Iron metabolism and management: focus on chronic kidney disease

  • Anil K. Agarwal
    Correspondence
    Correspondence: Anil K. Agarwal, Department of Medicine, VA Central California Health Care System, University of California, San Francisco, 2615 E Clinton Ave, Fresno, California 93703, USA.
    Affiliations
    Department of Medicine, VA Central California Health Care System, University of California, San Francisco, San Francisco, California, USA
    Search for articles by this author
      Anemia is common in patients with chronic kidney disease (CKD) and results from the dysregulation of iron metabolism and erythropoiesis. Hepcidin is a key regulator of iron availability and leads to iron sequestration during the state of iron repletion. Decreases in the level of hepcidin in the presence of hypoxia and/or iron limitation allow for greater iron availability for erythropoiesis. However, kidney excretion of hepcidin decreases as the severity of CKD increases, whereas production of hepcidin is increased under inflammatory conditions often present in patients with CKD, both of which contribute to anemia. Assessment of iron status is, therefore, essential in the treatment of anemia. However, current laboratory tests for the determination of the adequate supply of iron have many limitations, including diurnal variation in the levels of biomarkers, lack of standardized reference methods across laboratories, and confounding by the presence of inflammation. In addition, the current treatment paradigm for anemia of CKD can further disrupt iron homeostasis; for example, treatment with erythropoiesis-stimulating agents in the absence of supplemental iron can induce functional iron deficiency. Moreover, supplemental iron can further increase levels of hepcidin. Several novel therapies, including hypoxia-inducible factor prolyl hydroxylase inhibitors and hepcidin inhibitors/antagonists, have shown promise in attenuating the levels and/or activity of hepcidin in anemia of CKD, thus ensuring the availability of iron for erythropoiesis.

      Graphical Abstract

      Keywords

      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

      References

        • 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
        • World Health Organization
        Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity.
        (Available at:)
        • Babitt J.L.
        • Lin H.Y.
        Mechanisms of anemia in CKD.
        J Am Soc Nephrol. 2012; 23: 1631-1634
        • 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
        • Moranne O.
        • Froissart M.
        • Rossert J.
        • et al.
        Timing of onset of CKD-related metabolic complications.
        J Am Soc Nephrol. 2009; 20: 164-171
        • Stauffer M.E.
        • Fan T.
        Prevalence of anemia in chronic kidney disease in the United States.
        PLoS One. 2014; 9e84943
        • Davis J.
        • Caspard H.
        • Little D.
        • et al.
        Prevalence and risk factors of CKD anemia in the United States [abstract SA-PO240].
        J Am Soc Nephrol. 2019; 30: 826
        • 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
        • Hunter H.N.
        • Fulton D.B.
        • Ganz T.
        • et al.
        The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis.
        J Biol Chem. 2002; 277: 37597-37603
        • 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
        • Ganz T.
        • Nemeth E.
        Iron balance and the role of hepcidin in chronic kidney disease.
        Semin Nephrol. 2016; 36: 87-93
        • Babitt J.L.
        • Huang F.W.
        • Wrighting D.M.
        • et al.
        Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression.
        Nat Genet. 2006; 38: 531-539
        • Corradini E.
        • Meynard D.
        • Wu Q.
        • et al.
        Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway in mice.
        Hepatology. 2011; 54: 273-284
        • Wrighting D.M.
        • Andrews N.C.
        Interleukin-6 induces hepcidin expression through STAT3.
        Blood. 2006; 108: 3204-3209
        • Pinnix Z.K.
        • Miller L.D.
        • Wang W.
        • et al.
        Ferroportin and iron regulation in breast cancer progression and prognosis.
        Sci Transl Med. 2010; 2: 43ra56
        • Zhang S.
        • Chen Y.
        • Guo W.
        • et al.
        Disordered hepcidin-ferroportin signaling promotes breast cancer growth.
        Cell Signal. 2014; 26: 2539-2550
        • Zhao B.
        • Li R.
        • Cheng G.
        • et al.
        Role of hepcidin and iron metabolism in the onset of prostate cancer.
        Oncol Lett. 2018; 15: 9953-9958
        • Silvestri L.
        • Pagani A.
        • Nai A.
        • et al.
        The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin.
        Cell Metab. 2008; 8: 502-511
        • Zhang A.S.
        • Anderson S.A.
        • Wang J.
        • et al.
        Suppression of hepatic hepcidin expression in response to acute iron deprivation is associated with an increase of matriptase-2 protein.
        Blood. 2011; 117: 1687-1699
        • Silvestri L.
        • Pagani A.
        • Camaschella C.
        Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis.
        Blood. 2008; 111: 924-931
        • Arezes J.
        • Foy N.
        • McHugh K.
        • et al.
        Erythroferrone inhibits the induction of hepcidin by BMP6.
        Blood. 2018; 132: 1473-1477
        • Mleczko-Sanecka K.
        • Roche F.
        • da Silva A.R.
        • et al.
        Unbiased RNAi screen for hepcidin regulators links hepcidin suppression to proliferative Ras/RAF and nutrient-dependent mTOR signaling.
        Blood. 2014; 123: 1574-1585
        • Yanatori I.
        • Kishi F.
        DMT1 and iron transport.
        Free Radic Biol Med. 2019; 133: 55-63
        • Nemeth E.
        • Tuttle M.S.
        • Powelson J.
        • et al.
        Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization.
        Science. 2004; 306: 2090-2093
        • Camaschella C.
        Iron deficiency.
        Blood. 2019; 133: 30-39
        • Dignass A.
        • Farrag K.
        • Stein J.
        Limitations of serum ferritin in diagnosing iron deficiency in inflammatory conditions.
        Int J Chronic Dis. 2018; 2018: 9394060
        • Ashby D.R.
        • Gale D.P.
        • Busbridge M.
        • et al.
        Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease.
        Kidney Int. 2009; 75: 976-981
        • Klausen T.
        • Dela F.
        • Hippe E.
        • et al.
        Diurnal variations of serum erythropoietin in trained and untrained subjects.
        Eur J Appl Physiol Occup Physiol. 1993; 67: 545-548
        • Kamei D.
        • Tsuchiya K.
        • Miura H.
        • et al.
        Inter-method variability of ferritin and transferrin saturation measurement methods in patients on hemodialysis.
        Ther Apher Dial. 2017; 21: 43-51
        • Pfeiffer C.M.
        • Looker A.C.
        Laboratory methodologies for indicators of iron status: strengths, limitations, and analytical challenges.
        Am J Clin Nutr. 2017; 106: 1606S-1614S
        • Murphy A.T.
        • Witcher D.R.
        • Luan P.
        • et al.
        Quantitation of hepcidin from human and mouse serum using liquid chromatography tandem mass spectrometry.
        Blood. 2007; 110: 1048-1054
        • Thomas D.W.
        • Hinchliffe R.F.
        • Briggs C.
        • et al.
        Guideline for the laboratory diagnosis of functional iron deficiency.
        Br J Haematol. 2013; 161: 639-648
        • National Clinical Guideline Center (UK)
        Anaemia Management in Chronic Kidney Disease: Partial Update 2015.
        Royal College of Physicians (UK), London, England2015
        • Worwood M.
        Indicators of the iron status of populations: ferritin.
        in: World Health Organization; Centers for Disease Control and Prevention Assessing the Iron Status of Populations. 2nd ed. WHO Press, Geneva, Switzerland2007
        • Wish J.B.
        Assessing iron status: beyond serum ferritin and transferrin saturation.
        Clin J Am Soc Nephrol. 2006; 1: S4-S8
        • Cobo G.
        • Lindholm B.
        • Stenvinkel P.
        Chronic inflammation in end-stage renal disease and dialysis.
        Nephrol Dial Transplant. 2018; 33: iii35-iii40
        • Chambers K.
        • Ashraf M.A.
        • Sharma S.
        Physiology, hepcidin. StatPearls. Treasure.
        StatPearls Publishing LLC, Island, FL2020
        • Devkota B.P.
        Iron-binding capacity.
        (Available at:)
        • Beard J.
        Indicators of the iron status of populations: free erythrocyte protoporphyrin and zinc protoporphyrin; serum and plasma iron, total iron binding capacity and transferrin saturation; and serum transferrin receptor.
        in: World Health Organization; Centers for Disease Control and Prevention Assessing the Iron Status of Populations. 2nd ed. WHO Press, Geneva, Switzerland2007
        • Northrup-Clewes C.A.
        The interpretation of indicators of iron status during an acute phase response.
        in: World Health Organization; Centers for Disease Control and Prevention Assessing the Iron Status of Populations. 2nd ed. WHO Press, Geneva, Switzerland2007
        • Tessitore N.
        • Solero G.P.
        • Lippi G.
        • et al.
        The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin.
        Nephrol Dial Transplant. 2001; 16: 1416-1423
        • Hayes W.
        Measurement of iron status in chronic kidney disease.
        Pediatr Nephrol. 2019; 34: 605-613
        • Kamei D.
        • Nagano M.
        • Hanafusa N.
        • et al.
        Comparison between a novel latex immunoassay and LC-MS/MS for hepcidin-25 measurement.
        J Am Soc Nephrol. 2019; 30: 828
        • 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
        • Peters H.P.
        • Laarakkers C.M.
        • Swinkels D.W.
        • et al.
        Serum hepcidin-25 levels in patients with chronic kidney disease are independent of glomerular filtration rate.
        Nephrol Dial Transplant. 2010; 25: 848-853
        • Uehata T.
        • Tomosugi N.
        • Shoji T.
        • et al.
        Serum hepcidin-25 levels and anemia in non-dialysis chronic kidney disease patients: a cross-sectional study.
        Nephrol Dial Transplant. 2012; 27: 1076-1083
        • Sonkar S.K.
        • Singh N.K.
        • Sonkar G.K.
        • et al.
        Association of hepcidin and anemia in early chronic kidney disease.
        Saudi J Kidney Dis Transpl. 2019; 30: 315-324
        • Hughes D.A.
        • Stuart-Smith S.E.
        • Bain B.J.
        How should stainable iron in bone marrow films be assessed?.
        J Clin Pathol. 2004; 57: 1038-1040
        • Goodnough L.T.
        • Nemeth E.
        • Ganz T.
        Detection, evaluation, and management of iron-restricted erythropoiesis.
        Blood. 2010; 116: 4754-4761
        • Kalantar-Zadeh K.
        • Hoffken B.
        • Wunsch H.
        • et al.
        Diagnosis of iron deficiency anemia in renal failure patients during the post-erythropoietin era.
        Am J Kidney Dis. 1995; 26: 292-299
        • Ferrari P.
        • Kulkarni H.
        • Dheda S.
        • et al.
        Serum iron markers are inadequate for guiding iron repletion in chronic kidney disease.
        Clin J Am Soc Nephrol. 2011; 6: 77-83
        • Mercadal L.
        • Metzger M.
        • Haymann J.P.
        • et al.
        A 3-marker index improves the identification of iron disorders in CKD anaemia.
        PLoS One. 2014; 9e84144
        • Costa E.
        • Swinkels D.W.
        • Laarakkers C.M.
        • et al.
        Hepcidin serum levels and resistance to recombinant human erythropoietin therapy in haemodialysis patients.
        Acta Haematol. 2009; 122: 226-229
        • El Sewefy D.A.
        • Farweez B.A.
        • Behairy M.A.
        • et al.
        Impact of serum hepcidin and inflammatory markers on resistance to erythropoiesis-stimulating therapy in haemodialysis patients.
        Int Urol Nephrol. 2019; 51: 325-334
        • Lee S.W.
        • Kim Y.H.
        • Chung W.
        • et al.
        Serum hepcidin and iron indices affect anemia status differently according to the kidney function of non-dialysis chronic kidney disease patients: Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD).
        Kidney Blood Press Res. 2017; 42: 1183-1192
        • Mikhail A.
        • Brown C.
        • Williams J.A.
        • et al.
        Renal association clinical practice guideline on anaemia of chronic kidney disease.
        BMC Nephrol. 2017; 18: 345
        • Macdougall I.C.
        • Hutton R.D.
        • Cavill I.
        • et al.
        Poor response to treatment of renal anaemia with erythropoietin corrected by iron given intravenously.
        BMJ. 1989; 299: 157-158
        • 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
        • Macdougall I.C.
        • Bock A.H.
        • Carrera F.
        • et al.
        FIND-CKD: a randomized trial of intravenous ferric carboxymaltose versus oral iron in patients with chronic kidney disease and iron deficiency anaemia.
        Nephrol Dial Transplant. 2014; 29: 2075-2084
        • Van Wyck D.B.
        • Roppolo M.
        • Martinez C.O.
        • et al.
        A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysis-dependent CKD.
        Kidney Int. 2005; 68: 2846-2856
        • Macdougall I.C.
        • White C.
        • Anker S.D.
        • et al.
        Intravenous iron in patients undergoing maintenance hemodialysis.
        N Engl J Med. 2019; 380: 447-458
        • Agarwal R.
        • Kusek J.W.
        • Pappas M.K.
        A randomized trial of intravenous and oral iron in chronic kidney disease.
        Kidney Int. 2015; 88: 905-914
        • Wang C.
        • Graham D.J.
        • Kane R.C.
        • et al.
        Comparative risk of anaphylactic reactions associated with intravenous iron products.
        JAMA. 2015; 314: 2062-2068
        • Litton E.
        • Xiao J.
        • Ho K.M.
        Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials.
        BMJ. 2013; 347: f4822
        • Macdougall I.C.
        • Bircher A.J.
        • Eckardt K.U.
        • et al.
        Iron management in chronic kidney disease: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference.
        Kidney Int. 2016; 89: 28-39
        • Fishbane S.
        • Shah H.H.
        Ferric pyrophosphate citrate as an iron replacement agent for patients receiving hemodialysis.
        Hemodial Int. 2017; 21: S104-S109
        • Gaillard C.A.
        • Bock A.H.
        • Carrera F.
        • et al.
        Hepcidin response to iron therapy in patients with non-dialysis dependent CKD: an analysis of the FIND-CKD Trial.
        PLoS One. 2016; 11e0157063
        • Jairam A.
        • Das R.
        • Aggarwal P.K.
        • et al.
        Iron status, inflammation and hepcidin in ESRD patients: the confounding role of intravenous iron therapy.
        Indian J Nephrol. 2010; 20: 125-131
        • Bailie G.R.
        • Larkina M.
        • Goodkin D.A.
        • et al.
        Data from the Dialysis Outcomes and Practice Patterns Study validate an association between high intravenous iron doses and mortality.
        Kidney Int. 2015; 87: 162-168
        • Kalantar-Zadeh K.
        • Regidor D.L.
        • McAllister C.J.
        • et al.
        Time-dependent associations between iron and mortality in hemodialysis patients.
        J Am Soc Nephrol. 2005; 16: 3070-3080
        • Holdstock L.
        • Meadowcroft A.M.
        • Maier R.
        • et al.
        Four-week studies of oral hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 for treatment of anemia.
        J Am Soc Nephrol. 2016; 27: 1234-1244
        • Brigandi R.A.
        • Johnson B.
        • Oei C.
        • et al.
        A novel hypoxia-inducible factor-prolyl hydroxylase inhibitor (GSK1278863) for anemia in CKD: a 28-day, phase 2A randomized trial.
        Am J Kidney Dis. 2016; 67: 861-871
        • Holdstock L.
        • Cizman B.
        • Meadowcroft A.M.
        • et al.
        Daprodustat for anemia: a 24-week, open-label, randomized controlled trial in participants with chronic kidney disease.
        Clin Kidney J. 2019; 12: 129-138
        • Akizawa T.
        • Tsubakihara Y.
        • Nangaku M.
        • et al.
        Effects of daprodustat, a novel hypoxia-inducible factor prolyl hydroxylase inhibitor on anemia management in Japanese hemodialysis subjects.
        Am J Nephrol. 2017; 45: 127-135
        • Cizman B.
        • Sykes A.P.
        • Paul G.
        • et al.
        An exploratory study of daprodustat in erythropoietin-hyporesponsive subjects.
        Kidney Int Rep. 2018; 3: 841-850
        • Meadowcroft A.M.
        • Cizman B.
        • Holdstock L.
        • et al.
        Daprodustat for anemia: a 24-week, open-label, randomized controlled trial in participants on hemodialysis.
        Clin Kidney J. 2019; 12: 139-148
        • Tsubakihara Y.
        • Akizawa T.
        • Nangaku M.
        • et al.
        A 24-week anemia correction study of daprodustat in Japanese dialysis patients.
        Ther Apher Dial. 2020; 24: 108-114
        • Parmar D.V.
        • Kansagra K.A.
        • Patel J.C.
        • et al.
        Outcomes of desidustat treatment in people with anemia and chronic kidney disease: a phase 2 study.
        Am J Nephrol. 2019; 49: 470-478
        • Akizawa T.
        • Nangaku M.
        • Yamaguchi T.
        • et al.
        A placebo-controlled, randomized trial of enarodustat in patients with chronic kidney disease followed by long-term trial.
        Am J Nephrol. 2019; 49: 165-174
        • Akizawa T.
        • Nangaku M.
        • Yamaguchi T.
        • et al.
        Enarodustat, conversion and maintenance therapy for anemia in hemodialysis patients: a randomized, placebo-controlled phase 2b trial followed by long-term trial.
        Nephron. 2019; 143: 77-85
        • Macdougall I.C.
        • Akizawa T.
        • Berns J.S.
        • et al.
        Effects of molidustat in the treatment of anemia in CKD.
        Clin J Am Soc Nephrol. 2019; 14: 28-39
        • Besarab A.
        • Provenzano R.
        • Hertel J.
        • et al.
        Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients.
        Nephrol Dial Transplant. 2015; 30: 1665-1673
        • 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.
        • Qian J.
        • Chen J.
        • et al.
        Phase 2 studies of oral hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 for treatment of anemia in China.
        Nephrol Dial Transplant. 2017; 32: 1373-1386
        • Provenzano R.
        • Besarab A.
        • Sun C.H.
        • et al.
        Oral hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) for the treatment of anemia in patients with CKD.
        Clin J Am Soc Nephrol. 2016; 11: 982-991
        • Besarab A.
        • Chernyavskaya E.
        • Motylev I.
        • et al.
        Roxadustat (FG-4592): correction of anemia in incident dialysis patients.
        J Am Soc Nephrol. 2016; 27: 1225-1233
        • Akizawa T.
        • Ueno M.
        • Shiga T.
        • et al.
        Oral roxadustat three times weekly in ESA-naive and ESA-converted patients with anemia of chronic kidney disease on hemodialysis: results from two phase 3 studies.
        Ther Apher Dial. 2020; 24: 628-641
        • 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.
        • Liu B.C.
        • et al.
        Roxadustat treatment for anemia in patients undergoing long-term dialysis.
        N Engl J Med. 2019; 381: 1011-1022
        • Pergola P.E.
        • Spinowitz B.S.
        • Hartman C.S.
        • et al.
        Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease.
        Kidney Int. 2016; 90: 1115-1122
        • Martin E.R.
        • Smith M.T.
        • Maroni B.J.
        • et al.
        Clinical trial of vadadustat in patients with anemia secondary to stage 3 or 4 chronic kidney disease.
        Am J Nephrol. 2017; 45: 380-388
        • Haase V.H.
        • Chertow G.M.
        • Block G.A.
        • et al.
        Effects of vadadustat on hemoglobin concentrations in patients receiving hemodialysis previously treated with erythropoiesis-stimulating agents.
        Nephrol Dial Transplant. 2019; 34: 90-99
        • Renders L.
        • Budde K.
        • Rosenberger C.
        • et al.
        First-in-human phase I studies of PRS-080#22, a hepcidin antagonist, in healthy volunteers and patients with chronic kidney disease undergoing hemodialysis.
        PLoS One. 2019; 14e0212023
        • Sheetz M.
        • Barrington P.
        • Callies S.
        • et al.
        Targeting the hepcidin-ferroportin pathway in anaemia of chronic kidney disease.
        Br J Clin Pharmacol. 2019; 85: 935-948
        • Miskulin D.C.
        • Majchrzak K.
        • Tighiouart H.
        • et al.
        Ergocalciferol supplementation in hemodialysis patients with vitamin D deficiency: a randomized clinical trial.
        J Am Soc Nephrol. 2016; 27: 1801-1810
        • Panwar B.
        • McCann D.
        • Olbina G.
        • et al.
        Effect of calcitriol on serum hepcidin in individuals with chronic kidney disease: a randomized controlled trial.
        BMC Nephrol. 2018; 19: 35
        • 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
        • Haase V.H.
        Hypoxia-inducible factor–prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease.
        Kidney Int Suppl. 2021; 11: 8-25
        • Scortegagna M.
        • Ding K.
        • Zhang Q.
        • et al.
        HIF-2alpha regulates murine hematopoietic development in an erythropoietin-dependent manner.
        Blood. 2005; 105: 3133-3140
        • Taylor M.
        • Qu A.
        • Anderson E.R.
        • et al.
        Hypoxia-inducible factor-2alpha mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice.
        Gastroenterology. 2011; 140: 2044-2055
        • 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
        • Paliege A.
        • Rosenberger C.
        • Bondke A.
        • et al.
        Hypoxia-inducible factor-2alpha-expressing interstitial fibroblasts are the only renal cells that express erythropoietin under hypoxia-inducible factor stabilization.
        Kidney Int. 2010; 77: 312-318
        • Bernhardt W.M.
        • Wiesener M.S.
        • Scigalla P.
        • et al.
        Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD.
        J Am Soc Nephrol. 2010; 21: 2151-2156
        • Liu Q.
        • Davidoff O.
        • Niss K.
        • et al.
        Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis.
        J Clin Invest. 2012; 122: 4635-4644
        • Haase V.H.
        Regulation of erythropoiesis by hypoxia-inducible factors.
        Blood Rev. 2013; 27: 41-53
        • Dhillon S.
        Roxadustat: first global approval.
        Drugs. 2019; 79: 563-572
      1. AstraZeneca. Roxadustat approved in China for the treatment of anaemia in non-dialysis-dependent patients with chronic kidney disease.
        (Available at:)
        • Astellas Pharma Inc
        Evrenzo® (roxadustat) tablets approved in Japan for the treatment of anemia associated with chronic kidney disease in dialysis patients.
        (Available at:)
        https://www.astellas.com/en/news/15096
        Date accessed: November 25, 2020
        • Akebia
        Akebia Therapeutics announces approval of vadadustat in Japan for the treatment of anemia due to chronic kidney disease in dialysis-dependent and non-dialysis dependent adult patients.
        (Available at:)
        • GlaxoSmithKline
        GSK receives first regulatory approval for Duvroq (daprodustat) in Japan for patients with anaemia due to chronic kidney disease.
        (Available at:)
        • Akizawa T.
        • Macdougall I.C.
        • Berns J.S.
        • et al.
        Iron regulation by molidustat, a daily oral hypoxia-inducible factor prolyl hydroxylase inhibitor, in patients with chronic kidney disease.
        Nephron. 2019; 143: 243-254
        • Nangaku M.
        • Kondo K.
        • Kokado Y.
        • et al.
        Randomized, open-label, active-controlled (darbepoetin alfa), phase 3 study of vadadustat for treating anemia in non-dialysis-dependent CKD patients in Japan.
        J Am Soc Nephrol. 2019; 30: 823
        • Nangaku M.
        • Kondo K.
        • Ueta K.
        • et al.
        Anemia and iron metabolism: clinical research randomized, double-blinded, active-controlled (darbepoetin alfa), phase 3 study of vadadustat in CKD patients with anemia on hemodialysis in Japan.
        J Am Soc Nephrol. 2019; 30: 6
        • Wang K.
        • Wu J.
        • Xu J.
        • et al.
        Correction of anemia in chronic kidney disease with Angelica sinensis polysaccharide via restoring EPO production and improving iron availability.
        Front Pharmacol. 2018; 9: 803
        • Boyce M.
        • Warrington S.
        • Cortezi B.
        • et al.
        Safety, pharmacokinetics and pharmacodynamics of the anti-hepcidin Spiegelmer lexaptepid pegol in healthy subjects.
        Br J Pharmacol. 2016; 173: 1580-1588
        • van Eijk L.T.
        • John A.S.
        • Schwoebel F.
        • et al.
        Effect of the antihepcidin Spiegelmer lexaptepid on inflammation-induced decrease in serum iron in humans.
        Blood. 2014; 124: 2643-2646
        • Sasu B.J.
        • Cooke K.S.
        • Arvedson T.L.
        • et al.
        Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia.
        Blood. 2010; 115: 3616-3624
        • Poli M.
        • Asperti M.
        • Ruzzenenti P.
        • et al.
        Non-anticoagulant heparins are hepcidin antagonists for the treatment of Anemia.
        Molecules. 2017; 22: 598
        • Kim S.M.
        • Choi H.J.
        • Lee J.P.
        • et al.
        Prevalence of vitamin D deficiency and effects of supplementation with cholecalciferol in patients with chronic kidney disease.
        J Ren Nutr. 2014; 24: 20-25
        • Bacchetta J.
        • Zaritsky J.J.
        • Sea J.L.
        • et al.
        Suppression of iron-regulatory hepcidin by vitamin D.
        J Am Soc Nephrol. 2014; 25: 564-572
        • Kaplan J.M.
        • Sharma N.
        • Dikdan S.
        Hypoxia-inducible factor and its role in the management of anemia in chronic kidney disease.
        Int J Mol Sci. 2018; 19: E389