FGF23 and mineral metabolism in Acute Kidney Injury

描述(申请人提供)：急性肾损伤(AKI)是急性疾病的一种破坏性并发症，仅在美国每年就有超过50万名住院患者受到影响。AKI显著增加住院死亡的风险，并增加发生慢性肾脏病(CKD)的风险，并使已建立的CKD进展更快。由于缺乏足够灵敏的诊断测试来在血清肌酐升高之前发现早期肾损伤，以及缺乏可操作的致病靶点用于临床干预，AKI改善预后的治疗进展受到了阻碍。迫切需要新的早期AKI诊断标记物和新的治疗靶点来改善结果。慢性肾脏病患者循环中磷酸调节激素成纤维细胞生长因子23(FGF23)的水平逐渐升高，从病程早期开始，此时肾功能只是轻微受损。这种对轻微肾功能障碍的敏感度表明，FGF23可能是AKI早期损伤的理想生物标志物。我们最近发表的关于AKI啮齿动物模型的研究支持这一范式：在诱导AKI后不久，FGF23水平急剧上升，然后才能检测到血清肌酐或AKI肾小管损伤生物标志物水平的变化。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，我们将对51名发生AKI的患者和51名心脏手术后仍未发生AKI的对照组进行FGF23和矿物质代谢的首次全面、前瞻性、嵌套式病例对照研究。使用为Brigham and Women‘s AKI队列收集的术前和术后样本，我们将重复测量完整和C末端的FGF23、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(25D)、维生素D激活(1，25D)、维生素D降解(24，25D)和维生素D结合蛋白的指数。心脏手术是达到这一目的的理想的AKI人体模型，因为基线肾功能和肾损伤的准确时间都是已知的，而且手术前后都可以获得两侧的血液样本。在慢性肾脏病中，FGF23水平升高和其他矿物质代谢产物的相关改变也与心血管疾病和死亡率的更高风险密切相关。相比之下，关于FGF23水平对AKI临床结果的影响的数据很少。在一项先导性研究中，我们报告了FGF23在AKI中升高，并与更高的死亡风险或需要肾脏替代治疗(RRT)相关。在目标2中，我们将在有效研究中对800名参与者进行有效的病例队列分析，以检验FGF23升高和矿物质代谢紊乱是否是不良结局的独立危险因素，这是一项大型的前瞻性关键研究。 使用储存的血液样本和高AKI、RRT和死亡率的护理队列。通过将密集的以患者为中心的生理研究和大型临床结果研究统一在一个主题下，我们将对FGF23在肾功能障碍状态中的新角色产生新的、临床相关的见解，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.