Heemann U W, Azuma H, Tullius S G, Mackenzie H, Brenner B M, Tilney N L
Surgical Research Laboratory, Harvard Medical School, Boston, Massachusetts 02115.
Transplantation. 1994 Dec 27;58(12):1317-22.
Chronic renal allograft dysfunction may become manifest months or years after transplantation by progressive functional deterioration associated with morphological changes that include vascular obliteration, glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Two hypotheses have evolved to explain the etiology of this process, usually described as "chronic rejection:" first, that it is primarily an antigen-dependent phenomenon influenced by continuing host alloresponsiveness; second, that nonimmunological, alloantigen-independent factors contribute to the progressive changes. Using an established model of chronic rejection of kidney transplants in rats in which the lesions progress relentlessly over time, we have determined the long-term effects of superimposing renal mass reduction on the indices of progressive allograft injury. Increasing proteinuria, a reproducible index of kidney graft dysfunction, developed after 12 weeks in all recipients of intact allografts, but was accelerated in kidneys with reduced mass, regardless of whether the organ was allogeneic or isogeneic. The coincident infiltration of macrophages and expression of cytokines and growth factors were associated with the development of glomerular sclerosis and interstitial fibrosis; such functional and morphological alterations occurred in an accelerated manner in all reduced-mass kidney allografts and isografts. Conversely, intact allografts in recipients also bearing a retained native kidney never manifested any chronic changes throughout the entire follow-up period. These findings emphasize the role of alloantigen-independent factors, particularly reduced renal mass, in the multi-factorial etiology of "chronic rejection" of kidney transplants.
慢性肾移植功能障碍可能在移植后数月或数年出现，表现为与形态学改变相关的进行性功能恶化，这些形态学改变包括血管闭塞、肾小球硬化、肾小管萎缩和间质纤维化。目前已形成两种假说来解释这一通常被称为“慢性排斥反应”的过程的病因：第一种，它主要是一种受持续的宿主同种异体反应影响的抗原依赖性现象；第二种，非免疫性、不依赖同种异体抗原的因素促成了这种进行性变化。利用一种已建立的大鼠肾移植慢性排斥反应模型，其中病变会随着时间的推移持续进展，我们确定了减少肾脏质量对移植肾进行性损伤指标的长期影响。蛋白尿增加是肾移植功能障碍的一个可重复指标，在所有接受完整同种异体移植的受体中，12周后出现蛋白尿增加，但在肾脏质量减少的情况下，无论器官是同种异体还是同基因的蛋白尿增加都加速。巨噬细胞的同时浸润以及细胞因子和生长因子的表达与肾小球硬化和间质纤维化的发展相关；这种功能和形态学改变在所有肾脏质量减少的同种异体移植肾和同基因移植肾中加速发生。相反，在同时保留有天然肾脏的受体中，完整的同种异体移植肾在整个随访期间从未表现出任何慢性变化。这些发现强调了不依赖同种异体抗原的因素，特别是减少的肾脏质量，在肾移植“慢性排斥反应”多因素病因中的作用。
