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

项目总结/摘要 顺铂是一种众所周知的化疗，其导致急性肾损伤（阿基）的高发病率， 在接受单次剂量的三分之一成年人中发生。尽管努力寻找毒性较小但同样 有效的替代方案，基于铂的治疗仍然被纳入高达40%的化疗方案， 仍然是许多癌症的一线治疗方法。肿瘤治疗（如顺铂）后发生的阿基 与显著的发病率和死亡率相关;因此，识别 旨在预防顺铂相关阿基（CP-AKI）的有效策略。 在目标1中，我们将检查4种药物（静脉[IV]镁[Mg]，甘露醇， 二甲双胍和他汀类药物）对CP-AKI发生率的影响。我们将利用一个独特的数据库， 在4个主要癌症中心接受IV顺铂治疗的患者中，应用靶向试验模拟的原则， 解决观察性研究中的常见偏差。 在目标2中，我们将建立动物模型，显示IV Mg对CP-AKI的保护作用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阿基独立相关 患者我们将进行一项随机临床试验（RCT）间皮瘤患者接受热 顺铂术中化疗（HIOCC）（n=80），比较IV Mg与安慰剂对 CP-AKI我们将在术前和术后收集血液和尿液样本，比较血清 肌酐和新的肾小管损伤标志物。 在目标3中，我们将招募150名接受IV顺铂治疗的高危患者，以检查顺铂治疗的副产物是否是化疗的副产物。 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 在CP-AKI。如果是这样的话，施用针对增加NAD+代谢物的药剂可能是有希望的。 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所需的培训，以1）成为 肿瘤学; 2）将先进的流行病学技术应用于观察数据集; 3）培养以下技能： 前瞻性患者招募; 4）建立生物样本库; 5）获得进行RCT的技能。主要研究者有 导师大卫叶博士的指导，他是阿基，RCT，生物标志物和肿瘤肾病学的专家，以及 博士Deborah Schrag，世界著名的肿瘤学家，结果研究员和临床试验家。主要研究者有 召集了一个由因果推理、镁稳态、统计学和翻译专家组成的咨询委员会， research.世界一流的导师团队，丰富的科学环境， 培训将支持PI的目标，成为一个独立的以患者为导向的研究人员在肿瘤肾病学。

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.