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      Hyporesponsiveness to erythropoiesis-stimulating agent in non-dialysis-dependent CKD patients: The BRIGHTEN study

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          Abstract

          Among non-dialysis-dependent chronic kidney disease (ND-CKD) patients, a low hematopoietic response to erythropoiesis-stimulating agents (ESAs) is a predictor for poor renal and cardiovascular outcome. To assess the method for evaluating hyporesponsiveness to ESA in patients with ND-CKD, a multicenter, prospective, observational study of 1,980 adult patients with ND-CKD with renal anemia was conducted. Darbepoetin alfa (DA) and iron supplement administrations were provided according to the recommendation of the attached document and the guidelines of JSDT (Japanese Society of Dialysis and Transplantation). The primary outcomes were progression of renal dysfunction and major adverse cardiovascular events. ESA responsiveness was assessed using pre-defined candidate formulae. During the mean follow-up period of 96 weeks, renal and cardiovascular disease (CVD) events occurred in 683 (39.6%) and 174 (10.1%) of 1,724 patients, respectively. Among pre-set candidate formulae, the one expressed by dividing the dose of DA by Hb level at the 12-week DA treatment was statistically significant in predicting renal (hazard ratio [HR], 1.449; 95% confidence interval [CI], 1.231–1.705; P<0.0001) and CVD events (HR, 1.719; 95% CI, 1.239–2.386; P = 0.0010). The optimum cut-off values for both events were close to 5.2. In conclusion, hyporesponsiveness to ESA in ND-CKD cases, which is associated with a risk for renal and CVD events, may be evaluated practicably as the dose of DA divided by the Hb level at the 12-week DA treatment, and the cut-off value of this index is 5.2. A search for the causes of poor response and measures for them should be recommended in such patients.

          Trial registration: ClinicalTrials. gov Identifier: NCT02136563; UMIN Clinical Trial Registry Identifier: UMIN000013464.

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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

                Contributors
                Ichiei Narita:
                ORCID: https://orcid.org/0000-0001-7692-3096
                Role: ConceptualizationRole: Writing – original draftRole: Writing – review & editing
                Terumasa Hayashi: Role: ConceptualizationRole: Writing – review & editing
                Shoichi Maruyama: Role: ConceptualizationRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Takao Masaki: Role: ConceptualizationRole: ValidationRole: Writing – review & editing
                Masaomi Nangaku: Role: ConceptualizationRole: Project administrationRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Tomoya Nishino: Role: ConceptualizationRole: InvestigationRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Hiroshi Sato: Role: ConceptualizationRole: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Tadashi Sofue: Role: ConceptualizationRole: InvestigationRole: ValidationRole: Writing – review & editing
                Takashi Wada: Role: ConceptualizationRole: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Enyu Imai: Role: Data curation
                Manabu Iwasaki: Role: Data curationRole: Formal analysis
                Kyoichi Mizuno: Role: Data curationRole: Validation
                Hiroki Hase: Role: Data curationRole: Formal analysisRole: Validation
                Masahiro Kamouchi: Role: Data curationRole: Formal analysisRole: Validation
                Hiroyasu Yamamoto: Role: Data curationRole: Formal analysisRole: Validation
                Tatsuo Kagimura: Role: Data curationRole: Formal analysisRole: MethodologyRole: Visualization
                Kenichiro Tanabe:
                ORCID: https://orcid.org/0000-0001-6271-2490
                Role: Data curationRole: Formal analysisRole: MethodologyRole: Visualization
                Hideki Kato: Role: MethodologyRole: Project administrationRole: ValidationRole: Writing – review & editing
                Takehiko Wada: Role: MethodologyRole: Project administrationRole: Writing – review & editing
                Tomoko Usui: Role: MethodologyRole: Project administrationRole: Writing – review & editing
                Tadao Akizawa: Role: SupervisionRole: Writing – review & editing
                Hideki Hirakata: Role: SupervisionRole: Writing – review & editing
                Yoshiharu Tsubakihara: Role: SupervisionRole: Writing – review & editing
                Gianpaolo Reboldi: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS One
                Journal ID (publisher-id): plos
                Title: PLOS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 29 November 2022
                Publication date Collection: 2022
                Volume: 17
                Issue: 11
                Electronic Location Identifier: e0277921
                Affiliations
                [001] Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
                Universita degli Studi di Perugia, ITALY
                Author notes

                Competing Interests: Dr Narita reported receiving lecture fee and grant from Kyowa Kirin (KK). Dr Hayashi reported receiving honoraria from KK. Dr Maruyama received honoraria and subsidies or donation from KK. Dr Masaki reported receiving lecture fee and grant from KK. Dr Nangaku reported receiving honoraria, manuscript fees, and subsidies or donations from KK. Dr Nishino reported receiving lecture fee and grant from KK. Dr Sofue reported receiving grant from KK. Dr Takashi Wada reported receiving honoraria and subsidies or donation from KK. Dr Hase reported receiving honoraria from KK. Dr Yamamoto reported receiving honoraria and manuscript fees from KK. Dr Takehiko Wada reported receiving honoraria from KK. Dr Akizawa received honoraria and manuscript fees from KK. Dr Tsubakihara received honoraria from KK. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                https://orcid.org/0000-0001-7692-3096
                https://orcid.org/0000-0001-6271-2490
                Article
                Publisher ID: PONE-D-22-05315
                DOI: 10.1371/journal.pone.0277921
                PMC ID: 9707758
                PubMed ID: 36445882
                SO-VID: 9a6ac44d-805d-45b9-8809-ca9d7290f73f
                Copyright © © 2022 Narita 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 : 23 February 2022
                Date accepted : 16 August 2022
                Page count
                Figures: 2, Tables: 4, Pages: 17
                Funding
                Funded by: Kyowa Kirin Co., Ltd. (KK)
                Translational Research Center for Medical Innovation has received a research grant, which was not specific for this study from Kyowa Kirin Co., Ltd. (KK). Kyowa Kirin was not involved in designing, data interpretation, and manuscript writing for this study, along with any other matters including employment, consultancy, patents, products in development, marketed products, etc.
                Categories
                Subject: Research Article
                Subject: Medicine and Health Sciences
                Subject: Medical Conditions
                Subject: Cardiovascular Diseases
                Subject: Medicine and Health Sciences
                Subject: Cardiology
                Subject: Cardiovascular Medicine
                Subject: Cardiovascular Diseases
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Renal System
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Renal System
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Proteins
                Subject: Hemoglobin
                Subject: Medicine and Health Sciences
                Subject: Nephrology
                Subject: Renal Diseases
                Subject: Chronic Kidney Disease
                Subject: Medicine and Health Sciences
                Subject: Hematology
                Subject: Anemia
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Hormones
                Subject: Peptide Hormones
                Subject: Renin-Angiotensin System
                Subject: Medicine and Health Sciences
                Subject: Epidemiology
                Subject: Medical Risk Factors
                Subject: Medicine and Health Sciences
                Subject: Nephrology
                Subject: Medical Dialysis
                Custom metadata
                Data Availability All relevant data are within the paper and its Supporting information files.

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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