FGF23 and mineral metabolism in Acute Kidney Injury

描述（由申请人提供）：急性肾损伤（阿基）是急性疾病的毁灭性并发症，仅在美国每年就影响超过50万名住院患者。阿基显着增加住院死亡的风险，并增加发生慢性肾病（CKD）的风险，并使已确诊的CKD进展更快。由于缺乏足够灵敏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可操作病原体靶标，因此改善阿基结局的治疗进展受到阻碍。迫切需要新的早期阿基诊断标志物和新的治疗靶点来改善结局。磷酸盐调节激素成纤维细胞生长因子23（FGF 23）的循环水平在CKD患者中逐渐增加，在疾病过程的早期开始，此时肾功能仅轻微受损。这种对轻度肾功能不全的敏感性表明，FGF 23可能是阿基早期损伤的理想生物标志物。我们最近发表的阿基啮齿动物模型研究支持这一范式：在诱导阿基后不久，在血清肌酐或阿基肾小管损伤生物标志物水平变化之前，FGF 23水平急剧上升。在这项提案中，我们提出了支持这些发现的新的初步人类数据。在目标1中，我们将在心脏手术后发生阿基的51例患者和未发生阿基的51例对照患者中进行第一项全面、前瞻性、巢式病例对照研究，研究FGF 23和矿物质代谢。使用已经为Brigham和Women's阿基队列收集的术前和术后样本，我们将重复测量完整和C-末端FGF 23、甲状旁腺激素、磷酸盐、钙和完整的维生素D组，包括维生素D储存指数（25 D）、维生素D活化指数（1，25 D）、维生素D降解指数（24，25 D）和维生素D结合蛋白。心脏手术是阿基的理想人体模型，因为基线肾功能和肾损伤的精确时间是已知的，并且在手术前后可以获得侧翼血液样本。FGF 23水平升高和其他矿物质代谢物的相关改变也与CKD患者心血管疾病和死亡率的风险增加密切相关。相反，关于FGF 23水平对阿基临床结局影响的数据很少。在一项初步研究中，我们报告了阿基患者的FGF 23升高，并与死亡风险或肾脏替代治疗（RRT）需求增加相关。在目标2中，我们将在VALID研究中对800名参与者进行有效的病例队列分析，以检验FGF 23升高和矿物质代谢紊乱是否是不良结局的独立危险因素，VALID研究是一项大型的前瞻性关键研究， 具有储存血液样本和高阿基、RRT和死亡发生率的护理队列。通过将一项密集的以患者为导向的生理学研究和一项大型临床结局研究统一在一个主题下，我们将对FGF 23在肾功能不全状态中的新作用产生新的临床相关见解，这可能具有重要的诊断和治疗意义。

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.