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

基本信息

批准号：
10549309
负责人：
Shruti Gupta
金额：
$ 18.91万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
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/10549309
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

项目摘要

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.

项目概要/摘要顺铂是一种众所周知的化疗药物，会导致急性肾损伤（AKI）的高发生率，尽管人们努力寻找毒性较小但同等剂量的药物，但多达三分之一的成年人会发生这种情况。有效的替代方案，基于铂的疗法仍然被纳入高达 40% 的化疗方案中，并且仍然是顺铂等肿瘤治疗后发生的许多癌症的一线治疗。与显着的发病率和死亡率相关；因此，确定这一点至关重要；旨在预防顺铂相关 AKI (CP-AKI) 的有效策略。在目标 1 中，我们将检查 4 种药物的效果（静脉注射 [IV] 镁 [Mg]、甘露醇、我们将利用超过 45,000 名成年人的独特数据库。在 4 个主要癌症中心接受 IV 顺铂治疗的患者，应用目标试验模拟的原则解决观察性研究中的常见偏见。在目标 2 中，我们将建立动物模型，展示静脉注射镁对 CP-AKI 和我们自己的保护作用初步数据显示，较低的血清镁水平与心脏手术中的 AKI 独立相关我们将对接受热疗的间皮瘤患者进行随机临床试验 (RCT)。术中化疗顺铂 (HIOCC) (n=80) 比较 IV Mg 与安慰剂的减弱效果我们将在术前和术后收集血液和尿液样本，比较血清的变化。两组之间的肌酐和肾小管损伤的新标志物。在目标 3 中，我们将招募 150 名接受静脉注射顺铂的高危患者来检查顺铂是否会产生副产物。烟酰胺腺嘌呤二核苷酸 (NAD+) 途径（尿喹啉酸标准化为色氨酸）升高如果是这样的话，施用针对增加 NAD+ 代谢物的药物可能是一种有前途的方法。未来研究中 CP-AKI 的预防策略。本 K23 申请中提出的项目将提供 1) 成为以下方面的专家所需的培训：肿瘤肾病学；2) 将先进的流行病学技术应用于观察数据集；3) 培养以下方面的技能：前瞻性患者招募； 4) 建立生物库； 5) 并获得进行随机对照试验的技能。来自导师 David Leaf 博士的指导，他是 AKI、RCT、生物标志物和肿瘤肾病学方面的专家， Deborah Schrag 博士是一位世界著名的肿瘤学家、结果研究员和临床试验师。组建了一个由因果推理、镁稳态、统计学和转化方面的专家组成的咨询委员会世界一流的导师团队、丰富的科学环境和提议的结合。培训将支持 PI 成为肿瘤肾病学领域独立的以患者为导向的研究员的目标。