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      Comparison of the effects of weekly and biweekly intravenous CERA administration on erythropoiesis: A randomized controlled trial

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          Abstract

          Although continuous erythropoietin receptor activators (CERAs) are widely used erythropoiesis‐stimulating agents for correcting renal anemia in patients undergoing hemodialysis (HD), few reports have examined weekly CERA administration. In this randomized controlled trial, we compared the efficacy and changes in the parameters of iron metabolism and erythropoiesis between weekly and biweekly CERA administration. In total, 120 patients undergoing maintenance HD were randomized to the weekly or biweekly group. The primary end point was the total CERA dose needed to maintain the target hemoglobin (Hb) levels during a 12‐week evaluation period. There was no significant difference in the total dose between the weekly and biweekly groups (median 175.0 [interquartile range (IQR) 93.8–337.5] µg/12 weeks vs. 300.0 [IQR 125.0–375.0] µg/12 weeks, P = .18). The mean Hb levels during the evaluation period were 10.9 ± 0.8 g/dL in the weekly group and 10.7 ± 0.8 g/dL in the biweekly group ( P = .25). Weekly CERA administration was well tolerated. Weekly CERA administration similarly managed anemia as biweekly administration in patients undergoing HD.

          Abstract

          Patients undergoing hemodialysis were randomized to once‐weekly or biweekly continuous erythropoietin receptor activator (CERA) treatment for 12 weeks. There were no differences in the total CERA dose to maintain hemoglobin levels between two groups.

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          Most cited references22

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          Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization.

          E Németh (2004)
          Hepcidin is a peptide hormone secreted by the liver in response to iron loading and inflammation. Decreased hepcidin leads to tissue iron overload, whereas hepcidin overproduction leads to hypoferremia and the anemia of inflammation. Ferroportin is an iron exporter present on the surface of absorptive enterocytes, macrophages, hepatocytes, and placental cells. Here we report that hepcidin bound to ferroportin in tissue culture cells. After binding, ferroportin was internalized and degraded, leading to decreased export of cellular iron. The posttranslational regulation of ferroportin by hepcidin may thus complete a homeostatic loop: Iron regulates the secretion of hepcidin, which in turn controls the concentration of ferroportin on the cell surface.
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            Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation.

            Tomas Ganz (2003)
            Human hepcidin, a 25-amino acid peptide made by hepatocytes, may be a new mediator of innate immunity and the long-sought iron-regulatory hormone. The synthesis of hepcidin is greatly stimulated by inflammation or by iron overload. Evidence from transgenic mouse models indicates that hepcidin is the predominant negative regulator of iron absorption in the small intestine, iron transport across the placenta, and iron release from macrophages. The key role of hepcidin is confirmed by the presence of nonsense mutations in the hepcidin gene, homozygous in the affected members, in 2 families with severe juvenile hemochromatosis. Recent evidence shows that deficient hepcidin response to iron loading may contribute to iron overload even in the much milder common form of hemochromatosis, from mutations in the HFE gene. In anemia of inflammation, hepcidin production is increased up to 100-fold and this may account for the defining feature of this condition, sequestration of iron in macrophages. The discovery of hepcidin and its role in iron metabolism could lead to new therapies for hemochromatosis and anemia of inflammation.
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              A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload.

              Considering that the development of hepatic lesions related to iron overload diseases might be a result of abnormally expressed hepatic genes, we searched for new genes up-regulated under the condition of iron excess. By suppressive subtractive hybridization performed between livers from carbonyl iron-overloaded and control mice, we isolated a 225-base pair cDNA. By Northern blot analysis, the corresponding mRNA was confirmed to be overexpressed in livers of experimentally (carbonyl iron and iron-dextran-treated mice) and spontaneously (beta(2)-microglobulin knockout mice) iron-overloaded mice. In addition, beta(2)-microglobulin knockout mice fed with a low iron content diet exhibited a decrease of hepatic mRNA expression. The murine full-length cDNA was isolated and was found to encode an 83-amino acid protein presenting a strong homology in its C-terminal region to the human antimicrobial peptide hepcidin. In addition, we cloned the corresponding rat and human orthologue cDNAs. Both mouse and human genes named HEPC are constituted of 3 exons and 2 introns and are located on chromosome 7 and 19, respectively, in close proximity to USF2 gene. In mouse and human, HEPC mRNA was predominantly expressed in the liver. During both in vivo and in vitro studies, HEPC mRNA expression was enhanced in mouse hepatocytes under the effect of lipopolysaccharide. Finally, to analyze the intracellular localization of the predicted protein, we used the green fluorescent protein chimera expression vectors. The murine green fluorescent protein-prohepcidin protein was exclusively localized in the nucleus. When the putative nuclear localization signal was deleted, the resulting protein was addressed to the cytoplasm. Taken together, our data strongly suggest that the product of the new liver-specific gene HEPC might play a specific role during iron overload and exhibit additional functions distinct from its antimicrobial activity.
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                Author and article information

                Contributors
                hiro1234@yokohama-cu.ac.jp
                Journal
                J Clin Hypertens (Greenwich)
                J Clin Hypertens (Greenwich)
                10.1111/(ISSN)1751-7176
                JCH
                The Journal of Clinical Hypertension
                John Wiley and Sons Inc. (Hoboken )
                1524-6175
                1751-7176
                22 January 2021
                April 2021
                : 23
                : 4 ( doiID: 10.1111/jch.v23.4 )
                : 870-878
                Affiliations
                [ 1 ] Department of Medical Science and Cardiorenal Medicine Yokohama City University Graduate School of Medicine Yokohama Japan
                [ 2 ] Center for Health Service Sciences Yokohama National University Yokohama Japan
                [ 3 ] Kohsaikai Kamioooka Jinsei Clinic Yokohama Japan
                [ 4 ] Kohsaikai Bunkojin Clinic Yokohama Japan
                [ 5 ] Yokodai Central Clinic Yokohama Japan
                [ 6 ] Kohsaikai Yokohama Jinsei Hospital Yokohama Japan
                Author notes
                [*] [* ] Correspondence

                Hiromichi Wakui, Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3‐9 Fukuura, Kanazawa‐ku, Yokohama 236‐0004, Japan.

                Email: hiro1234@ 123456yokohama-cu.ac.jp

                Author information
                https://orcid.org/0000-0001-8023-922X
                Article
                JCH14171
                10.1111/jch.14171
                8678717
                33481341
                7ec9c829-7cf5-40f3-9c94-bd271dfa5f38
                © 2021 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 16 December 2020
                : 20 November 2020
                : 22 December 2020
                Page count
                Figures: 6, Tables: 2, Pages: 9, Words: 4946
                Categories
                Original Paper
                Erythropoietin
                Custom metadata
                2.0
                April 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.7.0 mode:remove_FC converted:17.12.2021

                continuous erythropoietin receptor activator,erythropoietin‐stimulating agent,iron metabolism,japanese hemodialysis patients,renal anemia

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