Anemia management: a historical perspective

  • Steven Fishbane
    Correspondence: Steven Fishbane, Zucker School of Medicine at Hofstra/Northwell, 100 Community Drive, Great Neck, New York 11021, USA.
    Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, New York, USA
    Search for articles by this author

      Graphical Abstract

      To read this article in full you will need to make a payment
      ISN Member Login
      ISN Members, full access to the journal is a member benefit. Use your society credentials to access all journal content and features.
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Purchase one-time access:

      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • World Health Organization
        Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity.
        • Kalantar-Zadeh K.
        History of erythropoiesis-stimulating agents, the development of biosimilars, and the future of anemia treatment in nephrology.
        Am J Nephrol. 2017; 45: 235-247
        • Bikbov 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: 709-733
        • Stauffer M.E.
        • Fan T.
        Prevalence of anemia in chronic kidney disease in the United States.
        PLoS One. 2014; 9e84943
        • St 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: 67
        • Davis J.
        • Caspard H.
        • Little D.
        • et al.
        Prevalence and risk factors of CKD anemia in the United States.
        J Am Soc Nephrol. 2019; 30: 826
        • Abramson 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: 610-615
        • Sarnak 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: 27-33
        • Portoles 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: 2
        • Toft 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: 147-156
        • Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group
        KDIGO clinical practice guideline for anemia in chronic kidney disease.
        Kidney Int Suppl. 2012; 2: 279-335
        • Tozoni S.S.
        • Dias G.F.
        • Bohnen G.
        • et al.
        Uremia and hypoxia independently induce eryptosis and erythrocyte redox imbalance.
        Cell Physiol Biochem. 2019; 53: 794-804
        • Schodel J.
        • Ratcliffe P.J.
        Mechanisms of hypoxia signalling: new implications for nephrology.
        Nat Rev Nephrol. 2019; 15: 641-659
        • Agarwal A.K.
        • Yee J.
        Adv Chronic Kidney Dis. 2019; 26: 298-305
        • Bunn H.F.
        Cold Spring Harb Perspect Med. 2013; 3: a011619
        • Jacobson L.O.
        • Goldwasser E.
        • Fried W.
        • et al.
        Role of the kidney in erythropoiesis.
        Nature. 1957; 179: 633-634
        • Nathan D.G.
        • Schupak E.
        • Stohlman Jr., F.
        • et al.
        Erythropoiesis in anephric man.
        J Clin Invest. 1964; 43: 2158-2165
        • Miyake T.
        • Kung C.K.
        • Goldwasser E.
        Purification of human erythropoietin.
        J Biol Chem. 1977; 252: 5558-5564
        • Weiss T.L.
        • Goldwasser E.
        The biological properties of endotoxin-free human erythropoietin.
        Biochem J. 1981; 198: 17-21
        • Shahani S.
        • Braga-Basaria M.
        • Maggio M.
        • et al.
        Androgens and erythropoiesis: past and present.
        J Endocrinol Invest. 2009; 32: 704-716
        • Eschbach J.W.
        • Adamson J.W.
        Anemia of end-stage renal disease (ESRD).
        Kidney Int. 1985; 28: 1-5
        • Jacobs K.
        • Shoemaker C.
        • Rudersdorf R.
        • et al.
        Isolation and characterization of genomic and cDNA clones of human erythropoietin.
        Nature. 1985; 313: 806-810
        • Lin 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: 7580-7584
        • Eschbach 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: 73-78
        • Eschbach 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: 992-1000
      1. Epogen® (epoetin alfa) injection, for intravenous or subcutaneous use. [Package Insert]. Amgen Inc., Thousand Oaks, CA2018
        • Singh 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: 2085-2098
        • Drueke 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: 2071-2084
        • Pfeffer 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: 2019-2032
        • Ritz 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: 194-207
        • Besarab 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: 584-590
        • United States Food and Drug Administration
        FDA drug safety communication: modified dosing recommendations to improve the safe use of erythropoiesis-stimulating agents (ESAs) in chronic kidney disease.
        • Koulouridis 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: 44-56
        • Sibbel 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: 144
        • Luo 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: 763-771
        • Mackay H.M.
        Anaemia in infancy: its prevalence and prevention.
        Arch Dis Child. 1928; 3: 117-147
        • Poskitt E.M.
        Early history of iron deficiency.
        Br J Haematol. 2003; 122: 554-562
        • Heath 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: 1293-1312
        • Hamstra R.D.
        • Block M.H.
        • Schocket A.L.
        Intravenous iron dextran in clinical medicine.
        JAMA. 1980; 243: 1726-1731
        • Auerbach M.
        • Ballard H.
        Clinical use of intravenous iron: administration, efficacy, and safety.
        Hematology Am Soc Hematol Educ Program. 2010; 2010: 338-347
        • Vaziri N.D.
        Safety issues in iron treatment in CKD.
        Semin Nephrol. 2016; 36: 112-118
        • Macdougall 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: 1118-1127
        • National 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.
        2017 (London)
        • Pergola P.E.
        • Fishbane S.
        • Ganz T.
        Novel oral iron therapies for iron deficiency anemia in chronic kidney disease.
        Adv Chronic Kidney Dis. 2019; 26: 272-291
        • Krause A.
        • Neitz S.
        • Magert H.J.
        • et al.
        LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity.
        FEBS Lett. 2000; 480: 147-150
        • Park C.H.
        • Valore E.V.
        • Waring A.J.
        • et al.
        Hepcidin, a urinary antimicrobial peptide synthesized in the liver.
        J Biol Chem. 2001; 276: 7806-7810
        • Nicolas 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: 1037-1044
        • Zaritsky 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: 1051-1056
        • Nobel Assembly at Karolinska Institutet
        Press release: The Nobel Prize in Physiology or Medicine 2019.
        • Huang 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: 7987-7992
        • Peyssonnaux 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: 1926-1932
        • Yeh 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: 7651-7668
        • Provenzano 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: 912-924
        • Chen N.
        • Hao C.
        • Peng X.
        • et al.
        Roxadustat for anemia in patients with kidney disease not receiving dialysis.
        N Engl J Med. 2019; 381: 1001-1010
        • Chen N.
        • Hao C.
        • Liu B.C.
        • et al.
        Roxadustat treatment for anemia in patients undergoing long-term dialysis.
        N Engl J Med. 2019; 381: 1011-1022
      2. Executive Order on Advancing American Kidney Health.
        (Available at:)
        • Saran 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-A7