Renal transplantation remains the best treatment option for patients with end-stage renal failure. However, the shortage of renalgrafts remains a big challenge. Renal graft ischemic injuries that occur before and after graft retrieval have a devastating effect on graft survival, especially on grafts from marginal donors. This study was conducted to assess the protective effect against ischemic injury of a preservative solution supplemented with xenon (Xe), when used on exvivo kidney grafts in a rat renal transplant model, and to explore the underlying mechanisms in vitro. Lewis rat renalgrafts were stored in Soltran preservative solution at 4°C, saturated with nitrogen (N₂) or Xe gas (70% Xe or N₂, with 5% CO₂ balanced with O₂) for 24 or 48 h. Grafts stored in Xe-saturated preservative solution demonstrated significantly less severe histopathologic changes, together with enhanced B-cell lymphoma (Bcl)-2 and heat shock protein (HSP)-70 expression. After engraftment in the Lewis rat recipient, renal function was significantly improved in the Xe-treated grafts, and macrophage infiltration and fibrosis were reduced. Xe exposure enhanced Bcl-2 and HSP-70 expression in human renal tubular epithelial (HK-2) cells and prevented mitochondrial and nuclear damage. The release of the apoptogenic factors cytochrome c, apoptosis-inducing factor (AIF), and proinflammatory high-mobility group protein B1 (HMGB-1) was effectively suppressed. This study thus demonstrated for the first time that Xe confers renoprotection on renalgraftsexvivo and is likely to stabilize cellular structure during ischemic insult. The current study has significant clinical implications, in which the use of Xe exvivo could enhance the marginaldonorpool of renalgrafts by preventing graft loss due to ischemia.-Zhao, H., Ning, J., Savage, S., Kang, H., Lu, K., Zheng, X., George, A. J. T., Ma D. A novelstrategy for preservingrenalgrafts in an exvivosetting: potential for enhancing the marginaldonorpool.