Deferoxamine for the Prevention of Acute Kidney Injury

去铁胺预防急性肾损伤

基本信息

批准号：
10249293
负责人：
David Evan Leaf
金额：
$ 65.46万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10249293
关键词：
Academic Medical Centers Acute Acute Renal Failure with Renal Papillary Necrosis Adult Affinity Animal Model Animals Atrial Fibrillation Attenuated Binding Biological Blood Blood Circulation Boston CD14 gene Cardiac Cardiac Surgery procedures Cardiac Volume Cardiopulmonary Bypass Cell surface Cessation of life Chronic Chronic Kidney Failure Clinical Complex Complication Conduct Clinical Trials Controlled Environment Creatinine Critical Illness Data Deferoxamine Delirium Development Double-Blind Method Enrollment Exposure to Feces Ferritin Flow Cytometry Functional disorder Heme Hemoglobin Hemolysis Hospitals Hour Human Hypotension Incidence Inflammation Inflammatory Infrastructure Infusion procedures Injury Injury to Kidney Interleukin-6 Intravenous infusion procedures Investigation Iron Iron Chelating Agents Iron Chelation Iron Overload Isoprostanes Kidney LCN2 gene Left Ventricular Ejection Fraction Measures Mechanical ventilation Mediating Myocardial Infarction Normal saline Operative Surgical Procedures Organ Outcome Output Oxidative Stress Pathogenesis Patients Peroxidases Pharmacology Phase Phenotype Physiological Placebos Plasma Play Postoperative Period Pre-Clinical Model Prevention Production Prospective cohort study Public Health Randomized Randomized Controlled Trials Renal Replacement Therapy Risk Role Sepsis Serum Severities Surgeon TNF gene Testing Therapeutic Transcript Transferrin Tubular formation Urine base cytokine experience high risk improved inflammatory marker injury prevention innovation insight iron metabolism monocyte mortality risk myocardial injury nephrotoxicity new therapeutic target next generation novel organ injury oxidative damage peripheral blood precision medicine prevent primary endpoint prophylactic research study secondary endpoint transcriptome transcriptome sequencing translational study urinary

项目摘要

PROJECT SUMMARY Acute kidney injury (AKI) is a common and often devastating complication of cardiac surgery, critical illness, and other clinical settings. No pharmacologic therapy reliably prevents or treats AKI. Abundant data from both animal models and humans indicates that iron plays a key role in the pathogenesis of AKI, particularly in the setting of cardiac surgery. We propose a phase II, double-blind, randomized controlled trial to test whether administration of the iron chelating agent, deferoxamine (DFO), prevents AKI following cardiac surgery. We will enroll 300 adult patients at high risk of AKI following cardiac surgery at three major academic medical centers in Boston. Patients will be randomly assigned, in a 1:1 fashion (n=150/group), to receive DFO (30 mg/kg) or an equal volume of normal saline. DFO (or normal saline) will be administered as a continuous 24-hour intravenous infusion beginning immediately prior to surgery. In Aim 1 we will test the effects of DFO compared to placebo on the incidence of postoperative AKI (primary endpoint). AKI will be defined by changes in serum creatinine and urine output, according to the KDIGO criteria. As secondary endpoints, we will assess longitudinal changes in urinary tubular injury markers, NGAL and KIM-1. We will also test the effects of DFO on the incidence of the following common and biologically plausible extrarenal postoperative endpoints: myocardial infarction, atrial fibrillation, delirium, prolonged mechanical ventilation, and sepsis. In Aim 2 we will tests the effects of DFO compared to placebo on longitudinal measures of circulating iron and oxidative stress, and the inflammatory phenotype of monocytes. Serum iron parameters will include catalytic iron – a toxic, non-physiologic iron species – as well as transferrin saturation and ferritin. Plasma markers of oxidative stress will include F(2)-isoprostane and myeloperoxidase. We will also assess the effect of DFO versus placebo on monocyte (CD14+) expression of IL-6, TNFα, and other markers of inflammation using flow cytometry. In exploratory analyses, we will use next-generation RNA sequencing (RNA-Seq) to assess the effect of DFO on the transcriptome of monocytes, which will facilitate discovery of novel transcripts influenced by DFO. We will also determine the extent to which the effect of DFO on renal and extrarenal acute organ injury (assessed in Aim 1) varies depending on the preoperative expression of key parameters measured in Aim 2. In aggregate, the studies proposed here will test a novel and promising therapeutic strategy for AKI prevention. These studies have strong potential to improve clinical outcomes in patients at risk for AKI. Further, the translational studies proposed here will yield important scientific insights into the role of iron metabolism in the pathophysiology of AKI.

项目概要急性肾损伤 (AKI) 是心脏手术的常见且往往是毁灭性的并发症，危急疾病和其他临床情况没有可靠的药物治疗可以预防或治疗 AKI。来自动物模型和人类的研究表明，铁在 AKI 的发病机制中发挥着关键作用，特别是在心脏手术的情况下，我们提出了一项 II 期、双盲、随机对照试验。测试服用铁螯合剂去铁胺 (DFO) 是否可以预防心脏病后 AKI 我们将在三个主要学术机构招募 300 名心脏手术后发生 AKI 高风险的成年患者。患者将以 1:1 的方式（n=150/组）被随机分配接受 DFO。（30 mg/kg）或等体积的生理盐水（或生理盐水）将连续给药。手术前立即开始 24 小时静脉输注。在目标 1 中，我们将测试 DFO 与安慰剂相比对术后 AKI 发生率的影响（主要终点）根据血清肌酐和尿量的变化来定义。作为次要终点，我们将评估尿管损伤标志物的纵向变化，我们还将测试 DFO 对以下常见和 KIM-1 发生率的影响。生物学上合理的肾外术后终点：心肌梗塞、心房颤动、谵妄、长时间机械通气和败血症。在目标 2 中，我们将测试 DFO 与安慰剂相比对循环纵向测量的影响铁和氧化应激，以及单核细胞的炎症表型将包括血清铁参数。催化铁（一种有毒的非生理性铁物质）以及转铁蛋白饱和度和血浆铁蛋白。氧化应激标志物包括 F(2)-异前列腺素和髓过氧化物酶，我们还将评估其效果。 DFO 与安慰剂相比对单核细胞 (CD14+) IL-6、TNFα 和其他炎症标志物表达的影响在探索性分析中，我们将使用新一代 RNA 测序 (RNA-Seq) 来进行分析。评估 DFO 对单核细胞转录组的影响，这将有助于发现新的转录本我们还将确定 DFO 对肾脏和肾外急性疾病的影响程度。器官损伤（目标 1 中评估）根据关键参数的术前表达而变化在目标 2 中测量。总的来说，这里提出的研究将测试一种新颖且有前途的 AKI 治疗策略这些研究具有改善 AKI 风险患者临床结果的巨大潜力。此外，这里提出的转化研究将对铁的作用产生重要的科学见解。 AKI 病理生理学中的代谢。