Novel Pathways and Therapeutic Targets for Cisplatin-Associated Acute Kidney Injury

顺铂相关急性肾损伤的新途径和治疗靶点

• 批准号: 10868783
• 负责人: Shruti Gupta
• 金额: $ 5.4万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10868783
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Adult; Advisory Committees; Animal Model; Anticoagulation; Apoptosis; Area; Area Under Curve; Attenuated; Biological Markers; Blood; COVID-19 patient; Cancer Center; Cardiac Surgery procedures; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical; Clinical Trials; Complication; Conduct Clinical Trials; Continuous Infusion; Creatinine; Critical Illness; Dana-Farber Cancer Institute; Data; Data Set; Databases; Dose; Double-Blind Method; Environment; Epidemiologic Methods; Epidemiology; Event; Extracorporeal Membrane Oxygenation; Future; Goals; Homeostasis; Hour; Hyperthermia; Hypomagnesemia; Impairment; Incidence; Injury; Injury to Kidney; Intervention; Intravenous; LCN2 gene; Laboratories; Magnesium; Malignant Neoplasms; Malignant neoplasm of testis; Mannitol; Mentors; Mentorship; Mesothelioma; Metabolic stress; Metformin; Morbidity - disease rate; Nephrology; Niacinamide; Nicotinamide adenine dinucleotide; Non-Small-Cell Lung Carcinoma; Observational Study; Oncologist; Oral; Outcome; Oxidative Stress; Pathway interactions; Patient Recruitments; Patients; Pharmaceutical Preparations; Placebos; Plant Leaves; Plasma; Platinum; Postoperative Period; Pre-Clinical Model; Prevention; Prevention strategy; Prone Position; Prospective, cohort study; Publishing; Randomized; Renal Replacement Therapy; Research Personnel; Risk Reduction; Saline; Sampling; Serum; Serum Magnesium Level; Specific qualifier value; Testing; Training; Translational Research; Tryptophan; Tubular formation; Urine; attenuation; biobank; cancer therapy; chemotherapy; comorbidity; demographics; design; efficacy testing; high risk; injury prevention; innovation; intravenous administration; mortality; new therapeutic target; novel; novel marker; patient oriented; patient oriented research; prevent; primary outcome; prophylactic; prospective; protective effect; quinolinate; randomized placebo controlled trial; randomized, clinical trials; rat KIM-1 protein; recruit; secondary outcome; skill acquisition; skills; statistics; therapeutic target; therapeutically effective; tocilizumab; translational approach; urinary

PROJECT SUMMARY/ABSTRACT Cisplatin is a well-known chemotherapy that results in a high incidence of acute kidney injury (AKI), occurring in up to one in three adults receiving a single dose. Despite efforts to find less toxic but equally effective alternatives, platin-based therapies are still incorporated in up to 40% of chemotherapy regimens, and remain first-line treatment for a number of cancers. AKI occurring after oncologic treatments such as cisplatin is associated with significant morbidity and mortality; it is therefore of paramount importance to identify effective strategies aimed at prevention of cisplatin-associated AKI (CP-AKI). In Aim 1, we will examine the effect of 4 medications (Intravenous [IV] magnesium [Mg], mannitol, metformin, and statins) on the incidence of CP-AKI. We will leverage a unique database of >45,000 adult patients treated with IV cisplatin at 4 major cancer centers, applying the principles of target trial emulation to address common biases in observational studies. In Aim 2, we will build upon animal models showing the protective effects of IV Mg on CP-AKI and our own preliminary data showing that lower serum Mg levels are independently associated with AKI in cardiac surgery patients. We will conduct a randomized clinical trial (RCT) in mesothelioma patients receiving hyperthermic intraoperative chemotherapy with cisplatin (HIOCC) (n=80) comparing IV Mg to placebo for the attenuation of CP-AKI. We will collect blood and urine samples pre- and postoperatively, comparing changes in serum creatinine and novel markers of tubular injury between the two groups. In Aim 3, we will recruit 150 high-risk patients receiving IV cisplatin to examine whether a byproduct of the nicotinamide adenine dinucleotide (NAD+) pathway, urinary quinolinate normalized to tryptophan, is elevated in CP-AKI. If so, administration of agents directed at increasing NAD+ metabolites may be a promising preventative strategy for CP-AKI in future studies. The projects proposed in this K23 application will provide the training needed to 1) become an expert in onco-nephrology; 2) apply advanced epidemiologic techniques to observational datasets; 3) develop skills in prospective patient recruitment; 4) build a biobank; 5) and acquire skills in the conduct of RCTs. The PI has guidance from mentors Dr. David Leaf, an expert in AKI, RCTs, biomarkers, and onco-nephrology, as well as Dr. Deborah Schrag, a world-renowned oncologist, outcomes researcher, and clinical trialist. The PI has assembled an advisory committee of experts in causal inference, Mg homeostasis, statistics, and translational research. The combination of a world-class mentorship team, a rich scientific environment, and proposed training will support the PI’s goal to become an independent patient-oriented researcher in onco-nephrology.

项目摘要/摘要 顺铂是一种众所周知的化学疗法，导致急性肾脏损伤（AKI）的高入射， 发生在三分之一的成年人中发生。尽管努力发现毒性较小，但同样 有效的替代方法，基于白platin的疗法仍在多达40％的化学疗法方案中纳入 仍然是许多癌症的一线治疗。 AKI发生在肿瘤学治疗（例如顺铂）之后 与明显的发病率和死亡率有关；因此，识别至关重要 旨在预防顺铂相关的AKI（CP-AKI）的有效策略。 在AIM 1中，我们将检查4种药物的作用（静脉内[IV]镁[mg]，甘露醇， CP-AKI事件的二甲双胍和统计。我们将利用> 45,000名成年人的独特数据库 在4个主要癌症中心用IV顺铂治疗的患者，将目标试验仿真原理应用于 解决观察研究中的常见偏见。 在AIM 2中，我们将建立在动物模型的基础上，显示IV MG对CP-AKI和我们自己的受保护作用 初步数据表明，较低的血清Mg水平与心脏手术中的AKI独立相关 患者。我们将对接受过度热的间皮瘤患者进行随机临床试验（RCT） 用顺铂（HIOCC）（n = 80）进行术中化学疗法（n = 80），将IV MG与安慰剂与安慰剂进行比较以衰减 CP-AKI。我们将在术前和术后收集血液和尿液样本，以比较系列的变化 两组之间的肌酐和新颖的肾小管损伤标记。 在AIM 3中，我们将招募150名接受IV顺铂的高危患者，以检查是否是副产品 烟酰胺腺嘌呤二核苷酸（NAD+）途径，尿喹啉蛋白升高到色氨酸，已升高 在CP-AKI中。如果是这样，则可以承诺，指示增加NAD+代谢物的代理商可能是一个承诺 CP-AKI的预防策略在未来的研究中。 本k23申请中提出的项目将提供所需的培训1） 鼻肺； 2）将高级流行病学技术应用于观察数据集； 3）发展技能 潜在的患者招募； 4）建造一个生物库； 5）并获得RCT行为的技能。 Pi具有 AKI，RCTS，生物标志物和Onco-Nephrology的专家David Leaf博士的指导 世界知名的肿瘤学家，成果研究员和临床试验者Deborah Schrag博士。 Pi具有 组建了一个因果推断，MG稳态，统计和转化的专家咨询委员会 研究。世界一流的心态团队，丰富的科学环境和拟议的结合 培训将支持PI的目标，成为一名以患者为导向的独立研究人员。