| 六基因编辑猪-食蟹猴异种肾移植围手术期监测初步报道 |
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| 引用本文： | 杨树军, 卫浩, 许勇, 等. 六基因编辑猪-食蟹猴异种肾移植围手术期监测初步报道[J]. 器官移植, 2023, 14(4): 521-528. doi: 10.3969/j.issn.1674-7445.2023.04.008 |
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| 作者姓名： | 杨树军 卫浩 许勇 王恒恩 宋翔宇 贾志博 彭江 崔梦一 杨博尧 陈蕾佳 郭爱桃 张小丽 潘登科 杜嘉祥 尚攀峰 孙圣坤 |
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| 作者单位： | 730030 兰州，兰州大学第二医院泌尿外科 兰州大学第二临床医学院（杨树军、尚攀峰）；青岛大学泌尿外科（卫浩）；中国人民解放军总医院第三医学中心泌尿外科（许勇、王恒恩、孙圣坤），病理科（郭爱桃），检验科（张小丽）；中国人民解放军总医院第四医学中心骨科医学部骨科研究所（宋翔宇、贾志博、彭江、崔梦一、杨博尧、陈蕾佳）；中科奥格生物科技有限公司（潘登科、杜嘉祥） |
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| 基金项目： | 国家重点专项研发计划（2019YFA0110704）； |
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| 摘 要： | 目的 探讨六基因编辑猪-非人灵长类动物异种肾移植模型的构建。方法 将人源化基因编辑猪（GTKO/β4GalNT2KO/CMAHKO/hCD55/hCD46/hTBM）的肾脏移植给食蟹猴，观察受体存活情况及恢复血流灌注后肾脏情况。定期监测肾脏实质回声、血流变化及大小；进行血常规、肾功能检测及电解质检测；监测尿液、粪便及体质量动态变化。食蟹猴生命终点取移植肾、心脏、肝脏、脾脏、肺脏、盲肠行病理学检查。结果 受体术后7 d死亡。恢复血流后，肾脏灌注良好，器官质地柔软，色泽正常。受体生命终点时见肾脏腹侧有少量脓性分泌物附着，明显充血肿大，呈“大红肾”外观。术后随时间延长，肾实质回声增高，血流减少，皮质逐渐增厚，肾周及腹腔有少量积液。受体术后外周血红细胞、血红蛋白、白蛋白及血小板进行性下降，血清肌酐在术后7 d升高至308 μmol/L，K+变化不大。术后即有淡黄色尿液排出，术后3 h内即恢复饮食及饮水并排淡黄色成形大便1次。术后1 d内尿液颜色逐渐变淡红至恢复正常，尿常规检测结果相符。术后2 d晨起排褐色血便2次，量较多，予以奥美拉唑进行抑酸治疗，至术后4 d大便恢复正常。β2-微球蛋白在术后7 d增至0.75 mg/L。体质量增加1.7 kg。尸检病理学检查发现移植肾间质水肿出血，大量淋巴细胞和巨噬细胞浸润，小动脉壁及动脉腔内淋巴细胞浸润，有动脉炎改变；盲肠间质有淋巴细胞浸润；脾脏组织有淤血表现；其余器官未见明显异常改变。结论 人源化基因编辑猪-非人灵长类动物异种肾移植模型构建获得初步成功，术后受体存活时间达1周。
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| 关 键 词： | 异种移植 肾移植 基因编辑猪 食蟹猴 排斥反应 α-1 3-半乳糖苷转移酶 β-1 4-N-乙酰氨基半乳糖转移酶2 补体调节蛋白 |
| 收稿时间： | 2023-04-04 |
Preliminary report of perioperative monitoring of six-gene-edited pig-to-cynomolgus monkey kidney xenotransplantation |
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| Yang Shujun, Wei Hao, Xu Yong, et al. Preliminary report of perioperative monitoring of six-gene-edited pig-to-cynomolgus monkey kidney xenotransplantation[J]. ORGAN TRANSPLANTATION, 2023, 14(4): 521-528. doi: 10.3969/j.issn.1674-7445.2023.04.008 |
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| Authors: | Yang Shujun Wei Hao Xu Yong Wang Heng'en Song Xiangyu Jia Zhibo Peng Jiang Cui Mengyi Yang Boyao Chen Leijia Guo Aitao Zhang Xiaoli Pan Dengke Du Jiaxiang Shang Panfeng Sun Shengkun |
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| Affiliation: | Department of Urology, Second Hospital of Lanzhou University, the Second Clinical Medical College of Lanzhou University, Lanzhou 730030, China |
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| Abstract: | Objective To investigate the establishment of a six-gene-edited pig-to-non-human primate kidney xenotransplantation model. Methods The kidney of humanized genetically-edited pig (GTKO/β4GalNT2KO/CMAHKO/hCD55/hCD46/hTBM) was transplanted into a cynomolgus monkey. The survival of the recipient and kidney condition after blood perfusion were observed. The parenchymal echo, blood flow changes, and size of the kidney were monitored on a regular basis. Routine blood test, kidney function test and electrolyte assessment were carried out. Dynamic changes of urine, feces and body mass were monitored. At the end of life, the transplant kidney, heart, liver, spleen, lung, and cecum were collected for pathological examination. Results The recipient died at postoperative 7 d. After blood flow was restored, the kidney was properly perfused, the organ was soft and the color was normal. At the end of the recipient's life, a slight amount of purulent secretion was attached to the ventral side of the kidney, with evident congestion and swelling, showing the appearance of "red kidney". Postoperatively, the echo of renal parenchyma was increased, blood flow was decreased, the cortex was gradually thickened, and a slight amount of effusion surrounded the kidney and abdominal cavity over time. In the recipient, the amount of peripheral red blood cells, hemoglobin, albumin, and platelets was progressively decreased, and serum creatinine level was increased to 308 μmol/L at postoperative 7 d, whereas the K+ concentration did not significantly change. Light yellow urine was discharged immediately after surgery, diet and drinking water were resumed within postoperative 3 h, and light yellow and normal-shape stool was discharged. The reddish urine was gradually restored to normal color within postoperative 1 d, which were consistent with the results of the routine urine test. A large amount of brown bloody stool was discharged twice in the morning of 2 d after surgery. Omeprazole was given for acid suppression, and the stool returned to normal at postoperative 4 d. The β2-microglobulin level was increased to 0.75 mg/L at postoperative 7 d. The body mass was increased by 1.7 kg. Autopsy pathological examination showed interstitial edema and bleeding of the transplant kidney, a large amount of infiltration of lymphocytes and macrophages, infiltration of lymphocytes in the arteriole wall and arterial cavity, accompanied by arteritis changes, lymphocyte infiltration in the cecal stroma and congestion in the spleen tissues. No significant abnormal changes were observed in other organs. Conclusions The humanized genetically-edited pig-to-non-human primate kidney xenotransplantation model is successfully established, and postoperative survival of the recipient is 1 week. |
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| Keywords: | Xenotransplantation Kidney transplantation Gene-edited pig Cynomolgus monkey Rejection α-1, 3-galactosyltransferase β-1, 4 N-acetylg alactosaminyltransferase 2 Complement regulatory protein |
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