PDF(Pubmed)
Abstract：
Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of medications for managing renal anemia in patients with chronic kidney disease (CKD). In addition to their erythropoietic activity, HIF-PHIs exhibit multifaceted effects on iron and glucose metabolism, mitochondrial metabolism, and angiogenesis through the regulation of a wide range of HIF-responsive gene expressions. However, the systemic biological effects of HIF-PHIs in CKD patients have not been fully explored. In this prospective, single-center study, we comprehensively investigated changes in plasma metabolomic profiles following the switch from an erythropoiesis-stimulating agent (ESA) to an HIF-PHI, daprodustat, in 10 maintenance hemodialysis patients. Plasma metabolites were measured before and three months after the switch from an ESA to an HIF-PHI. Among 106 individual markers detected in plasma, significant changes were found in four compounds (erythrulose, n-butyrylglycine, threonine, and leucine), and notable but non-significant changes were found in another five compounds (inositol, phosphoric acid, lyxose, arabinose, and hydroxylamine). Pathway analysis indicated decreased levels of plasma metabolites, particularly those involved in phosphatidylinositol signaling, ascorbate and aldarate metabolism, and inositol phosphate metabolism. Our results provide detailed insights into the systemic biological effects of HIF-PHIs in hemodialysis patients and are expected to contribute to an evaluation of the potential side effects that may result from long-term use of this class of drugs.
摘要：
低氧诱导因子脯氨酸酰羟化酶抑制剂（HIF-PHIs）是一类新的治疗慢性肾病（CKD）患者肾性贫血的药物。除了它们的红细胞生成活性，HIF-PHIs对铁和葡萄糖代谢表现出多方面的影响，线粒体代谢，和血管生成通过调节广泛的HIF反应基因表达。然而,HIF-PHIs在CKD患者中的系统性生物学效应尚未得到充分研究.在这个前景中，单中心研究,我们全面调查了从红细胞生成刺激剂（ESA）转换为HIF-PHI后血浆代谢组学的变化，daprodustat,10例维持性血液透析患者。在从ESA转换为HIF-PHI之前和之后三个月测量血浆代谢物。在血浆中检测到的106个单独的标志物中，在四种化合物中发现了显著的变化(赤霉素，正丁酰基甘氨酸,苏氨酸,和亮氨酸)，并且在另外五个化合物(肌醇，磷酸,lyxose,阿拉伯糖,和羟胺）。途径分析表明血浆代谢物水平降低，特别是那些参与磷脂酰肌醇信号传导的，抗坏血酸和醛盐代谢，和肌醇磷酸代谢。我们的结果为血液透析患者中HIF-PHIs的系统性生物学效应提供了详细的见解，并有望有助于评估长期使用此类药物可能导致的潜在副作用。
