First clinical-grade porcine kidney xenotransplant using a human decedent model
First clinical-grade porcine kidney xenotransplant using a human decedent model
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DOI：
10.1111/ajt.16930
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发表时间：
2022-01-20
影响因子：
8.8
通讯作者：
Locke, Jayme E.
中科院分区：
文献类型：
--
作者：
Porrett, Paige M.;Orandi, Babak J.;Locke, Jayme E.
器官供应危机需要一个根本的解决方案，而家猪是一个有前途的器官来源。为了准备异种移植的临床试验，我们开发了一种体内临床前人体模型，以测试在动物模型中建立的安全性和可行性原则。在进行了一项新的、前瞻性相容性交叉配型后，我们对一名脑死亡的死者进行了双侧自体肾切除术，随后从一只经过基因工程改造的猪身上移植了两个肾脏用于人类异种移植。死亡动物在再灌注过程中血流动力学稳定，尽管异种移植物暴露于人体血压，但血管完整性得以维持。未观察到超急性排斥反应，肾脏保持活力，直至74小时后处死。未检测到嵌合体或猪逆转录病毒的传播。纵向活检显示血栓性微血管病的严重程度没有进展，没有细胞排斥反应或抗体或补体蛋白沉积的证据。尽管异种移植物产生了不同量的尿液，但肌酐清除率没有恢复。肾恢复是否受到脑死亡和/或微血管损伤环境的影响仍不清楚。总之，我们的研究表明，人类异种移植的主要障碍已经被克服，并确定了优化人类异种移植结果所需的新知识。
A radical solution is needed for the organ supply crisis, and the domestic pig is a promising organ source. In preparation for a clinical trial of xenotransplantation, we developed an in vivo pre-clinical human model to test safety and feasibility tenets established in animal models. After performance of a novel, prospective compatible crossmatch, we performed bilateral native nephrectomies in a human brain-dead decedent and subsequently transplanted two kidneys from a pig genetically engineered for human xenotransplantation. The decedent was hemodynamically stable through reperfusion, and vascular integrity was maintained despite the exposure of the xenografts to human blood pressure. No hyperacute rejection was observed, and the kidneys remained viable until termination 74 h later. No chimerism or transmission of porcine retroviruses was detected. Longitudinal biopsies revealed thrombotic microangiopathy that did not progress in severity, without evidence of cellular rejection or deposition of antibody or complement proteins. Although the xenografts produced variable amounts of urine, creatinine clearance did not recover. Whether renal recovery was impacted by the milieu of brain death and/or microvascular injury remains unknown. In summary, our study suggests that major barriers to human xenotransplantation have been surmounted and identifies where new knowledge is needed to optimize xenotransplantation outcomes in humans.