Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, Western University, London, Ontario, Canada; Multi-Organ Transplant Program, Western University, London Health Sciences Center, Western University, London, Ontario, Canada.
Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, Western University, London, Ontario, Canada; Department of Surgery, Division of Urology, London Health Sciences Center, Western University, London, Ontario, Canada; Multi-Organ Transplant Program, Western University, London Health Sciences Center, Western University, London, Ontario, Canada; Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon, Accra, Ghana.
Biomed Pharmacother. 2022 Jan;145:112435. doi: 10.1016/j.biopha.2021.112435. Epub 2021 Nov 17.
Cold ischemia-reperfusion injury (IRI) is an inevitable event that increases post-transplant complications. We have previously demonstrated that supplementation of University of Wisconsin (UW) solution with non-FDA-approved hydrogen sulfide (HS) donor molecules minimizes cold IRI and improves renal graft function after transplantation. The present study investigates whether an FDA-approved HS donor molecule, sodium thiosulfate (STS), will have the same or superior effect in a clinically relevant rat model of syngeneic orthotopic kidney transplantation.
Thirty Lewis rats underwent bilateral nephrectomy followed by syngeneic orthotopic transplantation of the left kidney after 24-hour preservation in either UW or UW+STS solution at 4 °C. Rats were monitored to post-transplant day 14 and sacrificed to assess renal function (urine output, serum creatinine and blood urea nitrogen). Kidney sections were stained with H&E, TUNEL, CD68, and myeloperoxidase (MPO) to detect acute tubular necrosis (ATN), apoptosis, macrophage infiltration, and neutrophil infiltration.
UW+STS grafts showed significantly improved graft function immediately after transplantation, with improved recipient survival compared to UW grafts (p < 0.05). Histopathological examination revealed significantly reduced ATN, apoptosis, macrophage and neutrophil infiltration and downregulation of pro-inflammatory and pro-apoptotic genes in UW+STS grafts compared to UW grafts (p < 0.05).
We show for the first time that preservation of renal grafts in STS-supplemented UW solution protects against prolonged cold IRI by suppressing apoptotic and inflammatory pathways, and thereby improving graft function and prolonging recipient survival. This could represent a novel clinically applicable therapeutic strategy to minimize the detrimental clinical outcome of prolonged cold IRI in kidney transplantation.
冷缺血再灌注损伤（IRI）是增加移植后并发症的不可避免事件。我们之前已经证明，在威斯康星大学（UW）溶液中补充非 FDA 批准的硫化氢（HS）供体分子可最大限度地减少冷 IRI，并改善移植后的肾脏移植物功能。本研究调查了 FDA 批准的 HS 供体分子硫代硫酸钠（STS）在同种异体原位肾移植的临床相关大鼠模型中是否具有相同或更好的效果。
30 只 Lewis 大鼠接受双侧肾切除术，然后在 4°C 下在 UW 或 UW+STS 溶液中保存 24 小时后进行左侧肾脏的同基因原位移植。大鼠在移植后第 14 天进行监测，并进行安乐死以评估肾功能（尿量、血清肌酐和血尿素氮）。肾脏切片用 H&E、TUNEL、CD68 和髓过氧化物酶（MPO）染色，以检测急性肾小管坏死（ATN）、凋亡、巨噬细胞浸润和中性粒细胞浸润。
UW+STS 移植物在移植后立即显示出明显改善的移植物功能，与 UW 移植物相比，受体存活率得到提高（p<0.05）。组织病理学检查显示，与 UW 移植物相比，UW+STS 移植物的 ATN、凋亡、巨噬细胞和中性粒细胞浸润明显减少，促炎和促凋亡基因的表达下调（p<0.05）。
我们首次表明，在 STS 补充的 UW 溶液中保存肾移植物可通过抑制凋亡和炎症途径来防止长时间的冷 IRI，从而改善移植物功能并延长受体的存活。这可能代表一种新的临床适用的治疗策略，可最大限度地减少肾移植中长时间冷 IRI 的不利临床结局。
