Protective benefits of sodium thiosulfate-supplemented UW solution against prolonged cold ischemia-reperfusion injury during renal transplantation.
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.