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.

项目总结

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

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

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