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      Effects of high-volume online mixed-hemodiafiltration on anemia management in dialysis patients

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          Abstract

          Background

          Anemia is a major comorbidity of patients with end-stage renal disease and poses an enormous economic burden to health-care systems. High dose erythropoiesis-stimulating agents (ESAs) have been associated with unfavorable clinical outcomes. We explored whether mixed-dilution hemodiafiltration (Mixed-HDF), based on its innovative substitution modality, may improve anemia outcomes compared to the traditional post-dilution hemodiafiltration (Post-HDF).

          Methods

          We included 174 adult prevalent dialysis patients (87 on Mixed-HDF, 87 on Post-HDF) treated in 24 NephroCare dialysis centers between January 2010 and August 2016 into this retrospective cohort study. All patients were dialyzed three times per week and had fistula/graft as vascular access. Patients were matched at baseline and followed over a one-year period. The courses of hemoglobin levels (Hb) and monthly ESA consumption were compared between the two groups with linear mixed models.

          Results

          Mean baseline Hb was 11.9±1.3 and 11.8±1.1g/dl in patients on Mixed- and Post-HDF, respectively. While Hb remained stable in patients on Mixed-HDF, it decreased slightly in patients on Post-HDF (at month 12: 11.8±1.2 vs 11.1±1.2g/dl). This tendency was confirmed by our linear mixed model (p = 0.0514 for treatment x time interaction). Baseline median ESA consumption was 6000 [Q1:0;Q3:16000] IU/4 weeks in both groups. Throughout the observation period ESA doses tended to be lower in the Mixed-HDF group (4000 [Q1:0;Q3:16000] vs 8000 [Q1:0;Q3:20000] IU/4 weeks at month 12; p = 0.0791 for treatment x time interaction). Sensitivity analyses, adjusting for differences not covered by matching at baseline, strengthened our results (Hb: p = 0.0124; ESA: p = 0.0687).

          Conclusions

          Results of our explorative study suggest that patients on Mixed-HDF may have clinical benefits in terms of anemia management. This may also have a beneficial economic impact. Future studies are needed to confirm our hypothesis-generating results and to provide additional evidence on the potential beneficial effects of Mixed-HDF.

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          Most cited references30

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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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              Mechanisms of anemia in CKD.

              Anemia is a common feature of CKD associated with poor outcomes. The current management of patients with anemia in CKD is controversial, with recent clinical trials demonstrating increased morbidity and mortality related to erythropoiesis stimulating agents. Here, we examine recent insights into the molecular mechanisms underlying anemia of CKD. These insights hold promise for the development of new diagnostic tests and therapies that directly target the pathophysiologic processes underlying this form of anemia.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing – original draft
                Role: ConceptualizationRole: MethodologyRole: Writing – original draft
                Role: MethodologyRole: Writing – original draft
                Role: Formal analysisRole: MethodologyRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: SupervisionRole: Writing – original draft
                Role: ConceptualizationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                22 February 2019
                2019
                : 14
                : 2
                : e0212795
                Affiliations
                [1 ] Department of Nephrology and Dialysis, NephroCare-ASST Bergamo-Est, Bolognini Hospital, Seriate, Italy
                [2 ] Fresenius Medical Care Deutschland GmbH, Clinical and Epidemiological Research, Bad Homburg, Germany
                [3 ] Fresenius Medical Care, Palazzo Pignano, Italy
                [4 ] Fresenius Medical Care Deutschland GmbH, Medical Office EMEA, Bad Homburg, Germany
                [5 ] Fresenius Medical Care Deutschland GmbH, Clinical &Therapeutical Governance, Bad Homburg, Germany
                University of Mississippi Medical Center, UNITED STATES
                Author notes

                Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: LAP has a consultancy agreement with NephroCare, Italy; PR and AnFe are employees of NephroCare, Italy. The other authors are employees of Fresenius Medical Care and may hold stock in the company. The realization of therapies investigated in this study has been performed with products mostly manufactured by Fresenius Medical Care. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0001-9353-2943
                Article
                PONE-D-18-30101
                10.1371/journal.pone.0212795
                6386285
                30794672
                e953b113-1576-46ef-a644-88d7550850dc
                © 2019 Pedrini et al

                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
                : 12 November 2018
                : 8 February 2019
                Page count
                Figures: 3, Tables: 4, Pages: 16
                Funding
                The authors received no specific funding for this work. As all authors are employees of Fresenius Medical Care or NephroCare, the salaries of all authors are paid by the two companies [Fresenius Medical Care: AMZ, ACW, JP, GK, MW, AsFe, CB, StSt, BC, AG; NephroCare: LAP, PR, AnFe]. The corporation did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript, whereas the specific roles of the individual authors are articulated in the ‘author contributions’ section.
                Categories
                Research Article
                Medicine and Health Sciences
                Nephrology
                Medical Dialysis
                Biology and Life Sciences
                Biochemistry
                Proteins
                Hemoglobin
                Medicine and Health Sciences
                Hematology
                Anemia
                Research and Analysis Methods
                Separation Processes
                Filtration
                Hemofiltration
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Blood
                Blood Flow
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Blood
                Blood Flow
                Biology and Life Sciences
                Physiology
                Body Fluids
                Blood
                Blood Flow
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Blood
                Blood Flow
                Physical Sciences
                Physics
                States of Matter
                Fluids
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Biology and Life Sciences
                Physiology
                Body Fluids
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Physical Sciences
                Mathematics
                Probability Theory
                Probability Distribution
                Normal Distribution
                Custom metadata
                All relevant data are within the manuscript and its Supporting Information files.

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