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      Indoxyl sulfate, homocysteine, and antioxidant capacities in patients at different stages of chronic kidney disease

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          Abstract

          BACKGROUND/OBJECTIVES

          Increased levels of uremic toxins and decreased antioxidant capacity have a significant impact on the progression of chronic kidney disease (CKD). However, it remains unclear whether they interact with each other to mediate the damage of kidney function. The purpose of this study was to investigate whether uremic toxins (i.e., homocysteine and indoxyl sulfate [IS]), as well as glutathione-dependent antioxidant enzyme activities are dependently or independently associated with kidney function during different stages of CKD patients.

          SUBJECTS/METHODS

          One hundred thirty-two patients diagnosed with CKD at stages 1 to 5 participated in this cross-sectional study.

          RESULTS

          Patients who had reached an advanced CKD stage experienced an increase in plasma uremic toxin levels, along with decreased glutathione peroxidase (GSH-Px) activity. Plasma homocysteine, cysteine, and IS concentrations were all positively associated with each other, but negatively correlated to GSH-Px activity levels after adjusting for potential confounders in all CKD patients. Although plasma homocysteine, cysteine, IS, and GSH-Px levels were significantly associated with kidney function, only plasma IS levels still had a significant association with kidney function after these parameters were simultaneously adjusted. In addition, plasma IS could interact with GSH-Px activity to be associated with kidney function.

          CONCLUSIONS

          IS plays a more dominant role than homocysteine and GSH-Px activity in relation to kidney function.

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          Most cited references49

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          KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease

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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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              Review on uremic toxins: classification, concentration, and interindividual variability.

              The choice of the correct concentration of potential uremic toxins for in vitro, ex vivo, and in vivo experiments remains a major area of concern; errors at this level might result in incorrect decisions regarding therpeutic correction of uremia and related clinical complications. An encyclopedic list of uremic retention solutes was composed, containing their mean normal concentration (CN), their highest mean/median uremic concentration (CU), their highest concentration ever reported in uremia (CMAX), and their molecular weight. A literature search of 857 publications on uremic toxicity resulted in the selection of data reported in 55 publications on 90 compounds, published between 1968 and 2002. For all compounds, CU and/or CMAX exceeded CN. Molecular weight was lower than 500 D for 68 compounds; of the remaining 22 middle molecules, 12 exceeded 12,000 D. CU ranged from 32.0 ng/L (methionine-enkephalin) up to 2.3 g/L (urea). CU in the ng/L range was found especially for the middle molecules (10/22; 45.5%), compared with 2/68 (2.9%) for a molecular weight <500 D (P < 0.002). Twenty-five solutes (27.8%) were protein bound. Most of them had a molecular weight <500 D except for leptin and retinol-binding protein. The ratio CU/CN, an index of the concentration range over which toxicity is exerted, exceeded 15 in the case of 20 compounds. The highest values were registered for several guanidines, protein-bound compounds, and middle molecules, to a large extent compounds with known toxicity. A ratio of CMAX/CU <4, pointing to a Gaussian distribution, was found for the majority of the compounds (74/90; 82%). For some compounds, however, this ratio largely exceeded 4 [e.g., for leptin (6.81) or indole-3-acetic acid (10.37)], pointing to other influencing factors than renal function, such as gender, genetic predisposition, proteolytic breakdown, posttranslation modification, general condition, or nutritional status. Concentrations of retention solutes in uremia vary over a broad range, from nanograms per liter to grams per liter. Low concentrations are found especially for the middle molecules. A substantial number of molecules are protein bound and/or middle molecules, and many of these exert toxicity and are characterized by a high range of toxic over normal concentration (CU/CN ratio). Hence, uremic retention is a complex problem that concerns many more solutes than the current markers of urea and creatinine alone. This list provides a basis for systematic analytic approaches to map the relative importance of the enlisted families of toxins.
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                Author and article information

                Journal
                Nutr Res Pract
                Nutr Res Pract
                NRP
                Nutrition Research and Practice
                The Korean Nutrition Society and the Korean Society of Community Nutrition
                1976-1457
                2005-6168
                August 2022
                02 December 2021
                : 16
                : 4
                : 464-475
                Affiliations
                [1 ]Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407219, Taiwan.
                [2 ]Department of Life Science, Tunghai University, Taichung 407224, Taiwan.
                [3 ]School of Medicine, China Medical University, Taichung 404333, Taiwan.
                [4 ]College of Medicine, National Chung Hsing University, Taichung 402202, Taiwan.
                [5 ]Department of Nutrition, Chung Shan Medical University, Taichung 402306, Taiwan.
                [6 ]Department of Nutrition, Chung Shan Medical University Hospital, Taichung 402306, Taiwan.
                [7 ]Department of Health Industry Technology Management, Chung Shan Medical University, Taichung 402306, Taiwan.
                [8 ]Department of Nutrition, College of Medical and Health Care, Hung-Kuang University, Taichung 433304, Taiwan.
                [9 ]School of Medicine, National Yang-Ming University, Taipei 112304, Taiwan.
                Author notes
                Corresponding Author: Yi-Chia Huang. Department of Nutrition, Chung Shan Medical University, Jianguo N Rd, Taichung 402306, Taiwan. Tel. +886-4-24730022, ych@ 123456csmu.edu.tw
                Author information
                https://orcid.org/0000-0002-1299-5055
                https://orcid.org/0000-0001-8305-9160
                https://orcid.org/0000-0001-9641-2082
                https://orcid.org/0000-0002-3883-3134
                https://orcid.org/0000-0002-6119-0587
                https://orcid.org/0000-0003-2234-4464
                Article
                10.4162/nrp.2022.16.4.464
                9314193
                d50212f8-99a3-47fe-ac8c-d9ca35b06dbf
                ©2021 The Korean Nutrition Society and the Korean Society of Community Nutrition

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 08 July 2021
                : 01 October 2021
                : 29 October 2021
                Funding
                Funded by: Taichung Veterans General Hospital, CrossRef https://doi.org/10.13039/501100010101;
                Award ID: TCVGH-1083601B
                Award ID: TCVGH-VHCY1088602
                Categories
                Original Research

                Nutrition & Dietetics
                uremic toxins,homocysteine,indoxyl sulfate,glutathione peroxidase,chronic kidney disease

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