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      α-klotho and anemia in patients with chronic kidney disease patients: A new perspective

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          Abstract

          Normocytic normochromic anemia is a common complication of chronic kidney disease (CKD) and is associated with numerous adverse consequences. Certain symptoms previously attributed to CKD are now known to be a consequence of anemia. Anemia contributes to an increased cardiac output, and the development of left ventricular hypertrophy, angina and congestive heart failure, leading to high morbidity and mortality in patients with CKD. The multifunctional α-klotho (KL) protein, which is predominantly expressed in the kidneys, is associated with the occurrence of anemia in patients with CKD. The present review presents current evidence on the potential role of α-KL in renal anemia. Low expression of α-KL appears to improve anemia in patients with CKD, and has been hypothesized to be a compensatory mechanism to attenuate the effects of anemia in patients with CKD. Further understanding of the role of α-KL in renal anemia may offer novel insights into the treatment of patients with CKD complicated with anemia.

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          Correction of anemia with epoetin alfa in chronic kidney disease.

          Ajay K. Singh, Lynda Szczech, Kezhen L Tang … (2006)
          Anemia, a common complication of chronic kidney disease, usually develops as a consequence of erythropoietin deficiency. Recombinant human erythropoietin (epoetin alfa) is indicated for the correction of anemia associated with this condition. However, the optimal level of hemoglobin correction is not defined. In this open-label trial, we studied 1432 patients with chronic kidney disease, 715 of whom were randomly assigned to receive a dose of epoetin alfa targeted to achieve a hemoglobin level of 13.5 g per deciliter and 717 of whom were assigned to receive a dose targeted to achieve a level of 11.3 g per deciliter. The median study duration was 16 months. The primary end point was a composite of death, myocardial infarction, hospitalization for congestive heart failure (without renal replacement therapy), and stroke. A total of 222 composite events occurred: 125 events in the high-hemoglobin group, as compared with 97 events in the low-hemoglobin group (hazard ratio, 1.34; 95% confidence interval, 1.03 to 1.74; P=0.03). There were 65 deaths (29.3%), 101 hospitalizations for congestive heart failure (45.5%), 25 myocardial infarctions (11.3%), and 23 strokes (10.4%). Seven patients (3.2%) were hospitalized for congestive heart failure and myocardial infarction combined, and one patient (0.5%) died after having a stroke. Improvements in the quality of life were similar in the two groups. More patients in the high-hemoglobin group had at least one serious adverse event. The use of a target hemoglobin level of 13.5 g per deciliter (as compared with 11.3 g per deciliter) was associated with increased risk and no incremental improvement in the quality of life. (ClinicalTrials.gov number, NCT00211120 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.
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            A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.

            Marc Pfeffer, Emmanuel A. Burdmann, Chao-Yin Chen … (2009)
            Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested. In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease. Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group. The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. (ClinicalTrials.gov number, NCT00093015.) 2009 Massachusetts Medical Society
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              Normalization of hemoglobin level in patients with chronic kidney disease and anemia.

              Tilman B. Drueke, Francesco Locatelli, Naomi Clyne … (2006)
              Whether correction of anemia in patients with stage 3 or 4 chronic kidney disease improves cardiovascular outcomes is not established. We randomly assigned 603 patients with an estimated glomerular filtration rate (GFR) of 15.0 to 35.0 ml per minute per 1.73 m2 of body-surface area and mild-to-moderate anemia (hemoglobin level, 11.0 to 12.5 g per deciliter) to a target hemoglobin value in the normal range (13.0 to 15.0 g per deciliter, group 1) or the subnormal range (10.5 to 11.5 g per deciliter, group 2). Subcutaneous erythropoietin (epoetin beta) was initiated at randomization (group 1) or only after the hemoglobin level fell below 10.5 g per deciliter (group 2). The primary end point was a composite of eight cardiovascular events; secondary end points included left ventricular mass index, quality-of-life scores, and the progression of chronic kidney disease. During the 3-year study, complete correction of anemia did not affect the likelihood of a first cardiovascular event (58 events in group 1 vs. 47 events in group 2; hazard ratio, 0.78; 95% confidence interval, 0.53 to 1.14; P=0.20). Left ventricular mass index remained stable in both groups. The mean estimated GFR was 24.9 ml per minute in group 1 and 24.2 ml per minute in group 2 at baseline and decreased by 3.6 and 3.1 ml per minute per year, respectively (P=0.40). Dialysis was required in more patients in group 1 than in group 2 (127 vs. 111, P=0.03). General health and physical function improved significantly (P=0.003 and P<0.001, respectively, in group 1, as compared with group 2). There was no significant difference in the combined incidence of adverse events between the two groups, but hypertensive episodes and headaches were more prevalent in group 1. In patients with chronic kidney disease, early complete correction of anemia does not reduce the risk of cardiovascular events. (ClinicalTrials.gov number, NCT00321919 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Exp Ther Med
                Journal ID (iso-abbrev): Exp Ther Med
                Journal ID (publisher-id): ETM
                Title: Experimental and Therapeutic Medicine
                Publisher: D.A. Spandidos
                ISSN (Print): 1792-0981
                ISSN (Electronic): 1792-1015
                Publication date (Print): December 2017
                Publication date (Electronic): 11 October 2017
                Publication date PMC-release: 11 October 2017
                Volume: 14
                Issue: 6
                Pages: 5691-5695
                Affiliations
                [1 ]Department of Nephrology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
                [2 ]Nanchang University School of Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
                Author notes
                Correspondence to: Dr Ben Ke, Department of Nephrology, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi 330006, P.R. China, E-mail: keben-1989125@ 123456163.com
                [*]

                Contributed equally

                Article
                Publisher ID: ETM-0-0-5287
                DOI: 10.3892/etm.2017.5287
                PMC ID: 5729369
                PubMed ID: 29250136
                SO-VID: 88dc86a8-8969-46bd-9679-9a36c4f7574b
                Copyright © Copyright: © Xu et al.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                Date received : 07 October 2016
                Date accepted : 11 April 2017
                Categories
                Subject: Review

                ScienceOpen disciplines: Medicine
                Keywords: klotho,anemia,erythropoietin,iron,vitamin d,chronic kidney disease
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: klotho, anemia, erythropoietin, iron, vitamin d, chronic kidney disease

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