Huang Edmund, Ammerman Noriko, Vo Ashley, Hou Jean, Kumar Sanjeev, Badash Nicole, Falk Ben, Hernando Kathleen, Gillespie Matthew, Kim Irene K, Lim Kathlyn, Najjar Reiad, Peng Alice, Shin Bongha, Steggerda Justin A, Todo Tsuyoshi, Brennan Todd V, Voidonikolas Georgios, Wisel Steven A, Heeger Peter S, Jordan Stanley C
Departments of Medicine and Surgery, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Departments of Medicine and Surgery, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Am J Transplant. 2025 Sep;25(9):1926-1939. doi: 10.1016/j.ajt.2025.05.003. Epub 2025 May 9.
Ischemia-reperfusion injury commonly causes delayed graft function (DGF) after kidney transplantation and is associated with poorer graft function and lower allograft survival. Activation of the lectin complement pathway is one mediator of ischemia-reperfusion injury. In this randomized double-blind placebo-controlled pilot study, we tested whether preimplantation intragraft administration of C1 esterase inhibitor (C1INH, a lectin/classical pathway inhibitor) into deceased donor organs improves graft function and/or reduces DGF. Forty patients were randomized 1:1 to receive allografts treated with 500 units C1INH or placebo (normal saline) into the transplant renal artery during back-table preparation. We observed no effect on DGF, but recipients of C1INH-treated allografts showed higher estimated glomerular filtration rate than recipients of placebo at 6 months (C1INH median: 55 mL/min/1.73 m, interquartile range [IQR]: 42-63; placebo median: 39 mL/min/1.73 m, IQR: 34-50; P = .02) and 30 months (C1INH median: 54 mL/min/1.73 m, IQR: 47-66; placebo median: 43 mL/min/1.73 m, IQR 38-51; P = .03), with no differences in adverse events. Analysis of postreperfusion biopsies showed positive intra-arterial C1INH staining and reduced C4d staining in C1INH-treated grafts compared with controls. Posttransplant serum mannose-binding lectin and classical pathway activity and bradykinin levels did not differ between study arms. We conclude that this treatment strategy improves allograft function independent of DGF, likely via local intragraft complement inhibition. Clinical trial registration number: NCT04696146.
缺血再灌注损伤通常会导致肾移植后出现移植肾功能延迟恢复（DGF），并与移植肾功能较差和移植肾存活率较低相关。凝集素补体途径的激活是缺血再灌注损伤的一种介质。在这项随机双盲安慰剂对照的试点研究中，我们测试了在植入前将C1酯酶抑制剂（C1INH，一种凝集素/经典途径抑制剂）经肾动脉注入脑死亡供体器官，是否能改善移植肾功能和/或降低DGF。40名患者按1:1随机分组，在后台准备期间，接受移植肾动脉内注入500单位C1INH或安慰剂（生理盐水）处理的同种异体移植物。我们观察到对DGF没有影响，但在6个月时，接受C1INH处理的同种异体移植物的受者的估计肾小球滤过率高于接受安慰剂的受者（C1INH中位数：55 mL/min/1.73 m²，四分位间距[IQR]：42 - 63；安慰剂中位数：39 mL/min/1.73 m²，IQR：34 - 50；P = 0.02），在30个月时也是如此（C1INH中位数：54 mL/min/1.73 m²，IQR：47 - 66；安慰剂中位数：43 mL/min/1.73 m²，IQR 38 - 51；P = 0.03），不良事件无差异。再灌注后活检分析显示，与对照组相比，C1INH处理的移植物中动脉内C1INH染色呈阳性，C4d染色减少。研究组之间移植后血清甘露糖结合凝集素、经典途径活性和缓激肽水平没有差异。我们得出结论，这种治疗策略可独立于DGF改善同种异体移植物功能，可能是通过移植物内局部补体抑制实现的。临床试验注册号：NCT04696146。
