1D.M., Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, 369 Fulham Rd., London SW10 9NH, UK.
FASEB J. 2013 Dec;27(12):4822-33. doi: 10.1096/fj.13-236810. Epub 2013 Aug 9.
Renal transplantation remains the best treatment option for patients with end-stage renal failure. However, the shortage of renal grafts 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 ex vivo kidney grafts in a rat renal transplant model, and to explore the underlying mechanisms in vitro. Lewis rat renal grafts 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 renal grafts ex vivo and is likely to stabilize cellular structure during ischemic insult. The current study has significant clinical implications, in which the use of Xe ex vivo could enhance the marginal donor pool of renal grafts by preventing graft loss due to ischemia.
肾移植仍然是终末期肾衰竭患者的最佳治疗选择。然而，肾移植物的短缺仍然是一个巨大的挑战。在移植物获取前后发生的肾移植物缺血性损伤对移植物的存活有破坏性影响，特别是对来自边缘供体的移植物。本研究旨在评估在大鼠肾移植模型中，用富含氙气（Xe）的保存液处理离体肾移植物对缺血性损伤的保护作用，并在体外探索其潜在机制。将Lewis 大鼠肾移植物保存在 Soltran 保存液中，在 4°C 下用氮气（N2）或氙气（70%Xe 或 N2，5%CO2 用 O2 平衡）饱和，保存 24 或 48 小时。保存在 Xe 饱和保存液中的移植物表现出明显较轻的组织病理学变化，同时 B 细胞淋巴瘤（Bcl）-2 和热休克蛋白（HSP）-70 的表达增强。在 Lewis 大鼠受体内移植后，Xe 处理的移植物的肾功能显著改善，巨噬细胞浸润和纤维化减少。Xe 暴露增强了人肾小管上皮（HK-2）细胞中的 Bcl-2 和 HSP-70 表达，并防止了线粒体和核损伤。凋亡原性因子细胞色素 c、凋亡诱导因子（AIF）和促炎高迁移率族蛋白 B1（HMGB-1）的释放得到有效抑制。因此，本研究首次证明 Xe 对离体肾移植物具有肾保护作用，并且可能在缺血性损伤期间稳定细胞结构。本研究具有重要的临床意义，因为 Xe 的离体应用可以通过防止因缺血导致的移植物丢失来增加肾移植物的边缘供体库。
