Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan,
Department of Renal Medicine, King's College Hospital, London, United Kingdom.
Nephron. 2019;143(4):243-254. doi: 10.1159/000502012. Epub 2019 Aug 6.
BACKGROUND/AIMS: The current treatment for anemia associated with chronic kidney disease (CKD) includes the administration of erythropoiesis stimulating agents (ESAs) combined with iron supplementation. Molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, has potential to treat anemia associated with CKD through increased erythropoietin production and improved iron availability. Here, we report the effect of molidustat on iron metabolism.
Parameters of iron metabolism were monitored in three 16-week, randomized, controlled, phase 2 studies assessing the safety and efficacy of molidustat in the treatment of anemia associated with CKD in different populations: treatment-naïve and previously ESA-treated patients not on dialysis, and previously ESA-treated patients on hemodialysis. Iron supplementation was left at the discretion of the investigator.
In treatment-naïve patients not on dialysis, transferrin saturation (TSAT), hepcidin, ferritin, and iron concentrations decreased with molidustat, whereas total iron binding capacity (TIBC) increased. Similar results were observed in previously ESA-treated patients not on dialysis, although changes in those parameters were larger in treatment-naïve than in previously ESA-treated patients. In previously ESA-treated patients receiving hemodialysis, hepcidin concentration and TIBC remained stable with molidustat, whereas TSAT and ferritin and iron concentrations increased. Generally, similar trends were observed in secondary analyses of subgroups of patients not receiving iron supplementation.
Molidustat is a potential alternative to standard treatment of anemia associated with CKD, with a different mechanism of action. In patients not receiving dialysis, molidustat increases iron availability. In patients receiving hemodialysis, further investigation is required to understand fully the mechanisms underlying iron mobilization associated with molidustat.
背景/目的：治疗慢性肾脏病（CKD）相关贫血的当前方法包括使用促红细胞生成素刺激剂（ESA）联合铁补充剂。脯氨酰羟化酶抑制剂莫立司他通过增加促红细胞生成素的产生和改善铁的可用性，具有治疗 CKD 相关贫血的潜力。在此，我们报告莫立司他对铁代谢的影响。
在三项为期 16 周的随机、对照、2 期研究中监测铁代谢参数，这些研究评估了莫立司他在不同人群中治疗 CKD 相关贫血的安全性和疗效：未接受透析的初治和之前未接受 ESA 治疗的患者，以及接受 ESA 治疗的正在接受血液透析的患者。铁补充剂由研究者自行决定。
在未接受透析的初治患者中，转铁蛋白饱和度（TSAT）、铁调素、铁蛋白和铁浓度随莫立司他而降低，而总铁结合能力（TIBC）增加。在之前未接受 ESA 治疗的未接受透析的患者中观察到类似的结果，尽管这些参数的变化在初治患者中比在之前接受 ESA 治疗的患者中更大。在接受血液透析的之前接受 ESA 治疗的患者中，莫立司他使铁调素浓度和 TIBC 保持稳定，而 TSAT 和铁蛋白和铁浓度增加。一般来说，在未接受铁补充剂的患者亚组的二次分析中观察到类似的趋势。
莫立司他是治疗 CKD 相关贫血的标准治疗的潜在替代方法，具有不同的作用机制。在未接受透析的患者中，莫立司他增加了铁的可用性。在接受血液透析的患者中，需要进一步研究以充分了解与莫立司他相关的铁动员的机制。
