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Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Physiology and Pharmacology

Supervisor

Urquhart, Bradley L.

Abstract

Cisplatin is an effective chemotherapeutic agent used for the treatment of a wide variety of solid tumors and hematologic cancers. Despite its effectiveness, cisplatin is associated with several toxic effects to non-cancerous tissues. Nephrotoxicity is the main dose-limiting toxicity in cisplatin therapy, manifesting as acute kidney injury (AKI) in approximately one-third of patients receiving cisplatin. AKI is defined as an abrupt decline in kidney function and is associated with several short- and long-term adverse outcomes, including chronic kidney disease, cardiovascular disease, and mortality. AKI is currently diagnosed by increased serum creatinine (SCr) concentrations. However, SCr is a marker of functional impairment of the kidneys and is only elevated after significant kidney injury. Novel biomarkers are necessary for early diagnosis of cisplatin-induced AKI and to identify high risk patients prior to cisplatin therapy. Untargeted metabolomics was utilized to characterize the metabolic alterations induced by cisplatin in a mouse model of cisplatin-induced nephrotoxicity, an adult cohort of head and neck cancer patients receiving cisplatin, and a cohort of pediatric cancer patients receiving cisplatin. In our mouse model, we identified 26 metabolites that show early alterations following cisplatin administration, prior to elevations in plasma creatinine and histological evidence of kidney injury. Many of these metabolites were indicative of mitochondrial dysfunction or gut-derived metabolites. In the metabolomic investigations of adult and pediatric cancer patients, patients who developed AKI (AKI group) after cisplatin therapy were compared with patients who did not develop AKI (no AKI group) to identify metabolites that discriminate between AKI and no AKI patients. The central role of mitochondria in cisplatin nephrotoxicity was further reinforced in the adult cohort where we identified markers of fatty acid β-oxidation as predictive markers of cisplatin-induced AKI. Metabolomic investigation of the pediatric cohort revealed metabolites involved with de novo NAD+ synthesis were consistently elevated in the urine of AKI patients compared to no AKI patients. Metabolites identified as early diagnostic markers or predictive markers must be further validated in larger patient cohorts. Collectively, these results should be used to guide future targeted metabolomics investigations and experiments to test therapeutic interventions against cisplatin-induced AKI.

Summary for Lay Audience

Cisplatin is an effective and commonly used drug to treat cancer. However, cisplatin has several toxic side effects. One of the main toxic effects of cisplatin is kidney toxicity. Kidney toxicity caused by cisplatin can lead to acute kidney injury (AKI) in one-third of patients receiving cisplatin. AKI is a sudden decline in kidney function and puts patients at greater risk of developing long-term consequences such as long-term kidney dysfunction, heart disease, and death. AKI is diagnosed by measuring creatinine levels in the blood. However, creatinine levels are only elevated in the blood after significant kidney injury has already occurred which usually takes almost a week after patients receive cisplatin. For prevention of AKI, new biological markers are necessary for earlier diagnosis and to identify patients at high risk of developing AKI. Metabolomics is an analytical technique used to take a snapshot of all the biochemical reactions occurring in the body at a given time; it does so by measuring the levels of metabolites, which are by-products of the biochemical reactions happening in the body. Evaluating changes in metabolite levels provides indications as to which metabolic reactions are altered/disrupted. We used metabolomics in mice treated with cisplatin to investigate which metabolites were changed early after cisplatin treatment; we found 26 metabolites that were changed before elevations in blood creatinine levels. Many of these metabolites were associated with dysfunctional mitochondria (powerhouse of the cell). Metabolomics was also used to compare patients who received cisplatin and developed AKI vs. those who did not develop AKI. The goal was to find metabolites that could predict which patients would develop AKI after receiving cisplatin. In adult patients, metabolites linked to mitochondrial breakdown of fats were found to predict which patients would go on to develop AKI. In children, metabolites involved in the synthesis of an important energy metabolite called NAD+ were consistently elevated in the urine of patients with AKI. These markers of AKI must be validated in larger groups of patients to confirm their utility. These findings can help guide future research to develop protective measures against kidney damage caused by cisplatin.

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