Dysregulated Mineral Metabolism in Acute Kidney Injury

急性肾损伤时矿物质代谢失调

• 批准号: 8588596
• 负责人: David Evan Leaf
• 金额: $ 6.04万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-30 至 2015-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588596
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Affect; Animals; Attenuated; Biochemical Markers; Biological Markers; Blood; Calcitriol; Cardiac Surgery procedures; Cardiovascular Diseases; Chronic Kidney Failure; Clinical; Cohort Studies; Critical Illness; Data; Development; Double-Blind Method; End stage renal failure; Enrollment; Functional disorder; Goals; Host Defense; Hour; Human; Human Cell Line; Hyperparathyroidism; Hypocalcemia result; Immune; Immune system; Immunity; Infection; Inflammation; Inflammatory; Injury; Interleukin-6; Kidney; Measures; Metabolism; Minerals; Modeling; Natural Immunity; Observational Study; Outcome; Participant; Patients; Pharmaceutical Preparations; Physiological; Pilot Projects; Placebo Control; Placebos; Plasma; Play; Postoperative Period; Production; Proteinuria; Randomized; Randomized Controlled Trials; Renin-Angiotensin System; Reporting; Research Design; Risk; Risk Factors; Role; Sampling; Sepsis; Septic Shock; Testing; Urine; Vitamin D; Vitamin D Deficiency; adverse outcome; cathelicidin; cathelicidin antimicrobial peptide; cytokine; fibroblast growth factor 23; improved; inflammatory marker; mortality; novel; public health relevance; rat KIM-1 protein; urinary

DESCRIPTION (provided by applicant): Dysregulated mineral metabolism is a universal feature of advanced chronic kidney disease (CKD) and is strongly associated with an increased burden of cardiovascular disease. In acute kidney injury (AKI), in contrast, relatively little is known about mineral metabolism. Our preliminary data indicate that many of the abnormalities in mineral metabolism that are observed in CKD, such as hypocalcemia, hyperphosphatemia, hyperparathyroidism, elevated Fibroblast Growth Factor-23 (FGF23), and vitamin D deficiency are also observed in AKI. Whether these derangements in mineral metabolism are associated with adverse outcomes in AKI, as they are in CKD, and whether intervening on them might impact clinical outcomes, has not been rigorously studied. We propose to study derangements in mineral metabolism in two groups of patients with AKI: AKI resulting from sepsis and AKI occurring after cardiac surgery. Among patients with sepsis and AKI, vitamin D deficiency is common and is strongly associated with adverse outcomes. Vitamin D has important effects on immunity and inflammation. We propose a pilot study evaluating the effects of activated vitamin D on immune, inflammatory, and renal injury biomarkers among critically-ill patients with sepsis with or without AKI. We will enroll 60 patients and randomly assign them 1:1 to receive a single administration of calcitriol 2mcg IV versus placebo. Participants with AKI will be stratified in equal numbers into the two groups. We will collect plasma and urine at 0, 6, 24, and 48 hours after study drug administration. We will test the hypotheses that calcitriol administration, compared to placebo, will result in favorable effects on markers of innate immunity and inflammation, identified by an increase in plasma cathelicidin and a decrease in plasma IL-6 levels, and will protect against AKI, identified by a decrease in urinary KIM-1 levels. Elevated FGF23 levels are associated with increased mortality in CKD and ESRD but have not been studied in detail in AKI. We propose to study FGF23 as a biomarker of adverse outcomes in cardiac surgery-associated AKI. We will use a case-cohort study design, comparing FGF23 levels among cases (those who develop AKI after cardiac surgery) to non- cases. We will test the hypothesis that elevated plasma FGF23 levels are an independent predictor of the composite clinical outcome of mortality or sustained kidney injury 90 days following cardiac surgery.

描述（由申请人提供）：矿物质代谢失调是晚期慢性肾脏疾病（CKD）的普遍特征，并且与心血管疾病负担增加密切相关。相比之下，在急性肾损伤（AKI）中，对矿物质代谢的了解相对较少。我们的初步数据表明，在CKD中观察到的许多矿物质代谢异常，如低钙血症、高磷血症、甲状旁腺功能亢进、成纤维细胞生长因子-23 （FGF23）升高和维生素D缺乏也在AKI中观察到。这些矿物质代谢紊乱是否与AKI的不良结局有关，是否与CKD的不良结局有关，以及干预它们是否会影响临床结果，尚未得到严格的研究。我们建议研究两组AKI患者的矿物质代谢紊乱：败血症引起的AKI和心脏手术后发生的AKI。在脓毒症和AKI患者中，维生素D缺乏是常见的，并且与不良结局密切相关。维生素D对免疫和炎症有重要作用。我们建议进行一项初步研究，评估活性维生素D对伴有或不伴有AKI的重症败血症患者的免疫、炎症和肾损伤生物标志物的影响。我们将招募60名患者，并随机将他们按1:1的比例分配，分别接受一次骨化三醇2mcg IV和安慰剂。患有AKI的参与者将以相同的人数分为两组。我们将在研究用药后0,6,24和48小时收集血浆和尿液。我们将验证与安慰剂相比，骨化三醇给药将对先天免疫和炎症标志物产生有利影响的假设，通过血浆抗菌肽的增加和血浆IL-6水平的降低来确定，并将防止AKI，通过尿KIM-1水平的降低来确定。FGF23水平升高与CKD和ESRD的死亡率增加有关，但在AKI中尚未得到详细研究。我们建议研究FGF23作为心脏手术相关AKI不良结局的生物标志物。我们将采用病例队列研究设计，比较病例（心脏手术后发生AKI的患者）与非病例的FGF23水平。我们将检验血浆FGF23水平升高是心脏手术后90天死亡率或持续肾损伤复合临床结果的独立预测因子的假设。