Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Pathology and Laboratory Medicine

Supervisor

Luke, Patrick

2nd Supervisor

Bhattacharjee, Rabindra

Co-Supervisor

Abstract

Kidney transplantation remains the optimal treatment option for patients with end-stage renal disease. We aim to improve organ preservation during transplantation by reducing damage from ischemia reperfusion injury (IRI) using existing clinically approved drugs. In this study, we developed and characterized an in vitro model that mimics the conditions of IRI in kidney transplant as a tool to screen and study the therapeutic effect of drugs in the context of IRI. We recapitulated several key outcomes in IRI in our model, including the induction of hypoxia, cell death, increased expression of damage markers (NGAL, HMBG-1) and pro-inflammatory cytokines in a sterile environment (IL-6, TNF- α). Additionally, we validated our model as a screening tool by testing select drugs for their ability to mitigate IRI. Overall, this study provides the foundation for further research that can improve organ preservation strategies, thereby increasing the quantity and quality of kidneys available for transplant.

Summary for Lay Audience

Over 40,000 Canadians suffer from kidney failure. Transplantation remains the best treatment for these individuals, providing better quality of life and survival than dialysis. However, the damage to organs during the transplant surgery, known as ischemia reperfusion injury, remains a challenge to the success of kidney transplant. Ischemia refers to reduced blood flow during organ retrieval and storage, where reperfusion is the restoration of blood flow upon transplantation of the organ into the recipient. This injury causes cell death and inflammation in the transplanted organ leading to poor function. Therapeutics that prevent damage from this injury will be helpful in preserving the quality of transplanted organs and allow them to function longer. Our group hopes to repurpose an existing drug in the context of kidney transplantation, however a relevant model to test these drugs is required. In this study, we have developed and characterized a human kidney cell model that accurately encompasses the damage experienced by donor kidneys during transplantation. Additionally, we have carried out preliminary drug testing to determine the usefulness of the model to screen drugs. In future, this model will be used for a large-scale drug screen and to study drugs for their ability to prevent kidney injury during the transplant process. Ultimately, we hope to improve the quality of kidney a transplant patient receives.

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