Date on Master's Thesis/Doctoral Dissertation

8-2018

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Siskind, Leah

Committee Co-Chair (if applicable)

Arteel, Gavin

Committee Member

Arteel, Gavin

Committee Member

Beverly, Levi

Committee Member

Clark, Geoffrey

Committee Member

Lederer, Eleanor

Author's Keywords

cisplatin; nephrotoxicity; renal fibrosis; chronic kidney disease; mouse models

Abstract

Cisplatin is a potent chemotherapeutic used for the treatment of many solid cancers, including testicular, ovarian, and lung cancer. Cisplatin causes many adverse side effects, of which nephrotoxicity leading to acute kidney injury is dose-limiting. Approximately 30% of patients will develop nephrotoxicity with cisplatin, and will either have their next dose of cisplatin lowered, skipped, or be switched to a less nephrotoxic chemotherapeutic altogether. These outcomes are not ideal when trying to treat cancer. Previously, it was believed that patients could recover from cisplatin-induced acute kidney injury with little to no lasting effects, but recent longitudinal studies have shown this is not the case. Patients who develop acute kidney injury are ten times more likely to develop chronic kidney disease, which often requires dialysis and has an increased mortality rate. Unfortunately, there are no treatment options available for either acute kidney injury or chronic kidney disease. This may be due to the fact that the mouse model used to study cisplatin-induced kidney injury is not physiologically relevant to patients. The work featured in this dissertation aims to develop a clinically relevant mouse model of cisplatin-induced kidney injury by developing a cisplatin dosing regimen that recapitulates the type of dosing regimen patients receive. In order to further improve clinical relevancy, the effects of aging and cancer are also explored with this mouse model. The ultimate goal of this work is to use this model to identify a novel target and therapeutic strategy for the treatment of cisplatin-induced kidney injury.

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