FGF23 and mineral metabolism in Acute Kidney Injury

描述（由申请人提供）：急性肾损伤（AKI）是一种毁灭性的急性疾病并发症，仅在美国每年就有超过50万住院患者受到影响。AKI显著增加住院死亡率的风险，并发慢性肾脏疾病（CKD）的风险更高，已建立的CKD进展更快。由于缺乏足够敏感的诊断测试来检测血清肌酐升高之前的早期肾损伤，以及缺乏可用于临床干预的致病靶点，改善AKI预后的治疗进展受到阻碍。迫切需要新的早期AKI诊断标志物和新的治疗靶点来改善预后。在CKD患者中，循环中的磷酸盐调节激素，成纤维细胞生长因子23 （FGF23）水平逐渐增加，在肾脏功能仅轻微受损的病程早期开始。这种对轻度肾功能障碍的敏感性表明，FGF23可能是AKI早期损伤的理想生物标志物。我们最近发表的对AKI啮齿动物模型的研究支持这一范式：在诱发AKI后不久，在血清肌酐或AKI小管损伤生物标志物水平检测到变化之前，FGF23水平急剧上升。在这项提议中，我们提出了新的初步人类数据来支持这些发现。在Aim 1中，我们将对51例发生AKI的患者和51例心脏手术后未发生AKI的对照组进行FGF23和矿物质代谢的首次全面、前瞻性、巢式病例对照研究。使用术前和术后已经收集的Brigham and Women’s AKI队列样本，我们将重复测量完整的和c端FGF23、甲状旁腺激素、磷酸盐、钙和完整的维生素D面板，包括维生素D储存（25D）、维生素D激活（1,25d）、维生素D降解（24,25d）和维生素D结合蛋白的指标。心脏手术是一种理想的AKI人体模型，因为基线肾功能和肾损伤的精确时间是已知的，并且术前和术后可获得侧翼血液样本。FGF23水平升高和其他矿物质代谢物的相关改变也与CKD中心血管疾病和死亡率的增加密切相关。相比之下，关于FGF23水平对AKI临床结果影响的数据很少。在一项初步研究中，我们报道了AKI中FGF23升高，并与更高的死亡风险或需要肾脏替代治疗（RRT）相关。在Aim 2中，我们将在一项有效的病例队列分析中测试FGF23升高和矿物质代谢紊乱是否为不良结果的独立危险因素，该研究有800名参与者，这是一项大型的前瞻性关键研究

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a devastating complication of acute illness that affects more than 500,000 hospitalized patients annually in the US alone. AKI markedly increases risk of in-hospital mortality, and confers greater risk of developing incident chronic kidney disease (CKD) and more rapid progression of established CKD. Therapeutic advances to improve outcomes in AKI have been impeded by lack of sufficiently sensitive diagnostics tests to detect early kidney injury before serum creatinine rise, and by a dearth of actionable pathogenic targets for clinical intervention. Novel diagnostic markers of early AKI and novel therapeutic targets are desperately needed to improve outcomes. Circulating levels of the phosphate-regulating hormone, fibroblast growth factor 23 (FGF23), increase progressively in patients with CKD, beginning early in the course of disease when kidney function is only subtly impaired. This exquisite sensitivity to even mild kidney dysfunction suggests that FGF23 could be an ideal biomarker for early injury in AKI. Our recently published study of rodent models of AKI supports this paradigm: FGF23 levels rise sharply soon after inducing AKI and before changes can be detected in serum creatinine or in levels of tubular injury biomarkers of AKI. In this proposal, we present new preliminary human data that support these findings. In Aim 1, we will perform the first comprehensive, prospective, nested case-control study of FGF23 and mineral metabolism in 51 patients who developed AKI and 51 controls who remained free of AKI after cardiac surgery. Using preoperative and postoperative samples that were already collected for the Brigham and Women's AKI cohort, we will repeatedly measure intact and C-terminal FGF23, parathyroid hormone, phosphate, calcium, and a complete vitamin D panel, including indices of vitamin D stores (25D), vitamin D activation (1,25D), vitamin D degradation (24,25D) and vitamin D binding protein. Cardiac surgery is an ideal human model of AKI for this Aim because baseline kidney function and the precise timing of renal injury are known, and flanking blood samples are available before and after surgery. Elevated FGF23 levels and associated alterations in other mineral metabolites are also strongly associated with greater risks of cardiovascular disease and mortality in CKD. In contrast, data on the impact of FGF23 levels on clinical outcomes in AKI are sparse. In a pilot study, we reported that FGF23 is elevated in AKI and associated with greater risk of death or need for renal replacement therapy (RRT). In Aim 2, we will test whether elevated FGF23 and disordered mineral metabolism are independent risk factors for adverse outcomes in an efficient case-cohort analysis of 800 participants in the VALID study, which is a large, prospective critical care cohort with stored blood samples and high rates of incident AKI, RRT, and death. By unifying an intensive patient-oriented physiological study and a large clinical outcomes study under one thematic umbrella, we will generate novel, clinically relevant insights into the emerging role of FGF23 in states of kidney dysfunction that could have important diagnostic and therapeutic implications.