Deferoxamine for the Prevention of Acute Kidney Injury

去铁胺预防急性肾损伤

• 批准号: 10670112
• 负责人: David Evan Leaf
• 金额: $ 73.48万
• 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/10670112
• 关键词: Academic Medical Centers; Acute; Acute Renal Failure with Renal Papillary Necrosis; Adult; Affinity; Animal Model; Animals; Atrial Fibrillation; Attenuated; Binding; Blood; Boston; CD14 gene; Cardiac; Cardiac Surgery procedures; Cardiac Volume; Cardiopulmonary Bypass; Cell surface; Cessation of life; Chronic; Chronic Kidney Failure; Circulation; Clinical; Complex; Complication; Conduct Clinical Trials; Controlled Environment; Creatinine; Critical Illness; Data; Deferoxamine; Delirium; Development; Double-Blind Method; Enrollment; Excretory function; 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; 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; 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; participant enrollment; peripheral blood; pharmacologic; 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 急性肾损伤（阿基）是心脏手术的常见且通常是毁灭性的并发症， 疾病和其他临床环境。没有药物治疗可以可靠地预防或治疗阿基。丰富的数据 表明铁在阿基的发病机制中起关键作用， 特别是在心脏手术的环境中。我们建议进行一项II期、双盲、随机对照试验 为了测试施用铁螯合剂去铁胺（DFO）是否预防心脏病后阿基， 手术我们将在三个主要学术机构招募300名心脏手术后阿基高风险的成年患者， 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治疗 (30 mg/kg）或等体积的生理盐水。DFO（或生理盐水）将作为连续给药 24-在手术前立即开始静脉输注1小时。 在目标1中，我们将测试DFO与安慰剂相比对术后阿基发生率的影响 （主要终点）。阿基将根据血清肌酐和尿量的变化定义， KDIGO标准。作为次要终点，我们将评估肾小管损伤标志物的纵向变化， NGAL和KIM-1。我们还将测试DFO对以下常见疾病发生率的影响 生物学上合理的肾外术后终点：心肌梗死、房颤、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系统纵向测量的影响。 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质-以及转铁蛋白饱和和铁蛋白。血浆 氧化应激的标志物包括F（2）-异前列烷和髓过氧化物酶。我们也会评估 DFO与安慰剂对单核细胞（CD 14+）表达IL-6、TNFα和其他炎症标志物的影响 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）， 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影响。我们还将确定DFO对肾和肾外急性炎症的影响程度， 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。 总的来说，本文提出的研究将测试一种新颖且有前途的阿基治疗策略。 预防这些研究具有很大的潜力来改善有阿基风险的患者的临床结果。 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 代谢在阿基的病理生理学中的作用。

项目成果

Sarcopenia, adiposity and large discordance between cystatin C and creatinine-based estimated glomerular filtration rate in patients with cancer.

癌症患者的肌肉减少症、肥胖以及胱抑素 C 和基于肌酐的估计肾小球滤过率之间的巨大不一致。

• DOI: 10.1002/jcsm.13469
• 发表时间: 2024
• 期刊: Journal of cachexia, sarcopenia and muscle
• 作者: Hanna,PaulE;Ouyang,Tianqi;Tahir,Ismail;Katz-Agranov,Nurit;Wang,Qiyu;Mantz,Lea;Strohbehn,Ian;Moreno,Daiana;Harden,Destiny;Dinulos,JamesE;Cosar,Duru;Seethapathy,Harish;Gainor,JustinF;Shah,SachinJ;Gupta,Shruti;Leaf,DavidE

Platelet Factor 4 Antibodies and Severe AKI.

• DOI: 10.34067/kid.0000000000000287
• 发表时间: 2023-12-01
• 期刊: Kidney360
• 作者: Thomas C;Ali R;Park I;Kim H;Short S;Kaunfer S;Durai L;Yilmam OA;Shenoy T;Battinelli EM;Al-Samkari H;Leaf DE
• 通讯作者: Leaf DE

Intraoperative Oxygen Practices in Cardiac Surgery: A National Survey.

• DOI: 10.1053/j.jvca.2022.01.019
• 发表时间: 2022-08
• 期刊: Journal of cardiothoracic and vascular anesthesia
• 影响因子: 2.8

Histopathologic Correlates of Kidney Function: Insights From Nephrectomy Specimens.

肾功能的组织病理学相关性：来自肾切除标本的见解。

• DOI: 10.1053/j.ajkd.2020.08.015
• 发表时间: 2021
• 期刊: American journal of kidney diseases : the official journal of the National Kidney Foundation
• 作者: Li,Ping;Gupta,Shruti;Mothi,SurajS;Rennke,HelmutG;Leaf,DavidE;Waikar,SushrutS;McMahon,GearoidM
• 通讯作者: McMahon,GearoidM

Tocilizumab in COVID-19: some clarity amid controversy.

• DOI: 10.1016/s0140-6736(21)00712-1
• 发表时间: 2021-05-01
• 期刊: Lancet (London, England)
• 作者: Gupta S;Leaf DE
• 通讯作者: Leaf DE