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      The role of hypoxia-inducible factor stabilizers in the treatment of anemia in patients with chronic kidney disease

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          Abstract

          Introduction

          The purpose of this study was to analyze the effects of hypoxia-inducible factor (HIF) stabilizers on anemia in non-dialysis-dependent (NDD) and dialysis-dependent (DD) chronic kidney disease (CKD) patients.

          Methods

          Published studies were extracted from PubMed, China Biological Medicine Database (CBM), Wanfang database, and Cochrane Library on March 10, 2018, and relevant studies were pooled and included in a meta-analysis. Data on hemoglobin (Hb), ferritin, and hepcidin levels, total iron-binding capacity (TIBC), and incidence of adverse events (AEs) were extracted and pooled using Review Manager Version 5.3.

          Results

          Data from nine selected studies were extracted. Meta-analysis of the included studies showed that HIF stabilizers reduced ferritin and hepcidin levels and increased Hb level and TIBC in NDD-CKD patients. However, HIF stabilizers only increased TIBC, and did not affect ferritin, hepcidin, and Hb levels in DD-CKD patients. Furthermore, no notable differences in AEs and severe AEs between NDD-CKD and DD-CKD patients were detected.

          Conclusion

          HIF stabilizers are effective for the treatment of anemia in NDD-CKD patients and safe for short-term use.

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          Most cited references 27

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          Update on Inflammation in Chronic Kidney Disease

           Oleh Akchurin (corresponding) ,  Frederick Kaskel (2015)
          Background: Despite recent advances in chronic kidney disease (CKD) and end-stage renal disease (ESRD) management, morbidity and mortality in this population remain exceptionally high. Persistent, low-grade inflammation has been recognized as an important component of CKD, playing a unique role in its pathophysiology and being accountable in part for cardiovascular and all-cause mortality, as well as contributing to the development of protein-energy wasting. Summary: The variety of factors contribute to chronic inflammatory status in CKD, including increased production and decreased clearance of pro-inflammatory cytokines, oxidative stress and acidosis, chronic and recurrent infections, including those related to dialysis access, altered metabolism of adipose tissue, and intestinal dysbiosis. Inflammation directly correlates with the glomerular filtration rate (GFR) in CKD and culminates in dialysis patients, where extracorporeal factors, such as impurities in dialysis water, microbiological quality of the dialysate, and bioincompatible factors in the dialysis circuit play an additional role. Genetic and epigenetic influences contributing to inflammatory activation in CKD are currently being intensively investigated. A number of interventions have been proposed to target inflammation in CKD, including lifestyle modifications, pharmacological agents, and optimization of dialysis. Importantly, some of these therapies have been recently tested in randomized controlled trials. Key Messages: Chronic inflammation should be regarded as a common comorbid condition in CKD and especially in dialysis patients. A number of interventions have been proven to be safe and effective in well-designed clinical studies. This includes such inexpensive approaches as modification of physical activity and dietary supplementation. Further investigations are needed to evaluate the effects of these interventions on hard outcomes, as well as to better understand the role of inflammation in selected CKD populations (e.g., in children).
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            Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD.

            The reasons for inadequate production of erythropoietin (EPO) in patients with ESRD are poorly understood. A better understanding of EPO regulation, namely oxygen-dependent hydroxylation of the hypoxia-inducible transcription factor (HIF), may enable targeted pharmacological intervention. Here, we tested the ability of fibrotic kidneys and extrarenal tissues to produce EPO. In this phase 1 study, we used an orally active prolyl-hydroxylase inhibitor, FG-2216, to stabilize HIF independent of oxygen availability in 12 hemodialysis (HD) patients, six of whom were anephric, and in six healthy volunteers. FG-2216 increased plasma EPO levels 30.8-fold in HD patients with kidneys, 14.5-fold in anephric HD patients, and 12.7-fold in healthy volunteers. These data demonstrate that pharmacologic manipulation of the HIF system can stimulate endogenous EPO production. Furthermore, the data indicate that deranged oxygen sensing--not a loss of EPO production capacity--causes renal anemia.
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              Roxadustat (FG-4592): Correction of Anemia in Incident Dialysis Patients.

               Anatole Besarab (corresponding) ,  Elena Chernyavskaya,  Igor Motylev (2016)
              Safety concerns with erythropoietin analogues and intravenous (IV) iron for treatment of anemia in CKD necessitate development of safer therapies. Roxadustat (FG-4592) is an orally bioavailable hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that promotes coordinated erythropoiesis through HIF-mediated transcription. We performed an open-label, randomized hemoglobin (Hb) correction study in anemic (Hb≤10.0 g/dl) patients incident to hemodialysis (HD) or peritoneal dialysis (PD). Sixty patients received no iron, oral iron, or IV iron while treated with roxadustat for 12 weeks. Mean±SD baseline Hb was 8.3±1.0 g/dl in enrolled patients. Roxadustat at titrated doses increased mean Hb by ≥2.0 g/dl within 7 weeks regardless of baseline iron repletion status, C-reactive protein level, iron regimen, or dialysis modality. Mean±SEM maximal change in Hb from baseline (ΔHb(max)), the primary endpoint, was 3.1±0.2 g/dl over 12 weeks in efficacy-evaluable patients (n=55). In groups receiving oral or IV iron, ΔHb(max) was similar and larger than in the no-iron group. Hb response (increase in Hb of ≥1.0 g/dl from baseline) was achieved in 96% of efficacy-evaluable patients. Mean serum hepcidin decreased significantly 4 weeks into study: by 80% in HD patients receiving no iron (n=22), 52% in HD and PD patients receiving oral iron (n=21), and 41% in HD patients receiving IV iron (n=9). In summary, roxadustat was well tolerated and corrected anemia in incident HD and PD patients, regardless of baseline iron repletion status or C-reactive protein level and with oral or IV iron supplementation; it also reduced serum hepcidin levels.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                18 September 2018
                : 12
                : 3003-3011
                Affiliations
                [1 ]Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China, zhoutb@ 123456aliyun.net
                [2 ]Department of Nephrology, Huadu District People’s Hospital of Guangzhou, Southern Medical University, Guangzhou, China
                Author notes
                Correspondence: Tianbiao Zhou, Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, No 69 Dongsha Road, Shantou 515041, China, Email zhoutb@ 123456aliyun.net
                [*]

                These authors contributed equally to this work

                Article
                dddt-12-3003
                10.2147/DDDT.S175887
                6151102
                © 2018 Zhong et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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