Deferoxamine for the Prevention of Acute Kidney Injury

去铁胺预防急性肾损伤

• 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
• 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

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.

项目摘要 急性肾脏损伤（AKI）是心脏手术的常见且经常毁灭性的并发症，关键 疾病和其他临床环境。没有药理治疗可靠地阻止或治疗AKI。丰富的数据 来自动物模型和人类都表明铁在AKI的发病机理中起关键作用， 特别是在心脏手术的情况下。我们提出了II期，双盲，随机对照试验 测试铁螯合剂的给药，脱氧胺（DFO）是否可以防止AKI心脏后AKI 外科手术。在三个主要学术的心脏手术后，我们将招募300名患有AKI高风险的成年患者 波士顿的医疗中心。将以1：1的方式随机分配患者（n = 150/组），以接收DFO （30 mg/kg）或同等体积的正常盐水。 DFO（或普通盐水）将作为连续 24小时静脉输注在手术前开始。 在AIM 1中，我们将测试DFO与安慰剂对术后AKI事件相比的影响 （主要终点）。 AKI将由血清肌酐和尿液输出的变化定义 Kdigo标准。作为次要终点，我们将评估尿管损伤标记的纵向变化， Ngal和Kim-1。我们还将测试DFO对以下常见事件的影响 生物学上合理的术后术后终点：心肌梗塞，心房颤动，del妄， 延长机械通气和败血症。 在AIM 2中，我们将测试DFO与安慰剂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。血清铁参数将包括 催化铁 - 一种有毒的非生理铁物种，以及转铁蛋白饱和和铁蛋白。等离子体 氧化应激的标记将包括F（2） - 异丙烷和髓过氧化物酶。我们还将评估效果 DFO与安慰剂在单核细胞（CD14+）表达IL-6，TNFα和其他炎症标志物的表达 使用流式细胞仪。在探索性分析中，我们将使用下一代RNA测序（RNA-Seq） 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 受DFO的影响。我们还将确定DFO对肾脏和肾外急性的影响的程度 器官损伤（在AIM 1中评估）因关键参数的术前表达而有所不同 在AIM 2中测量。 总体而言，这里提出的研究将测试AKI的新颖和承诺治疗策略 预防。这些研究具有改善AKI风险患者的临床结局的强大潜力。 此外，这里提出的翻译研究将产生有关铁的作用的重要科学见解。 AKI的病理生理学中的代谢。