Division of Nephrology and Hypertension, Department of Medicine, and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Division of Nephrology, Department of Medicine, and Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA.
Kidney Int. 2019 Dec;96(6):1346-1358. doi: 10.1016/j.kint.2019.07.026. Epub 2019 Aug 30.
Iron deficiency, anemia, hyperphosphatemia, and increased fibroblast growth factor 23 (FGF23) are common and interrelated complications of chronic kidney disease (CKD) that are linked to CKD progression, cardiovascular disease and death. Ferric citrate is an oral phosphate binder that decreases dietary phosphate absorption and serum FGF23 concentrations while increasing iron stores and hemoglobin in patients with CKD. Here we compared the effects of ferric citrate administration versus a mineral sufficient control diet using the Col4a3 knockout mouse model of progressive CKD and age-matched wild-type mice. Ferric citrate was given to knockout mice for four weeks beginning at six weeks of age when they had overt CKD, or for six weeks beginning at four weeks of age when they had early CKD. Ten-week-old knockout mice on the control diet showed overt iron deficiency, anemia, hyperphosphatemia, increased serum FGF23, hypertension, decreased kidney function, and left ventricular systolic dysfunction. Ferric citrate rescued iron deficiency and anemia in knockout mice regardless of the timing of treatment initiation. Circulating levels and bone expression of FGF23 were reduced in knockout mice given ferric citrate with more pronounced reductions observed when ferric citrate was initiated in early CKD. Ferric citrate decreased serum phosphate only when it was initiated in early CKD. While ferric citrate mitigated systolic dysfunction in knockout mice regardless of timing of treatment initiation, early initiation of ferric citrate also reduced renal fibrosis and proteinuria, improved kidney function, and prolonged life span. Thus, initiation of ferric citrate treatment early in the course of murine CKD lowered FGF23, slowed CKD progression, improved cardiac function and significantly improved survival.
铁缺乏、贫血、高磷血症和成纤维细胞生长因子 23（FGF23）的增加是慢性肾脏病（CKD）的常见且相互关联的并发症，与 CKD 进展、心血管疾病和死亡有关。柠檬酸铁是一种口服磷酸盐结合剂，可降低饮食中磷酸盐的吸收和血清 FGF23 浓度，同时增加 CKD 患者的铁储存量和血红蛋白水平。在这里，我们比较了柠檬酸铁给药与矿物质充足对照饮食对进展性 CKD 的 Col4a3 敲除小鼠模型和年龄匹配的野生型小鼠的影响。从 6 周龄开始，当敲除小鼠出现明显的 CKD 时，或从 4 周龄开始，当敲除小鼠出现早期 CKD 时，给予柠檬酸铁治疗 4 周。10 周龄的对照饮食敲除小鼠表现出明显的缺铁性贫血、高磷血症、血清 FGF23 升高、高血压、肾功能下降和左心室收缩功能障碍。无论治疗开始时间如何，柠檬酸铁均可纠正敲除小鼠的缺铁性和贫血。无论何时开始给予柠檬酸铁，敲除小鼠的循环 FGF23 水平和骨表达均降低，当柠檬酸铁在早期 CKD 时开始给予时，降低更为明显。柠檬酸铁仅在早期 CKD 时才降低血清磷酸盐。尽管柠檬酸铁无论何时开始治疗均可减轻敲除小鼠的收缩功能障碍，但早期开始给予柠檬酸铁还可减少肾纤维化和蛋白尿，改善肾功能并延长寿命。因此，在 CKD 小鼠病程早期开始给予柠檬酸铁治疗可降低 FGF23，减缓 CKD 进展，改善心功能，并显著提高生存率。
