A spotlight on using HIF-PH inhibitors in renal anemia

References

• Sofue T, Nakagawa N, Kanda E, et al. Prevalence of anemia in patients with chronic kidney disease in Japan: a nationwide, cross-sectional cohort study using data from the Japan chronic kidney disease database (J-CKD-DB. PLOS ONE. 2020;15(7):e0236132. doi: 10.1371/journal.pone.0236132
   PubMed Web of Science ®Google Scholar
• Stauffer ME, Fan T, Moura IC. Prevalence of anemia in chronic kidney disease in the United States. PLOS ONE. 2014;9(1):e84943. doi: 10.1371/journal.pone.0084943
   PubMed Web of Science ®Google Scholar
• Sugahara M, Tanaka T, Nangaku M. Prolyl hydroxylase domain inhibitors as a novel therapeutic approach against anemia in chronic kidney disease. Kidney Int. 2017;92(2):306–312. doi: 10.1016/j.kint.2017.02.035
   PubMed Web of Science ®Google Scholar
• Eshbach JW, Abdulhadi MH, Browne JK, 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(12):992–1000. doi: 10.7326/0003-4819-111-12-992
   PubMed Web of Science ®Google Scholar
• Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int Suppl. 2012;4:279–335.
   Google Scholar
• Besarab A, Bolton WK, Browne JK, 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(9):584–590. doi: 10.1056/NEJM199808273390903
   PubMed Web of Science ®Google Scholar
• Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355(20):2085–2098. doi: 10.1056/NEJMoa065485
   PubMed Web of Science ®Google Scholar
• Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361(21):2019–2032. doi: 10.1056/NEJMoa0907845
   PubMed Web of Science ®Google Scholar
• 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. American Journal Of Kidney Diseases. 2016;67(6):912–924. doi: 10.1053/j.ajkd.2015.12.020
   PubMed Web of Science ®Google Scholar
• Kaelin WG Jr and Ratcliffe PJ. Oxygen sensing by metazoans; the central role of the HIF hydroxylase pathway. Molecular Cell. 2008;30(4):393–402. doi: 10.1016/j.molcel.2008.04.009
   PubMed Web of Science ®Google Scholar
• Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148(3):399–408. doi: 10.1016/j.cell.2012.01.021
   PubMed Web of Science ®Google Scholar
• Rabinowitz MH. Inhibition of hypoxia-inducible factor prolyl hydroxylase domain oxygen sensors: tricking the body into mounting orchestrated survival and repair responses. J Med Chem. 2013;56(23):9369–9402. doi: 10.1021/jm400386j
   PubMed Web of Science ®Google Scholar
• Ivan M, Kondo K, Kim W, et al. HIFα targeted for VHL-Mediated destruction by Proline Hydroxylation: implications for O 2 sensing. Science. 2001;292(5516):464–468. doi: 10.1126/science.1059817
   PubMed Web of Science ®Google Scholar
• Epstein AC, Gleadle JM, McNeill LA, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001;107(1):43–54. doi: 10.1016/S0092-8674(01)00507-4
   PubMed Web of Science ®Google Scholar
• Chifman J, Laubenbacher R, and Torti SV. A systems biology approach to iron metabolism. Adv Exp Med Biol. 2014;844:201–225.
   PubMed Web of Science ®Google Scholar
• van Swelm RPL, Wetzels JFM, and Swinkels DW. The multifaceted role of iron in renal health and disease. Nat Rev Nephrol. 2020;16:77–98. doi: 10.1038/s41581-019-0197-5
   PubMed Web of Science ®Google Scholar
• Rolfs A, Kvietikova I, Gassmann M, et al. Oxygen-regulated transferrin expression is mediated by hypoxia-inducible factor-1. J Biol Chem. 1997;272(32):20055–20062. doi: 10.1074/jbc.272.32.20055
   PubMed Web of Science ®Google Scholar
• Bianchi L, Tacchini L, Cairo G. HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation. Nucleic Acids Res. 1999;27(21):4223–4227. doi: 10.1093/nar/27.21.4223
   PubMed Web of Science ®Google Scholar
• Shah YM, Matsubara T, Ito S, et al. Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency. Cell Metab. 2009;9(2):152–164. doi: 10.1016/j.cmet.2008.12.012
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Eltzschig HK, Bratton DL, Colgan SP. Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases. Nat Rev Drug Discov. 2014;13(11):852–869. doi: 10.1038/nrd4422
   PubMed Web of Science ®Google Scholar
• Mima A. Hypoxia-inducible factor-prolyl hydroxylase inhibitors for renal anemia in chronic kidney disease: advantages and disadvantages. Eur J Pharmacol. 2021;912:174583. doi: 10.1016/j.ejphar.2021.174583
   PubMed Web of Science ®Google Scholar
• Singh AK, Carroll K, McMurray JJV, et al. Daprodustat for the treatment of anemia in patients not undergoing dialysis. N Engl J Med 2021. 2021;385(25):2313–2324. doi: 10.1056/NEJMoa2113380
   Google Scholar
• Singh AK, Carroll K, Perkovic V, et al. Daprodustat for the treatment of anemia in patients undergoing dialysis. N Engl J Med. 2021;385(25):2325–2335. doi: 10.1056/NEJMoa2113379
   PubMed Web of Science ®Google Scholar
• Singh AK, Cizman B, Carroll K, et al. Efficacy and safety of daprodustat for treatment of anemia of chronic kidney disease in incident diaysis patients: a randomized clinical trial. JAMA Intern Med. 2022;182(6):592–602. doi: 10.1001/jamainternmed.2022.0605
   PubMed Web of Science ®Google Scholar
• Coyne DW, Singh AK, Lopes RD, et al. Three times weekly dosing of daprodustat versus conventional epoetin for treatment of anemia in hemodialysis patients: ASCEND-TD: a phase 3 randomized, double-blind, noninferiority trial. Clin J Am Soc Nephrol. 2022;17(9):1325–1336. doi: 10.2215/CJN.00550122
   PubMed Web of Science ®Google Scholar
• Nangaku M, Hamano T, Akizawa T, et al. Daprodustat compared with epoetin beta pegol for anemia in Japanese patients not on dialysis: a 52-week randomized open-label phase 3 trial. Am J Nephrol. 2021;52(1):26–35. doi: 10.1159/000513103
   PubMed Web of Science ®Google Scholar
• Akizawa T, Nangaku M, Yonekawa T, et al. Efficacy and safety of daprodustat compared with darbepoetin alfa in Japanese hemodialysis patients with anemia: a randomized, double-blind, phase 3 trial. Clin J Am Soc Nephrol. 2020;15(8):1155–1165. doi: 10.2215/CJN.16011219
   PubMed Web of Science ®Google Scholar
• Provenzano R, Shutov E, Eremeeva L, et al. Roxadustat for anemia in patients with end-stage renal disease incident to dialysis. Nephrol Dial Transplant. 2021;36(9):1717–1730. doi: 10.1093/ndt/gfab051
   PubMed Web of Science ®Google Scholar
• Csiky B, Schömig M, Esposito C, et al. Roxadustat for the maintenance treatment of anemia in patients with end-Stage kidney disease on stable dialysis: a European phase 3, randomized, open-label, active-controlled study (PYRENEES). Adv Ther. 2021;38(10):5361–5380. doi: 10.1007/s12325-021-01904-6
   PubMed Web of Science ®Google Scholar
• 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. doi: 10.1016/j.ekir.2021.04.007
   PubMed Web of Science ®Google Scholar
• Fishbane S, Pollock CA, El-Shahawy M, et al. Roxadustat versus epoetin alfa for treating anemia in patients with chronic kidney disease on dialysis: results from the randomized phase 3 ROCKIES study. J Am Soc Nephrol. 2022;33(4):850–866. doi: 10.1681/ASN.2020111638
   PubMed Web of Science ®Google Scholar
• Chen N, Hao C, Liu BC, et al. Roxadustat treatment for anemia in patients undergoing long-term dialysis. N Engl J Med. 2019;381(11):1011–1022. doi: 10.1056/NEJMoa1901713
   PubMed Web of Science ®Google Scholar
• Hou YP, Mao XY, Wang C, et al. Roxadustat treatment for anemia in peritoneal dialysis patients: a randomized controlled trial. J Formos Med Assoc. 2022;121(2):529–538. doi: 10.1016/j.jfma.2021.06.004
   PubMed Web of Science ®Google Scholar
• Akizawa T, Iwasaki M, Yamaguchi Y, et al. Phase 3, randomized, double-blind, active-comparator (darbepoetin alfa) study of oral roxadustat in CKD patients with anemia on hemodialysis in Japan. J Am Soc Nephrol. 2020;31(7):1628–1639. doi: 10.1681/ASN.2019060623
   PubMed Web of Science ®Google Scholar
• Barratt J, Andric B, Tataradze A, et al. Roxadustat for the treatment of anemia in chronic kidney disease patients not on dialysis: a phase 3, randomized, open-label, active-controlled study (DOLOMITES). Nephrology Dialysis Transplantation. 2021;36(9):1616–1628. doi: 10.1093/ndt/gfab191
   PubMed Web of Science ®Google Scholar
• Chertow GM, Pergola PE, Farag YMK, et al. Vadadustat in patients with anemia and non–dialysis-Dependent CKD. N Engl J Med 2021. 2021;384(17):1589–1600. doi: 10.1056/NEJMoa2035938
   Google Scholar
• Eckardt KU, Agarwal R, Aswad A, et al. Safety and efficacy of Vadadustat for anemia in patients undergoing dialysis. N Engl J Med 2021. 2021;384(17):1601–1612. doi: 10.1056/NEJMoa2025956
   Google Scholar
• Nangaku M, Kondo K, Ueta K, et al. Efficacy and safety of vadadustat compared with darbepoetin alfa in Japanese anemic patients on hemodialysis: a phase 3, multicenter, randomized, double-blind study. Nephrol Dial Transplant. 2021;36(9):1731–1741. doi: 10.1093/ndt/gfab055
   PubMed Web of Science ®Google Scholar
• Nangaku M, Kondo K, Kokado Y, et al. Phase 3 randomized study comparing vadadustat with darbepoetin alfa for anemia in Japanese patients with nondialysis-dependent CKD. J Am Soc Nephrol. 2021;32(7):1779–1790. doi: 10.1681/ASN.2020091311
   PubMed Web of Science ®Google Scholar
• Yamamoto H, Nobori K, Matsuda Y, et al. Molidustat for renal anemia in nondialysis patients Previously treated with erythropoiesis-stimulating agents: a randomized, open-label, phase 3 study. Am J Nephrol. 2021;52(10–11):884–893. doi: 10.1159/000518072
   PubMed Web of Science ®Google Scholar
• Yamamoto H, Nobori K, Matsuda Y, et al. Efficacy and safety of molidustat for anemia in ESA-Naïve nondialysis patients: a randomized, phase 3 trial. Am J Nephrol. 2021;52(10–11):871–883. doi: 10.1159/000518071
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• 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 2021. 2021;7(6):494–502. doi: 10.1159/000517053
   Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• 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) doi: 10.1093/ckj/sfad143
   Web of Science ®Google Scholar
• Kurata Y, Tanaka T, Nangaku M. An evaluation of roxadustat for the treatment of anemia associated with chronic kidney disease. Expert Opin Pharmacother. 2022;23(1):19–28. doi: 10.1080/14656566.2021.1993821
   PubMed Web of Science ®Google Scholar
• Shen GM, Zhao YZ, Chen MT, et al. Hypoxia-inducible factor-1 (HIF-1) promotes LDL and VLDL uptake through inducing VLDLR under hypoxia. Biochem J. 2012;441(2):675–683. doi: 10.1042/BJ20111377
   PubMedGoogle Scholar
• Cunningham JW, Claggett BL, Lopes RD, et al. Daprodustat and heart failure in CKD. J Am Soc Nephrol. 2024;35(5):607–617. doi: 10.1681/ASN.0000000000000321
   PubMed Web of Science ®Google Scholar
• Barratt J, Sulowicz W, Schömig M, et al. Efficacy and cardiovascular safety of Roxadustat in dialysis-dependent chronic kidney disease: pooled analysis of four phase 3 studies. Adv Ther. 2021;38(10):5345–5360. doi: 10.1007/s12325-021-01903-7
   PubMed Web of Science ®Google Scholar
• 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
   PubMedGoogle Scholar
• Singh AK, McCausland FR, Claggett BL, et al. Analysis of on-treatment cancer safety events with daprodustat versus conventional erythropoiesis-stimulating agents— post hoc analyses of the ASCEND-ND and ASCEND-D trials. Nephrology Dialysis Transplantation. 2023;38(8):1890–1897. doi: 10.1093/ndt/gfac342
   PubMed Web of Science ®Google Scholar
• Yap DYH, McMahon LP, Hao CM, et al. Recommendations by the Asian pacific society of nephrology (APSN) on the appropriate use of HIF-PH inhibitors. Nephrol. 2021;26(2):105–118. doi: 10.1111/nep.13835
   PubMed Web of Science ®Google Scholar
• Kouki Y, Okada N, Saga K, et al. Disproportionality analysis on hypothyroidism with roxadustat using the Japanese adverse Drug event database. J Clin Pharmacol. 2023;63(10):1141–1146. doi: 10.1002/jcph.2300
   PubMed Web of Science ®Google Scholar
• Zheng Q, Wang Y, Yang H, et al. Cardiac and kidney adverse effects of HIF prolyl-hydroxylase inhibitors for anemia in patients with CKD not receiving dialysis: a systematic review and meta-analysis. Am J Kidney Dis. 2023;81(4):434–45.e1. doi: 10.1053/j.ajkd.2022.09.014
   PubMed Web of Science ®Google Scholar
• Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental Health Bureau. Ministry of health, labour and welfare. Report on the deliberation results. [updated 2019 Sep 4 cited 2019 Sep 4]. Available from: https://www.pmda.go.jp/files/000234811.pdf
   Google Scholar
• Ku E, Vecchio LD, Eckardt KU, et al. Novel anemia therapies in chronic kidney disease: conclusions from a kidney disease: improving global outcomes (KDIGO) controversies conference. Kidney Int. 2023;104(4):655–680. doi: 10.1016/j.kint.2023.05.009
   PubMed Web of Science ®Google Scholar
• Lu HY, Liao KM. Increased risk of deep vein thrombosis in end-stage renal disease patients. BMC Nephrol. 2018;19(1):204. doi: 10.1186/s12882-018-0989-z
   PubMedGoogle Scholar