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      Achievement of renal anemia KDIGO targets by two different clinical strategies – a European hemodialysis multicenter analysis

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          Abstract

          Background

          The optimal treatment algorithm for iron therapy and the use of erythropoiesis-stimulating agents (ESA) in anemic hemodialysis (HD) patients has not been established. Hemoglobin (Hb) target levels can be achieved through more frequent intravenous (IV) iron use with lower ESA dose, or with less iron dosing but higher ESA. ESA therapy to correct anemia may result in severe arterial and venous thrombotic complications and the evidence base evaluating hard clinical outcomes related to the use of IV iron is sparse.

          Methods

          A total of 1247 maintenance HD patients from 12 dialysis centers in Portugal ( n = 730) and Poland ( n = 517) were considered. We assessed achievement of KDIGO renal anemia targets with focus on treatment strategies, which typically differ between countries. In Poland the use and dose of IV iron was 35–72% higher than that in Portugal ( p <  0.001) during three consecutive months; use and dose of ESA was 61% higher in Portugal (5034 vs 3133 IU (adjusted)/week, p <  0.001).

          Results

          Mean Hb concentration was similar (11.0 vs 11.0 g/dL) in patients treated in both countries and the proportion of patients within KDIGO anemia target was 69.5% in Poland vs 65.8% in Portugal (NS). Ferritin and TSAT levels and the proportion of patients with TSAT > 20 and > 50% were both significantly higher in patients in Poland (88.8 and 14.6%) than in Portugal (76.3 and 5.7% respectively, p <  0.001). Significantly more patients in Poland had a ferritin concentration > 800 μg/L (35.6%) compared to Portugal (15.8%, p <  0.001). The ESA resistance index (ERI) was significantly higher in patients treated in Portugal (p <  0.001). Correlation analyses showed confounding by treatment indication in unadjusted models. Multiple and logistic regression analyses showed that with ferritin within KDIGO recommended range of 200–800 μg/L the odds for Hb within guidelines increased significantly. Annual gross mortality was 16% in Poland and 13% in Portugal (NS); there were no differences in cause-specific mortality.

          Conclusions

          Administration of high doses of IV iron in routine clinical HD practice may not be associated with considerable harm. However, large randomized controlled trials are needed to provide absolute evidence of iron safety.

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          Most cited references27

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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
                Maciej.drozdz@davita.com
                Andre.weigert@davita.pt
                Fatima.silva@davita.com
                Joao.frazao@davita.pt
                Abdulkareem.alsuwaida@davita.com
                Mahesh.krishnan@davita.com
                Werner.kleophas@davita-dialyse.de
                Szymon.brzosko@davita.com
                Fredrik.k.johansson@sll.se
                +46707591890 , Stefan.Jacobson@sll.se
                Journal
                BMC Nephrol
                BMC Nephrol
                BMC Nephrology
                BioMed Central (London )
                1471-2369
                7 January 2019
                7 January 2019
                2019
                : 20
                : 5
                Affiliations
                [1 ]DaVita Poland, Krakow, Poland
                [2 ]DaVita Portugal, Lisbon, Portugal
                [3 ]ISNI 0000 0001 2288 671X, GRID grid.413421.1, Nephrology Department, , Hospital Santa Cruz, ; Carnaxide, Portugal
                [4 ]ISNI 0000 0001 2181 4263, GRID grid.9983.b, School of Medicine, , University of Lisbon, ; Lisbon, Portugal
                [5 ]ISNI 0000 0000 9375 4688, GRID grid.414556.7, Department of Nephrology, , São João Hospital Center, ; Porto, Portugal
                [6 ]ISNI 0000 0001 1503 7226, GRID grid.5808.5, School of Medicine, , University of Porto, ; Porto, Portugal
                [7 ]DaVita Saudi Arabia, Riyadh, Saudi Arabia
                [8 ]ISNI 0000 0004 1773 5396, GRID grid.56302.32, King Saud University, ; Riyadh, Saudi Arabia
                [9 ]DaVita, Inc, Denver, CO USA
                [10 ]DaVita Germany, Dusseldorf, Germany
                [11 ]ISNI 0000 0001 2176 9917, GRID grid.411327.2, Clinic for Nephrology, , Heinrich-Heine –University, ; Dusseldorf, Germany
                [12 ]ISNI 0000000122482838, GRID grid.48324.39, 1st Department of Nephrology and Transplantation, , Medical University of Bialystok, ; Bialystok, Poland
                [13 ]DaVita Poland, Bialystok, Poland
                [14 ]ISNI 0000 0004 0636 5158, GRID grid.412154.7, Unit for Medical Statistics, Department of Clinical Sciences, Karolinska Institutet, , Danderyd University Hospital, ; Stockholm, Sweden
                [15 ]ISNI 0000 0004 0636 5158, GRID grid.412154.7, Division of Nephrology, Department of Clinical Sciences, Karolinska Institutet, , Danderyd University Hospital, ; Stockholm, Sweden
                Article
                1196
                10.1186/s12882-018-1196-7
                6323791
                30616548
                8b015dfd-c407-4574-8cf7-0f2853f2a94d
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 13 August 2018
                : 26 December 2018
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2019

                Nephrology
                anemia,erythropoiesis-stimulating agent,ferritin,hemodialysis,hemoglobin,iron,mortality,tsat
                Nephrology
                anemia, erythropoiesis-stimulating agent, ferritin, hemodialysis, hemoglobin, iron, mortality, tsat

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