HIF-PHI治疗肾性贫血的作用机制及罗沙司他的研究进展
The Mechanism of HIF-PHI in the Treatment of Renal Anemia and the Research Progress of Roxadustat
DOI: 10.12677/ACM.2022.126853, PDF,   
作者: 王加如, 李欣绪, 杨照玉, 杨 雨, 翟文娟：山东第一医科大学，山东 济南；张宏涛：锦州医科大学，辽宁 锦州 ；周忠启*：临沂市人民医院，山东 临沂
关键词: 慢性肾脏病；贫血；低氧诱导因子脯氨酰羟化酶抑制剂；罗沙司他；Chronic Kidney Disease； Anemia； Hypoxia Inducible Factor Prolyl Hydroxylase Inhibitor； Rosastat
摘要: 作为慢性肾脏病(CKD)不容忽视的常见并发症，肾性贫血的发生增加了患者的临床痛苦，降低患者的生活、生存质量。既往对肾性贫血的主要治疗方式在改善贫血的同时，也使患者发生心血管疾病的风险增加。低氧诱导因子(HIF)信号转导通路的发现，使我们对肾性贫血机制有了更加全面的认识。随后低氧诱导因子脯氨酰羟化酶抑制剂(HIF-PHI)研发成功，罗沙司他是第一种应用于临床的HIF-PHI类药物。不同于以往的红细胞生成刺激剂(ESA)，罗沙司他引起促红细胞生成素(EPO)的升高在生理范围内，同时降低机体铁调素，调节铁代谢。本文就HIF-PHI对合并贫血的CKD患者作用机制及罗沙司他的临床研究进展作一综述。
Abstract: As a common complication of chronic kidney disease (CKD), renal anemia increases the clinical pain of patients and reduces the quality of life and life of patients. In the past, the main treatment of re-nal anemia not only improved anemia, but also increased the risk of cardiovascular disease. The discovery of hypoxia inducible factor (HIF) signal transduction pathway makes us have a more comprehensive understanding of the mechanism of renal anemia. Subsequently, the hypoxia in-ducible factor prolyl hydroxylase inhibitor (hif-phi) was successfully developed. Roxastat is the first hif-phi drug used in clinic. Different from the previous erythropoiesis stimulant (ESA), rosastat causes the increase of erythropoietin (EPO) within the physiological range, reduces the body’s ferri-tin and regulates iron metabolism. This paper reviews the mechanism of hif-phi on CKD patients with anemia and the progress of clinical research on rosastat.
文章引用：王加如, 李欣绪, 张宏涛, 杨照玉, 杨雨, 翟文娟, 周忠启. HIF-PHI治疗肾性贫血的作用机制及罗沙司他的研究进展[J]. 临床医学进展, 2022, 12(6): 5891-5896. https://doi.org/10.12677/ACM.2022.126853

参考文献

[1] 沈海燕. 肾性贫血机制和治疗的研究进展[J]. 现代医药卫生, 2022, 38(1): 81-85.
[2] Eriksson, D., Goldsmith, D., Teitsson, S., Jackson, J. and van Nooten, F. (2016) Cross-Sectional Survey in CKD Patients across Europe Describing the Association between Quality of Life and Anaemia. BMC Nephrology, 17, Article No. 97. [Google Scholar] [CrossRef] [PubMed]
[3] 董建华, 范文静, 吴边, 黄力, 李川, 樊蓉, 葛永纯. 罗沙司他治疗血液透析患者红细胞生成素低反应性贫血的疗效观察[J]. 肾脏病与透析肾移植杂志, 2021, 30(3): 211-216.
[4] Koulouridis, I., Alfayez, M., Trikalinos, T.A., Balk, E.M. and Jaber, B.L. (2013) Dose of Erythropoie-sis-Stimulating Agents and Adverse Outcomes in CKD: A Metaregression Analysis. American Journal of Kidney Dis-eases the Official Journal of the National Kidney Foundation, 61, 44-56. [Google Scholar] [CrossRef] [PubMed]
[5] 王培培, 吴涛. 口服罗沙司他对慢性肾脏病并肾性贫血的治疗效果观察[J]. 山东医药, 2020, 60(33): 73-75.
[6] 司倩楠, 建刚, 刘新宇. 维持性血液透析患者微炎症状态与铁缺乏的相关性分析[J]. 山东医药, 2020, 60(2): 69-71.
[7] Babitt, J.L. and Lin, H.Y. (2012) Mechanisms of Anemia in CKD. Journal of the American Society of Nephrology, 23, 1631-1634. [Google Scholar] [CrossRef] 
[8] Fishbane, S. and Spinowitz, B. (2018) Update on Anemia in ESRD and Earlier Stages of CKD: Core Curriculum 2018. American Journal of Kidney Diseases, 71, 423-435. [Google Scholar] [CrossRef] [PubMed]
[9] Maxwell, P.H., Osmond, M.K., Pugh, C.W., Heryet, A., Nicholls, L.G., Tan, C.C., Doe, B.G., Ferguson, D., Johnson, M.H. and Ratcliffe, P.J. (1993) Identification of the Renal Erythro-poietin-Producing Cells Using Transgenic Mice. Kidney International, 44, 1149-1162. [Google Scholar] [CrossRef] [PubMed]
[10] Semenza, G.L., Koury, S.T., Nejfelt, M.K., Gearhart, J.D. and Anto-narakis, S.E. (1991) Cell-Type-Specific and Hypoxia-Inducible Expression of the Human Erythropoietin Gene in Trans-genic Mice. Proceedings of the National Academy of Sciences of the United States of America, 88, 8725-8729. [Google Scholar] [CrossRef] [PubMed]
[11] Kaplan, J.M., Sharma, N. and Dikdan, S. (2018) Hypoxia-Inducible Factor and Its Role in the Management of Anemia in Chronic Kidney Disease. International Journal of Molecular Sci-ences, 19, Article No. 389. [Google Scholar] [CrossRef] [PubMed]
[12] Kaelin Jr., W.G. and Ratcliffe, P.J. (2008) Oxygen Sensing by Meta-zoans: The Central Role of the HIF Hydroxylase Pathway. Molecular Cell, 30, 393-402. [Google Scholar] [CrossRef] [PubMed]
[13] Schödel, J., Oikonomopoulos, S., Ragoussis, J., Pugh, C.W., Ratcliffe, P.J. and Mole, D.R. (2011) High-Resolution Genome-Wide Mapping of HIF-Binding Sites by ChIP-Seq. Blood, 117, e207-e217. [Google Scholar] [CrossRef] [PubMed]
[14] Luo, X., Hill, M., Johnson, A. and Latunde-Dada, G.O. (2014) Modulation of Dcytb (Cybrd 1) Expression and Function by Iron, Dehydroascorbate and Hif-2α in Cultured Cells. Bio-chimica et Biophysica Acta (BBA), 1840, 106-112.
[15] Mastrogiannaki, M., Matak, P., Keith, B., Simon, M.C. and Peyssonnaux, C. (2009) HIF-2α, but Not HIF-1α, Promotes Iron Absorption in Mice. Journal of Clinical Investigation, 119, 1159-1166. [Google Scholar] [CrossRef] 
[16] Provenzano, R., Besarab, A., Sun, C.H., Diamond, S.A., Durham, J.H., Cangiano, J.L., Aiello, J.R., Novak, J.E., Lee, T. and Leong, R. (2016) Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for the Treatment of Anemia in Patients with CKD. Clinical Journal of the American Society of Nephrology, 11, 982-991. [Google Scholar] [CrossRef] 
[17] Pergola, P.E., Spinowitz, B.S., Hartman, C.S., Maroni, B.J. and Haase, V.H. (2016) Vadadustat, a Novel Oral HIF Stabilizer, Provides Effective Anemia Treatment in Nondialy-sis-Dependent Chronic Kidney Disease. Kidney International, 90, 1115-1122. [Google Scholar] [CrossRef] [PubMed]
[18] Semenza, G.L. (2014) Oxygen Sensing, Hypoxia-Inducible Factors, and Disease Pathophysiology. Annual Review of Pathology: Mechanisms of Disease, 9, 47-71. [Google Scholar] [CrossRef] [PubMed]
[19] Choudhry, H. and Harris, A.L. (2018) Advances in Hypoxia-Inducible Factor Biology. Cell Metabolism, 27, 281-298. [Google Scholar] [CrossRef] [PubMed]
[20] Heidbreder, M., Frohlich, F., Johren, O., Dendorfer, A., Qadri, F. and Dominiak, P. (2003) Hypoxia Rapidly Activates HIF-3α mRNA Expression. The FASEB Journal, 17, 1541-1543. [Google Scholar] [CrossRef] [PubMed]
[21] Fong, G.H. and Takeda, K. (2008) Role and Regulation of Prolyl Hy-droxylase Domain Proteins. Cell Death and Differentiation, 15, 635-641. [Google Scholar] [CrossRef] [PubMed]
[22] Liu, Q.D., Davidoff, O., Niss, K. and Haase, V.H. (2012) Hypox-ia-Inducible Factor Regulates Hepcidin via Erythropoietin-Induced Erythropoiesis. Journal of Clinical Investigation, 122, 4635-4644. [Google Scholar] [CrossRef] 
[23] Drevytska, T., Gavenauskas, B., Drozdovska, S., et al. (2012) HIF-3α mRNA Expression Changes in Different Tissues and Their Role in Adaptation to Intermittent Hypoxia and Physical Exercise. Pathophysiology, 19, 205-214. [Google Scholar] [CrossRef] [PubMed]
[24] Provenzano, R., Besarab, A., Wright, S., Dua, S., Zeig, S., Nguyen, P., Poole, L., Saikali, K.G., Saha, G. and Hemmerich, S. (2016) Roxadustat (FG-4592) versus Epoetin Alfa for Anemia in Patients Receiving Maintenance Hemodialysis: A Phase 2, Randomized, 6- to 19-Week, Open-Label, Ac-tive-Comparator, Dose-Ranging, Safety and Exploratory Efficacy Study. American Journal of Kidney Diseases: The Of-ficial Journal of the National Kidney Foundation, 67, 912-924. [Google Scholar] [CrossRef] [PubMed]
[25] Yeh, T.L., Leissing, T.M., Abboud, M.I., Thinnes, C.C., Atasoylu, O., Holt-Martyn, J.P., Zhang, D., Tumber, A., Lippl, K. and Lohans, C.T. (2017) Molecular and Cellular Mechanisms of HIF Prolyl Hydroxylase Inhibitors in Clinical Trials. Chemical Science, 8, 7651-7688. [Google Scholar] [CrossRef] 
[26] Bernhardt, W.M., Wiesener, M.S., Scigalla, P., Chou, J., Schmieder, R.E., Gunzler, V. and Eckardt, K.U. (2010) Inhibition of Prolyl Hydroxylases Increases Erythropoietin Production in ESRD. Journal of the American Society of Nephrology, 21, 2151-2156. [Google Scholar] [CrossRef] 
[27] Akizawa, T., Otsuka, T., Reusch, M. and Ueno, M. (2019) Inter-mittent Oral Dosing of Roxadustat in Peritoneal Dialysis Chronic Kidney Disease Patients with Anemia: A Randomized, Phase 3, Multicenter, Open-Label Study. Therapeutic Apheresis and Dialysis, 24, 115-125. [Google Scholar] [CrossRef] [PubMed]
[28] Gupta, N. and Wish, J.B. (2017) Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors: A Potential New Treatment for Anemia in Patients with CKD. American Journal of Kidney Dis-eases, 69, 815-826. [Google Scholar] [CrossRef] [PubMed]
[29] Chen, N., Hao, C., Peng, X., Lin, H. and Yu, K. (2019) Roxadu-stat for Anemia in Patients with Kidney Disease Not Receiving Dialysis. New England Journal of Medicine, 381, 1001-1010. [Google Scholar] [CrossRef] 
[30] 陈楠. 罗沙司他在慢性肾脏病患者肾性贫血治疗中的应用[J]. 中华内科杂志, 2019, 58(12): 919-920.
[31] 陈豫闽, 刘俊英, 贾国强, 郭志玲. 罗沙司他在维持性腹膜透析患者肾性贫血治疗中的应用效果[J]. 广东医学, 2021, 42(2): 216-220. [Google Scholar] [CrossRef] 
[32] 程红娟, 魏芝薇, 史慧, 李桂珍, 吴晓蓉. 罗沙司他治疗维持性血液透析患者难治性肾性贫血的疗效观察[J]. 实用临床医药杂志, 2021, 25(14): 75-77+83.
[33] 谷茜, 景三辉, 吴歌. 罗沙司他口服治疗肾性贫血效果观察[J]. 山东医药, 2022, 62(12): 60-63.

为你推荐