Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Microbiology and Immunology

Abstract

Kidney transplantation is the preferred treatment for patients with end-stage renal disease. However, ischemia-reperfusion injury (IRI) is an inevitable consequence of renal transplantation, with prolonged IRI periods associated with decreased graft survival and function. We have previously demonstrated that the supplementation of University of Wisconsin (UW) organ preservation solution with hydrogen sulfide (H2S) donor molecules, such as AP39, leads to improved renal graft function and reduced transplantation-associated IRI. However, the approval of these experimental donor drugs for clinical use may be years away. In this study, we investigate the effects of an FDA-approved H2S donor molecule, sodium thiosulfate (STS), to determine whether STS could mitigate cold renal IRI. In an in vitro model of renal IRI, adding STS to serum free media improved cell viability for cold preservation at 40C in a dose-dependent manner. Using a syngeneic renal transplantation model, we investigate the effect of adding STS to University of Wisconsin (UW) preservation solution, the clinical standard for preservation solution in static cold storage. Adding 150µM STS to UW solution improves graft survival, urine output and serum creatinine and blood urea nitrogen levels compared to preservation storage with UW solution alone.. Histopathological examination reveals a reduction in apoptosis and acute tubular necrosis along with decreased macrophage and neutrophil infiltration. Additionally, STS-supplemented preservation solution induced mitochondrial biogenesis and reduced renal apoptosis and inflammation gene expression. These data suggest that STS treatment on cold IRI-associated renal injury could represent a novel clinically applicable strategy to minimize the detrimental outcomes of prolonged cold IRI during renal transplantation.

Summary for Lay Audience

Kidney transplantation is inherently associated with ischemia-reperfusion injury (IRI), a biological event that causes tissue damage to the transplanted kidney organ. Current methods to minimize IRI involves preserving the kidney in University of Wisconsin (UW) solution at cold temperatures. However, this kidney preservation method has persisted in its most simple form, as this method has not changed since its conception 60 years ago. Contrastingly, due to its low supply, more kidneys with increased cold IRI times are being accepted and used for transplantation to keep up with its high demand. Sodium thiosulfate (STS) is a clinical drug used to treat patients with calciphylaxis and cyanide poisoning. In the past decade, numerous studies have elucidated some of the protective effects of STS on hypertension and IRI on other organs, such as liver, heart and brain. Here we sought to determine if STS plays a beneficial role in minimizing cold IRI associated with kidney transplantation. We concluded that preservation of renal grafts in STS-supplemented UW solution protects against prolonged IRI by suppressing apoptotic and inflammatory pathways, and thereby improving graft function and recipient survival. With STS being an FDA-approved compound, its protective benefits could serve as a novel clinically applicable therapeutic strategy to mitigate the harmful outcomes of prolonged IRI during kidney transplantation.

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