Idouz Kaoutar, Belhaj Asmae, Rondelet Benoit, Dewachter Laurence, Flamion Bruno, Kirschvink Nathalie, Dogné Sophie
Molecular Physiology Research Unit (URPhyM), Namur Research Institute for Life Sciences (NARILIS), University of Namur (Unamur), Namur, Belgium.
Department of Cardio-Vascular, Thoracic Surgery and Lung Transplantation, CHU UCL Namur, UCLouvain, Yvoir, Belgium.
Front Cell Dev Biol. 2024 Aug 6;12:1449209. doi: 10.3389/fcell.2024.1449209. eCollection 2024.
Brain death (BD) is a complex medical state that triggers systemic disturbances and a cascade of pathophysiological processes. This condition significantly impairs both kidney function and structural integrity, thereby presenting considerable challenges to graft viability and the long-term success of transplantation endeavors. Tacrolimus (FK506), an immunosuppressive drug, was used in this study to assess its impact as a pretreatment on brain death-induced renal injury. This study aimed to investigate changes associated with brain death-induced renal injury in a 4-month-old female porcine model. The experimental groups included brain death placebo-pretreated (BD; n = 9), brain death tacrolimus-pretreated using the clinical dose of 0.25 mg/kg the day before surgery, followed by 0.05 mg/kg/day 1 hour before the procedure (BD + FK506; n = 8), and control (ctrl, n = 7) piglets, which did not undergo brain death induction. Furthermore, we aimed to assess the effect of FK506 on these renal alterations through graft preconditioning. We hypothesized that immunosuppressive properties of FK506 reduce tissue inflammation and preserve the glycocalyx. Our findings revealed a series of interconnected events triggered by BD, leading to a deterioration of renal function and increased proteinuria, increased apoptosis in the vessels, glomeruli and tubules, significant leukocyte infiltration into renal tissue, and degradation of the glycocalyx in comparison with ctrl group. Importantly, treatment with FK506 demonstrated significant efficacy in attenuating these adverse effects. FK506 helped reduce apoptosis, maintain glycocalyx integrity, regulate neutrophil infiltration, and mitigate renal injury following BD. This study offers new insights into the pathophysiology of BD-induced renal injury, emphasizing the potential of FK506 pretreatment as a promising therapeutic intervention for organ preservation, through maintaining endothelial function with the additional benefit of limiting the risk of rejection.
脑死亡（BD）是一种复杂的医学状态，会引发全身紊乱和一系列病理生理过程。这种情况会严重损害肾功能和结构完整性，从而给移植器官的存活能力以及移植手术的长期成功带来巨大挑战。他克莫司（FK506）是一种免疫抑制药物，本研究使用该药物来评估其作为预处理对脑死亡诱导的肾损伤的影响。本研究旨在调查4月龄雌性猪模型中与脑死亡诱导的肾损伤相关的变化。实验组包括脑死亡安慰剂预处理组（BD；n = 9）、术前一天使用0.25mg/kg临床剂量的他克莫司进行预处理，然后在手术前1小时使用0.05mg/kg/天进行预处理的脑死亡他克莫司预处理组（BD + FK506；n = 8），以及未进行脑死亡诱导的对照组（ctrl，n = 7）仔猪。此外，我们旨在通过移植预处理评估FK506对这些肾脏改变的影响。我们假设FK506的免疫抑制特性可减轻组织炎症并保留糖萼。我们的研究结果揭示了由BD引发的一系列相互关联的事件，导致肾功能恶化、蛋白尿增加、血管、肾小球和肾小管中的细胞凋亡增加、肾组织中大量白细胞浸润以及与ctrl组相比糖萼降解。重要的是，FK506治疗在减轻这些不良反应方面显示出显著疗效。FK506有助于减少细胞凋亡、维持糖萼完整性、调节中性粒细胞浸润并减轻BD后的肾损伤。本研究为BD诱导的肾损伤的病理生理学提供了新的见解，强调了FK506预处理作为一种有前景的器官保存治疗干预措施的潜力，通过维持内皮功能并额外降低排斥风险。
