移植肾慢性排异反应与肾内微淋巴管的增生

Chronic rejection and microlymphatic vessel hyperplasia of transplanted kidney

背景:在慢性肾移植排斥反应中,随着排斥的加重,微淋巴管增生程度亦随之增高,排斥反应时,组织间浸润的巨噬细胞分泌血管内皮细胞生长因子C、D,激活血管内皮细胞生长因子受体3,从而引起微淋巴管增生。但尚无实验证实该理论。目的:采用肾小球足细胞膜黏蛋白及血管内皮生长因子受体、CD68分别双重免疫组织化学染色方法,量化移植肾组织中的微淋巴管密度、血管内皮细胞生长因子受体及CD68密度,探讨3者关系及内在意义。设计、时间及地点:以细胞为对象的观察实验,于2005-09/2007-05在解放军南京军区福州总医院器官移植中心完成。材料:50份移植肾切除组织标本来自福州总院器官移植中心1998/2005手术切除标本存档蜡块,慢性排斥25份,急性排斥17份,尿瘘致移植肾带功切除8份。方法:双重免疫组织化学染色法检测50份移植肾切除组织标本存档蜡块切片中肾小球足细胞膜黏蛋白及血管内皮细胞生长因子受体、CD68表达,并量化微淋巴管密度、血管内皮细胞生长因子受体及CD68密度。主要观察指标:结合临床病理资料分析微淋巴管密度、血管内皮细胞生长因子受体及CD68密度表达及与肾移植排斥反应之间的相互关系。结果:急性排斥组中肾小球足细胞膜黏蛋白多伴随肾内动脉的大分支零星分布在动脉周围的细胞间质内,血管内皮细胞生长因子受体基本为零星染色。慢性排斥组可见有大量微淋巴管增生,主要集中在间质内浸润的局灶性单核细胞群周围,并且深入到肾小管周边的间质内,管腔扩张,扭曲,微淋巴管周围可见血管内皮细胞生长因子受体高表达。随着肾小球足细胞膜黏蛋白在不同肾组织表达的高低,血管内皮细胞生长因子受体阳性率亦随之变化,两者之间呈正比(P<0.05);慢性排斥组中血管内皮细胞生长因子受体的强阳性率明显增高,与其他两组比较差异显著(P<0.05)。肾小球足细胞膜黏蛋白染色显示在慢性排异反应组中,随着排异程度的加重,淋巴管密度也增加(P<0.05)。结论:移植肾组织中的微淋巴管密度与血管内皮细胞生长因子受体及CD68密度密切相关,分析:肾移植后微淋巴管增生与单核细胞的浸润互为因果,导致移植肾组织局部单核细胞的大量堆积,最终致使移植物失功。

BACKGROUND： Microlymphatic vessel increases with chronic renal rejection. Infiltrative macrophages in tissues secrete vascular endothelial cell growth factor-C and vascular endothelial cell growth factor-D, which activates vascular endothelial cell growth factor recepter-3, and then causes the proliferation of microlymphatic vessels. But, this theory has not been proved by any experiments. OBJECTIVE： Respectively using double immunohistochemistry staining for podoplanin, vascular endothelial cell growth factor receptor and CD68. Quantizating the density of lymphaticvessel, vascular endothelial cell growth factor receptor and CD68, then we investigate the relationships and associations of them. DESIGN, TIME AND SETTING： The cell observation experiment was conducted at the Organ Transplantation Center of Fuzhou General Hospital of Nanjing Military Area Command of Chinese PLA from september 2005 to May 2007. MATERIALS： Totally 50 transplanted kidney recipients＇ samples were obtained from Organ Transplantation Center of Fuzhou General Hospital of Chinese PLA from 1998 to 2005. There were 25 chronic rejection patients, 17 acute rejection patients and 8 patients with transplanted kidney with normal function ones. METHODS： Using double immunohistochemistry staining to test the expression of podoplanin, vascular endothelial cell growth factor receptor and CD68 in 50 samples. The densities of lymphaticvessel, vascular endothelial cell growth factor receptor and CD68 were quantizated. MAIN OUTCOME MEASURES： Combining clinical pathology materials, we analyzed the densities of lymphaticvessel, vascular endothelial cell growth factor receptor and CD68, and investigated the relationship of chronic renal rejection to lymphaticvessel, vascular endothelial cell growth factor receptor and CD68. RESULTS： Following the main renal artery branches, podoplannin was distributed sporadicy in intercellular substance in acute renal rejection, where vascular endothelial cell growth factor receptor was only sporadic staining. Microlymphatic vessel was great proliferated in pathological section of chronic rejection, mainly concentrated around monocytes which infiltrated in intercellular substance and penetrated deeply into intercellular substance around renal tubules. Lumen expanded and got distorted. In these pathological sections, vascular endothelial cell growth factor receptor was highly expressed around microlymphatic vessels. Podoplanin was in direct ratio to positive rate of vascular endothelial cell growth factor receptor （P 〈 0.05）. The rate was obviously high in chronic rejection （P 〈 0.05）. Podoplanin proved that the density of lymphatic vessels increased as the rejection extent intensified in chronic rejection （P 〈 0.05 ） . CONCLUSION： The density of microlymphatic vessel is closely related to the density of vascular endothelial cell growth factor receptor and CD68. It proves that the proliferation of microlymphatic vessels and the infiltration of monocytes have a mutual cause-and-effect relationship, which causes large accumulation of monocytes in renal transplant tissue and at last, leads to the loss of kidney function.