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      Large uremic toxins: an unsolved problem in end-stage kidney disease

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          Abstract

          Patients with end-stage kidney disease (ESKD) on maintenance hemodialysis are subject to a high burden of inflammation and cardiovascular disease, driven at least in part by retention of uremic solutes. Existing dialysis technologies using high-flux membranes offer limited clearance of solutes >15 kDa. New approaches to improve the removal of large uremic toxins include the novel medium cut-off dialysis membranes with pores larger than those in high-flux membranes. These new membranes provide the potential to improve the clearance of large middle molecules up to 50 kDa. In this review, we discuss 18 uremic toxins with molecular weights between 15 and 60 kDa that are retained in ESKD, for which there is evidence of a link to inflammation and/or cardiovascular disease. These include inflammatory proteins, cytokines, adipokines and other signaling proteins. Improved clearance of this group of difficult to remove molecules has the potential to lead to improved outcomes in dialysis patients by reducing the burden of cardiovascular disease, which now needs to be assessed in robust clinical trials.

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          Inflammation and atherosclerosis: a review of the role of interleukin-6 in the development of atherosclerosis and the potential for targeted drug therapy.

          Joshua Hartman, William Frishman (2015)
          It has recently been appreciated that atherosclerosis is predominantly an inflammatory process. Atherosclerosis begins with a fatty streak, which is made up almost entirely of monocyte-derived macrophages. The development of an atheroma continues as T-cells, mast cells, and other inflammatory cells are recruited to the intima. This collection of inflammatory cells promotes smooth muscle cell replication and extracellular matrix elaboration, thereby increasing the lesion size. Various studies have highlighted that interleukin-6 (IL-6) is an upstream inflammatory cytokine that plays a central role in propagating the downstream inflammatory response responsible for atherosclerosis. IL-6 release is stimulated by acute infections, chronic inflammatory conditions, obesity, and physiologic stress. The high level of IL-6 found in such conditions has a myriad of functions, including hepatic synthesis of acute-phase reactants, activation of endothelial cells, increased coagulation, activation of the hypothalamic-pituitary-adrenal axis, and promotion of lymphocyte proliferation and differentiation. Considering the importance of IL-6 in the development of coronary artery disease, targeting its actions could prove to be beneficial. Individuals with a variant in the IL-6 receptor that impairs classic IL-6 signaling were found to have a decreased risk for coronary heart disease. Tocilizumab is a monoclonal antibody that targets the IL-6 receptor and has been show to alleviate symptoms in patients with rheumatoid arthritis, a disease largely driven by the proinflammatory actions of IL-6. Therefore, further studies are needed to determine the role of tocilizumab and other IL-6 receptor blockers in decreasing the inflammatory response key in the development of atherosclerosis.
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            Plasma leptin and the risk of cardiovascular disease in the west of Scotland coronary prevention study (WOSCOPS).

            Heath A. Kelly, N Sattar, Alex Shepherd … (2001)
            Leptin plays a role in fat metabolism and correlates with insulin resistance and other markers of the metabolic syndrome, independent of total adiposity. Therefore, we hypothesized that raised leptin levels may identify men at increased risk of a coronary event in the West of Scotland Coronary Prevention Study (WOSCOPS). Methods and Results- Plasma leptin levels were measured at baseline in 377 men (cases) who subsequently experienced a coronary event and in 783 men (controls) who remained free of an event during the 5-year follow-up period of the study. Controls were matched to cases on the basis of age and smoking history and were representative of the entire WOSCOPS cohort. Leptin levels were significantly higher in cases than controls (5.87+/-2.04 ng/mL versus 5.04+/-2.09 ng/mL, P<0.001). In univariate analysis, for each 1 SD increase in leptin, the relative risk (RR) of an event increased by 1.25 (95% confidence interval [CI], 1.10 to 1.43; P<0.001). There was minimal change in this RR with correction for body mass index (RR, 1.24; 95% CI, 1.06 to 1.45; P=0.006) or with further correction for classic risk factors, including age, lipids, and systolic blood pressure (RR, 1.20; 95% CI, 1.02 to 1.42; P=0.03). Leptin correlated with C-reactive protein (r=0.24, P<0.001) and, even with this variable added to the model, leptin retained significance as a predictor of coronary events (RR, 1.18; 95% CI, 1.00 to 1.39; P=0.05) at the expense of C-reactive protein. We show, for the first time, in a large prospective study that leptin is a novel, independent risk factor for coronary heart disease.
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              TNFalpha in atherosclerosis, myocardial ischemia/reperfusion and heart failure.

              Petra Kleinbongard, Gerd Heusch, Rainer Schulz (2010)
              TNFalpha is crucially involved in the pathogenesis and progression of atherosclerosis, myocardial ischemia/reperfusion injury and heart failure. The formation and release of TNFalpha and its downstream signal transduction cascade following activation of its two receptor subtypes is characterized, with special emphasis on the cardiovascular system. In the vasculature, TNFalpha alters endothelial and vascular smooth muscle cell function as well as endothelial cell-blood cell interaction; the importance of such alterations for vascular dysfunction, the initiation and progression of atherosclerosis are discussed. In the myocardium, TNFalpha contributes to reversible and irreversible ischemia/reperfusion injury, post-myocardial infarction remodeling and heart failure development. Simultaneously, TNFalpha also contributes to cardioprotection by ischemic conditioning. Emphasis is placed on such ambivalent (detrimental vs. beneficial) role of TNFalpha, which appears to be dose- and time-dependent and in part related to the activation of the specific receptor subtype. Given the ambivalent role of TNFalpha and its receptors, it is not surprising that clinical trials using compounds that antagonize TNFalpha revealed ambiguous and largely disappointing results in cardiovascular disease, notably in heart failure. Future perspectives to antagonize and/or potentially recruit TNFalpha in the cardiovascular system are critically discussed. 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Nephrol Dial Transplant
                Journal ID (iso-abbrev): Nephrol. Dial. Transplant
                Journal ID (publisher-id): ndt
                Title: Nephrology Dialysis Transplantation
                Publisher: Oxford University Press
                ISSN (Print): 0931-0509
                ISSN (Electronic): 1460-2385
                Publication date (Print): October 2018
                Publication date (Electronic): 03 October 2018
                Publication date PMC-release: 03 October 2018
                Volume: 33
                Issue: Suppl 3 , Expanded hemodialysis: translating innovation to clinical outcomes
                Pages: iii6-iii11
                Affiliations
                [1 ]Department of Renal Medicine, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia
                [2 ]Faculty of Medicine, University of Queensland, Herston, QLD, Australia
                [3 ]Department of Medicine, Hawke’s Bay District Health Board, Hastings, New Zealand
                Author notes
                Correspondence and offprint requests to: Colin A. Hutchison; E-mail: Colin.Hutchison@ 123456hawkesbaydhb.govt.nz
                Article
                Publisher ID: gfy179
                DOI: 10.1093/ndt/gfy179
                PMC ID: 6168891
                PubMed ID: 30281131
                SO-VID: b96fabe9-c022-41a4-9e60-ddfcd877d52f
                Copyright © © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                Date received : 10 April 2018
                Date accepted : 16 May 2018
                Page count
                Pages: 6
                Funding
                Funded by: Baxter Healthcare Corporation 10.13039/100007658
                Categories
                Subject: Reviews

                ScienceOpen disciplines: Nephrology
                Keywords: cardiovascular disease,haemodialysis, inflammation,middle molecules,uremic toxins
                Data availability:
                ScienceOpen disciplines: Nephrology
                Keywords: cardiovascular disease, haemodialysis, inflammation, middle molecules, uremic toxins

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