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      Immune Dysfunction in Uremia—An Update

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          Abstract

          Kidney dysfunction leads to disturbed renal metabolic activities and to impaired glomerular filtration, resulting in the retention of toxic solutes affecting all organs of the body. Cardiovascular disease (CVD) and infections are the main causes for the increased occurrence of morbidity and mortality among patients with chronic kidney disease (CKD). Both complications are directly or indirectly linked to a compromised immune defense. The specific coordinated roles of polymorphonuclear leukocytes (PMNLs), monocytes/macrophages, lymphocytes and antigen-presenting cells (APCs) in maintaining an efficient immune response are affected. Their normal response can be impaired, giving rise to infectious diseases or pre-activated/primed, leading to inflammation and consequently to CVD. Whereas the coordinated removal via apoptosis of activated immune cells is crucial for the resolution of inflammation, inappropriately high apoptotic rates lead to a diminished immune response. In uremia, the balance between pro- and anti-inflammatory and between pro- and anti-apoptotic factors is disturbed. This review summarizes the interrelated parameters interfering with the immune response in uremia, with a special focus on the non-specific immune response and the role of uremic toxins.

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          Chronic kidney disease and mortality risk: a systematic review.

          Marcello Tonelli, Natasha Wiebe, Bruce Culleton … (2006)
          Current guidelines identify people with chronic kidney disease (CKD) as being at high risk for cardiovascular and all-cause mortality. Because as many as 19 million Americans may have CKD, a comprehensive summary of this risk would be potentially useful for planning public health policy. A systematic review of the association between non-dialysis-dependent CKD and the risk for all-cause and cardiovascular mortality was conducted. Patient- and study-related characteristics that influenced the magnitude of these associations also were investigated. MEDLINE and EMBASE databases were searched, and reference lists through December 2004 were consulted. Authors of 10 primary studies provided additional data. Cohort studies or cohort analyses of randomized, controlled trials that compared mortality between those with and without chronically reduced kidney function were included. Studies were excluded from review when participants were followed for < 1 yr or had ESRD. Two reviewers independently extracted data on study setting, quality, participant and renal function characteristics, and outcomes. Thirty-nine studies that followed a total of 1,371,990 participants were reviewed. The unadjusted relative risk for mortality in participants with reduced kidney function compared with those without ranged from 0.94 to 5.0 and was significantly more than 1.0 in 93% of cohorts. Among the 16 studies that provided suitable data, the absolute risk for death increased exponentially with decreasing renal function. Fourteen cohorts described the risk for mortality from reduced kidney function, after adjustment for other established risk factors. Although adjusted relative hazards were consistently lower than unadjusted relative risks (median reduction 17%), they remained significantly more than 1.0 in 71% of cohorts. This review supports current guidelines that identify individuals with CKD as being at high risk for cardiovascular mortality. Determining which interventions best offset this risk remains a health priority.
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            Aspects of immune dysfunction in end-stage renal disease.

            Sawako Kato, Michal Chmielewski, Hirokazu Honda … (2008)
            End-stage renal disease (ESRD) is associated with significantly increased morbidity and mortality resulting from cardiovascular disease (CVD) and infections, accounting for 50% and 20%, respectively, of the total mortality in ESRD patients. It is possible that these two complications are linked to alterations in the immune system in ESRD, as uremia is associated with a state of immune dysfunction characterized by immunodepression that contributes to the high prevalence of infections among these patients, as well as by immunoactivation resulting in inflammation that may contribute to CVD. This review describes disorders of the innate and adaptive immune systems in ESRD, underlining the specific role of ESRD-associated disturbances of Toll-like receptors. Finally, based on the emerging links between the alterations of immune system, CVD, and infections in ESRD patients, it emphasizes the potential role of the immune dysfunction in ESRD as an underlying cause for the high mortality in this patient population and the need for more studies in this area.
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              The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia.

              Jonathan Himmelfarb, Peter Stenvinkel, T Alp Ikizler … (2002)
              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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                Author and article information

                Journal
                Journal ID (nlm-ta): Toxins (Basel)
                Journal ID (iso-abbrev): Toxins (Basel)
                Journal ID (publisher-id): toxins
                Title: Toxins
                Publisher: MDPI
                ISSN (Electronic): 2072-6651
                Publication date (Electronic): 24 October 2012
                Publication date Collection: November 2012
                Volume: 4
                Issue: 11
                Pages: 962-990
                Affiliations
                Abteilung für Nephrologie und Dialyse, Univ.-Klinik für Innere Medizin III, Währinger Gürtel 18-20, Wien A-1090, Austria; Email: walter.hoerl@ 123456meduniwien.ac.at
                Author notes
                [* ] Author to whom correspondence should be addressed; Email: gerald.cohen@ 123456meduniwien.ac.at ; Tel.: +43-1-40100-4343; Fax: +43-1-40400-7790.
                Article
                Publisher ID: toxins-04-00962
                DOI: 10.3390/toxins4110962
                PMC ID: 3509694
                PubMed ID: 23202302
                SO-VID: c8a2b681-ebe2-4ca5-8e3e-2f6c2f6d3fba
                Copyright © © 2012 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 : 06 August 2012
                Date revision received : 26 September 2012
                Date accepted : 08 October 2012
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular medicine
                Keywords: cardiovascular disease,oxidative stress,inflammation,infection,priming,apoptosis,uremic toxins,polymorphonuclear leukocytes,monocytes,antigen-presenting cells
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: cardiovascular disease, oxidative stress, inflammation, infection, priming, apoptosis, uremic toxins, polymorphonuclear leukocytes, monocytes, antigen-presenting cells

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