Li Weiying, Zhao Yuliang, Fu Ping
Division of Nephrology, West China Hospital, Sichuan University, Chengdu, China.
Front Med (Lausanne). 2018 Jan 22;4:259. doi: 10.3389/fmed.2017.00259. eCollection 2017.
Many studies have shown evidence that erythropoiesis-stimulating agents (ESAs), as a classic treatment for chronic kidney disease (CKD)-related anemia, have several disadvantages and may trigger various adverse events with long-term use. The hypoxia-induced factor (HIF) pathway has been intensively investigated in kidney disease, especially in CKD, as research has shown that HIF-mediated erythropoiesis might work as a potential therapeutic strategy for managing CKD-related anemia. Development of prolyl hydroxylase domain inhibitors (PHIs), as an effective HIF activator, is a valuable step toward finding a replacement for ESAs, which showed an effective erythropoiesis through a comprehensive and physiological approach by promoting erythropoietin production, increasing iron bioavailability and improving chronic inflammatory status. Heretofore no adverse events or obvious off-target effects have been reported in clinical trials of PHIs. Nevertheless, a cautious inspection with extended follow-up period is warranted to validate the safety of prolonged HIF elevation, especially considering its ambiguous role in fibrogenesis and inflammation responses and possible risks in accelerating vascular calcification and tumorigenesis. A weighed dosing strategy might be the key to circumvent the unexpected side-effect brought by pleotropic effects of HIF elevation and achieve a selective augmentation of HIF-mediated signaling pathway. New studies with longer follow-up period and adequate analysis about the risks for proinflammation, vascular calcification and tumorigenesis are needed to ensure the drugs are safe for long-term use before being widely accepted in daily clinical practice.
许多研究表明，促红细胞生成素（ESAs）作为慢性肾脏病（CKD）相关贫血的经典治疗方法，存在诸多弊端，长期使用可能引发各种不良事件。缺氧诱导因子（HIF）途径在肾脏疾病，尤其是CKD中受到了深入研究，因为研究表明，HIF介导的红细胞生成可能成为治疗CKD相关贫血的潜在治疗策略。脯氨酰羟化酶结构域抑制剂（PHIs）作为一种有效的HIF激活剂，其开发是寻找ESAs替代品的重要一步，PHIs通过促进促红细胞生成素的产生、提高铁的生物利用度和改善慢性炎症状态，以全面和生理的方式显示出有效的红细胞生成作用。迄今为止，在PHIs的临床试验中尚未报告不良事件或明显的脱靶效应。然而，鉴于其在纤维化和炎症反应中的作用尚不明确，以及在加速血管钙化和肿瘤发生方面可能存在的风险，有必要进行更长随访期的谨慎检查，以验证长期HIF升高的安全性。权衡给药策略可能是规避HIF升高的多效性带来的意外副作用，并实现HIF介导的信号通路选择性增强的关键。需要进行更长随访期的新研究，并对促炎、血管钙化和肿瘤发生的风险进行充分分析，以确保这些药物在被日常临床实践广泛接受之前长期使用是安全的。
