Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Pathology and Laboratory Medicine

Supervisor

Bhattacharjee, Rabindra N.

2nd Supervisor

Luke, Patrick

Co-Supervisor

Abstract

Recent evidence demonstrates that oxygenated perfusion at 22°C is superior to static cold storage for preserving pre-transplanted kidneys; nonetheless, there is opportunity for improvement. Therefore, we aim to repurpose existing off-patent drugs in combination with oxygenated perfusion to further reduce organ damage caused by ischemia reperfusion injury. Through the development and characterization of both cold and room temperature injury models, the room temperature-based model demonstrated decreased pro-inflammatory cytokines and increased cell viability compared to previously developed cold IRI model. These findings provide evidence that the room temperature-based model can not only mitigate the risk associated with cold IRI, but also serve as a viable platform for conducting large-scale drug repositioning studies. Piloting this model for a small-scale drug screening, we identified several candidates with potential anti-inflammatory properties applicable to mitigating IRI. Consequently, the development of a novel preservation system can increase the availability of healthy donor kidneys for transplant and enhance patient long-term outcomes.

Summary for Lay Audience

Approximately 1.2 million people globally die from kidney failure each year. While kidney transplantation is better for patients than dialysis, there are not enough organs available for transplant to meet the ever-increasing demand. This is because there is an entire category of organs not eligible for transplantation, known as donation after circulatory death (DCD) kidneys. DCD kidneys are too damaged for transplant because blood has stopped flowing within the organ for a prolonged period of time. A well-known phenomenon called ischemia reperfusion injury, is the process of an organ temporarily losing oxygen, followed by the return of oxygen, which results in harm to the organ and can have detrimental effects for organ recipients down the road. Cold storage, the current standard for preserving a kidney during transplantation, would not prevent further damage. As a result, research has proven that preservation at room temperature using a machine pump (that can circulate blood through the organ) can protect the organ long enough to be transplanted. While machine preservation is known to reduce injury in organs during preservation, there is still a considerable gap. Therefore, our goal is to discover drugs that can protect the organ from harm during storage and transport. Drugs that are already on the market for a specific purpose, may have additional effects that are not yet known, and their secondary uses can be just as helpful in clinical practice. This thesis has implemented a laboratory-created simulation using kidney cells that mimics the events that take place during transplantation and machine pump preservation. Using this simulated cell-based model, a small-scale drug screening was conducted, where several drugs were identified as having some protective effects against the damage relating to IRI. By developing this novel preservation system, we can create better preservation methods to protect at-risk kidneys for more long-term organ function, which can ultimately lead to better quality of life and improved survival rates.

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