Anemia is a common complication of chronic kidney disease; it is mainly treated with erythropoiesis-stimulating agents (ESAs) and iron. Experimental studies extensively investigated the mechanisms involved in the body’s response to hypoxia and led to the discovery of the hypoxia-inducible factor (HIF) pathway and the enzymes regulating its function. HIF-prolyl-hydroxyl domain (PHD) inhibitors are a new class of oral drugs developed to treat anemia in chronic kidney disease. By inhibiting the function of PHD enzymes, they mimic the exposure to moderate hypoxia and stimulate the production of endogenous erythropoietin and very likely increase iron availability. Some data also suggest that their efficacy and, consequently, dose needs are less influenced by inflammation than ESAs. Overall, data from phases 2 and 3 clinical development showed efficacy in anemia correction and maintenance for all of the class molecules compared with placebo (superiority) or erythropoiesis-stimulating agents (noninferiority). Three molecules, roxadustat, vadadustat, and daprodustat, underwent extensive clinical investigation to assess their safety on hard cardiovascular end points, mortality, and special interest events (including cancer and thrombosis). Aside from vadadustat in the nondialysis population, at the prespecified primary analyses, all three molecules met the noninferiority margin for the risk of major cardiovascular events compared with erythropoiesis-stimulating agents or placebo. The reason for this discrepancy is difficult to explain. Other safety signals came from secondary analyses of some of the other randomized clinical trials, including a higher incidence of thrombosis. A more extensive clinical experience with post-marketing data on hard safety issues is needed to define better when and how to use HIF-PHD inhibitors compared with already available ESAs.

贫血是慢性肾脏病的常见并发症；它主要用红细胞生成刺激剂 (ESAs) 和铁进行治疗。实验研究广泛调查了机体对缺氧反应的机制，并发现了缺氧诱导因子 (HIF) 通路和调节其功能的酶。HIF-脯氨酰-羟基结构域 (PHD) 抑制剂是一类新型口服药物，用于治疗慢性肾病患者的贫血。通过抑制 PHD 酶的功能，它们模拟暴露于中度缺氧并刺激内源性促红细胞生成素的产生，并且很可能增加铁的可用性。一些数据还表明，与 ESAs 相比，它们的疗效和剂量需求受炎症的影响更小。全面的，来自 2 期和 3 期临床开发的数据显示，与安慰剂（优效性）或红细胞生成刺激剂（非劣效性）相比，所有类别分子在纠正和维持贫血方面均有效。roxadustat、vadadustat 和 daprodustat 这三种分子进行了广泛的临床研究，以评估它们在硬心血管终点、死亡率和特殊事件（包括癌症和血栓形成）方面的安全性。除了非透析人群中的 vadadustat 外，在预先指定的主要分析中，与红细胞生成刺激剂或安慰剂相比，所有三种分子都达到了主要心血管事件风险的非劣效性界限。这种差异的原因很难解释。其他安全信号来自对其他一些随机临床试验的二次分析，包括更高的血栓形成率。与现有的 ESAs 相比，需要更广泛的临床经验和关于硬安全问题的上市后数据来更好地定义何时以及如何使用 HIF-PHD 抑制剂。