Bonsib S M, Abul-Ezz S R, Ahmad I, Young S M, Ellis E N, Schneider D L, Walker P D
Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Kidney Int. 2000 Nov;58(5):2206-14. doi: 10.1111/j.1523-1755.2000.00395.x.
Acute rejection is a major risk factor for chronic allograft nephropathy, although the link(s) between these events is not understood. The hypothesis of this study is that alterations in tubular basement membranes (TBMs) that occur during acute rejection may be irreversible and thereby play a role in the development of chronic allograft nephropathy.
Fourteen renal transplant patients were selected, each having had two or more biopsies performed (42 total). All biopsies were scored for acute and chronic rejection using Banff 1997 criteria. The initial biopsy showed only acute interstitial rejection (type I rejection). No biopsies contained significant chronic arterial lesions of chronic vascular rejection. The entire cortex was examined on Jones methenamine silver-stained sections at x400 for interruption in TBM staining. The number of tubules with TBM abnormalities was counted, and the renal cortical area was measured by image analysis. Periodic acid-Schiff/immunoperoxidase stain was performed on 12 acute rejection biopsies stained for laminin, cytokeratin 7, CD3, CD20, and CD68. Controls consisted of 11 biopsies (8 negative for rejection and 3 acute tubular necrosis).
Numerous TBM alterations in silver staining were identified as being associated with acute rejection and tubulitis, consisting of abrupt TBM discontinuities and/or extreme attenuation with segmental or complete absence of TBM. A loss of TBM matrix proteins was confirmed by absent laminin staining in areas of acute rejection and tubulitis. There was herniation of tubular cells into the interstitium through TBM defects confirmed by cytokeratin staining. The TBM defects were spatially associated with inflammatory cells, particularly macrophages. When the biopsies were divided into two groups, <10 and> 10 TBM breaks/mm2, there were statistically significant morphologic and clinical correlations. The number of TBM disruptions correlated with the serum creatinine at the time of biopsy, a combined Banff t + i score, the difference in tubular atrophy between the initial and most recent biopsy and the difference between the nadir creatinine and most recent creatinine.
Damage to TBM develops in acute rejection as a consequence of interstitial inflammation and tubulitis. These lytic events correlate with the later development of clinical and morphologic evidence of chronic injury in the absence of arterial injury of chronic rejection. We suggest that chronic allograft nephropathy may have an inflammatory interstitial origin.
急性排斥反应是慢性移植肾肾病的主要危险因素，尽管这些事件之间的联系尚不清楚。本研究的假设是，急性排斥反应期间发生的肾小管基底膜（TBM）改变可能是不可逆的，从而在慢性移植肾肾病的发展中起作用。
选择14例肾移植患者，每人进行了两次或更多次活检（共42次）。所有活检均按照1997年班夫标准对急性和慢性排斥反应进行评分。初次活检仅显示急性间质排斥反应（I型排斥反应）。没有活检包含慢性血管排斥反应的显著慢性动脉病变。在Jones六胺银染色切片上以400倍镜检查整个皮质，观察TBM染色中断情况。计数TBM异常的肾小管数量，并通过图像分析测量肾皮质面积。对12例急性排斥反应活检标本进行高碘酸-希夫/免疫过氧化物酶染色，检测层粘连蛋白、细胞角蛋白7、CD3、CD20和CD68。对照组包括11例活检标本（8例排斥反应阴性，3例急性肾小管坏死）。
银染色中发现许多与急性排斥反应和肾小管炎相关的TBM改变，包括TBM突然中断和/或极度变薄，节段性或完全缺失TBM。急性排斥反应和肾小管炎区域层粘连蛋白染色缺失证实了TBM基质蛋白的丢失。细胞角蛋白染色证实肾小管细胞通过TBM缺陷疝入间质。TBM缺陷在空间上与炎症细胞，特别是巨噬细胞相关。当活检标本分为两组，TBM断裂数<10个/mm²和>10个/mm²时，存在统计学上显著的形态学和临床相关性。TBM破坏的数量与活检时的血清肌酐、班夫t+i综合评分、初次活检和最近一次活检之间肾小管萎缩的差异以及最低肌酐水平与最近肌酐水平之间的差异相关。
急性排斥反应中TBM的损伤是间质炎症和肾小管炎的结果。在没有慢性排斥反应动脉损伤的情况下，这些溶解事件与慢性损伤的临床和形态学证据的后期发展相关。我们认为慢性移植肾肾病可能起源于炎症性间质。
