Department of Surgery, University of Cambridge, Cambridge, UK.
MRC Mitochondrial Biology Unit, Cambridge, UK.
Br J Surg. 2021 Sep 27;108(9):1072-1081. doi: 10.1093/bjs/znab108.
Ischaemia-reperfusion (IR) injury makes a major contribution to graft damage during kidney transplantation. Oxidative damage to mitochondria is an early event in IR injury. Therefore, the uptake, safety, and efficacy of the mitochondria-targeted antioxidant MitoQ were investigated in models of transplant IR injury.
MitoQ uptake by warm and cooled pairs of pig and declined human kidneys was measured when preserved in cold static storage or by hypothermic machine perfusion. Pairs of pigs' kidneys were exposed to defined periods of warm and cold ischaemia, flushed and stored at 4°C with or without MitoQ (50 nmol/l to 250 µmol/l), followed by reperfusion with oxygenated autologous blood in an ex vivo normothermic perfusion (EVNP). Pairs of declined human kidneys were flushed and stored with or without MitoQ (5-100 µmol/l) at 4°C for 6 h and underwent EVNP with ABO group-matched blood.
Stable and concentration-dependent uptake of MitoQ was demonstrated for up to 24 h in pig and human kidneys. Total blood flow and urine output were significantly greater in pig kidneys treated with 50 µmol/l MitoQ compared with controls (P = 0.006 and P = 0.007 respectively). In proof-of-concept experiments, blood flow after 1 h of EVNP was significantly greater in human kidneys treated with 50 µmol/l MitoQ than in controls (P ≤ 0.001). Total urine output was numerically higher in the 50-µmol/l MitoQ group compared with the control, but the difference did not reach statistical significance (P = 0.054).
Mitochondria-targeted antioxidant MitoQ can be administered to ischaemic kidneys simply and effectively during cold storage, and may improve outcomes after transplantation.
缺血再灌注（IR）损伤在肾移植过程中对移植物损伤有重要贡献。线粒体的氧化损伤是 IR 损伤的早期事件。因此，研究了靶向线粒体的抗氧化剂 MitoQ 在移植 IR 损伤模型中的摄取、安全性和疗效。
当在冷静态保存或低温机器灌注中保存时，测量了温暖和冷却的猪和人类供肾对 MitoQ 的摄取，并测量了冷缺血期间配对的猪和人类供肾的摄取。将猪的肾脏暴露于规定的温热和冷缺血期，冲洗并在 4°C 下用或不用 MitoQ（50nmol/L 至 250µmol/L）保存，然后在离体常温灌注（EVNP）中用含氧自体血液再灌注。将冷保存的人类供肾用或不用 MitoQ（5-100µmol/L）在 4°C 下保存 6 小时，并与 ABO 匹配的血液进行 EVNP。
在猪和人类肾脏中，MitoQ 的摄取稳定且呈浓度依赖性，可达 24 小时。与对照组相比，用 50µmol/L MitoQ 处理的猪肾的总血流量和尿量明显增加（P=0.006 和 P=0.007）。在概念验证实验中，与对照组相比，用 50µmol/L MitoQ 处理的人类肾脏在 EVNP 后 1 小时的血流量明显增加（P≤0.001）。与对照组相比，50µmol/L MitoQ 组的总尿量较高，但差异无统计学意义（P=0.054）。
在冷保存期间，简单有效地给予缺血肾脏靶向线粒体抗氧化剂 MitoQ，可能改善移植后的结局。
