Inserm U927, Ischémie-Reperfusion en Transplantation Rénale; Université de Poitiers Faculté de Medecine et de Pharmacie, Poitiers, France.
Transplantation. 2010 Sep 27;90(6):612-21. doi: 10.1097/tp.0b013e3181d72117.
Ischemia-reperfusion injury (IRI) is an unavoidable component of transplantation and correlates with delayed graft function, acute rejection, chronic fibrosis, and graft loss. Currently, new donor pools are considered to alleviate pressure on waiting lists, such as deceased after cardiac death donors (DCD) and extended criteria donors. Because these organs are particularly sensitive to IRI, there is a need for novel preservation paradigms. We assessed the effect of anticoagulation therapy during graft preservation on IRI and graft outcome.
In a large white autotransplanted pig model, kidneys underwent warm ischemia for 60 min, mimicking DCD, then were preserved for 24 hr at 4°C, in University of Wisconsin solution. Animals were followed up 3 months, functional, histologic, and molecular parameters were assessed. In treated groups, antithrombin was added to collection and preservation protocols.
Treatment improved chronic graft function, reduced tubular atrophy, and substantially increased animal survival. Quantitative polymerase chain reaction analysis determined that markers of inflammation, such as interferon-[gamma], tumor necrosis factor-[alpha], interleukin (IL)-2, -1Rn, and -10, were significantly reduced in treated grafts. Histologic analysis revealed a lowering of CD3+ invasion. P selectin and C3 mRNA expressions were reduced in treated groups, indicative of lowered complement production and endothelial cell activation. Vascular endothelium growth factor protein expression was up-regulated, suggesting vascular network remodeling.
Inhibition of thrombin during preservation of DCD graft preserved renal integrity and function, protecting against chronic inflammation and tissue damage. Thus, coagulation seems to be a critical target for the development of therapeutic strategies to improve kidney quality for transplantation.
缺血再灌注损伤（IRI）是移植过程中不可避免的组成部分，与延迟移植物功能、急性排斥反应、慢性纤维化和移植物丢失有关。目前，新的供体来源被认为可以缓解等待名单的压力，例如心脏死亡后供体（DCD）和扩展标准供体。由于这些器官对 IRI 特别敏感，因此需要新的保存范式。我们评估了在保存过程中抗凝治疗对 IRI 和移植物结局的影响。
在大型白色自体移植猪模型中，肾脏经历了 60 分钟的热缺血，模拟 DCD，然后在 4°C 的威斯康星大学溶液中保存 24 小时。动物被随访 3 个月，评估功能、组织学和分子参数。在治疗组中，在收集和保存方案中添加了抗凝血酶。
治疗改善了慢性移植物功能，减少了肾小管萎缩，并大大提高了动物存活率。定量聚合酶链反应分析确定，干扰素-[γ]、肿瘤坏死因子-[α]、白细胞介素（IL）-2、-1Rn 和-10 等炎症标志物在治疗组的移植物中显著减少。组织学分析显示 CD3+浸润减少。治疗组 P 选择素和 C3mRNA 的表达降低，表明补体产生和内皮细胞激活降低。血管内皮生长因子蛋白表达上调，提示血管网络重塑。
在 DCD 移植物保存过程中抑制凝血酶可保持肾脏完整性和功能，防止慢性炎症和组织损伤。因此，凝血似乎是开发改善移植质量的治疗策略的关键靶点。
