Department of Surgery, University of Saskatchewan, St. Paul's Hospital, 1702 - 20th Street West, Saskatoon, SK, S7M 0Z9, Canada.
Saskatchewan Renal Transplant Program, Saskatoon, SK, Canada.
Sci Rep. 2020 Dec 17;10(1):22272. doi: 10.1038/s41598-020-79440-6.
Kidney injury during donation after circulatory determination of death (DCDD) includes warm ischemic (WI) injury from around the time of asystole, and cold ischemic (CI) injury during cold preservation. We have previously shown that Matrix Metalloproteinases (MMPs) are involved in CI injury and that Doxycycline (Doxy), an antibiotic and known MMP inhibitor, protects the transplant kidney during CI. The purpose of our study was to determine if Doxy given before asystole can also prevent injury during WI. A rat model of DCDD was used, including Control, Preemptive Doxy (45 mg/kg iv), and Preemptive and Perfusion (100 microM) Doxy groups. Thirty minutes after asystole, both kidneys were removed. The left kidney was perfused at 4 °C for 22 h, whereas the right was used to establish the degree of warm ischemic injury prior to cold preservation. MMP-2 in the perfusate was significantly reduced in both treatment groups [Control 43.7 ± 7.2 arbitrary units, versus Preemptive Doxy group 23.2 ± 5.5 (p = 0.03), and 'Preemptive and Perfusion' group 18.0 ± 5.6 (p = 0.02)]. Reductions in NGAL, LDH, and MMP-9 were also seen. Electron microscopy showed a marked reduction in mitochondrial injury scores in the treatment groups. Pre-arrest Doxy was associated with a reduction in injury markers and morphologic changes. Doxy may be a simple and safe means of protecting transplant kidneys from both WI and CI.
在循环判定死亡（DCDD）后的供体器官捐献过程中，肾脏损伤包括心脏停搏时的热缺血（WI）损伤和冷保存期间的冷缺血（CI）损伤。我们之前已经表明，基质金属蛋白酶（MMPs）参与了 CI 损伤，并且多西环素（Doxy）作为一种抗生素和已知的 MMP 抑制剂，在 CI 期间可以保护移植肾脏。我们的研究目的是确定在心脏停搏前给予 Doxy 是否也可以预防 WI 期间的损伤。我们使用了大鼠 DCDD 模型，包括对照组、预防性 Doxy（45mg/kg iv）组和预防性加灌注（100 microM）Doxy 组。心脏停搏后 30 分钟，取出双侧肾脏。左侧肾脏在 4°C 下进行灌注 22 小时，而右侧肾脏用于在冷保存前建立 WI 损伤的程度。两种治疗组的灌流液中 MMP-2 明显减少[对照组 43.7±7.2 任意单位，而预防性 Doxy 组 23.2±5.5（p=0.03），以及“预防性加灌注”组 18.0±5.6（p=0.02）]。NGAL、LDH 和 MMP-9 的减少也被观察到。电子显微镜显示，治疗组的线粒体损伤评分明显降低。心脏停搏前的 Doxy 与损伤标志物和形态学变化的减少有关。Doxy 可能是一种简单而安全的方法，可以保护移植肾脏免受 WI 和 CI 的损伤。
