Keywords
Erythropoietin
Erythropoiesis-Stimulating Agents
Hypoxia-Inducible factor
Hypoxia-Inducible factor inhibitors
acute and chronic kidney disease
How to Cite
Abstract
Background: The kidney plays a fundamental role in erythropoiesis, through the endogenous production of erythropoietin, in response to hypoxia. Exogenous erythropoietin supplementation, through the use of erythropoiesis-stimulating agents, together with correction of iron deficiency, has been the standard treatment for the treatment of anemia associated with kidney disease.
Contents: The need for high doses of erythropoiesis-stimulating agents to achieve a target hemoglobin level has been related to resistance to erythropoietin, a greater number of adverse effects, and higher mortality. This review analyzes the role of new molecules in the treatment of renal anemia, focusing on the benefit that their use can have in cases of resistance to erythropoietin.
Conclusions: The development of new molecules to treat renal anemia, such as stabilizers of hypoxia-inducible factor, allow endogenous stimulation of erythropoietin and improve the bioavailability of iron, in patients with resistance to erythropoietin where they could play a prominent role with close supervision.
References
Nandakumar SK, Ulirsch JC, Sankaran VG. Advances in understanding erythropoiesis: evolving perspectives. Br J Haematol. 2016;173(2):206-18. https://doi.org/10.1111/bjh.13938
Tsiftsoglou AS. Erythropoietin (EPO) as a key regulator of erythropoiesis, bone remodeling and endothelial transdifferentiation of multipotent Mesenchymal Stem Cells (MSCs): implications in regenerative medicine. Cells. 2021;10(8):2140. https://doi.org/10.3390/cells10082140
Adamson JW. Regulation of red blood cell production. Am J Med. 1996;101(2A):4S-6S. https://doi.org/10.1016/s0002-9343(96)00160-x
Nemeth E, Ganz T. Hepcidin-Ferroportin interaction controls systemic iron homeostasis. Int J Mol Sci. 2021;22(12):6493. https://doi.org/10.3390/ijms22126493
Heras-Benito M. Anemia renal: tratamientos actuales y moléculas emergentes. Rev Clin Esp. 2023;223(7):433-9. https://doi.org/10.1016/j.rce.2023.04.005
Tong EM, Nissenson AR. Erythropoietin and anemia. Semin Nephrol 2001;21(2):190-203. https://doi.org/10.1053/snep.2001.20939
Drüeke T. Hyporesponsiveness to recombinant human erythropoietin. Nephrol Dial Transplant. 2001;16(supl. 7):25-8. https://doi.org/10.1093/ndt/16.suppl_7.25
Wang GL, Semenza GL. Oxigen sensing and response to hipoxia by mammalian cells. Redox Rep. 1996;2(2):89-96. https://doi.org/10.1080/13510002.1996.11747034
Bernhardt WM, Warnecke C, Willam C, Tanaka T, Wiesener MS, Eckardt KU. Organ protection by hypoxia and hypoxia-inducible factors. Methods Enzymol. 2007;435:221-45. https://doi.org/10.1016/s0076-6879(07)35012-x
Bright R. Cases and observations illustrative of renal disease, accompanied with the secretion of albuminous urine. Med Chir Rev. 1836;25(49):23-35.
Jacobson O, Goldwasser E, Fried W, Plzak L. Role of the kidney in erithropoiesis. Nature. 1957;179(4560):633-4. https://doi.org/10.1038/179633a0
Priyadarshi A, Shapiro JI. Erythropoietin resistance in the treatment of the anemia of chronic renal failure. Semin Dial. 2006;19(4):273-8. https://doi.org/10.1111/j.1525-139x.2006.00172.x
Fishbane S, Nissenson AR. Anemia management in chronic kidney disease. Kidney Int Suppl. 2010;78(supl. 117):s3-9. https://doi.org/10.1038/ki.2010.188
Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int Suppl. 2(2012):279-335.
Ku E, Del Vecchio L, Eckardt KU, Haase VH, Johansen KL, Nangaku M, 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):655-80. https://doi.org/10.1016/j.kint.2023.05.009
Cases A, Egocheaga MI, Tranche S, Pallarés V, Ojeda R, Górriz JL, et al. [Anemia of chronic kidney disease: protocol of study, management and referral to Nephrology]. Aten Primaria. 2018;50(1):60-4. https://doi.org/10.1016/j.aprim.2017.09.007
Del Vecchio L, Pozzoni P, Andrulli S, Locatelli F. Inflammation and resistance to treatment with recombinant human erythropoietin. J Ren Nutr. 2005;15(1):137-41. https://doi.org/10.1053/j.jrn.2004.09.024
Kaysen GA, Müller HG, Ding J, Chertow GM. Challenging the validity of the EPO index. Am J Kidney Dis. 2006;47(1):157-66. https://doi.org/10.1053/j.ajkd.2005.09.013
López-Gómez JM, Portolés JM, Aljama P. Factors that condition the response to erythropoietin in patients on hemodialysis and their relation to mortality. Kidney Int Suppl. 2008;74(supl. 111):S75-81. https://doi.org/10.1038/ki.2008.523
Okazaki M, Komatsu M, Kawaguchi H, Tsuchiya K, Nitta K. Erythropoietin resistance index and the all-cause mortality of chronic hemodialysis patients. Blood Purif. 2014;37(2):106-12. https://doi.org/10.1159/000358215
Guerreros-Riscos MA, Montes-Delgado R, Seda-Guzmán M, Praena-Fernández JM. Erythropoietin resistance and survival in non-dialysis patients with stage 4-5 chronic kidney disease and heart disease. Nefrología. 2012;32(3):343-52. https://doi.org/10.3265/nefrologia.pre2012.jan.11111
van der Putten K, Braam B, Jie KE, Gaillard CA. Mechanisms of disease: erythropoietin resistance in patients with both heart and kidney failure. Nat Clin Pract Nephrol. 2008;4(1):47-57. https://doi.org/10.1038/ncpneph0655
Ginzburg YZ. Hepcidin-ferroportin axis in health and disease. Vitam Horm. 2019;110:17-45. https://doi.org/10.1016/bs.vh.2019.01.002
Camaschella C, Nai A, Silvestri L. Iron metabolism and disorders revisited in the hepcidin era. Haematologica. 2020;105(2):260-72. https://doi.org/10.3324/haematol.2019.232124
Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995;92(12):5510-4. https://doi.org/10.1073/pnas.92.12.5510
Gupta N, Wish JB. Hypoxia-inducible factor prolyl hydroxylase inhibitors: a potential new treatment for anemia in patients with CKD. Am J Kidney Dis. 2017;69(6):815-26. https://doi.org/10.1053/j.ajkd.2016.12.011
Kaplan JM, 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(2):389. https://doi.org/10.3390/ijms19020389
Bonomini M, Del Vecchio L, Sirolli V, Locatelli F. New treatment approaches for the anemia of CKD. Am J Kidney Dis. 2016;67(1):133-42. https://doi.org/10.1053/j.ajkd.2015.06.030
Singh AK, Carroll K, McMurray JJ, Solomon S, Jha V, Johansen KL, et al. Daprodustat for the treatment of anemia in patients not undergoing dialysis. N Engl J Med. 2021;385(25):2313-24. https://doi.org/10.1056/nejmoa2113380
Nangaku M, Hamano T, Akizawa T, Tsubakihara Y, Nagai R, Okuda N, et al. Daprodustat compared with epoetin beta pegol for anemia in japanese not on dialysis: a 52-week randomized open label phase 3 trial. Am J Nephrol. 2021;52(1):26-35. https://doi.org/10.1159/000513103
Akizawa T, Nangaku M, Yonekawa T, Okuda N, Kawamatsu S, Onoue 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):1155-65. https://doi.org/10.2215/cjn.16011219
Singh AK, Carroll K, Perkovic V, Solomon S, Jha V, Johansen KL, et al. Daprodustat for the treatment of anemia in patients undergoing dialysis. N Engl J Med. 2021;385(25):2325-35. https://doi.org/10.1056/nejmoa2113379
Kanai H, Nangaku M, Nagai R, Okuda N, Kurata K, Nagakubo T, et al. Efficacy and safety of daprodustat in Japanese peritoneal dialysis patients. Ther Apher Dial. 2021;25(6):979-87. https://doi.org/10.1111/1744-9987.13686
Singh AK, Cizman B, Carroll K, McMurray JJ, Perkovic V, Jha V, 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. https://doi.org/10.1001/jamainternmed.2022.0605
Dhillon S. Roxadustat: first global approval. Drugs. 2019;79(5):563-72. https://doi.org/10.1007/s40265-019-01077-1
Markham A. Vadadustat: first approval. Drugs. 2020;80(13):1365-71. https://doi.org/10.1007/s40265-020-01383-z
Dhillon S. Daprodustat: first approval. Drugs. 2020;80(14):1491-97. https://doi.org/10.1007/s40265-020-01384-y
Markham A. Enarodustat: first approval. Drugs. 2021;81(1):169-74. https://doi.org/10.1007/s40265-020-01444-3
Dhillon S. Desidustat: first approval. Drugs. 2022;82(11):1207-12. https://doi.org/10.1007/s40265-022-01744-w
Yap DHY, McMahon LP, Hao CM, Hu N, Okada H, Suzuki Y, et al. Recommendations by the Asian Pacific society ofnephrology (APSN) on the appropriate use of HIF-PH inhibitors. Nephrology. 2021;26(2):105-18. https://doi.org/10.1111/nep.13835
Roger SD, Coyne DW. HIF-prolil hydroxilase inhibitors: confirmed efficacy with uncertain safety. Am J Nephrol. 2021;52(10-11):894-8. https://doi.org/10.1159/000518073
Mima A. Hypoxia-inducible factor-prolyl hydroxylase inhibitors for renal anemia in chronic kidney disease: advantages and disadvantages. Eur J Pharmacol. 2021;912:174583. https://doi.org/10.1016/j.ejphar.2021.174583
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