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Cited by 19Erythropoietin and Anemia TreatmentIron Metabolism and DisordersDialysis and Renal Disease Management

Hypoxia-inducible factor activators: a novel class of oral drugs for the treatment of anemia of chronic kidney disease

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Haase, Volker H., Tanaka, Tetsuhiro, Koury, Mark J.·2024·Hematology
DOI 10.1182/hematology.2024000655PMC PMC11665514
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Abstract

Anemia is a hallmark of chronic kidney disease (CKD), worsens with disease progression, and profoundly affects a patient's well-being. Major pathogenic factors are inadequate kidney erythropoietin (EPO) production and absolute and functional iron deficiency. The 2 mainstays of current anemia treatment are a) replacement therapy with recombinant EPO or 1 of its glycosylated derivatives, administered subcutaneously or intravenously, and b) intravenous (IV) iron injections. Over the past 5 years, hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitors (HIF-PHIs) have been approved in many countries for the management of anemia in both nondialysis and dialysis-dependent patients with CKD. Due to cardiovascular safety concerns, only 2 HIF-PHIs, daprodustat and vadadustat, have been approved for marketing in the United States, and only for patients on maintenance dialysis. HIF-PHIs are oral agents that are effective at improving and maintaining hemoglobin levels by activating HIF signaling in anemic patients with CKD. They stimulate the production of endogenous EPO, increase total iron-binding capacity through their direct effects on transferrin gene transcription, lower plasma hepcidin indirectly, and have beneficial effects on red blood cell parameters. Here, we discuss the mechanisms of action and pharmacologic properties of different HIF-PHIs. We discuss unwanted on-target and off-target effects, review cardiovascular and other safety concerns, and provide a benefit/risk-based perspective on how this new class of oral drugs might impact current anemia management in CKD. A clinical case is presented that highlights the clinical complexities and therapeutic challenges in managing anemia in CKD.

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  1. Koury MJ, Haase VH. Anaemia in kid ney dis ease: harnessing hyp oxia responses for ther apy. Nat Rev Nephrol. 2015;11:394-410.
  2. Kidney Disease Improving Global Outcomes Anemia Work Group. KDIGO clin i cal prac tice guide line for ane mia in chronic kid ney dis ease. Kidney Int Suppl. 2012;2:279-335.
  3. Horl WH. Anaemia man age ment and mor tal ity risk in chronic kid ney dis- ease. Nat Rev Nephrol. 2013;9:291-301.
  4. Haase VH. Hypoxia-induc ible fac tor-prolyl hydrox y lase inhib i tors in the treat ment of ane mia of chronic kid ney dis ease. Kidney Int Suppl (2011). 2021;11:8-25.
  5. Babitt JL, Eisenga MF, Haase VH, et al. Controversies in opti mal ane mia man age ment: con clu sions from a Kidney Disease: Improving Global Out- comes (KDIGO) con fer ence. Kidney Int. 2021;99:1280-1295.
  6. Ku E, Del Vecchio L, Eckardt KU, et al. Novel ane mia ther a pies in chronic kid ney dis ease: con clu sions from a Kidney Disease: Improving Global Out- comes (KDIGO) Controversies Conference. Kidney Int. 2023;104:655-680.
  7. Locatelli F, Del Vecchio L. Hypoxia-induc ible fac tor-prolyl hydroxyl domain inhib i tors: from the o ret i cal supe ri or ity to clin i cal noninferiority com pared with cur rent ESAs? J Am Soc Nephrol. 2022;33(11):1966-1979.
  8. Singh AK, Carroll K, McMurray JJV, et al. Daprodustat for the treat ment of ane mia in patients not under go ing dial y sis. N Engl J Med. 2021;385:2313- 2324.
  9. Singh AK, Cizman B, Carroll K, et al. Efficacy and safety of daprodustat for treat ment of ane mia of chronic kid ney dis ease in inci dent dial y sis patients: a ran dom ized clin i cal trial. JAMA Intern Med. 2022;182(6):592.
  10. Singh AK, Carroll K, Perkovic V, et al. Daprodustat for the treat ment of ane- mia in patients under go ing dial y sis. N Engl J Med. 2021;385:2325-2335.
  11. Coyne DW, Singh AK, Lopes RD, et al. Three times weekly dos ing of dapro- dustat ver sus con ven tional epoetin for treat ment of ane mia in hemo di al y sis patients: ASCEND-TD: a phase 3 ran dom ized, dou ble-blind, noninferiority trial. Clin J Am Soc Nephrol. 2022;17(9):1325-1336.
  12. Chertow GM, Pergola PE, Farag YMK, et al. Vadadustat in patients with ane mia and non-dial y sis-depen dent CKD. N Engl J Med. 2021;384:1589- 1600.
  13. Eckardt KU, Agarwal R, Aswad A, et al. Safety and effi cacy of vadadustat for ane mia in patients under go ing dial y sis. N Engl J Med. 2021;384:1601- 1612.
  14. Kapitsinou PP, Liu Q , Unger TL, et al. Hepatic HIF-2 reg u lates eryth ro poi- etic responses to hyp oxia in renal ane mia. Blood. 2010;116:3039-3048.
  15. Kobayashi H, Davidoff O, Pujari-Palmer S, et al. EPO syn the sis induced by HIF-PHD inhi bi tion is depen dent on myofibroblast transdifferentiation and colocalizes with non-injured neph ron seg ments in murine kid ney fibro sis. Acta Physiol (Oxf). 2022;235:e13826.
  16. Flamme I, Oehme F, Ellinghaus P, et al. Mimicking Hypoxia to treat ane mia: HIF-sta bi lizer BAY 85-3934 (molidustat) stim u lates eryth ro poi e tin pro duc- tion with out hyper ten sive effects. PLoS One. 2014;9:e111838.
  17. Bhute VJ, Harte J, Houghton JW, Maxwell PH. Mannose bind ing lectin is hydrox yl ated by col la gen prolyl-4-hydrox y lase and inhibited by some PHD inhib i tors. Kidney360. 2020;1(6):447-457.
  18. Kiriakidis S, Hoer SS, Burrows N, et al. Complement C1q is hydrox yl ated by col la gen prolyl 4 hydrox y lase and is sen si tive to off-tar get inhi bi tion by prolyl hydrox y lase domain inhib i tors that sta bi lize hyp oxia-induc ible fac- tor. Kidney Int. 2017;92(4):900-908.
  19. Maxwell PH, Eckardt KU. HIF prolyl hydrox y lase inhib i tors for the treat ment of renal anae mia and beyond. Nat Rev Nephrol. 2016;12(3):157-168.
  20. Hara K, Takahashi N, Wakamatsu A, Caltabiano S. Pharmacokinetics, phar- ma co dy nam ics and safety of sin gle, oral doses of GSK1278863, a novel HIF-prolyl hydrox y lase inhib i tor, in healthy Jap a nese and Cau ca sian sub- jects. Drug Metab Pharmacokinet. 2015;30(6):410-418.
  21. Bailey CK, Caltabiano S, Cobitz AR, et al. A ran dom ized, 29-day, dose- rang ing, effi cacy and safety study of daprodustat, admin is tered three times weekly in patients with ane mia on hemo di al y sis. BMC Nephrol. 2019;20:372.
  22. Chang YL, Hung SH, Ling W, et al. Association between ische mic stroke and iron-defi ciency ane mia: a pop u la tion-based study. PLoS One. 2013; 8:e82952.
  23. Jimenez K, Leitner F, Leitner A, et al. Iron defi ciency-induced thrombo- cytosis increases throm botic ten dency in rats. Haematologica. 2021; 106:782-794.
  24. Parrow NL, Li Y, Feola M, et al. Lobe spec i fic ity of iron bind ing to trans- fer rin mod u lates murine eryth ro poi e sis and iron homeo sta sis. Blood. 2019;134:1373-1384.
  25. Lin L, Valore EV, Nemeth E, Goodnough JB, Gabayan V, Ganz T. Iron trans- fer rin reg u lates hepcidin syn the sis in pri mary hepa to cyte cul ture through hemojuvelin and BMP2/4. Blood. 2007;110(6):2182-2189.
  26. Koury MJ, Agarwal R, Chertow GM, et al. Erythropoietic effects of vadadu- stat in patients with ane mia asso ci ated with chronic kid ney dis ease. Am J Hematol. 2022;97(9):1178-1188.
  27. Tang X, Fang M, Cheng R, et al. Iron-defi ciency and estro gen are asso ci- ated with ische mic stroke by up-reg u lat ing trans fer rin to induce hyper co- ag u la bil ity. Circ Res. 2020;127(5):651-663.
  28. Gupta N, Zhao YY, Evans CE. The stim u la tion of throm bo sis by hyp oxia. Thromb Res. 2019;181(9):77-83.
  29. Rankin EB, Giaccia AJ. The role of hyp oxia-induc ible fac tors in tumor i gen e- sis. Cell Death Differ. 2008;15(4):678-685.
  30. Wicks EE, Semenza GL. Hypoxia-induc ible fac tors: can cer pro gres sion and clin i cal trans la tion. J Clin Invest. 2022;132(11):e159839.
  31. Chappell JC, Payne LB, Rathmell WK. Hypoxia, angio gen e sis, and metab- o lism in the hered i tary kid ney can cers. J Clin Investig. 2019;129(2): 442-451.
  32. Gordeuk V, Prchal J. Vascular com pli ca tions in Chuvash poly cy the mia. Semin Thromb Hemost. 2006;32(3):289-294.
  33. Seeley TW, Sternlicht MD, Klaus SJ, et al. Induction of eryth ro poi e sis by hyp oxia-induc ible fac tor prolyl hydrox y lase inhib i tors with out pro mo tion of tumor ini ti a tion, pro gres sion, or metas ta sis in a VEGF-sen si tive model of spon ta ne ous breast can cer. Hypoxia (Auckl). 2017;5:1-9.
  34. Beck J, Henschel C, Chou J, Lin A, del Balzo U. Evaluation of the car ci no- genic poten tial of roxadustat (FG-4592), a small mol e cule inhib i tor of hyp- oxia-induc ible fac tor prolyl hydrox y lase in CD-1 mice and Sprague Dawley rats. Int J Toxicol. 2017;36(6):427-439.
  35. Adams DF, Watkins MS, Durette L, et al. Carcinogenicity assess ment of daprodustat (GSK1278863), a hyp oxia-induc ible fac tor (HIF)-prolyl hydrox- y lase inhib i tor. Toxicol Pathol. 2020;48(2):362-378.
  36. Buchholz B, Eckardt KU. Role of oxy gen and the HIF-path way in poly cys tic kid ney dis ease. Cell Signal. 2020;69:109524.
  37. Dunwoodie SL. The role of hyp oxia in devel op ment of the mam ma lian embryo. Dev Cell. 2009;17(6):755-773.
  38. Shimoda LA, Yun X, Sikka G. Revisiting the role of hyp oxia-induc ible fac tors in pul mo nary hyper ten sion. Curr Opin Physiol. 2019;7(62):33-40.
  39. Penn JS, Madan A, Caldwell RB, Bartoli M, Caldwell RW, Hartnett ME. Vascular endo the lial growth fac tor in eye dis ease. Prog Retin Eye Res. 2008;27(4):331-371.
  40. Lin M, Chen Y, Jin J, et al. Ischaemia-induced ret i nal neovascularisation and dia betic ret i nop a thy in mice with con di tional knock out of hyp oxia- induc ible fac tor-1 in ret i nal Muller cells. Diabetologia. 2011;54:1554-1566.
  41. Rossert J, Gassmann-Mayer C, Frei D, et al. Prevalence and pre dic tors of epoetin hyporesponsiveness in chronic kid ney dis ease patients. Nephrol Dial Transplant. 2007;22:794-800.
  42. Luo J, Jensen DE, Maroni BJ, et al. Spectrum and bur den of eryth ro poi e sis- stim u lat ing agent hyporesponsiveness among con tem po rary hemo di al y sis patients. Am J Kidney Dis. 2016;68:763-771.
  43. Ingrasciotta Y, Lacava V, Marciano I, et al. In search of poten tial pre dic- tors of eryth ro poi e sis-stim u lat ing agents (ESAs) hyporesponsiveness: a pop u la tion-based study. BMC Nephrol. 2019;20:359.
  44. Narita I, Hayashi T, Maruyama S, et al. Hyporesponsiveness to eryth ro poi e sis-stim u lat ing agent in non-dial y sis-depen dent CKD patients: The BRIGHTEN study. PLoS One. 2022;17:e0277921.
  45. Goodkin DA, Zhao J, Cases A, Nangaku M, Karaboyas A. Resistance to Erythropoiesis-stim u lat ing agents among patients on hemo di al y sis is typ i- cally tran sient. Am J Nephrol. 2022;53(5):333-342.
  46. Sol o mon SD, Uno H, Lewis EF, et al. Erythropoietic response and out comes in kid ney dis ease and type 2 dia be tes. N Engl J Med. 2010;363(12):1146-1155.
  47. Panichi V, Rosati A, Bigazzi R, et al. Anaemia and resis tance to eryth ro- poi e sis-stim u lat ing agents as prog nos tic fac tors in haemodialysis patients: results from the RISCAVID study. Nephrol Dial Transplant. 2011;26:2641- 2648.
  48. Minutolo R, Conte G, Cianciaruso B, et al. Hyporesponsiveness to eryth ro poi e sis-stim u lat ing agents and renal sur vival in non-dial y sis CKD patients. Nephrol Dial Transplant. 2012;27:2880-2886.
  49. Okazaki M, Komatsu M, Kawaguchi H, Tsuchiya K, Nitta K. Erythropoie- tin resis tance index and the all -cause mor tal ity of chronic hemo di al y sis patients. Blood Purif. 2014;37(2):106-112.
  50. Gillespie IA, Macdougall IC, Richards S, et al. Factors pre cip i tat ing eryth ro poi e sis-stim u lat ing agent respon sive ness in a Euro pean haemo- dialysis cohort: case-cross over study. Pharmacoepidemiol Drug. 2015; 24(4):414-426.
  51. Raichoudhury R, Spinowitz BS. Treatment of ane mia in dif fi cult-to-man age patients with chronic kid ney dis ease. Kidney Int Suppl. 2021;11(1):26-34.
  52. Kalantar-Zadeh K, McAllister CJ, Lehn RS, Lee GH, Nissenson AR, Kopple JD. Effect of mal nu tri tion-inflam ma tion com plex syn drome on EPO hypo- responsiveness in main te nance hemo di al y sis patients. Am J Kidney Dis. 2003;42(4):761-773.
  53. Malyszko J, Malyszko JS, Mysliwiec M. Hyporesponsiveness to eryth ro poi e- tin ther apy in hemodialyzed patients: poten tial role of prohepcidin, hepci- din, and inflam ma tion. Ren Fail. 2009;31(7):544-548.
  54. Bradbury BD, Critchlow CW, Weir MR, et al. Impact of ele vated C-reac tive pro tein lev els on eryth ro poi e sis-stim u lat ing agent (ESA) dose and respon- sive ness in hemo di al y sis patients. Nephrol Dial Transplant. 2009;24:919- 925.
  55. Inrig JK, Bryskin SK, Patel UD, et al. Association between high-dose eryth ro poi e sis-stim u lat ing agents, inflam ma tory bio mark ers, and sol u ble eryth ro poi e tin recep tors. BMC Nephrol. 2011;12:67.
  56. Lee SW, Kim JM, Lim HJ, et al. Serum hepcidin may be a novel ure mic toxin, which might be related to eryth ro poi e tin resis tance. Sci Rep. 2017;7:4260.
  57. Petrulienė K, Žiginskienė E, Kuzminskis V, Nedzelskienė I, Bumblytė IA. Hep- cidin serum lev els and resis tance to recom bi nant human eryth ro poi e tin ther apy in hemo di al y sis patients. Medicina. 2017;53(2):90-100.
  58. Karaboyas A, Morgenstern H, Fleischer NL, et al. Inflammation and Erythropoiesis-stim u lat ing agent response in hemo di al y sis patients: a self-matched lon gi tu di nal study of ane mia man age ment in the Dialy- sis Outcomes and Practice Patterns Study (DOPPS). Kidney Med. 2020; 2(3):286-296.
  59. Kimachi M, Fukuma S, Yamazaki S, et al. Minor ele va tion in C-reac tive pro- tein lev els pre dicts inci dence of eryth ro poi e sis-stim u lat ing agent hypore- sponsiveness among hemo di al y sis patients. Nephron. 2015;131(2):123-130.
  60. Charytan C, Manllo-Karim R, Martin ER, et al. A ran dom ized trial of roxadu- stat in ane mia of kid ney fail ure: Sierras study. Kidney Int Rep. 2021;6(7):1829- 1839.
  61. Zhou Y, Chen X, Zhang Y, Lou J, Yuan H. Roxadustat for dial y sis patients with eryth ro poi e tin hypo-respon sive ness: a sin gle-cen ter, pro spec tive inves ti ga tion. Intern Emerg Med. 2021;16(8):2193-2199.
  62. Yamamoto H, Nishi S, Tomo T, et al. 2015 Jap a nese Society for Dialysis Ther- apy: guide lines for renal ane mia in chronic kid ney dis ease. Ren Replace Ther. 2017;3:36.
  63. Mikhail A, Brown C, Williams JA, et al. Renal asso ci a tion clin i cal prac tice guide line on anae mia of chronic kid ney dis ease. BMC Nephrol. 2017;18:345.

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Authors
Haase, V. H., Tanaka, T., & Koury, M. J.
Affiliations
  • Vanderbilt University (US)
  • Tohoku University (JP)
Corresponding author
Haase, Volker H.
ORCID
Venue
Hematology
Publisher
American Society of Hematology
Published
2024-12-06
Volume
2024
Issue
1
Pages
409-418
ISSN
  • 1520-4383 (ISSN-L)
  • 1520-4391
DOI
10.1182/hematology.2024000655
PMC
PMC11665514
OpenAlex
W4405108476
Cited by
19
References
66
Citations by year
2026: 7 · 2025: 11 · 2024: 1
FWCI
1.51
Type
journal article
Language
en
Open access
Locations
  • Hematology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Veterans Affairs (I01 BX002348, BX002348)
  • Vanderbilt University
  • National Institutes of Health (R01-DK135308)
  • Japan Society for the Promotion of Science (23K07713)
  • National Institute on Aging (R21AG082416)
  • National Institute of General Medical Sciences (R35GM145375)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK081646, U24DK128851, R01DK135308)
Topics
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Health Sciences › Medicine › Nephrology › Dialysis and Renal Disease Management
Keywords
hypoxia-inducible factor prolyl hydroxylase inhibitor, anemia of chronic kidney disease, erythropoietin, hepcidin, iron deficiency, dialysis, daprodustat, vadadustat, cardiovascular safety, hemoglobin
MeSH terms
Administration, Oral, Anemia, Erythropoietin, Humans, Male, Renal Insufficiency, Chronic, Hypoxia-Inducible Factor-Proline Dioxygenases, Prolyl-Hydroxylase Inhibitors

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