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      Uraemia-induced immune senescence and clinical outcomes in chronic kidney disease patients

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          Abstract

          Background

          Patients with chronic kidney disease (CKD) are more prone to develop premature age-related diseases. Data on immune senescence are scarce in CKD populations, except in end-stage renal disease and dialysis. We designed a longitudinal prospective study to evaluate immune senescence at different CKD stages and its influence on CKD patient outcomes.

          Methods

          Clinical and biological data collections were performed on 222 patients at different CKD stages [1–2 (n = 85), 4 (n = 53) and 5 (n = 84)]. Immune senescence biomarkers were measured by cytometry on T cells (CD28, CD57, CD45RA, CD31, γH2A.X) or by quantitative polymerase chain reaction [relative telomere length (RTL)] on peripheral blood mononuclear cells and analysed according to CKD stages and outcomes.

          Results

          CKD was associated with an increase in immune senescence and inflammation biomarkers, as follows: low thymic output (197 ± 25 versus 88 ± 13 versus 73 ± 21 CD4+CD45RA+CD31+ T cells/mm3), an increased proportion of terminally differentiated T cells (CD8+CD28−CD57+) (24 ± 18 versus 32 ± 17 versus 35 ± 19%) restricted to cytomegalovirus-positive patients, telomere shortening (1.11 ± 0.36 versus 0.78 ± 0.24 versus 0.97 ± 0.21 telomere:single copy ratio) and an increase in C-reactive protein levels [median 2.9 (range 1.8–4.9) versus 5.1 (27–9.6) versus 6.2 (3.4–10.5) mg/L]. In multivariate analysis, shorter RTL was associated with death {hazard ratio [HR] 4.12 [95% confidence interval (CI) 1.44–11.75]}. Low thymic output was associated with infections [HR 1.79 (95% CI (1.34–9.58)] and terminally differentiated CD8+ T-cell expansion with a risk of cardiovascular events [CEs; HR 4.86 (95% CI 1.72–13.72)].

          Conclusion

          CKD was associated with premature immune ageing. Each of these alterations increased the risk of specific age-related diseases, such as RTL and death, thymic function and infections and terminally differentiated CD8+ T-cell expansion and CEs.

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          Most cited references38

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          Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999.

          Knowledge of the excess risk posed by specific cardiovascular syndromes could help in the development of strategies to reduce premature mortality among patients with chronic kidney disease (CKD). The rates of atherosclerotic vascular disease, congestive heart failure, renal replacement therapy, and death were compared in a 5% sample of the United States Medicare population in 1998 and 1999 (n = 1,091,201). Patients were divided into the following groups: 1, no diabetes, no CKD (79.7%); 2, diabetes, no CKD (16.5%); 3, CKD, no diabetes (2.2%); and 4, both CKD and diabetes (1.6%). During the 2 yr of follow-up, the rates (per 100 patient-years) in the four groups were as follows: atherosclerotic vascular disease, 14.1, 25.3, 35.7, and 49.1; congestive heart failure, 8.6, 18.5, 30.7, and 52.3; renal replacement therapy, 0.04, 0.2, 1.6, and 3.4; and death, 5.5, 8.1, 17.7, and 19.9, respectively (P < 0.0001). With use of Cox regression, the corresponding adjusted hazards ratios were as follows: atherosclerotic vascular disease, 1, 1.30, 1.16, and 1.41 (P < 0.0001); congestive heart failure, 1, 1.44, 1.28, and 1.79 (P < 0.0001); renal replacement therapy, 1, 2.52, 23.1, and 38.9 (P < 0.0001); and death, 1, 1.21, 1.38, and 1.56 (P < 0.0001). On a relative basis, patients with CKD were at a much greater risk for the least frequent study outcome, renal replacement therapy. On an absolute basis, however, the high death rates of patients with CKD may reflect accelerated rates of atherosclerotic vascular disease and congestive heart failure.
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            Immune cell dysfunction and inflammation in end-stage renal disease.

            Uraemia causes inflammation and reduces immune system function as evidenced by an increased risk of viral-associated cancers, increased susceptibility to infections and decreased vaccination responses in patients with end-stage renal disease (ESRD). The substantially increased risk of atherosclerosis in these patients is also probably related to uraemia-associated inflammation. Uraemia is associated with a reduction in the number and function of lymphoid cells, whereas numbers of myeloid cells in uraemic patients are normal or increased with increased production of inflammatory cytokines and reactive oxygen species. Similar to healthy elderly individuals, patients with ESRD have increased numbers of specific proinflammatory subsets of T cells and monocytes, suggesting the presence of premature immunological ageing in these patients. These cells might contribute to inflammation and destabilization of atherosclerotic plaques, and have, therefore, been identified as novel nonclassical cardiovascular risk factors. The cellular composition of the immune system does not normalize after successful kidney transplantation despite a rapid reduction in inflammation and oxidative stress. This finding suggests that premature ageing of the immune system in patients with ESRD might be related to a permanent skewing of the haematopoetic stem cell population towards myeloid-generating subsets, similar to that seen in healthy elderly individuals.
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              Inflamm-ageing.

              Inflamm-ageing, defined as the chronic low-grade inflammation typical of ageing, seems to be the common biological factor responsible for the decline and the onset of disease in the elderly. The major age-related diseases share a common inflammatory pathogenesis, giving rise to the so-called 'diseasome of inflamm-ageing'. Main objective of this review is to provide a comprehensive view of the complex interactions responsible for inflamm-ageing, underlining its relationship with metaflammation and the role of senescent cells, gut microbiota and nutrition in determining when, where and how much this phenomenon impacts on the health status during human lifespan. The ageing process and the health status of elderly people may be improved by facing and slowing down inflamm-ageing. Among the inflammation modulators, gut microbiota and nutrition should be exploited as potential powerful tools to promote healthy ageing and to extend the lifespan in humans. The possibility to control inflamm-ageing represents a powerful tool to modulate and counteract the major age-related pathologies and it is urgent to clarify the shady areas of the complex mechanisms underpinning inflamm-ageing in order to carry out targeted therapeutic interventions towards an improvement of the health status in the elderly population.
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                Author and article information

                Journal
                Nephrology Dialysis Transplantation
                Oxford University Press (OUP)
                0931-0509
                1460-2385
                April 2020
                April 01 2020
                September 06 2018
                April 2020
                April 01 2020
                September 06 2018
                : 35
                : 4
                : 624-632
                Affiliations
                [1 ]INSERM, UMR1098, Federation Hospitalo-Universitaire, INCREASE, Besançon, France
                [2 ]University of Bourgogne-Franche-Comté, Faculté de Médecine et de Pharmacie, LabEx LipSTIC, Besançon and Dijon, France
                [3 ]CHU Besançon, Department of Nephrology, Dialysis, and Renal Transplantation, Besançon, France
                [4 ]CHU Besançon, CIC Biothérapie, INSERM CIC-1431, Besançon, France
                [5 ]EFS Bourgogne Franche-Comté, Plateforme de Biomonitoring, INSERM CIC-1431/UMR1098, Besançon, France
                Article
                10.1093/ndt/gfy276
                30202981
                5c244d7e-6753-4fa0-83e9-4724aeea580a
                © 2018

                https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

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