?

              Patients with end-stage renal failure undergoing haemodialysis (HD) are exposed to oxidative stress. Increased levels of malondialdehyde (MDA) were demonstrated in plasma of uraemic patients, indicating accelerated lipid peroxidation (LPO) as a consequence of multiple pathogenetic factors. The aim of our investigation was to examine the role of renal anaemia in oxidative stress in HD patients. MDA and 4-hydroxynonenal (HNE) were measured in three groups of patients undergoing HD: group I comprised eight patients with a blood haemoglobin (Hb) 10 g/dl (mean Hb=12.4+/-1.9g/dl); none of these 16 patients had been treated with human recombinant erythropoietin (rHuEpo). Group III comprised 27 patients with a mean Hb of 10.5+/-1.6 g/dl after long-term rHuEpo treatment. Mean plasma concentrations of both MDA and HNE were significantly higher (P 10g/dl (MDA 2.77+/-0.58 UM, HNE 0.25+/-0.05 microM), and than HD patients treated with rHuEpo (MDA 2.50+/-0.12 microM, HNE 0.29+/-0.03 microM). Furthermore, an inverse correlation between plasma concentration of LPO products and haemoglobin levels was seen (r=0.62, P<0.0001). Radical generation in HD patients might be caused in part by renal anemia itself. Treatment with rHuEpo may decrease radical generation effectively in HD patients due to the increase in the number of red blood cells and blood haemoglobin concentration.
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                Author and article information

                Journal
                NEC
                Nephron Clin Pract
                10.1159/issn.1660-2110
                Nephron Clinical Practice
                S. Karger AG
                1660-2110
                2007
                September 2007
                31 July 2007
                : 107
                : 1
                : c20-c25
                Affiliations
                Departments of aNephrology and Clinical Transplantation and bMonitored Pharmacotherapy, Medical University, Bialystok, Poland
                Article
                106508 Nephron Clin Pract 2007;107:c20–c25
                10.1159/000106508
                17671395
                © 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.

                Page count
                Tables: 3, References: 24, Pages: 1
                Categories
                Original Paper

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