Noris Marina, Mister Marilena, Pezzotta Anna, Azzollini Nadia, Cassis Paola, Benigni Ariela, Gagliardini Elena, Perico Norberto, Remuzzi Giuseppe
Department of Medicine and Transplantation, Ospedali Riuniti Bergamo-Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Kidney Int. 2003 Dec;64(6):2253-61. doi: 10.1046/j.1523-1755.2003.00318.x.
Inhibition of the renin-angiotensin system (RAS) prevents development of chronic allograft dysfunction in experimental animals. Whether this therapeutic approach is effective even if started when signs of allograft nephropathy are already manifested has not been investigated.
To address this issue, we studied the effect of a late treatment with the angiotensin-convertine enzyme (ACE) inhibitor trandolapril in the Fisher 344 to Lewis rat kidney transplant model. Seven months after transplant a renal biopsy was done for graft histology examination. Thereafter rats received either no treatment (allograft-none) or trandolapril until sacrifice at month 13.
All animals were alive at the end of the study with the exception of a rat in the untreated group that died of renal insufficiency at day 292. Despite the fact that the grafts had already signs of structural injury and function impairment at the time treatment was stated, trandolapril completely restored renal function to baseline pretransplant values. Trandolapril also halted the progression of glomerular damage and suppressed intragraft T-lymphocyte infiltration and reduced the expression of the chemokine monocyte chemoattractant protein-1 (MCP-1). However, trandolapril had no direct effect on T cell function, since in vivo treatment did not modify recipient T-cell alloreactivity against donor antigens.
These findings provide the basis for a novel treatment intervention with RAS blockade that, together with pharmacologic inhibition of the immune response, could interrupt progression of chronic allograft dysfunction and injury.
在实验动物中，抑制肾素 - 血管紧张素系统（RAS）可预防慢性移植肾功能障碍的发生。即便在移植肾肾病的症状已经出现时才开始采用这种治疗方法是否有效，尚未得到研究。
为解决此问题，我们在费希尔344大鼠至刘易斯大鼠肾移植模型中研究了血管紧张素转换酶（ACE）抑制剂群多普利的晚期治疗效果。移植7个月后进行肾活检以检查移植肾组织学。此后，大鼠要么不接受治疗（移植肾 - 无治疗组），要么接受群多普利治疗，直至第13个月处死。
除未治疗组的1只大鼠在第292天死于肾功能不全外，所有动物在研究结束时均存活。尽管在开始治疗时移植肾已经有结构损伤和功能损害的迹象，但群多普利完全将肾功能恢复到移植前的基线值。群多普利还阻止了肾小球损伤的进展，抑制了移植肾内T淋巴细胞浸润，并降低了趋化因子单核细胞趋化蛋白 - 1（MCP - 1）的表达。然而，群多普利对T细胞功能没有直接影响，因为体内治疗并未改变受体T细胞对供体抗原的同种异体反应性。
这些发现为一种新的RAS阻断治疗干预措施提供了依据，该措施与免疫反应的药物抑制相结合，可能会中断慢性移植肾功能障碍和损伤的进展。
