Deferoxamine for the Prevention of Acute Kidney Injury

项目总结 急性肾损伤(AKI)是心脏手术常见且常常是毁灭性的并发症，严重的 疾病，以及其他临床环境。没有可靠的药物疗法可以预防或治疗AKI。丰富的数据 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背景下。我们提出了一项二期双盲随机对照试验。 为了测试服用铁络合剂去铁胺(DFO)是否能预防心脏术后急性心肌梗死 做手术。我们将在三个主要学术机构招募300名心脏手术后AKI高危成人患者 波士顿的医疗中心。患者将以1：1的方式随机分配(n=150/组)接受DFO (30 mg/kg)或等量生理盐水。DFO(或生理盐水)将作为连续给药 手术前立即开始24小时静脉输液。 在目标1中，我们将测试DFO与安慰剂对术后AKI发生率的影响。 (主端点)。Aki将通过血清肌酐和尿量的变化来定义，根据 KDIGO标准。作为次要终点，我们将评估尿小管损伤标志物的纵向变化， NGAL和Kim-1。我们还将测试DFO对以下常见和 生物学上看似合理的肾外术后终点：心肌梗死、房颤、精神错乱、 机械通气时间过长，以及败血症。 在目标2中，我们将测试DFO与安慰剂对血液循环纵向指标的影响 铁与氧化应激，单核细胞炎症表型。血清铁参数将包括 催化铁--一种有毒的、非生理性的铁物种--以及转铁蛋白饱和和铁蛋白。电浆 氧化应激的标志物将包括F(2)-异前列腺素和髓过氧化物酶。我们还将评估影响 地塞米松与安慰剂对单核细胞IL-6、肿瘤坏死因子α及其他炎症标志物表达的影响 使用流式细胞术。在探索性分析中，我们将使用下一代RNA测序(RNA-Seq)来 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 器官损伤(在目标1中评估)取决于关键参数的术前表达。 在目标2中测量。 总而言之，这里提出的研究将测试一种新的、有前景的AKI治疗策略 预防。这些研究有很强的潜力改善AKI风险患者的临床结果。 此外，这里提出的翻译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。

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.