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

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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.