Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India.
Transpl Int. 2010 Apr 1;23(4):407-16. doi: 10.1111/j.1432-2277.2009.00988.x. Epub 2009 Nov 13.
Calcineurin inhibitors (cyclosporine and tacrolimus; CNIs) continue to be used as constituents of post-transplant immunosuppression in most centers. However, renal toxicity associated with the use of these drugs remains a problem adversely affecting the long-term graft survival. Fifteen adequate protocol renal allograft biopsies, with histological features of CNI toxicity among 140 protocol biopsies performed at 1-, 6-, and 12-month post-transplant, were included. Mitochondrial alterations in the tubular epithelial cells and endothelia of glomerular, peritubular capillaries and arterioles were graded semiquantitatively and further ultrastructural morphometric evaluation of numerical density and area of the mitochondria was performed. Immunohistochemical staining for nitrotyrosine (marker of peroxynitrite formation) and vascular endothelial growth factor (VEGF) was performed and expression graded semiquantitatively. Higher grades of alterations were seen in endothelial mitochondria as compared with tubular mitochondria in biopsies with calcineurin inhibitor toxicity (CNIT). Endothelial mitochondrial numerical density showed progressive decline over 1-, 6- and 12-month biopsies while area showed progressive increase in biopsies with CNIT as compared with controls. Upregulation of nitrotyrosine was seen even at 1-month post-transplant, persisted at 6 and 12 months, and was significantly greater than that in control biopsies. Intense VEGF expression was noted in early CNIT while progressive reduction was seen in 6- and 12-month protocol biopsies. This study shows a relatively high incidence of CNIT in protocol renal allograft biopsies, indicating that this might be an important mechanism of background damage to the allograft. Structural alterations in endothelial mitochondria are consistent findings in protocol biopsies with CNIT and this relatively specific mitochondrial damage may stem from the peroxynitrite-mediated damage associated with progressive loss of protective function of VEGF.
钙调磷酸酶抑制剂（环孢素和他克莫司；CNIs）继续作为大多数中心移植后免疫抑制的组成部分使用。然而，与这些药物使用相关的肾毒性仍然是一个问题，对长期移植物存活率产生不利影响。在 1 个月、6 个月和 12 个月移植后进行的 140 次协议活检中，有 15 次充分的协议肾移植活检显示出 CNI 毒性的组织学特征，包括在内。对肾小管上皮细胞和肾小球、肾小管周围毛细血管和小动脉内皮细胞的线粒体改变进行半定量分级，并进一步对线粒体的数值密度和面积进行超微结构形态计量学评估。进行硝基酪氨酸（过氧亚硝酸盐形成的标志物）和血管内皮生长因子（VEGF）的免疫组织化学染色，并进行半定量分级表达。在有钙调磷酸酶抑制剂毒性（CNIT）的活检中，与肾小管线粒体相比，内皮线粒体的改变程度更高。内皮线粒体的数值密度在 1 个月、6 个月和 12 个月的活检中呈逐渐下降趋势，而在有 CNIT 的活检中，线粒体的面积呈逐渐增加趋势，与对照组相比。即使在移植后 1 个月也观察到硝基酪氨酸的上调，并在 6 个月和 12 个月持续存在，且明显高于对照组。在早期的 CNIT 中观察到强烈的 VEGF 表达，而在 6 个月和 12 个月的协议活检中观察到逐渐减少。这项研究表明，在协议性肾移植活检中，CNIT 的发生率相对较高，表明这可能是移植物背景损伤的一个重要机制。在有 CNIT 的协议活检中，内皮线粒体的结构改变是一致的发现，这种相对特异性的线粒体损伤可能源于与 VEGF 保护功能逐渐丧失相关的过氧亚硝酸盐介导的损伤。
