Overview of HIF-PHI in the treatment of anemia in patients with chronic kidney disease
Main Article Content
Abstract
In recent years, hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have attracted considerable attention in the management of anemia associated with chronic kidney disease (CKD). These agents act by stabilizing hypoxia-inducible factors (HIFs), thereby stimulating endogenous erythropoietin production and regulating iron metabolism through a more physiological pathway compared with recombinant erythropoietin therapy. Administered orally, HIF-PHIs offer greater convenience for patients and contribute to optimizing erythropoiesis. Several large-scale clinical trials have demonstrated that HIF-PHIs effectively increase hemoglobin levels, reduce the need for intravenous iron supplementation and decrease blood transfusion requirements. Some agents in this class have already been approved for clinical use in Japan, China, United Statesand several European countries. This review aims to provide updated insights into the mechanisms of action, clinical efficacy and therapeutic potential of HIF-PHIs in the treatment of anemia in patients with CKD, thereby contributing to the expansion of therapeutic options and improvement of patient care quality.
Article Details
Keywords
HIF-prolyl hydroxylase inhibitor, anemia, chronic kidney disease, erythropoietin
References
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3. Dasgupta I, Bagnis CI, Floris M, et al. Anaemia and quality of life in chronic kidney disease: a consensus document from the European Anaemia of CKD Alliance. Clin Kidney J. 2024; 17(8): sfae205. doi:10.1093/ckj/sfae205.
4. Portolés J, Martín L, Broseta JJ, Cases A. Anemia in Chronic Kidney Disease: From Pathophysiology and Current Treatments, to Future Agents. Front Med (Lausanne). 2021; 8:642296. doi:10.3389/fmed.2021.642296.
5. Palmer SC, Navaneethan SD, Craig JC, et al. Meta-analysis: erythropoiesis-stimulating agents in patients with chronic kidney disease. Ann Intern Med. 2010; 153(1): 23-33. doi:10.7326/0003-4819-153-1-201007060-00252.
6. Koulouridis I, Alfayez M, Trikalinos TA, Balk EM, Jaber BL. Dose of erythropoiesis-stimulating agents and adverse outcomes in CKD: a metaregression analysis. Am J Kidney Dis. 2013; 61(1): 44-56. doi:10.1053/j.ajkd.2012.07.014.
7. Ogawa T, Nitta K. Erythropoiesis-stimulating agent hyporesponsiveness in end-stage renal disease patients. Contrib Nephrol. 2015; 185: 76-86. doi:10.1159/000380972.
8. Atzinger C, Arens HJ, Neri L, et al. Hyporesponsiveness to Erythropoiesis-Stimulating Agents in Dialysis-Dependent Patients with Anaemia of Chronic Kidney Disease: A Retrospective Observational Study. Adv Ther. 2025; 42(1): 471-489. doi:10.1007/s12325-024-03015-4.
9. Semenza GL. The Genomics and Genetics of Oxygen Homeostasis. Annu Rev Genomics Hum Genet. 2020; 21: 183-204. doi:10.1146/annurev-genom-111119-073356.
10. Del Vecchio L, Locatelli F. Investigational hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) for the treatment of anemia associated with chronic kidney disease. Expert Opin Investig Drugs. 2018; 27(7): 613-621. doi:10.1080/13543784.2018.1493455.
11. Haase VH. Hypoxia-inducible factor-prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease. Kidney Int Suppl. 2021; 11(1): 8-25. doi:10.1016/j.kisu.2020.12.002.
12. Ogawa C, Tsuchiya K, Maeda K. Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors and Iron Metabolism. Int J Mol Sci. 2023; 24(3): 3037. doi:10.3390/ijms24033037.
13. Minutolo R, Liberti ME, Simeon V, et al. Efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitors in patients with chronic kidney disease: meta-analysis of phase 3 randomized controlled trials. Clin Kidney J. 2023; 17(1): sfad143. doi:10.1093/ckj/sfad143.
14. Akizawa T, Iwasaki M, Otsuka T, Yamaguchi Y, Reusch M. Phase 3 Study of Roxadustat to Treat Anemia in Non-Dialysis-Dependant CKD. Kidney Int Rep. 2021; 6(7): 1810-1828. doi:10.1016/j.ekir.2021.04.003.
15. Shutov E, Sułowicz W, Esposito C, et al. Roxadustat for the treatment of anemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, double-blind, placebo-controlled study (ALPS). Nephrol Dial Transplant. 2021; 36(9): 1629-1639. doi:10.1093/ndt/gfab057.
16. Singh AK, Carroll K, McMurray JJV, et al. Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis. N Engl J Med. 2021; 385(25): 2313-2324. doi:10.1056/NEJMoa2113380.
17. Gang S, Khetan P, Varade D, et al. Desidustat in Anemia due to Dialysis-Dependent Chronic Kidney Disease: A Phase 3 Study (DREAM-D). Am J Nephrol. 2022; 53(5): 343-351. doi:10.1159/000523949.
18. Agrawal D, Varade D, Shah H, et al. Desidustat in Anemia due to Non-Dialysis-Dependent Chronic Kidney Disease: A Phase 3 Study (DREAM-ND). Am J Nephrol. 2022; 53(5): 352-360. doi:10.1159/000523961.
19. Akizawa T, Nangaku M, Yamaguchi T, et al. A Phase 3 Study of Enarodustat (JTZ-951) in Japanese Hemodialysis Patients for Treatment of Anemia in Chronic Kidney Disease: SYMPHONY HD Study. Kidney Dis (Basel). 2021; 7(6): 494-502. doi:10.1159/000517053.
20. Akizawa T, Nangaku M, Yamaguchi T, et al. A Phase 3 Study of Enarodustat in Anemic Patients with CKD not Requiring Dialysis: The SYMPHONY ND Study. Kidney Int Rep. 2021; 6(7): 1840-1849. doi:10.1016/j.ekir.2021.04.037.
21. Eckardt KU, Agarwal R, Farag YM, et al. Global Phase 3 programme of vadadustat for treatment of anaemia of chronic kidney disease: rationale, study design and baseline characteristics of dialysis-dependent patients in the INNO2VATE trials. Nephrol Dial Transplant. 2021; 36(11): 2039-2048. doi:10.1093/ndt/gfaa204.
22. Akizawa T, Yamada T, Nobori K, et al. Molidustat for Japanese Patients With Renal Anemia Receiving Dialysis. Kidney Int Rep. 2021; 6(10): 2604-2616. doi:10.1016/j.ekir.2021.07.015.
23. Stoumpos S, Crowe K, Sarafidis P, et al. Hypoxia-inducible factor prolyl hydroxylase inhibitors for anaemia in chronic kidney disease: a clinical practice document by the European Renal Best Practice board of the European Renal Association. Nephrol Dial Transplant. 2024; 39(10): 1710-1730. doi:10.1093/ndt/gfae075.
24. Macdougall IC. Hypoxia-inducible factor prolyl hydroxylase enzyme inhibitors: ready for primetime?. Curr Opin Nephrol Hypertens. 2022; 31(5): 399-405. doi:10.1097/MNH.0000000000000813.
25. Charytan C, Manllo-Karim R, Martin ER, et al. A Randomized Trial of Roxadustat in Anemia of Kidney Failure: SIERRAS Study. Kidney Int Rep. 2021; 6(7): 1829-1839. Published 2021 Apr 17. doi:10.1016/j.ekir.2021.04.007.
26. 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(11): 1001-1010. doi:10.1056/NEJMoa1813599.
27. Pergola PE, Charytan C, Little DJ, et al. Changes in Iron Availability with Roxadustat in Nondialysis- and Dialysis-Dependent Patients with Anemia of CKD. Kidney360. 2022; 3(9): 1511-1528. doi:10.34067/KID.0001442022.
28. Singh AK, Cizman B, Carroll K, et al. Efficacy and Safety of Daprodustat for Treatment of Anemia of Chronic Kidney Disease in Incident Dialysis Patients: A Randomized Clinical Trial. JAMA Intern Med. 2022; 182(6): 592-602. doi:10.1001/jamainternmed.2022.0605.
29. Baker DE. Daprodustat. Hosp Pharm. 2023; 58(6): 530-543. doi:10.1177/00185787231172382.
30. Joharapurkar A, Pandya V, Patel H, Jain M, Desai R. Desidustat: a novel PHD inhibitor for the treatment of CKD-induced anemia. Front Nephrol. 2024; 4: 1459425. doi:10.3389/fneph.2024.1459425.
31. Akizawa T, Nangaku M, Yamaguchi T, et al. Two long-term phase 3 studies of enarodustat (JTZ-951) in Japanese anemic patients with chronic kidney disease not on dialysis or on maintenance hemodialysis: SYMPHONY ND-Long and HD-Long studies. Ther Apher Dial. 2022; 26(2): 345-356. doi:10.1111/1744-9987.13724.
32. Jain S, Patil R, Sharma S. Bioanalysis, Analysis, Chemistry, and Pharmacological Aspects of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors. Curr Top Med Chem. 2025; 25(12): 1451-1466. doi:10.2174/0115680266324419241227102847.
33. Winkelmayer WC, Arnold S, Burke SK, et al. Safety Endpoints With Vadadustat Versus Darbepoetin Alfa in Patients With Non-Dialysis-Dependent CKD: A Post Hoc Regional Analysis of the PRO2TECT Randomized Clinical Trial of ESA-Naïve Patients. Kidney Med. 2023; 5(7): 100666. doi:10.1016/j.xkme.2023.100666.
34. Johansen KL, Cobitz AR, Singh AK, et al. The ASCEND-NHQ randomized trial found positive effects of daprodustat on hemoglobin and quality of life in patients with non-dialysis chronic kidney disease. Kidney Int. 2023; 103(6): 1180-1192. doi:10.1016/j.kint.2023.02.019.
35. Toka HR, Bernardo M, Burke SK, et al. Vadadustat Three Times Weekly in Patients With Anemia Due to Dialysis-Dependent CKD. Am J Kidney Dis. 2025; 85(4): 454-464.e1. doi:10.1053/j.ajkd.2024.09.006.
36. Liang XL, Huang RW, Xie JT, et al. Enarodustat for the Treatment of Anemia in Chinese Patients with Non-Dialysis Chronic Kidney Disease: A Phase 3 Trial. Kidney Dis (Basel). 2024; 11(1): 49-62. Published 2024 Dec 20. doi:10.1159/000543193.
37. Arastu AH, Elstrott BK, Martens KL, et al. Analysis of Adverse Events and Intravenous Iron Infusion Formulations in Adults With and Without Prior Infusion Reactions. JAMA Netw Open. 2022; 5(3): e224488. doi:10.1001/jamanetworkopen.2022.4488.
38. Shah AA, Donovan K, Seeley C, et al. Risk of Infection Associated With Administration of Intravenous Iron: A Systematic Review and Meta-analysis. JAMA Netw Open. 2021; 4(11): e2133935. Published 2021 Nov 1. doi:10.1001/jamanetworkopen.2021.33935.
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