Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Microbiology and Immunology

Supervisor

Sener, Alp

Abstract

Kidney transplantation is preferred for patients with end-stage renal disease. The current gold standard for preserving kidneys is static cold storage (SCS) at 4°C in University of Wisconsin (UW) solution. However, SCS contributes to ischemia-reperfusion injury (IRI), which involves cell death and inflammation. Our group showed that SCS of kidneys with hydrogen sulfide donors, like sodium thiosulfate (STS), that reduce tissue injury enhanced kidney survival. Though, there is still a risk of cold renal IRI at 4°C. Recent evidence suggests that preserving organs at 10°C enhanced graft function and survival. Therefore, this thesis will evaluate the effect of 10°C kidney preservation with STS and Hemopure, a clinically viable blood substitute that delivers oxygen to hypoxic tissues. In an in vitro model of rat renal IRI, 10°C STS treatment improved cell viability compared to 4°C conditions. Additionally, 10°C storage of rat renal grafts with STS- and Hemopure-supplemented UW solution improved kidney function and reduced tissue necrosis and apoptosis. Overall, we showed that renal graft preservation at 10°C may be a viable kidney preservation approach to mitigate the risks associated with cold renal IRI.

Summary for Lay Audience

Kidney transplantation is the preferred treatment for patients with end-stage renal disease. Yet, the demand for transplantable kidneys outweighs the supply of donor kidneys. The current standard for kidney preservation is 4°C storage; however, recent evidence emerged that suggests that 4°C kidney storage is contributing to tissue damage and injury. As such, we have shown that other temperatures may be better suited for kidney preservation, especially with hydrogen sulfide donors, which reduce tissue injury during storage, and blood substitutes that deliver oxygen to tissues in need. However, warmer temperatures require greater oxygen and nutrients to meet kidney metabolic needs. Our previous research has shown that when we added a hydrogen sulfide donor to a blood substitute at 21°C and 37°C, although kidney functional outcomes improved, the experimental setup required significant manpower to meet kidney metabolic demands. Further, while hydrogen sulfide-based organ storage at 4°C demonstrates good results, recent evidence reveals that 4°C storage could be contributing to kidney injury. Previous studies suggest that organs stored at 10°C do not require extensive oxygen due to reduced organ metabolism at this temperature. Moreover, preservation of human lungs, liver, and hearts at 10°C improved patient outcomes. Therefore, the aim of this thesis is to evaluate the impact of supplementing kidney preservation solutions with sodium thiosulfate (STS), a clinically approved hydrogen sulfide donor, and Hemopure, a clinically viable blood substitute, for 10°C rat kidney storage and evaluate functional outcomes following transplantation. We used a combination of cellular and rat kidney perfusion models to investigate the effects of adding STS and Hemopure during kidney preservation at 10°C. We found that kidney preservation at 10°C with STS and Hemopure reduced kidney injury and improved kidney function. Overall, we provided a novel approach to kidney preservation that may reduce the incidence of tissue damage that is associated with cold preservation. The eventual clinical translation of these findings may pave the way for future clinical studies to improve kidney transplant patient outcomes.

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