Li Zuo-Lin, Tu Yan, Liu Bi-Cheng
Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China.
Kidney Dis (Basel). 2020 Mar;6(2):65-73. doi: 10.1159/000504850. Epub 2020 Jan 10.
Although renal anemia has attracted widespread attention, a large proportion of chronic kidney disease (CKD) patients with anemia still do not meet the hemoglobin (Hb) targets. The discovery of prolyl hydroxylase domain (PHD) enzymes as regulators of hypoxia-inducible factor (HIF)-dependent erythropoiesis has led to the development of novel therapeutic agents for renal anemia. Roxadustat, the first small-molecule HIF-PHD inhibitor, has completed the phase 3 trials. There are currently more than 15 phase 3 clinical trials worldwide assessing the efficacy and safety of roxadustat in CKD patients with anemia. This review will summarize recent findings of roxadustat in the treatment of renal anemia.
Although the administration of erythropoiesis-stimulating agents (ESAs) and iron supplementation are a well-established and highly effective therapeutic approach for renal anemia, there are several safety concerns. Current findings from phase 2 and 3 trials suggest that roxadustat is clinically effective and well tolerated. On the one hand, roxadustat could increase endogenous erythropoietin (EPO) levels within or near physiological range in a titratable manner by inducing HIF pathway activation transiently. On the other hand, roxadustat also improves iron metabolism by decreasing serum hepcidin and increasing intestinal iron absorption, which is beneficial to functional iron deficiency and absolute iron deficiency. More importantly, the erythropoietic response of roxadustat is independent of baseline inflammatory state of CKD patients. Thus, the discovery of roxadustat will revolutionize the treatment strategy for renal anemia.
Roxadustat is an emerging and promising therapeutic approach against anemia in CKD patients, which differs from those of conventional ESAs. Roxadustat corrects anemia of CKD patients through multiple pathways, beyond elevating EPO levels within physiological range, and also by handling iron metabolism (particularly decreasing the hepcidin levels). Furthermore, the Hb response of roxadustat is independent of the inflammatory microenvironment.
尽管肾性贫血已引起广泛关注，但仍有很大比例的慢性肾脏病（CKD）贫血患者未达到血红蛋白（Hb）目标。脯氨酰羟化酶结构域（PHD）酶作为缺氧诱导因子（HIF）依赖性红细胞生成的调节因子被发现后，新型肾性贫血治疗药物得以研发。罗沙司他作为首个小分子HIF-PHD抑制剂，已完成3期试验。目前全球有超过15项3期临床试验在评估罗沙司他治疗CKD贫血患者的疗效和安全性。本综述将总结罗沙司他治疗肾性贫血的近期研究结果。
尽管促红细胞生成素（ESA）和铁补充剂的应用是治疗肾性贫血的成熟且高效的方法，但仍存在一些安全问题。2期和3期试验的当前研究结果表明，罗沙司他在临床上有效且耐受性良好。一方面，罗沙司他可通过短暂诱导HIF途径激活，以可滴定的方式将内源性促红细胞生成素（EPO）水平提高到生理范围内或接近生理范围。另一方面，罗沙司他还可通过降低血清铁调素和增加肠道铁吸收来改善铁代谢，这对功能性缺铁和绝对性缺铁有益。更重要的是，罗沙司他的促红细胞生成反应与CKD患者的基线炎症状态无关。因此，罗沙司他的发现将彻底改变肾性贫血的治疗策略。
罗沙司他是一种针对CKD患者贫血的新兴且有前景的治疗方法，与传统ESA不同。罗沙司他通过多种途径纠正CKD患者的贫血，不仅能将EPO水平提高到生理范围内，还能处理铁代谢（特别是降低铁调素水平）。此外，罗沙司他的Hb反应与炎症微环境无关。
