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: 10370876
• 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
• 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/10370876
• 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; 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; Randomized Clinical Trials; Renal Replacement Therapy; Research Personnel; Risk; Saline; Sampling; Serum; Serum Magnesium Level; Testing; Training; Translational Research; Tryptophan; Tubular formation; Urine; attenuation; base; biobank; cancer therapy; chemotherapy; comorbidity; demographics; design; efficacy testing; high risk; injury prevention; innovation; mortality; new therapeutic target; novel; novel marker; patient oriented; patient oriented research; prevent; primary outcome; prophylactic; prospective; protective effect; quinolinate; randomized placebo controlled trial; rat KIM-1 protein; recruit; secondary outcome; 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.

项目总结/文摘