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      Genomic Damage in Endstage Renal Disease—Contribution of Uremic Toxins

      review-article
      Author(s): 1 , * , 2 , 1
      Publication date (Electronic):
      Journal: Toxins
      Publisher: MDPI
      Keywords: dialysis, genotoxicity, uremic toxins

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          Abstract

          Patients with end-stage renal disease (ESRD), whether on conservative, peritoneal or hemodialysis therapy, have elevated genomic damage in peripheral blood lymphocytes and an increased cancer incidence, especially of the kidney. The damage is possibly due to accumulation of uremic toxins like advanced glycation endproducts or homocysteine. However, other endogenous substances with genotoxic properties, which are increased in ESRD, could be involved, such as the blood pressure regulating hormones angiotensin II and aldosterone or the inflammatory cytokine TNF-α. This review provides an overview of genomic damage observed in ESRD patients, focuses on possible underlying causes and shows modulations of the damage by modern dialysis strategies and vitamin supplementation.

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          Oxidative stress is progressively enhanced with advancing stages of CKD.

          Kostas Siamopoulos, Areti Makedou, Evangelia Dounousi … (2006)
          Oxidative stress appears to have a central role in the pathophysiological process of uremia and its complications, including cardiovascular disease. However, there is little evidence to suggest how early oxidative stress starts developing during the progression of chronic kidney disease (CKD). The aim of this study is to assess oxidative stress activity in a cross-sectional study of patients with CKD stages 1 to 4. Eighty-seven steady patients (47 men, 40 women) with a median age of 62 years (range, 28 to 84 years) and mean estimated glomerular filtration rate (eGFR) of 57 mL/min (0.95 mL/s) were studied. Levels of plasma 8-isoprostanes (8-epiPGF2a) and serum total antioxidant status (TAS) were used as markers of oxidative stress. 8-epiPGF2a levels were determined by using an enzyme-linked immunosorbent assay method, whereas a chromatometric method was used to determine TAS. Plasma 8-epiPGF2a levels increased significantly as CKD stages advanced (P < 0.001). There was a highly significant inverse correlation between 8-epiPGF2a level and GFR (P < 0.01). Serum TAS levels also increased in a similar fashion (P < 0.009) and showed a significant inverse correlation with GFR (P < 0.01). 8-epiPGF2a and TAS levels showed a positive correlation (P < 0.05). Multiple regression analysis showed that the most significant predictor variable for 8-epiPGF2a level was eGFR, whereas the association between eGFR and TAS was affected strongly by confounding variables, mainly uric acid level. Oxidative stress appears to increase as CKD progresses and correlates significantly with level of renal function. Increased TAS seems to be dependent on several confounding variables, including increased uric acid levels, and therefore does not seem to be a reliable method for assessing the antioxidant capacity of patients with CKD. These results suggest that larger studies using the correct markers to assess the timing and complex interplay of oxidative stress and other risk factors during the progression of CKD should be carried out.
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            The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses.

            Claudio D. Stern, Michael Schmidt, Pearlly S Yan (2001)
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              Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy.

              Hans-Peter Hammes, Angelika Bierhaus, Ida Giardino … (2003)
              Three of the major biochemical pathways implicated in the pathogenesis of hyperglycemia induced vascular damage (the hexosamine pathway, the advanced glycation end product (AGE) formation pathway and the diacylglycerol (DAG)-protein kinase C (PKC) pathway) are activated by increased availability of the glycolytic metabolites glyceraldehyde-3-phosphate and fructose-6-phosphate. We have discovered that the lipid-soluble thiamine derivative benfotiamine can inhibit these three pathways, as well as hyperglycemia-associated NF-kappaB activation, by activating the pentose phosphate pathway enzyme transketolase, which converts glyceraldehyde-3-phosphate and fructose-6-phosphate into pentose-5-phosphates and other sugars. In retinas of diabetic animals, benfotiamine treatment inhibited these three pathways and NF-kappaB activation by activating transketolase, and also prevented experimental diabetic retinopathy. The ability of benfotiamine to inhibit three major pathways simultaneously might be clinically useful in preventing the development and progression of diabetic complications.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Toxins (Basel)
                Journal ID (publisher-id): toxins
                Title: Toxins
                Publisher: MDPI
                ISSN (Electronic): 2072-6651
                Publication date (Electronic): 11 October 2010
                Publication date Collection: October 2010
                Volume: 2
                Issue: 10
                Pages: 2340-2358
                Affiliations
                [1 ]Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Straße 9, 97078 Würzburg, Germany; Email: stopper@ 123456toxi.uni-wuerzburg.de
                [2 ]Department of Internal Medicine, University of Würzburg, Josef-Schneider-Straße 2, 97080 Würzburg, Germany; Email: august.heidland@ 123456t-online.de
                Author notes
                [* ] Author to whom correspondence should be addressed; Email: nicole.schupp@ 123456toxi.uni-wuerzburg.de ; Tel.: +49-931-20148722; Fax: +49-931-20148446.
                Article
                Publisher ID: toxins-02-02340
                DOI: 10.3390/toxins2102340
                PMC ID: 3153169
                PubMed ID: 22069557
                SO-VID: bedbe0f9-4692-414c-a35d-9077d14da1ac
                Copyright © © 2010 by the authors; licensee MDPI, Basel, Switzerland
                License:

                This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 27 August 2010
                Date revision received : 23 September 2010
                Date accepted : 26 September 2010
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular medicine
                Keywords: dialysis,genotoxicity,uremic toxins
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: dialysis, genotoxicity, uremic toxins

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