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

项目摘要/摘要 顺铂是一种众所周知的化疗药物，它会导致急性肾损伤(AKI)的高发生率， 在接受单剂注射的成年人中，多达三分之一会发生这种情况。尽管努力寻找毒性较低但同样 作为有效的替代方案，以铂为基础的疗法仍被纳入高达40%的化疗方案中，并且 仍然是一些癌症的一线治疗方法。顺铂等肿瘤治疗后发生急性心肌梗死 与严重的发病率和死亡率有关；因此，最重要的是确定 旨在预防顺铂相关急性KI(CP-AKI)的有效战略。 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，其中包含45,000名成人 在4个主要癌症中心接受静脉注射顺铂治疗的患者，应用靶向试验模拟的原则 解决观察性研究中常见的偏见。 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急性心肌梗死独立相关。 病人。我们将对接受热疗的间皮瘤患者进行随机临床试验(RCT) 术中化疗联合顺铂(HIOCC)(n=80)：比较静脉注射毫克与安慰剂对脑出血的抑制作用 CP-AKI。我们将采集手术前和术后的血和尿样本，比较血清的变化。 肌酐和肾小管损伤的新标记物。 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，以检查 烟酰胺腺嘌呤二核苷酸(NAD+)途径，尿喹啉酸归一化为色氨酸，升高 在CP-AKI中。如果是这样的话，以增加NAD+代谢物为目标的药物的管理可能是一个有希望的方法 CP-AKI的预防策略在未来的研究中。 此K23申请中建议的项目将提供所需的培训，以便1)成为以下领域的专家 肿瘤肾病；2)将先进的流行病学技术应用于观察性数据集；3)发展技能 预期的患者招募；4)建立生物库；5)获得进行随机对照试验的技能。少年派有 导师大卫·利夫博士的指导，他是AKI、RCT、生物标记物和肿瘤肾病方面的专家，以及 黛博拉·施拉格博士，世界著名的肿瘤学家、结果研究员和临床试验人员。少年派有 组建了一个由因果推断、镁动态平衡、统计和翻译方面的专家组成的咨询委员会 研究。结合了世界级的导师团队，丰富的科学环境，并提出 培训将支持PI成为一名独立的、以患者为导向的肿瘤肾病研究人员的目标。

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.