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      ESA Hyporesponsiveness Is Associated with Adverse Events in Maintenance Hemodialysis (MHD) Patients, But Not with Iron Storage

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          Abstract

          Objective

          It has been reported that hyporesponsiveness to erythropoiesis-stimulating agent (ESA) is associated with adverse events in patients on maintenance hemodialysis (MHD). However, it has not been determined whether higher iron storage is associated with an improved response, including better survival, to ESA.

          Design and Method

          We measured serum ferritin, hemoglobin (Hb), and transferrin saturation (TSAT) levels every three months for two years in 1,095 MHD patients. The weekly dose of ESA to Hb ratio was also calculated as an index of ESA responsiveness (ERI).

          Results

          A significant correlation (p<0.001, R = 0.89) between ferritin and Hb was only observed in the patients with ferritin levels <50 ng/mL. High-dose (≥50 mg/week) intravenous iron administration, female sex, low serum albumin, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were significant predictors of a high ERI value (>280); however, serum ferritin and TSAT levels did not predict a higher ERI. In the time-dependent Cox hazard model, the risk for a composite event in the patients with a high ERI (≥280) and a high ferritin level (≥100 ng/mL) was significantly greater (hazard ratio [HR], 2.09, P = 0.033) than that for patients with a high ERI and a low ferritin (<100 ng/mL) level.

          Conclusion

          Hb was dependent upon ferritin levels in patients with ferritin levels <50 ng/mL but not in patients with ferritin levels ≥50 ng/mL. Patients with hyporesponsiveness to ESA had a greater risk of composite events, but ERI was unrelated to iron storage.

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          Most cited references28

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          Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes.

          Jula Inrig, Eshan Patel, Robert Califf … (2008)
          Trials of anemia correction in chronic kidney disease have found either no benefit or detrimental outcomes of higher targets. We did a secondary analysis of patients with chronic kidney disease enrolled in the Correction of Hemoglobin in the Outcomes in Renal Insufficiency trial to measure the potential for competing benefit and harm from achieved hemoglobin and epoetin dose trials. In the 4 month analysis, significantly more patients in the high-hemoglobin compared to the low-hemoglobin arm were unable to achieve target hemoglobin and required high-dose epoetin-alpha. In unadjusted analyses, the inability to achieve a target hemoglobin and high-dose epoetin-alpha were each significantly associated with increased risk of a primary endpoint (death, myocardial infarction, congestive heart failure or stroke). In adjusted models, high-dose epoetin-alpha was associated with a significant increased hazard of a primary endpoint but the risk associated with randomization to the high hemoglobin arm did not suggest a possible mediating effect of higher target via dose. Similar results were seen in the 9 month analysis. Our study demonstrates that patients achieving their target had better outcomes than those who did not; and among subjects who achieved their randomized target, no increased risk associated with the higher hemoglobin goal was detected. Prospective studies are needed to confirm this relationship and determine safe dosing algorithms for patients unable to achieve target hemoglobin.
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            Erythropoietic response and outcomes in kidney disease and type 2 diabetes.

            Robert Toto, Emmanuel A. Burdmann, Sharon D Solomon … (2010)
            Non–placebo-controlled trials of erythropoiesis-stimulating agents (ESAs) comparing lower and higher hemoglobin targets in patients with chronic kidney disease indicate that targeting of a lower hemoglobin range may avoid ESA-associated risks. However, target-based strategies are confounded by each patient's individual hematopoietic response. We assessed the relationship among the initial hemoglobin response to darbepoetin alfa after two weight-based doses, the hemoglobin level achieved after 4 weeks, the subsequent darbepoetin alfa dose, and outcomes in 1872 patients with chronic kidney disease and type 2 diabetes mellitus who were not receiving dialysis. We defined a poor initial response to darbepoetin alfa (which occurred in 471 patients) as the lowest quartile of percent change in hemoglobin level (<2%) after the first two standardized doses of the drug. Patients who had a poor initial response to darbepoetin alfa had a lower average hemoglobin level at 12 weeks and during follow-up than did patients with a better hemoglobin response (a change in hemoglobin level ranging from 2 to 15% or more) (P<0.001 for both comparisons), despite receiving higher doses of darbepoetin alfa (median dose, 232 μg vs. 167 μg; P<0.001). Patients with a poor response, as compared with those with a better response, had higher rates of the composite cardiovascular end point (adjusted hazard ratio, 1.31; 95% confidence interval [CI], 1.09 to 1.59) or death (adjusted hazard ratio, 1.41; 95% CI, 1.12 to 1.78). A poor initial hematopoietic response to darbepoetin alfa was associated with an increased subsequent risk of death or cardiovascular events as doses were escalated to meet target hemoglobin levels. Although the mechanism of this differential effect is not known, these findings raise concern about current target-based strategies for treating anemia in patients with chronic kidney disease. (Funded by Amgen; ClinicalTrials.gov number, NCT00093015.)
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              Efficacy and safety of epoetin alfa in critically ill patients.

              Howard Corwin, Andrew Gettinger, Timothy C. Fabian … (2007)
              Anemia, which is common in the critically ill, is often treated with red-cell transfusions, which are associated with poor clinical outcomes. We hypothesized that therapy with recombinant human erythropoietin (epoetin alfa) might reduce the need for red-cell transfusions. In this prospective, randomized, placebo-controlled trial, we enrolled 1460 medical, surgical, or trauma patients between 48 and 96 hours after admission to the intensive care unit. Epoetin alfa (40,000 U) or placebo was administered weekly, for a maximum of 3 weeks; patients were followed for 140 days. The primary end point was the percentage of patients who received a red-cell transfusion. Secondary end points were the number of red-cell units transfused, mortality, and the change in hemoglobin concentration from baseline. As compared with the use of placebo, epoetin alfa therapy did not result in a decrease in either the number of patients who received a red-cell transfusion (relative risk for the epoetin alfa group vs. the placebo group, 0.95; 95% confidence interval [CI], 0.85 to 1.06) or the mean (+/-SD) number of red-cell units transfused (4.5+/-4.6 units in the epoetin alfa group and 4.3+/-4.8 units in the placebo group, P=0.42). However, the hemoglobin concentration at day 29 increased more in the epoetin alfa group than in the placebo group (1.6+/-2.0 g per deciliter vs. 1.2+/-1.8 g per deciliter, P<0.001). Mortality tended to be lower at day 29 among patients receiving epoetin alfa (adjusted hazard ratio, 0.79; 95% CI, 0.56 to 1.10); this effect was also seen in prespecified analyses in those with a diagnosis of trauma (adjusted hazard ratio, 0.37; 95% CI, 0.19 to 0.72). A similar pattern was seen at day 140 (adjusted hazard ratio, 0.86; 95% CI, 0.65 to 1.13), particularly in those with trauma (adjusted hazard ratio, 0.40; 95% CI, 0.23 to 0.69). As compared with placebo, epoetin alfa was associated with a significant increase in the incidence of thrombotic events (hazard ratio, 1.41; 95% CI, 1.06 to 1.86). The use of epoetin alfa does not reduce the incidence of red-cell transfusion among critically ill patients, but it may reduce mortality in patients with trauma. Treatment with epoetin alfa is associated with an increase in the incidence of thrombotic events. (ClinicalTrials.gov number, NCT00091910 [ClinicalTrials.gov].). Copyright 2007 Massachusetts Medical Society.
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                Author and article information

                Contributors
                Hideharu Abe: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 2 March 2016
                Publication date Collection: 2016
                Volume: 11
                Issue: 3
                Electronic Location Identifier: e0147328
                Affiliations
                [1 ]Department of Internal Medicine, Division of Kidney and Dialysis, Hyogo College of Medicine, Nishinomiya, Japan
                [2 ]The Third Department of Internal Medicine Faculty of Medicine, The University of Yamanashi, Chuo, Japan
                [3 ]Department of Nephrology and Blood Purification, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
                [4 ]Division of Nephrology and Dialysis, Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kida, Japan
                [5 ]Division of Integrated Nephrology and Telemedicine, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
                [6 ]Division of Nephrology and Rheumatology, Department of Internal Medicine, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
                [7 ]Department of Hemovascular Medicine and Artificial Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
                [8 ]Department of Nephrology, Toho University Ohashi Medical Center, Tokyo, Japan
                [9 ]Department of Internal Medicine, Yachiyo Hospital, Anjyo, Japan
                [10 ]Department of Internal Medicine, Higashikouri Hospital, Osaka, Japan
                [11 ]Department of Internal Medicine, Itakura Clinic, Tokorozawa, Japan
                Tokushima University Graduate School, JAPAN
                Author notes

                Competing Interests: Takeshi Nakanishi was awarded grants from Chugai Pharmaceutical Company and Takeda Pharmaceutical Company. Kyowa Kirin received a speaker fee from Chugai Pharmaceutical Company, Kyowa Kirin, and Bayer Yakuhin. Takahiro Kuragano received a speaker fee from Chugai Pharmaceutical Company. Nobuhiko Joki received honoraria (as a speaker) from Chugai Pharmaceutical Company, Roche Diagnostics, and Kyowa Kirin. Hiroki Hase received honoraria as a speaker for Chugai Pharmaceutical Company and Kyowa Kirin. Hideyasu Kiyomoto received a speaker fee from Chugai Pharmaceutical Company, Kyowa Kirin, and Bayer Yakuhin. Shouichi Fujimoto received a speaker fee from Chugai Pharmaceutical Company and Kyowa Kirin. There are no patents, products in development, or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

                Conceived and designed the experiments: TK TN. Performed the experiments: TK KK OM AM TH HK TM SF HH NJ AF TI YI TN. Analyzed the data: TK TN. Wrote the paper: TK KK OM AM TH HK TM SF HH NJ AF TI YI TN.

                Article
                Publisher ID: PONE-D-15-19038
                DOI: 10.1371/journal.pone.0147328
                PMC ID: 4774978
                PubMed ID: 26933949
                SO-VID: 31b61bbf-90d4-473e-9ce2-14bd78bc20fb
                Copyright © © 2016 Kuragano et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 17 July 2015
                Date accepted : 1 January 2016
                Page count
                Figures: 7, Tables: 2, Pages: 17
                Funding
                The authors received no specific funding for this work.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Proteins
                Subject: Protein Complexes
                Subject: Ferritin
                Subject: Research and Analysis Methods
                Subject: Research Design
                Subject: Clinical Research Design
                Subject: Adverse Events
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Proteins
                Subject: Albumins
                Subject: Medicine and Health Sciences
                Subject: Pharmaceutics
                Subject: Dose Prediction Methods
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Proteins
                Subject: Protein Complexes
                Subject: Ferritin
                Subject: Serum Ferritin Levels
                Subject: Physical sciences
                Subject: Chemistry
                Subject: Chemical compounds
                Subject: Organic compounds
                Subject: Vitamins
                Subject: Vitamin D
                Subject: Physical sciences
                Subject: Chemistry
                Subject: Organic chemistry
                Subject: Organic compounds
                Subject: Vitamins
                Subject: Vitamin D
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Physiological Processes
                Subject: Erythropoiesis
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Physiological Processes
                Subject: Erythropoiesis
                Subject: Medicine and Health Sciences
                Subject: Nephrology
                Subject: Medical Dialysis
                Custom metadata
                Data Availability All relevant data are within the paper.

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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