{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T09:00:28Z","timestamp":1793782828453,"version":"4.6.1"},"reference-count":127,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T00:00:00Z","timestamp":1616716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Anemia is a common complication in chronic kidney disease (CKD), and is associated with a reduced quality of life, and an increased morbidity and mortality. The mechanisms involved in anemia associated to CKD are diverse and complex. They include a decrease in endogenous erythropoietin (EPO) production, absolute and\/or functional iron deficiency, and inflammation with increased hepcidin levels, among others. Patients are most commonly managed with oral or intravenous iron supplements and with erythropoiesis stimulating agents (ESA). However, these treatments have associated risks, and sometimes are insufficiently effective. Nonetheless, in the last years, there have been some remarkable advances in the treatment of CKD-related anemia, which have raised great expectations. On the one hand, a novel family of drugs has been developed: the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs). These agents induce, among other effects, an increase in the production of endogenous EPO, improve iron availability and reduce hepcidin levels. Some of them have already received marketing authorization. On the other hand, recent clinical trials have elucidated important aspects of iron supplementation, which may change the treatment targets in the future. This article reviews the current knowledge of the pathophysiology CKD-related anemia, current and future therapies, the trends in patient management and the unmet goals.<\/jats:p>","DOI":"10.3389\/fmed.2021.642296","type":"journal-article","created":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T05:20:46Z","timestamp":1616736046000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":322,"title":["Anemia in Chronic Kidney Disease: From Pathophysiology and Current Treatments, to Future Agents"],"prefix":"10.3389","volume":"8","author":[{"given":"Jose","family":"Portol\u00e9s","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leyre","family":"Mart\u00edn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Jes\u00fas","family":"Broseta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleix","family":"Cases","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1093\/ndt\/11.supp2.125","article-title":"Nephrology dialysis transplantation quality of life in dialysis patients. A Spanish multicentre study","volume":"11","author":"Moreno","year":"1996","journal-title":"NDT"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1929","DOI":"10.1185\/030079906X132541","article-title":"Relationship between hemoglobin level and quality of life in anemic patients with chronic kidney disease receiving epoetin alfa","volume":"22","author":"Lefebvre","year":"2006","journal-title":"Curr Med Res Opin"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2880","DOI":"10.1093\/ndt\/gfs007","article-title":"Hyporesponsiveness to erythropoiesis-stimulating agents and renal survival in non-dialysis CKD patients","volume":"27","author":"Minutolo","year":"2012","journal-title":"Nephrol Dial Transplant"},{"key":"B4","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1016\/j.ahj.2005.03.055","article-title":"Kidney function and anemia as risk factors for coronary heart disease and mortality: the atherosclerosis risk in communities (ARIC) study","volume":"151","author":"Astor","year":"2006","journal-title":"Am Hear J"},{"key":"B5","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1038\/sj.ki.5000105","article-title":"Association of anemia with outcomes in men with moderate and severe chronic kidney disease","volume":"69","author":"Kovesdy","year":"2006","journal-title":"Kidney Int"},{"key":"B6","doi-asserted-by":"publisher","first-page":"565","DOI":"10.18553\/jmcp.2005.11.7.565","article-title":"Economic burden of anemia in an insured population","volume":"11","author":"Nissenson","year":"2005","journal-title":"J Manag Care Pharm"},{"key":"B7","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1371\/journal.pone.0084943","article-title":"Prevalence of anemia in chronic kidney disease in the United States","volume":"9","author":"Stauffer","year":"2014","journal-title":"PLoS ONE"},{"key":"B8","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1053\/j.ajkd.2018.08.013","article-title":"Relationship of estimated GFR and albuminuria to concurrent laboratory abnormalities: an individual participant data meta- analysis in a global consortium","volume":"73","author":"Inker","year":"2019","journal-title":"Am J Kidney Dis"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/1471-2369-14-2","article-title":"The development of anemia is associated to poor prognosis in NKF\/KDOQI stage 3 chronic kidney disease","volume":"14","author":"Portol\u00e9s","year":"2013","journal-title":"BMC Nephrol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"3035","DOI":"10.1093\/ndt\/gft338","article-title":"Anaemia management in non-dialysis chronic kidney disease (CKD) patients: a multicentre prospective study in renal clinics","volume":"28","author":"Minutolo","year":"2013","journal-title":"Nephrol Dial Transplant"},{"key":"B11","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1093\/ckj\/sfaa054","article-title":"Contemporary management of anaemia, erythropoietin resistance and cardiovascular risk in patients with advanced chronic kidney disease: a nationwide analysis","volume":"13","author":"Evans","year":"2020","journal-title":"Clin Kidney J"},{"key":"B12","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1093\/ckj\/sfx060","article-title":"Quality of care and practice patterns in anaemia management at specialist kidney clinics in Ireland: a national study","volume":"11","author":"Stack","year":"2018","journal-title":"Clin Kidney J"},{"key":"B13","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1038\/kisup.2012.38","article-title":"KDIGO clinical practice guideline for anemia in chronic kidney disease","volume":"2","year":"2012","journal-title":"Kidney Int"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e0025839","DOI":"10.1371\/journal.pone.0025839","article-title":"Isolation and characterization of renal erythropoietin- producing cells from genetically produced anemia mice","volume":"6","author":"Pan","year":"2011","journal-title":"PLoS ONE"},{"key":"B15","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1038\/28867","article-title":"Role of HIF-1 in hypoxia- mediated apoptosis, cell proliferationand tumourangiogenesis Peter","volume":"394","author":"Carmeliet","year":"1998","journal-title":"Nature"},{"key":"B16","doi-asserted-by":"publisher","first-page":"4527","DOI":"10.1128\/MCB.00200-09","article-title":"Hypoxia-inducible factor 2 regulates hepatic lipid metabolism","volume":"29","author":"Rankin","year":"2009","journal-title":"Mol Cell Biol"},{"key":"B17","doi-asserted-by":"crossref","first-page":"2993","DOI":"10.1093\/eurheartj\/ehw156","article-title":"Deficiency of the oxygen sensor prolyl hydroxylase 1 attenuates hypercholesterolaemia, atherosclerosis, and hyperglycaemia","volume":"37","author":"Marsch","year":"2016","journal-title":"Eur Heart J."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e008","DOI":"10.1016\/j.immuni.2014.09.008","article-title":"HIF transcription factors, inflammation, and immunity","volume":"41","author":"Palazon","year":"2014","journal-title":"Immunity"},{"key":"B19","doi-asserted-by":"publisher","first-page":"982","DOI":"10.2215\/CJN.06890615","article-title":"Oral hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) for the treatment of anemia in patients with CKD","volume":"11","author":"Provenzano","year":"2016","journal-title":"Clin J Am Soc Nephrol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"27436","DOI":"10.1074\/jbc.M704976200","article-title":"Hypoxia stimulates degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase through accumulation of lanosterol and hypoxia-inducible factor-mediated induction of insigs","volume":"282","author":"Nguyen","year":"2007","journal-title":"J Biol Chem"},{"key":"B21","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1007\/BF01075997","article-title":"Changes in plasma lipids and lipoprotein cholesterol during a high altitude mountaineering expedition (4800 m)","volume":"57","author":"F\u00e9r\u00e9zou","year":"1988","journal-title":"Eur J Appl Physiol Occup Physiol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"33756","DOI":"10.1074\/jbc.M110.132985","article-title":"Prolyl hydroxylase domain (PHD) 2 affects cell migration and F-actin formation via RhoA\/Rho-associated kinase-dependent cofilin phosphorylation","volume":"285","author":"Vogel","year":"2010","journal-title":"J Biol Chem"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1965","DOI":"10.1056\/NEJMra1612008","article-title":"Physiological effects of chronic hypoxia","volume":"376","author":"West","year":"2017","journal-title":"NEJM"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1250","DOI":"10.1016\/j.kint.2019.10.007","article-title":"The noblesse of kidney physiology","volume":"96","author":"Eckardt","year":"2019","journal-title":"Kidney Int"},{"key":"B25","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1126\/science.1068592","article-title":"Asparagine hydroxylation of the HIF transactivation domain: a hypoxic switch","volume":"295","author":"Lando","year":"2002","journal-title":"Science"},{"key":"B26","doi-asserted-by":"publisher","first-page":"5367","DOI":"10.1073\/pnas.082117899","article-title":"Structural basis for recruitment of CBP p300 by hypoxia-inducible factor-1","volume":"99","author":"Freedman","year":"2002","journal-title":"PNAS"},{"key":"B27","doi-asserted-by":"publisher","first-page":"20661","DOI":"10.1074\/jbc.M116.749291","article-title":"Tuning the transcriptional response to hypoxia by inhibiting hypoxia-inducible factor (HIF) prolyl and asparaginyl","volume":"291","author":"Chan","year":"2016","journal-title":"J Biol Chem"},{"key":"B28","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1091\/mbc.e07-06-0612","article-title":"Hypoxia-inducible factor-1 stabilization in nonhypoxic conditions: role of oxidation and intracellular ascorbate depletion","volume":"19","author":"Pag\u00e9","year":"2008","journal-title":"Mol Biol Cell"},{"key":"B29","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1007\/s004249900238","article-title":"Dose-dependent effect of angiotensin II on human erythropoietin production","volume":"439","author":"Freudenthaler","year":"2000","journal-title":"Pfl\u00fcgers Arch Eur J Physiol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1111\/j.1365-2125.1992.tb05644.x","article-title":"Effect of angiotensin converting enzyme inhibitors on erythropoietin concentrations in healthy volunteers","volume":"34","author":"Pratt","year":"1992","journal-title":"Br J Clin Pharmacol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"389","DOI":"10.3390\/ijms19020389","article-title":"Hypoxia-inducible factor and its role in the management of anemia in chronic kidney disease","volume":"19","author":"Kaplan","year":"2018","journal-title":"Int J Mol Sci"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1206","DOI":"10.1111\/j.1523-1755.2004.00880.x","article-title":"Interpretation of erythropoietin levels in patients with various degrees of renal insufficiency and anemia","volume":"66","author":"Fehr","year":"2004","journal-title":"Kidney Int"},{"key":"B33","doi-asserted-by":"publisher","first-page":"F1287","DOI":"10.1152\/ajprenal.00736.2009","article-title":"Regulated oxygen sensing by protein hydroxylation in renal erythropoietin-producing cells","volume":"298","author":"Wenger","year":"2010","journal-title":"Am J Physiol Ren Physiol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1987","DOI":"10.1182\/blood.V79.8.1987.1987","article-title":"Effect of inflammatory cytokines on hypoxia-induced erythropoietin production","volume":"79","author":"Faquin","year":"1992","journal-title":"Blood"},{"key":"B35","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1111\/j.1749-6632.1991.tb17252.x","article-title":"Interleukin-1 and tumor necrosis factor-alpha inhibit erythropoietin production in vitro","volume":"628","author":"Fandrey","year":"1991","journal-title":"Ann N Y Acad Sci"},{"key":"B36","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1038\/sj.ki.5002391","article-title":"Cytokine gene polymorphism and progression of renal and cardiovascular diseases","volume":"72","author":"Rao","year":"2007","journal-title":"Kidney Int"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1546","DOI":"10.2215\/CJN.13121215","article-title":"Inflammation and progression of CKD: the CRIC study","volume":"11","author":"Amdur","year":"2016","journal-title":"Clin J Am Soc Nephrol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1681\/ASN.2014121184","article-title":"Erythropoietin synthesis in renal myo fi broblasts is restored by activation of hypoxia signaling","volume":"27","author":"Souma","year":"2016","journal-title":"JASN"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1389","DOI":"10.1681\/ASN.2007111181","article-title":"The effect of altitude on dosing and response to erythropoietin in ESRD","volume":"19","author":"Brookhart","year":"2008","journal-title":"J Am Soc Nephrol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1573","DOI":"10.2215\/CJN.00380111","article-title":"Endogenous erythropoietin and the association with inflammation and mortality in diabetic chronic kidney disease","volume":"6","author":"Wagner","year":"2011","journal-title":"Clin J Am Soc Nephrol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"2578","DOI":"10.1182\/blood-2010-10-315218","article-title":"Chronic IFN-\u03b3 production in mice induces anemia by reducing erythrocyte life span and inhibiting erythropoiesis through an IRF-1\/PU.1 axis","volume":"118","author":"Libregts","year":"2011","journal-title":"Blood"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.1056\/NEJMra1804281","article-title":"Anemia of inflammation","volume":"381","author":"Ganz","year":"2019","journal-title":"N Engl J Med"},{"key":"B43","doi-asserted-by":"publisher","first-page":"29338","DOI":"10.1074\/jbc.M003456200","article-title":"CIS3\/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2","volume":"275","author":"Sasaki","year":"2000","journal-title":"J Biol Chem"},{"key":"B44","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1093\/ndt\/17.suppl_11.39","article-title":"Erythropoietin resistance: the role of inflammation and pro-inflammatory cytokines","volume":"17","author":"Macdougall","year":"2002","journal-title":"Nephrol Dial Transpl"},{"key":"B45","doi-asserted-by":"publisher","first-page":"2244","DOI":"10.1182\/blood.V90.6.2244","article-title":"Price and SBK, interferon. interferon g downregulates stem cell factor and erythropoietin receptors but not insulin-like growth factor-i receptors in human erythroid colony-forming cells","volume":"90","author":"Taniguchi","year":"1997","journal-title":"Blood"},{"key":"B46","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/ncpneph0655","article-title":"Mechanisms of Disease : erythropoietin resistance in patients with both heart and kidney failure","volume":"4","author":"Van Der","year":"2008","journal-title":"Nature"},{"key":"B47","doi-asserted-by":"publisher","first-page":"2792","DOI":"10.1182\/blood-2005-07-2854","article-title":"Hepcidin inhibits in vitro erythroid colony formation at reduced erythropoietin concentrations","volume":"107","author":"Dallalio","year":"2006","journal-title":"Blood"},{"key":"B48","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/S0272-6386(99)70258-1","article-title":"Neocytolysis contributes to the anemia of renal disease","volume":"33","author":"Rice","year":"1999","journal-title":"AJKD"},{"key":"B49","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1093\/ndt\/gft424","article-title":"The FIND-CKD study\u2014A randomized controlled trial of intravenous iron versus oral iron in non-dialysis chronic kidney disease patients: background and rationale","volume":"29","author":"Macdougall","year":"2014","journal-title":"Nephrol Dial Transplant"},{"key":"B50","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1002\/ejhf.473","article-title":"Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure : a meta-analysis of randomized controlled trials","volume":"18","author":"Jankowska","year":"2016","journal-title":"Eur J Heart Fail"},{"key":"B51","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1159\/000107927","article-title":"Nonhematological benefits of iron","volume":"46202","author":"Agarwal","year":"2007","journal-title":"Am J Nephrol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1186\/s12882-018-1021-3","article-title":"Association of different iron deficiency cutoffs with adverse outcomes in chronic kidney disease","volume":"19","author":"Eisenga","year":"2018","journal-title":"BMC Nephrol"},{"key":"B53","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1016\/j.kint.2019.04.029","article-title":"An increased mortality risk is associated with abnormal iron status in diabetic and non-diabetic Veterans with predialysis chronic kidney disease","volume":"96","author":"Cho","year":"2019","journal-title":"Kidney Int"},{"key":"B54","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1093\/ndt\/gfz192","article-title":"Prevalence, correlates and outcomes of absolute and functional iron deficiency anemia in nondialysis-dependent chronic kidney disease","volume":"36","author":"Awan","year":"2021","journal-title":"Nephrol Dial Transplant"},{"key":"B55","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1038\/s41581-019-0197-5","article-title":"The multifaceted role of iron in renal health and disease","volume":"16","author":"van Swelm","year":"2020","journal-title":"Nat Rev Nephrol"},{"key":"B56","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1681\/ASN.2019020213","article-title":"Iron deficiency in chronic kidney disease: updates on pathophysiology, diagnosis, and treatment","volume":"31","author":"Batchelor","year":"2020","journal-title":"J Am Soc Nephrol"},{"key":"B57","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1038\/ng.2996","article-title":"Identification of erythroferrone as an erythroid regulator of iron metabolism","volume":"46","author":"Kautz","year":"2014","journal-title":"Nat Genet"},{"key":"B58","doi-asserted-by":"publisher","first-page":"1926","DOI":"10.1172\/JCI31370","article-title":"Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs)","volume":"117","author":"Peyssonnaux","year":"2007","journal-title":"J Clin Invest"},{"key":"B59","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1002\/biof.1148","article-title":"The regulation of iron transport","volume":"40","author":"Frazer","year":"2014","journal-title":"Biofactors"},{"key":"B60","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1093\/ckj\/sfz091","article-title":"Anemia and iron deficiency among chronic kidney disease Stages 3-5ND patients in the chronic kidney disease outcomes and practice patterns study: often unmeasured, variably treated","volume":"13","author":"Wong","year":"2019","journal-title":"Clin Kidney J."},{"key":"B61","doi-asserted-by":"publisher","first-page":"1784","DOI":"10.1038\/s41598-020-79254-6","article-title":"A real-world longitudinal study of anemia management in non-dialysis-dependent chronic kidney disease patients: a multinational analysis of CKDopps","volume":"11","author":"Lopes","year":"2021","journal-title":"Sci Rep"},{"key":"B62","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1093\/ndt\/gfn653","article-title":"Anaemia management in patients with chronic kidney disease: a position statement by the Anaemia Working Group of European Renal Best Practice (ERBP)","volume":"24","author":"Locatelli","year":"2009","journal-title":"Nephrol Dial Transplant"},{"key":"B63","unstructured":"Chronic Kidney Disease: Managing Anaemia2015"},{"key":"B64","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1093\/ndt\/gfm579","article-title":"Darbepoetin alpha in lower-than-equimolar doses maintains haemoglobin levels in stable haemodialysis patients converting from epoetin alpha\/beta","volume":"23","author":"Bock","year":"2008","journal-title":"Nephrol Dial Transplant"},{"key":"B65","doi-asserted-by":"publisher","first-page":"CD010590","DOI":"10.1002\/14651858.CD010590","article-title":"Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis (Review)","volume":"2013","author":"Palmer","year":"2014","journal-title":"Cochrane Database Syst Rev"},{"key":"B66","doi-asserted-by":"publisher","first-page":"CD011690","DOI":"10.1002\/14651858.CD011690.pub2","article-title":"Short-acting erythropoiesis-stimulating agents for anaemia in predialysis patients","volume":"1","author":"Hahn","year":"2017","journal-title":"Cochrane Database Syst Rev"},{"key":"B67","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1681\/ASN.2018101007","article-title":"Types of erythropoietin-stimulating agents and mortality among patients undergoing hemodialysis","volume":"30","author":"Sakaguchi","year":"2019","journal-title":"J Am Soc Nephrol"},{"key":"B68","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1093\/ndt\/gfaa088","article-title":"Types of erythropoiesisstimulating agents and risk of ESKD and death in patients with non-dialysis chronic kidney disease","volume":"26","author":"Minutolo","year":"2021","journal-title":"NDT"},{"key":"B69","doi-asserted-by":"publisher","first-page":"1701","DOI":"10.2215\/CJN.01380219","article-title":"Cardiovascular safety and all-cause mortality of methoxy polyethylene glycol-epoetin beta and other erythropoiesis-stimulating agents in anemia of CKD a randomized noninferiority trial","volume":"14","author":"Locatelli","year":"2019","journal-title":"CJASN"},{"key":"B70","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1053\/j.ajkd.2009.09.019","article-title":"Impact of erythropoiesis- stimulating agents on energy and physical function in nondialysis CKD patients with anemia: a systematic review","volume":"55","author":"Gandra","year":"2010","journal-title":"Am J Kidney Dis"},{"key":"B71","doi-asserted-by":"publisher","first-page":"2418","DOI":"10.1093\/ndt\/gfr697","article-title":"Systematic review of the impact of erythropoiesis-stimulating agents on fatigue in dialysis patients","volume":"27","author":"Johansen","year":"2012","journal-title":"Nephrol Dial TransplantDialTransplant"},{"key":"B72","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1056\/NEJM199808273390903","article-title":"The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin","volume":"339","author":"Besarab","year":"1998","journal-title":"N Engl J Med"},{"key":"B73","doi-asserted-by":"publisher","first-page":"2071","DOI":"10.1056\/NEJMoa062276","article-title":"Normalization of hemoglobin level in patients with chronic kidney disease and anemia","volume":"335","author":"Dr\u00fceke","year":"2006","journal-title":"NEJM"},{"key":"B74","doi-asserted-by":"publisher","first-page":"2085","DOI":"10.1056\/NEJMoa065485","article-title":"Correction of anemia with epoetin alfa in chronic kidney disease","volume":"355","author":"Singh","year":"2006","journal-title":"N Engl J Med"},{"key":"B75","doi-asserted-by":"publisher","first-page":"2019","DOI":"10.1056\/NEJMoa0907845","article-title":"A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease","volume":"361","author":"Pfeffer","year":"2009","journal-title":"NEJM"},{"key":"B76","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1093\/ndt\/gfn601","article-title":"Potential mechanisms of adverse outcomes in trials of anemia correction with erythropoietin in chronic kidney disease","volume":"24","author":"Vaziri","year":"2009","journal-title":"Nephrol Dial Transplant"},{"key":"B77","doi-asserted-by":"publisher","first-page":"2180","DOI":"10.1681\/ASN.2004121039","article-title":"Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease","volume":"16","author":"Parfrey","year":"2005","journal-title":"J Am Soc Nephrol"},{"key":"B78","doi-asserted-by":"publisher","first-page":"2578","DOI":"10.1681\/ASN.2014080842","article-title":"Ferric citrate reduces intravenous iron and erythropoiesis-stimulating agent use in ESRD","volume":"26","author":"Umanath","year":"2015","journal-title":"J Am Soc Nephrol"},{"key":"B79","doi-asserted-by":"publisher","first-page":"1851","DOI":"10.1681\/ASN.2016101053","article-title":"Effects of ferric citrate in patients with nondialysis-dependent CKD and iron deficiency anemia","volume":"28","author":"Fishbane","year":"2017","journal-title":"J Am Soc Nephrol"},{"key":"B80","doi-asserted-by":"publisher","first-page":"3262","DOI":"10.1093\/ndt\/gfr024","article-title":"Do two intravenous iron sucrose preparations have the same efficacy?","volume":"26","author":"Rottembourg","year":"2011","journal-title":"Nephrol Dial Transplant"},{"key":"B81","doi-asserted-by":"publisher","first-page":"S28","DOI":"10.1111\/hdi.12553","article-title":"Oral iron supplementation: potential implications for the gut microbiome and metabolome in patients with CKD","volume":"21","author":"Kortman","year":"2017","journal-title":"Hemodial Int"},{"key":"B82","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.nefro.2016.05.008","article-title":"Microbiota intestinal en la enfermedad renal cr\u00f3nica","volume":"37","author":"Cigarran Guldris","year":"2017","journal-title":"Nefrologia"},{"key":"B83","doi-asserted-by":"publisher","first-page":"1958","DOI":"10.1001\/jama.2017.5427","article-title":"Effect of oral iron repletion on exercise capacity in patients with heart failure with reduced ejection fraction and iron deficiency: the IRONOUT HF randomized clinical trial","volume":"317","author":"Lewis","year":"2017","journal-title":"JAMA"},{"key":"B84","doi-asserted-by":"publisher","first-page":"2436","DOI":"10.1056\/NEJMoa0908355","article-title":"Ferric carboxymaltose in patients with heart failure and iron deficiency","volume":"361","author":"Anker","year":"2009","journal-title":"N Engl J Med"},{"key":"B85","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1093\/eurheartj\/ehu385","article-title":"Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency","volume":"36","author":"Ponikowski","year":"2015","journal-title":"Eur Heart J"},{"key":"B86","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.1161\/CIRCULATIONAHA.117.027497","article-title":"Effect of ferric carboxymaltose on exercise capacity in patients with chronic heart failure and iron deficiency","volume":"136","author":"Van Veldhuisen","year":"2017","journal-title":"Circulation"},{"key":"B87","doi-asserted-by":"publisher","first-page":"1895","DOI":"10.1016\/S0140-6736(20)32339-4","article-title":"Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial","volume":"396","author":"Ponikowski","year":"2020","journal-title":"Lancet"},{"key":"B88","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1093\/eurjhf\/hft099","article-title":"Intravenous ferric carboxymaltose in iron-deficient chronic heart failure patients with and without anaemia: a subanalysis of the FAIR-HF trial","volume":"15","author":"Filippatos","year":"2013","journal-title":"Eur J Hear Fail"},{"key":"B89","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1016\/j.hlc.2014.12.161","article-title":"Changes in echocardiographic parameters in iron deficiency patients with heart failure and chronic kidney disease treated with intravenous iron","volume":"24","author":"Toblli","year":"2015","journal-title":"Hear Lung Circ"},{"key":"B90","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1002\/ehf2.12101","article-title":"Left ventricular ejection fraction recovery in patients with heart failure treated with intravenous iron: a pilot study","volume":"3","author":"N\u00fa\u00f1ez","year":"2016","journal-title":"ESC Hear Fail"},{"key":"B91","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1002\/ejhf.84","article-title":"The additive burden of iron deficiency in the cardiorenal-anaemia axis: scope of a problem and its consequences","volume":"16","author":"Klip","year":"2014","journal-title":"Eur J Hear Fail"},{"key":"B92","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/j.hfc.2008.03.008","article-title":"Epidemiology of chronic kidney disease in heart failure","volume":"4","author":"Ahmed","year":"2008","journal-title":"Hear Fail Clin"},{"key":"B93","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1016\/j.nefroe.2017.11.009","article-title":"Heart failure in patients with kidney disease and iron deficiency; the role of iron therapy","volume":"37","author":"Cases","year":"2017","journal-title":"Nefrologia"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1016\/j.nefro.2020.11.003","article-title":"Iron replacement therapy in the management of anaemia in non-dialysis chronic renal failure patients: perspective of the Spanish Nephrology Society Anaemia Group","author":"Cases","year":"2021","journal-title":"Nefrologia"},{"key":"B95","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1007\/s10534-015-9845-9","article-title":"Physico-chemical properties of the new generation IV iron preparations ferumoxytol, iron isomaltoside 1000 and ferric carboxymaltose","volume":"28","author":"Neiser","year":"2015","journal-title":"Biometals"},{"key":"B96","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1016\/j.ejpb.2011.03.016","article-title":"A comparative study of the physicochemical properties of iron isomaltoside 1000 (Monofer), a new intravenous iron preparation and its clinical implications","volume":"78","author":"Jahn","year":"2011","journal-title":"Eur J Pharm Biopharm"},{"key":"B97","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1056\/NEJMoa1810742","article-title":"Intravenous iron in patients undergoing maintenance hemodialysis","volume":"380","author":"Macdougall","year":"2019","journal-title":"N Engl J Med"},{"key":"B98","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1016\/j.ebiom.2018.11.020","article-title":"Liver iron load influences hepatic fat fraction in end-stage renal disease patients on dialysis: a proof of concept study","volume":"39","author":"Rostoker","year":"2019","journal-title":"EBioMedicine"},{"key":"B99","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1016\/j.amjmed.2012.01.015","article-title":"Hemodialysis associated hemosiderosis in the era of erythropoiesis-stimulating agents: a MRI study","volume":"125","author":"Rostoker","year":"2012","journal-title":"Am J Med"},{"key":"B100","first-page":"68","article-title":"Liver and cardiac iron deposition in patients on maintenance hemodialysis by magnetic resonance imaging T2","volume":"10","author":"Tolouian","year":"2016","journal-title":"Iran J Kidney Dis"},{"key":"B101","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1111\/nep.12735","article-title":"Characterisation of hepatic and cardiac iron deposition during standard treatment of anaemia in haemodialysis","volume":"22","author":"Holman","year":"2017","journal-title":"Nephrol (Carlton)"},{"key":"B102","doi-asserted-by":"publisher","first-page":"457","DOI":"10.2215\/CJN.05390517","article-title":"Safety of intravenous iron in dialysis a systematic review and meta-analysis","volume":"13","author":"Hougen","year":"2018","journal-title":"Clin J Am Soc Nephrol"},{"key":"B103","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.1681\/ASN.2019090972","article-title":"Intravenous iron dosing and infection risk in patients on hemodialysis: a prespecified secondary analysis of the PIVOTAL trial","volume":"31","author":"Macdougall","year":"2020","journal-title":"JASN"},{"key":"B104","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.molmed.2018.10.006","article-title":"Inflammation and hypoxia: HIF and PHD isoform selectivity","volume":"25","author":"Watts","year":"2019","journal-title":"Trends Mol Med"},{"key":"B105","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1056\/NEJMoa1813599","article-title":"Roxadustat for anemia in patients with kidney disease not receiving dialysis","volume":"381","author":"Chen","year":"2019","journal-title":"N Engl J Med"},{"key":"B106","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1056\/NEJMoa1901713","article-title":"Roxadustat treatment for anemia in patients undergoing long-term dialysis","volume":"381","author":"Chen","year":"2019","journal-title":"N Engl J Med"},{"key":"B107","doi-asserted-by":"publisher","first-page":"1628","DOI":"10.1681\/ASN.2019060623","article-title":"Phase 3, randomized, double-blind, active-comparator (Darbepoetin Alfa) study of oral roxadustat in CKD patients with anemia on hemodialysis in Japan","volume":"31","author":"Akizawa","year":"2020","journal-title":"J Am Soc Nephrol"},{"key":"B108","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1111\/1744-9987.12888","article-title":"Intermittent oral dosing of roxadustat in peritoneal dialysis chronic kidney disease patients with anemia: a randomized, phase 3, multicenter, open-label study","volume":"24","author":"Akizawa","year":"2020","journal-title":"Ther Apher Dial"},{"key":"B109","first-page":"6","article-title":"ROCKIES: an international, phase 3, randomized, open-label, active-controlled study of roxadustat for anemia in dialysis-dependent CKD patients. Abstract TH-OR022","volume":"30","author":"Fishbane","year":"2019","journal-title":"JASN"},{"key":"B110","first-page":"822","article-title":"Two phase 3, multicenter, randomized studies of intermittent oral roxadustat in anemic CKD patients on (PYRENEES) and not on (ALPS) dialysis. Abstract SA-PO225","volume":"30","author":"Esposito","year":"2019","journal-title":"J Am Soc Nephrol"},{"key":"B111","first-page":"822","article-title":"SIERRAS: a phase 3, open-label, randomized, active-controlled study of the efficacy and safety of roxadustat in the maintenance treatment of anemia in subjects with ESRD on stable dialysis. Abstract SA-PO227 P","volume":"30","author":"Charytan","year":"2019","journal-title":"JASN"},{"key":"B112","first-page":"5","article-title":"HIMALAYAS: a phase 3, randomized, open-label, active-controlled study of the efficacy and safety of roxadustat in the treatment of anemia in incident-dialysis patients. Abstract TH-OR021 Washington, DC: American Society of Nephrology","volume":"30","author":"Provenzano","year":"2019","journal-title":"JASN"},{"key":"B113","volume-title":"Pooled Efficacy and Cardiovascular (CV) Analyses of Roxadustat in the Treatment of Anemia in CKD Patients on and Not on Dialysis","author":"Provenzano","year":"2019"},{"key":"B114","first-page":"6","article-title":"OLYMPUS: a phase 3, randomized, double-blind, placebo-controlled, international study of roxadustat efficacy in patients with non-dialysis-dependent (NDD) CKD and anemia. Abstract TH-OR023 O","volume":"30","author":"Fishbane","year":"2019","journal-title":"JASN"},{"key":"B115","first-page":"822","article-title":"ANDES: a phase 3, randomized, double-blind, placebo controlled study of the efficacy and safety of roxadustat for the treatment of anemia in CKD patients not on dialysis. Abatract SA-PO228","volume":"30","author":"Coyne","year":"2019","journal-title":"JASN"},{"key":"B116","doi-asserted-by":"publisher","first-page":"gfaa140","DOI":"10.1093\/ndt\/gfaa140.MO001","article-title":"Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a phase 3, randomised, open-label, active-controlled study","volume":"35","author":"Barratt","year":"2020","journal-title":"Nephrol Dial Transplant"},{"key":"B117","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1681\/ASN.20203110S11b","article-title":"Roxadustat for the Treatment of Anemia in CKD Patients Not on Dialysis (NDD): A Phase 3, Randomized, Open-Label, Active-Controlled Study","volume":"31","author":"Barratt","year":"2020","journal-title":"J Am Soc Nephrol"},{"key":"B118","first-page":"823","article-title":"Randomized, open-label, active-controlled (darbepoetin alfa), phase 3 study of vadadustat for treating anemia in non-dialysis-dependent CKD patients in Japan. Abstract SA-PO229 P","volume":"30","author":"Nangaku","year":"2019","journal-title":"JASN"},{"key":"B119","first-page":"6","article-title":"Randomized, double-blinded, active-controlled (Darbepoetin Alfa), phase 3 study of vadadustat in CKD patients with anemia on hemodialysis in Japan. Abstract TH-OR024 O","volume":"30","author":"Nangaku","year":"2019","journal-title":"JASN"},{"key":"B120","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1159\/000499111","article-title":"Long-term efficacy and safety of molidustat for anemia in chronic kidney disease: DIALOGUE extension studies","volume":"49","author":"Akizawa","year":"2019","journal-title":"Am J Nephrol"},{"key":"B121","doi-asserted-by":"publisher","first-page":"CD013751","DOI":"10.1002\/14651858.CD013751","article-title":"Hypoxia-inducible factor stabilisers for the anaemia of chronic kidney disease","author":"Natale","year":"2020","journal-title":"Cochrane Database Syst Rev."},{"key":"B122","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1053\/j.ajkd.2015.12.020","article-title":"Roxadustat (FG-4592) versus epoetin alfa for anemia in patients receiving maintenance hemodialysis: a phase 2, randomized, 6- to 19-week, open-label, active-comparator, dose-ranging, safety and exploratory efficacy study","volume":"67","author":"Provenzano","year":"2016","journal-title":"Am J Kidney Dis"},{"key":"B123","doi-asserted-by":"publisher","first-page":"2052","DOI":"10.1001\/jama.2020.6775","article-title":"Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area","volume":"323","author":"Richardson","year":"2020","journal-title":"JAMA"},{"key":"B124","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1053\/j.ajkd.2020.05.002","article-title":"Erythropoiesis-stimulating agent treatment in patients with COVID-19","volume":"6","author":"Fishbane","year":"2020","journal-title":"Am J Kidney Dis"},{"key":"B125","doi-asserted-by":"publisher","first-page":"1539","DOI":"10.1038\/s41401-020-00554-8","article-title":"Hypoxia, HIF-1\u03b1, and COVID-19: from pathogenic factors to potential therapeutic targets","volume":"41","author":"Serebrovska","year":"2020","journal-title":"Acta Pharmacol Sin"},{"key":"B126","doi-asserted-by":"publisher","first-page":"225256","DOI":"10.1016\/bs.enz.2019.08.003","article-title":"Iron-sulfur clusters in nucleic acid metabolism: varying roles of ancient cofactors","volume":"45","author":"Khodour","year":"2019","journal-title":"Enzymes"},{"key":"B127","doi-asserted-by":"publisher","first-page":"110173","DOI":"10.1007\/s40588-020-00140-w","article-title":"Depriving iron supply to the virus represents a promising adjuvant therapeutic against viral survival","volume":"143","author":"Liu","year":"2020","journal-title":"Curr Clin Microbiol Reports"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.642296\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T21:46:17Z","timestamp":1724708777000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.642296\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,26]]},"references-count":127,"alternative-id":["10.3389\/fmed.2021.642296"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2021.642296","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,26]]},"article-number":"642296"}}