FGF23 and mineral metabolism in Acute Kidney Injury

急性肾损伤中的 FGF23 和矿物质代谢

• 批准号: 8914611
• 负责人: Tamara Isakova
• 金额: $ 19.82万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8914611
• 关键词: 1,25 (OH) vitamin D; 25-hydroxyvitamin D; Acute; Acute Lung Injury; Acute Renal Failure with Renal Papillary Necrosis; Affect; Bioavailable; Biological Markers; Biology; Blood specimen; C-terminal; Calcium; Cardiac Surgery procedures; Catabolism; Cessation of life; Chronic Kidney Failure; Clinical; Cohort Analysis; Complication; Creatinine; Critical Care; Critical Illness; Data; Development; Diagnosis; Diagnostic; Diagnostic tests; Dihydroxycholecalciferols; Disease; End stage renal failure; Evolution; Fibroblast Growth Factor Receptors; Functional disorder; Future; Goals; Health; Heart; Hormones; Hospital Mortality; Hospitals; Human; Incidence; Injury; Intervention; Kidney; Measures; Mediating; Metabolism; Minerals; Modeling; Nested Case-Control Study; Operative Surgical Procedures; Organ; Outcome; Outcome Study; Parathyroid gland; Participant; Patients; Physiological; Pilot Projects; Postoperative Period; Production; Publishing; Regulation; Relative (related person); Renal Replacement Therapy; Renal function; Reporting; Research; Risk; Risk Factors; Rodent Model; Role; Sample Size; Sampling; Serum; Severities; Testing; Therapeutic; Time; Tubular formation; Validation; Vitamin D; Vitamin D-Binding Protein; Woman; adjudicate; adverse outcome; animal data; base; calcium phosphate; cardiovascular disorder risk; cardiovascular infection; case control; clinically relevant; cohort; design; fibroblast growth factor 23; high risk; human data; human study; improved; indexing; innovation; inorganic phosphate; insight; mortality; new therapeutic target; novel; novel diagnostics; novel marker; patient oriented; prospective; research study; standard measure; translational approach

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.

描述（由申请人提供）：急性肾脏损伤（AKI）是急性疾病的毁灭性并发症，仅在美国，每年就会影响500,000多名住院患者。 AKI明显增加了院内死亡率的风险，并赋予了患病慢性肾脏疾病（CKD）的更大风险和已建立的CKD的快速发展。由于缺乏足够敏感的诊断测试，无法在血清肌酐上升之前检测早期肾脏损伤，并缺少对临床干预的可行的致病靶标，这阻碍了改善AKI结局的治疗进展。早期AKI和新型治疗靶标的新型诊断标记迫切需要改善预后。 CKD患者的磷酸激素的循环水平，成纤维细胞生长因子23（FGF23）逐渐增加，始于疾病的早期，当时肾脏功能仅受到细微损害。这种对轻度肾功能障碍的精致敏感性表明，FGF23可能是AKI早期受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了这种范式：FGF23水平在诱导AKI和在血清肌酐或AKI的管状损伤生物标志物水平中检测到变化之前很快就会急剧上升。在此提案中，我们介绍了支持这些发现的新的初步人类数据。在AIM 1中，我们将对51例患者进行了FGF23和矿物质代谢的首次全面，前瞻性，嵌套的病例对照研究，这些患者患有AKI和51例对照，他们在心脏手术后仍然没有AKI。使用术前和术后样品，这些样本已经收集到杨百翰和女性AKI队列，我们​​将反复测量完整和C末端FGF23，甲状旁腺激素，磷酸盐，钙，钙和完整的维生素D面板，包括维生素D商店（25D），维生素DD DD DD DD DD DET（1,25D） （24,25D）和维生素D结合蛋白。心脏手术是该目标的理想人类模型，因为已经知道基线肾脏功能和肾脏损伤的确切时机，并且在手术前后都可以使用侧翼血液样本。其他矿物代谢产物中FGF23水平升高以及相关的改变也与CKD中心血管疾病和死亡率的更大风险密切相关。相反，关于FGF23水平对AKI临床结果的影响的数据很少。在一项试点研究中，我们报道了FGF23在AKI中升高，并且与更大的死亡风险或肾脏替代疗法（RRT）有关。在AIM 2中，我们将测试在有效研究中对800名参与者的有效病例分析中，FGF23和无序矿物代谢是不利结果的独立风险因素，这是一项大型，前瞻性的关键。 护理队列储存的血液样本和高发生的AKI，RRT和死亡率。通过统一一项以患者为导向的生理研究和一项大量临床结果研究，我们将在一个主题伞下进行大型的临床相关见解，以对FGF23在肾脏功能障碍状态的新兴作用中产生重要的诊断和治疗性含义。