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      Iron deficiency across chronic inflammatory conditions: International expert opinion on definition, diagnosis, and management

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          Abstract

          Iron deficiency, even in the absence of anemia, can be debilitating, and exacerbate any underlying chronic disease, leading to increased morbidity and mortality. Iron deficiency is frequently concomitant with chronic inflammatory disease; however, iron deficiency treatment is often overlooked, partially due to the heterogeneity among clinical practice guidelines. In the absence of consistent guidance across chronic heart failure, chronic kidney disease and inflammatory bowel disease, we provide practical recommendations for iron deficiency to treating physicians: definition, diagnosis, and disease‐specific diagnostic algorithms. These recommendations should facilitate appropriate diagnosis and treatment of iron deficiency to improve quality of life and clinical outcomes.

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          Correction of anemia with epoetin alfa in chronic kidney disease.

          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.

            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.

              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

                Contributors
                maria.cappellini@unimi.it
                Journal
                Am J Hematol
                Am. J. Hematol
                10.1002/(ISSN)1096-8652
                AJH
                American Journal of Hematology
                John Wiley and Sons Inc. (Hoboken )
                0361-8609
                1096-8652
                07 July 2017
                October 2017
                : 92
                : 10 ( doiID: 10.1002/ajh.v92.10 )
                : 1068-1078
                Affiliations
                [ 1 ] Rare Diseases Centre Department of Medicine and Medical Specialties, Fondazione IRCCS Ca'Granda—Ospedale Maggiore Policlinico Milan Italy
                [ 2 ] Department of Clinical Sciences and Community Health Università degli Studi di Milano Milan Italy
                [ 3 ] Community Heart Failure Program Department of Cardiology, Bellvitge University Hospital, University of Barcelona and Biomedical Research Institut (IDIBELL), Hospitalet de Liobregat Barcelona Spain
                [ 4 ] Department of Nephrology Valdecilla Universitario Hospital, University of Cantabria Santander Spain
                [ 5 ] Department of Medicine I Agaplesion Markus Hospital Frankfurt Germany
                [ 6 ] Center for Stroke Research CSB and Department of Cardiology Virchow Campus, Charité Universitätsmedizin Berlin Berlin Germany
                [ 7 ] Department of Cardiology National Heart Centre Singapore and Duke‐NUS Medical School Singapore
                [ 8 ] Department of Renal Medicine King's College Hospital London United Kingdom
                [ 9 ] Division of Gastroenterology and Hepatology University of Zurich Zurich Switzerland
                [ 10 ] Division of Genetics and Cell Biology San Raffaele Scientific Institute and Vita‐Salute University Milan Italy
                [ 11 ] Department of Obstetrics & Gynaecology Royal Free Foundation Hospital and University College Hospital London United Kingdom
                [ 12 ] Institute for Health Metrics and Evaluation, University of Washington Seattle Washington, DC
                [ 13 ] Department of Anesthesiology and Pain Medicine Seattle Children's Hospital, University of Washington Seattle Washington, DC
                [ 14 ] Institute of Anaesthesiology, University of Zurich and University Hospital Zurich Zurich Switzerland
                [ 15 ] Department of Internal Medicine American University of Beirut Medical Center Beirut Lebanon
                [ 16 ] International Network of Hematology London United Kingdom
                Author notes
                [*] [* ] Correspondence Maria Domenica Cappellini, Fondazione Ca' Granda Policlinico, Via F. Sforza 35, 20122 Milano, Italy. Email: maria.cappellini@ 123456unimi.it
                Author information
                http://orcid.org/0000-0001-8676-6864
                http://orcid.org/0000-0001-8515-2238
                Article
                AJH24820
                10.1002/ajh.24820
                5599965
                28612425
                9575f1de-ea67-4082-ac63-c1a28c41aab0
                © 2017 The Authors American Journal of Hematology Published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 12 April 2017
                : 01 June 2017
                : 05 June 2017
                Page count
                Figures: 4, Tables: 2, Pages: 11, Words: 8553
                Funding
                Funded by: Vifor Pharma
                Categories
                Critical Review
                Critical Reviews
                Custom metadata
                2.0
                ajh24820
                October 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.9 mode:remove_FC converted:15.09.2017

                Hematology
                Hematology

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