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• W3136277648 abstract "The capacity of blood to carry oxygen throughout the body depends on circulating red blood cells (RBCs) and the hemoglobin (Hb) protein they contain. Decreased Hb levels result in anemia, defined in the general adult population as an Hb level of ≤13 g/dl in men and ≤12 g/dl in nonpregnant women.1World Health OrganizationHaemoglobin concentrations for the diagnosis of anaemia and assessment of severity.https://www.who.int/vmnis/indicators/haemoglobin/en/Date accessed: December 7, 2020Google Scholar Symptoms of anemia include fatigue, dyspnea, and weakness.2Kalantar-Zadeh K. History of erythropoiesis-stimulating agents, the development of biosimilars, and the future of anemia treatment in nephrology.Am J Nephrol. 2017; 45: 235-247Crossref PubMed Scopus (29) Google Scholar Patients with chronic kidney disease (CKD) are at increased risk of developing anemia. In 2017, approximately 38 million individuals in the United States (US) and 700 million globally were estimated to have CKD, many of whom are likely to have anemia of CKD.3Bikbov B. Purcell C.A. Levey A.S. et al.GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2020; 395: 709-733Abstract Full Text Full Text PDF PubMed Scopus (713) Google Scholar More than 5 million people in the US have anemia of CKD,4Stauffer M.E. Fan T. Prevalence of anemia in chronic kidney disease in the United States.PLoS One. 2014; 9e84943Crossref PubMed Scopus (223) Google Scholar the prevalence of which increases with age and CKD stage.5St Peter W.L. Guo H. Kabadi S. et al.Prevalence, treatment patterns, and healthcare resource utilization in Medicare and commercially insured non-dialysis-dependent chronic kidney disease patients with and without anemia in the United States.BMC Nephrol. 2018; 19: 67Crossref PubMed Scopus (20) Google Scholar A recent analysis of data from the United States National Health and Nutrition Examination Survey found that nearly one-quarter of those with non–dialysis-dependent stage 3–5 CKD,6Davis J. Caspard H. Little D. et al.Prevalence and risk factors of CKD anemia in the United States.J Am Soc Nephrol. 2019; 30: 826Google Scholar whereas an earlier analysis showed that approximately half of patients with stage 4 or 5 CKD also had anemia.4Stauffer M.E. Fan T. Prevalence of anemia in chronic kidney disease in the United States.PLoS One. 2014; 9e84943Crossref PubMed Scopus (223) Google Scholar Anemia of CKD is associated with an elevated risk of hospitalization, cardiovascular disease and stroke, greater health care resource utilization, worsened quality of life, and increased mortality.5St Peter W.L. Guo H. Kabadi S. et al.Prevalence, treatment patterns, and healthcare resource utilization in Medicare and commercially insured non-dialysis-dependent chronic kidney disease patients with and without anemia in the United States.BMC Nephrol. 2018; 19: 67Crossref PubMed Scopus (20) Google Scholar,7Abramson J.L. Jurkovitz C.T. Vaccarino V. et al.Chronic kidney disease, anemia, and incident stroke in a middle-aged, community-based population: the ARIC Study.Kidney Int. 2003; 64: 610-615Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar, 8Sarnak M.J. Tighiouart H. Manjunath G. et al.Anemia as a risk factor for cardiovascular disease in the Atherosclerosis Risk in Communities (ARIC) study.J Am Coll Cardiol. 2002; 40: 27-33Crossref PubMed Scopus (359) Google Scholar, 9Portoles J. Gorriz J.L. Rubio E. et al.The development of anemia is associated to poor prognosis in NKF/KDOQI stage 3 chronic kidney disease.BMC Nephrol. 2013; 14: 2Crossref PubMed Scopus (45) Google Scholar, 10Toft G. Heide-Jorgensen U. van Haalen H. et al.Anemia and clinical outcomes in patients with non-dialysis dependent or dialysis dependent severe chronic kidney disease: a Danish population-based study.J Nephrol. 2020; 33: 147-156Crossref PubMed Scopus (19) Google Scholar In CKD, anemia is caused by low erythropoietic activity (necessary to produce RBCs), consistent with insufficient production of erythropoietin in the kidneys.11Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work GroupKDIGO clinical practice guideline for anemia in chronic kidney disease.Kidney Int Suppl. 2012; 2: 279-335Abstract Full Text Full Text PDF Scopus (583) Google Scholar Reduced red blood cell lifespan due to a variety of accumulating uremic toxins also contributes to and exacerbates anemia of CKD.12Tozoni S.S. Dias G.F. Bohnen G. et al.Uremia and hypoxia independently induce eryptosis and erythrocyte redox imbalance.Cell Physiol Biochem. 2019; 53: 794-804Crossref PubMed Scopus (10) Google Scholar More recently there has been recognition of the contributions of dysregulated iron homeostasis and hypoxia-induced transcriptional control mechanisms.13Schodel J. Ratcliffe P.J. Mechanisms of hypoxia signalling: new implications for nephrology.Nat Rev Nephrol. 2019; 15: 641-659Crossref PubMed Scopus (75) Google Scholar,14Agarwal A.K. Yee J. Hepcidin.Adv Chronic Kidney Dis. 2019; 26: 298-305Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar As elaborated on in the articles in this supplement, an understanding of the complex mechanisms contributing to anemia of CKD and the pharmacologic tools available to modify these mechanisms have implications for therapeutic options and their availability to patients, including complex patients with multiple comorbidities. The observation in the late 19th century that RBC counts increased in travelers to high altitudes led to the proposal of a link between erythropoiesis and hypoxia.15Bunn H.F. Erythropoietin.Cold Spring Harb Perspect Med. 2013; 3: a011619Crossref PubMed Scopus (9) Google Scholar In 1906, Carnot and Deflandre first described a humoral factor responsible for inducing erythropoiesis.15Bunn H.F. Erythropoietin.Cold Spring Harb Perspect Med. 2013; 3: a011619Crossref PubMed Scopus (9) Google Scholar Ensuing work through the mid-20th century confirmed the presence of the responsible factor, erythropoietin, and demonstrated that erythropoietin production mainly occurs in the kidneys.16Jacobson L.O. Goldwasser E. Fried W. et al.Role of the kidney in erythropoiesis.Nature. 1957; 179: 633-634Crossref PubMed Scopus (478) Google Scholar,17Nathan D.G. Schupak E. Stohlman Jr., F. et al.Erythropoiesis in anephric man.J Clin Invest. 1964; 43: 2158-2165Crossref PubMed Scopus (56) Google Scholar Erythropoietin was purified in large quantities from the urine of patients with anemia in 1977 and was later shown to increase Hb synthesis in cell culture.18Miyake T. Kung C.K. Goldwasser E. Purification of human erythropoietin.J Biol Chem. 1977; 252: 5558-5564Abstract Full Text PDF PubMed Google Scholar,19Weiss T.L. Goldwasser E. The biological properties of endotoxin-free human erythropoietin.Biochem J. 1981; 198: 17-21Crossref PubMed Scopus (7) Google Scholar Despite scientific progress in understanding erythropoiesis and the role of erythropoietin, before the mid-1980s, patients with anemia of CKD still lacked successful treatment options. Although blood transfusions and oral androgens to increase endogenous erythropoietin production were available,20Shahani S. Braga-Basaria M. Maggio M. et al.Androgens and erythropoiesis: past and present.J Endocrinol Invest. 2009; 32: 704-716Crossref PubMed Google Scholar they were not always effective and were fraught with drawbacks.21Eschbach J.W. Adamson J.W. Anemia of end-stage renal disease (ESRD).Kidney Int. 1985; 28: 1-5Abstract Full Text PDF PubMed Scopus (281) Google Scholar Blood transfusions conferred increased risk of infections, iron overload, and allosensitization that could impact future kidney transplantation,20Shahani S. Braga-Basaria M. Maggio M. et al.Androgens and erythropoiesis: past and present.J Endocrinol Invest. 2009; 32: 704-716Crossref PubMed Google Scholar whereas oral androgens were not consistently effective and had substantial adverse effects.20Shahani S. Braga-Basaria M. Maggio M. et al.Androgens and erythropoiesis: past and present.J Endocrinol Invest. 2009; 32: 704-716Crossref PubMed Google Scholar A paradigm shift in the treatment of anemia of CKD came with the identification and cloning of the gene encoding human erythropoietin in 1985.22Jacobs K. Shoemaker C. Rudersdorf R. et al.Isolation and characterization of genomic and cDNA clones of human erythropoietin.Nature. 1985; 313: 806-810Crossref PubMed Scopus (830) Google Scholar,23Lin F.K. Suggs S. Lin C.H. et al.Cloning and expression of the human erythropoietin gene.Proc Natl Acad Sci U S A. 1985; 82: 7580-7584Crossref PubMed Scopus (934) Google Scholar This breakthrough enabled the subsequent mass production of recombinant human erythropoietin, now known as an erythropoiesis-stimulating agent (ESA). Clinical trials testing recombinant human erythropoietin in the treatment of anemia of CKD yielded positive results in patients with end-stage renal disease on dialysis, including increases in hematocrit and no subsequent requirements for transfusions.24Eschbach J.W. Egrie J.C. Downing M.R. et al.Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial.N Engl J Med. 1987; 316: 73-78Crossref PubMed Scopus (1744) Google Scholar,25Eschbach J.W. Abdulhadi M.H. Browne J.K. et al.Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial.Ann Intern Med. 1989; 111: 992-1000Crossref PubMed Scopus (691) Google Scholar On the basis of these and similar trials, the Food and Drug Administration approved epoetin alfa in 1989 in the US for the treatment of anemia in patients with chronic renal failure,26Epogen® (epoetin alfa) injection, for intravenous or subcutaneous use. [Package Insert]. Amgen Inc., Thousand Oaks, CA2018Google Scholar revolutionizing the treatment of patients with anemia of CKD. The aim of epoetin alfa treatment in anemia of CKD (Hb <10 g/dl), both for dialysis and nondialysis patients, is to decrease the need for RBC transfusion.26Epogen® (epoetin alfa) injection, for intravenous or subcutaneous use. [Package Insert]. Amgen Inc., Thousand Oaks, CA2018Google Scholar Although ESAs were a game changer for the treatment of anemia of CKD, their use has not been without complications. Before the introduction of ESAs, treatment was primarily focused on patients with severe anemia with relatively few options for mild-to-moderate cases. However, with the advent of ESAs, treatment began to occur in patients with mild-to-moderate anemia (8.0–12.9 g/dl for men and 8.0–11.9 g/dl for nonpregnant women1World Health OrganizationHaemoglobin concentrations for the diagnosis of anaemia and assessment of severity.https://www.who.int/vmnis/indicators/haemoglobin/en/Date accessed: December 7, 2020Google Scholar). Several large, randomized controlled trials on patients with anemia of CKD tested the usage of ESAs to higher target Hb levels, including Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR),27Singh A.K. Szczech L. Tang K.L. et al.Correction of anemia with epoetin alfa in chronic kidney disease.N Engl J Med. 2006; 355: 2085-2098Crossref PubMed Scopus (2164) Google Scholar Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE),28Drueke T.B. Locatelli F. Clyne N. et al.Normalization of hemoglobin level in patients with chronic kidney disease and anemia.N Engl J Med. 2006; 355: 2071-2084Crossref PubMed Scopus (1704) Google Scholar Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT),29Pfeffer M.A. Burdmann E.A. Chen C.Y. et al.A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.N Engl J Med. 2009; 361: 2019-2032Crossref PubMed Scopus (1539) Google Scholar Anemia Correction in Diabetes (ACORD),30Ritz E. Laville M. Bilous R.W. et al.Target level for hemoglobin correction in patients with diabetes and CKD: primary results of the Anemia Correction in Diabetes (ACORD) Study.Am J Kidney Dis. 2007; 49: 194-207Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar and Normal Hematocrit Cardiac Trial (NHCT).31Besarab A. Bolton W.K. Browne J.K. et al.The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.N Engl J Med. 1998; 339: 584-590Crossref PubMed Scopus (1803) Google Scholar However, these studies found little advantage and increased risks for thromboembolic and cardiovascular events and mortality with ESA treatment to target Hb levels of 13–15 g/dl.27Singh A.K. Szczech L. Tang K.L. et al.Correction of anemia with epoetin alfa in chronic kidney disease.N Engl J Med. 2006; 355: 2085-2098Crossref PubMed Scopus (2164) Google Scholar, 28Drueke T.B. Locatelli F. Clyne N. et al.Normalization of hemoglobin level in patients with chronic kidney disease and anemia.N Engl J Med. 2006; 355: 2071-2084Crossref PubMed Scopus (1704) Google Scholar, 29Pfeffer M.A. Burdmann E.A. Chen C.Y. et al.A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.N Engl J Med. 2009; 361: 2019-2032Crossref PubMed Scopus (1539) Google Scholar, 30Ritz E. Laville M. Bilous R.W. et al.Target level for hemoglobin correction in patients with diabetes and CKD: primary results of the Anemia Correction in Diabetes (ACORD) Study.Am J Kidney Dis. 2007; 49: 194-207Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 31Besarab A. Bolton W.K. Browne J.K. et al.The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.N Engl J Med. 1998; 339: 584-590Crossref PubMed Scopus (1803) Google Scholar As a result of these findings, the Food and Drug Administration issued a black box warning in 2011 for ESA labels; this lowered target Hb levels, recommended that physicians should consider initiating ESA treatment only in severe anemia when a patient’s Hb is <10 g/dl, and suggested that dosing of ESAs should be individualized to use the lowest dose that would reduce the need for RBC transfusions.32United States Food and Drug AdministrationFDA drug safety communication: modified dosing recommendations to improve the safe use of erythropoiesis-stimulating agents (ESAs) in chronic kidney disease.https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-modified-dosing-recommendations-improve-safe-use-erythropoiesisDate accessed: May 6, 2020Google Scholar In agreement with this, the most recent Kidney Disease: Improving Global Outcomes (KDIGO) guideline recommends that patients with Hb levels ≥10 g/dl should not start ESA therapy.11Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work GroupKDIGO clinical practice guideline for anemia in chronic kidney disease.Kidney Int Suppl. 2012; 2: 279-335Abstract Full Text Full Text PDF Scopus (583) Google Scholar Further analysis from the trials noted above showed that large doses of ESAs were often used to attempt to achieve these higher Hb levels. For example, in CHOIR, almost 2-fold higher doses of epoetin alfa were used to achieve the higher Hb targets (13.5 g/dl) compared with lower Hb levels (11.3 g/dl).27Singh A.K. Szczech L. Tang K.L. et al.Correction of anemia with epoetin alfa in chronic kidney disease.N Engl J Med. 2006; 355: 2085-2098Crossref PubMed Scopus (2164) Google Scholar In addition, a meta-analysis of 31 clinical trials suggested that it was higher ESA doses rather than higher Hb levels that were associated with the adverse effects seen in the aforementioned trials.33Koulouridis I. Alfayez M. Trikalinos T.A. et al.Dose of erythropoiesis-stimulating agents and adverse outcomes in CKD: a metaregression analysis.Am J Kidney Dis. 2013; 61: 44-56Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar Although they have revolutionized the treatment of anemia in CKD, ESAs have not been a straightforward panacea. In addition to the complexities of managing ESA dosages to balance risk and benefit, not all patients respond equally to ESAs. Some patients, designated ESA hyporesponders, do not reach target Hb levels despite higher ESA doses.34Sibbel S.P. Koro C.E. Brunelli S.M. et al.Characterization of chronic and acute ESA hyporesponse: a retrospective cohort study of hemodialysis patients.BMC Nephrol. 2015; 16: 144Crossref PubMed Scopus (21) Google Scholar,35Luo J. Jensen D.E. Maroni B.J. et al.Spectrum and burden of erythropoiesis-stimulating agent hyporesponsiveness among contemporary hemodialysis patients.Am J Kidney Dis. 2016; 68: 763-771Abstract Full Text Full Text PDF PubMed Scopus (31) Google ScholarApproximately 10%–15% of patients with dialysis-dependent CKD are ESA hyporesponders.34Sibbel S.P. Koro C.E. Brunelli S.M. et al.Characterization of chronic and acute ESA hyporesponse: a retrospective cohort study of hemodialysis patients.BMC Nephrol. 2015; 16: 144Crossref PubMed Scopus (21) Google Scholar,35Luo J. Jensen D.E. Maroni B.J. et al.Spectrum and burden of erythropoiesis-stimulating agent hyporesponsiveness among contemporary hemodialysis patients.Am J Kidney Dis. 2016; 68: 763-771Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Higher doses of ESAs have not improved the hyporesponse and are associated with a significantly higher mortality risk.33Koulouridis I. Alfayez M. Trikalinos T.A. et al.Dose of erythropoiesis-stimulating agents and adverse outcomes in CKD: a metaregression analysis.Am J Kidney Dis. 2013; 61: 44-56Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar,35Luo J. Jensen D.E. Maroni B.J. et al.Spectrum and burden of erythropoiesis-stimulating agent hyporesponsiveness among contemporary hemodialysis patients.Am J Kidney Dis. 2016; 68: 763-771Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Subgroups of patients with anemia of CKD, such as elderly patients or those with comorbid conditions (e.g., malignancies, cardiovascular disease, diabetes, systemic inflammation, post-transplantation, etc.), may have suboptimal responses to ESAs and require additional treatment considerations. One cause of ESA hyporesponse is iron deficiency.11Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work GroupKDIGO clinical practice guideline for anemia in chronic kidney disease.Kidney Int Suppl. 2012; 2: 279-335Abstract Full Text Full Text PDF Scopus (583) Google Scholar Many patients with CKD are iron deficient—either absolute or functional—due to impaired intestinal absorption of iron, chronic inflammation, blood loss, and increased iron requirements during ESA therapy.11Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work GroupKDIGO clinical practice guideline for anemia in chronic kidney disease.Kidney Int Suppl. 2012; 2: 279-335Abstract Full Text Full Text PDF Scopus (583) Google Scholar As early as the late 1920s oral iron supplementation was used to ameliorate anemia.36Mackay H.M. Anaemia in infancy: its prevalence and prevention.Arch Dis Child. 1928; 3: 117-147Crossref PubMed Google Scholar,37Poskitt E.M. Early history of iron deficiency.Br J Haematol. 2003; 122: 554-562Crossref PubMed Scopus (19) Google Scholar Although injectable iron supplementation for anemia was described in the 1930s, intravenous use of iron did not become widespread in the US until the 1980s, after the publication of a prospective study on its clinical use.38Heath C.W. Strauss M.B. Castle W.B. Quantitative aspects of iron deficiency in hypochromic anemia: the parenteral administration of iron.J Clin Invest. 1932; 11: 1293-1312Crossref PubMed Google Scholar,39Hamstra R.D. Block M.H. Schocket A.L. Intravenous iron dextran in clinical medicine.JAMA. 1980; 243: 1726-1731Crossref PubMed Scopus (246) Google Scholar Despite the clinical benefits of intravenous iron supplementation on its own and alongside ESA therapy, there have been safety concerns (particularly with older, high-molecular-weight dextran formulations) including the risk of anaphylactoid reactions and unknown long-term effects.11Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work GroupKDIGO clinical practice guideline for anemia in chronic kidney disease.Kidney Int Suppl. 2012; 2: 279-335Abstract Full Text Full Text PDF Scopus (583) Google Scholar,40Auerbach M. Ballard H. Clinical use of intravenous iron: administration, efficacy, and safety.Hematology Am Soc Hematol Educ Program. 2010; 2010: 338-347Crossref PubMed Scopus (200) Google Scholar Furthermore, intravenous iron may promote oxidative stress by sharply increasing the amount of labile iron, exacerbating inflammation, and increasing the risk of infections.41Vaziri N.D. Safety issues in iron treatment in CKD.Semin Nephrol. 2016; 36: 112-118Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar,42Macdougall I.C. Bhandari S. White C. et al.Intravenous iron dosing and infection risk in patients on hemodialysis: a prespecified secondary analysis of the PIVOTAL trial.J Am Soc Nephrol. 2020; 31: 1118-1127Crossref PubMed Scopus (26) Google Scholar Discussions are ongoing regarding the risk-benefit balance of iron supplementation, which formulations are best, the most appropriate target iron levels, and monitoring approaches.11Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work GroupKDIGO clinical practice guideline for anemia in chronic kidney disease.Kidney Int Suppl. 2012; 2: 279-335Abstract Full Text Full Text PDF Scopus (583) Google Scholar,40Auerbach M. Ballard H. Clinical use of intravenous iron: administration, efficacy, and safety.Hematology Am Soc Hematol Educ Program. 2010; 2010: 338-347Crossref PubMed Scopus (200) Google Scholar In patients with non–dialysis-dependent CKD, guidelines often recommend a trial of oral iron supplementation as first-line therapy (depending on disease severity and other factors) before proceeding to intravenous iron therapy, whereas patients with hemodialysis-dependent CKD are typically recommended to initiate intravenous iron therapy.11Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work GroupKDIGO clinical practice guideline for anemia in chronic kidney disease.Kidney Int Suppl. 2012; 2: 279-335Abstract Full Text Full Text PDF Scopus (583) Google Scholar,43National Institute for Health and Care Excellence (UK)Surveillance report 2017—Chronic kidney disease (stage 4 or 5): management of hyperphosphataemia (2013) NICE guideline CG157, Chronic kidney disease in adults: assessment and management (2014) NICE guideline CG182 and Chronic kidney disease: managing anaemia (2015) NICE guideline NG8.2017Google Scholar,44Pergola P.E. Fishbane S. Ganz T. Novel oral iron therapies for iron deficiency anemia in chronic kidney disease.Adv Chronic Kidney Dis. 2019; 26: 272-291Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar New insights into iron metabolism and its influence on anemia resulted from the early 21st century discovery of the iron regulator hepcidin.45Krause A. Neitz S. Magert H.J. et al.LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity.FEBS Lett. 2000; 480: 147-150Crossref PubMed Scopus (1027) Google Scholar,46Park C.H. Valore E.V. Waring A.J. et al.Hepcidin, a urinary antimicrobial peptide synthesized in the liver.J Biol Chem. 2001; 276: 7806-7810Abstract Full Text Full Text PDF PubMed Scopus (1661) Google Scholar High hepcidin levels are observed during inflammation and in CKD anemia, and are associated with reduced intestinal iron absorption and iron recycling.47Nicolas G. Chauvet C. Viatte L. et al.The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation.J Clin Invest. 2002; 110: 1037-1044Crossref PubMed Scopus (1291) Google Scholar,48Zaritsky J. Young B. Wang H.J. et al.Hepcidin—a potential novel biomarker for iron status in chronic kidney disease.Clin J Am Soc Nephrol. 2009; 4: 1051-1056Crossref PubMed Scopus (240) Google Scholar Around a century after the initial observation of the link between hypoxia and erythropoiesis, the mechanisms of cellular oxygen regulation began to unfold. The 2019 Nobel Prize in Physiology or Medicine was shared among William Kaelin, Peter Ratcliffe, and Gregg Semenza for their work on cellular sensing and adaptation to the availability of oxygen.49Nobel Assembly at Karolinska InstitutetPress release: The Nobel Prize in Physiology or Medicine 2019.2019Google Scholar These discoveries included hypoxia-inducible factor (HIF), a transcription factor that is degraded under oxygen-rich conditions but which, under hypoxic conditions, activates the expression of the erythropoietin gene and genes involved in iron metabolism.50Huang L.E. Gu J. Schau M. et al.Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway.Proc Natl Acad Sci U S A. 1998; 95: 7987-7992Crossref PubMed Scopus (1789) Google Scholar,51Peyssonnaux C. Zinkernagel A.S. Schuepbach R.A. et al.Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs).J Clin Invest. 2007; 117: 1926-1932Crossref PubMed Scopus (471) Google Scholar The identification of HIF paved the way for a new class of drugs under investigation, HIF-prolyl hydroxylase inhibitors, which stabilize HIF by decreasing its degradation52Yeh T.L. Leissing T.M. Abboud M.I. et al.Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials.Chem Sci. 2017; 8: 7651-7668Crossref PubMed Google Scholar and show promise in the treatment of anemia of CKD. These new therapeutics improve iron homeostasis and raise Hb levels, doing so without the large supraphysiological increases in serum erythropoietin that can occur with ESAs.44Pergola P.E. Fishbane S. Ganz T. Novel oral iron therapies for iron deficiency anemia in chronic kidney disease.Adv Chronic Kidney Dis. 2019; 26: 272-291Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar,53Provenzano R. Besarab A. Wright S. et al.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.Am J Kidney Dis. 2016; 67: 912-924Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 54Chen N. Hao C. Peng X. et al.Roxadustat for anemia in patients with kidney disease not receiving dialysis.N Engl J Med. 2019; 381: 1001-1010Crossref PubMed Scopus (196) Google Scholar, 55Chen N. Hao C. Liu B.C. et al.Roxadustat treatment for anemia in patients undergoing long-term dialysis.N Engl J Med. 2019; 381: 1011-1022Crossref PubMed Scopus (198) Google Scholar Management of anemia of CKD occurs within the broader context of comprehensive CKD treatment. In the US an Executive Order issued in July 2019, Advancing American Kidney Health, aims to increase awareness of kidney disease, improve clinical outcomes, broaden the range of care options available to delay or prevent disease progression, make more dialysis options available to a greater number of patients, update systems and regulations related to kidney donation, and encourage the development of artificial kidneys.56Executive Order on Advancing American Kidney Health.https://aspe.hhs.gov/system/files/pdf/262046/AdvancingAmericanKidneyHealth.pdfDate accessed: April 23, 2020Google Scholar In 2017, most patients (63%) in the US with end-stage renal disease received hemodialysis therapy, and nearly all (98%) of those patients did so at a specialized dialysis center.57Saran R. Robinson B. Abbott K.C. et al.US Renal Data System 2019 Annual Data Report: epidemiology of kidney disease in the United States.Am J Kidney Dis. 2020; 75: A6-A7Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar A transition toward more patients receiving home dialysis will require new skills for patients, physicians, and dialysis providers in the management of CKD and, consequently, anemia of CKD. Together, our increased understanding of the interplay between erythropoiesis and iron utilization, the novel therapies in development, and emerging public policy initiatives make this an exciting time in the treatment of anemia of CKD. This supplement features 5 articles providing insight into anemia pathophysiology and management in patients with CKD. First, Dr. Haase describes the development of HIF-prolyl hydroxylase inhibitors, illustrating the progress made in understanding and modifying fundamental mechanisms of erythropoiesis. Second, Drs. Raichoudhury and Spinowitz discuss the clinical complexities of patients with difficult to manage anemia of CKD, and how new treatments may address some of these issues. Third, Dr. McCullough continues the theme of complex patients by describing treatment of patients with cardiorenal syndrome. Fourth, Dr. Agarwal discusses iron homeostasis and potential mechanisms underlying poor responsiveness to current therapies. Finally, Drs. Rastogi and Lerma discuss the proposed changes in care for patients with CKD intended to make treatment of late-stage CKD including those with anemia more accessible and broadly available. SF reports personal fees and nonfinancial support from AstraZeneca outside the submitted work. This article is published as part of a supplement supported by AstraZeneca . Jennifer Giel, PhD, on behalf of inScience Communications, Springer Healthcare (New York, NY, USA) provided medical writing support funded by AstraZeneca. Roxadustat is being developed for clinical use by an alliance of FibroGen, Astellas, and AstraZeneca. SF meets the International Committee of Medical Journal Editors criteria for authorship for this manuscript and takes responsibility for the integrity of the work as a whole. SF and the medical writer from inScience Communications wrote the first draft of the manuscript. SF reviewed and edited subsequent drafts, approved the submission of the manuscript, and is fully accountable for all aspects of the work." @default.
• W3136277648 created "2021-03-29" @default.
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• W3136277648 date "2021-04-01" @default.
• W3136277648 modified "2023-10-16" @default.
• W3136277648 title "Anemia management: a historical perspective" @default.
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