Rangan Gopala K
Centre for Transplant and Renal Research, Westmead Millennium Institute, The University of Sydney at Westmead Hospital, Sydney, New South Wales, Australia.
Drug Saf. 2006;29(12):1153-61. doi: 10.2165/00002018-200629120-00006.
Sirolimus is a novel immunosuppressant with potent antiproliferative actions through its ability to inhibit the raptor-containing mammalian target of rapamycin protein kinase. Sirolimus represents a major therapeutic advance in the prevention of acute renal allograft rejection and chronic allograft nephropathy. Its role in the therapy of glomerulonephritis, autoimmunity, cystic renal diseases and renal cancer is under investigation. Because sirolimus does not share the vasomotor renal adverse effects exhibited by calcineurin inhibitors, it has been designated a 'non-nephrotoxic drug'. However, clinical reports suggest that, under some circumstances, sirolimus is associated with proteinuria and acute renal dysfunction. A common risk factor appears to be presence of pre-existing chronic renal damage. The mechanisms of sirolimus-associated proteinuria are multifactorial and may be due to an increase in glomerular capillary pressure following calcineurin inhibitor withdrawal. It has also been suggested that sirolimus directly causes increased glomerular permeability/injury, but evidence for this mechanism is currently inconclusive. The acute renal dysfunction associated with sirolimus (such as in delayed graft function) may be due to suppression of compensatory renal cell proliferation and survival/repair processes. Although these adverse effects occur in some patients, their occurrence could be minimised by knowledge of the molecular effects of sirolimus on the kidney, the use of sirolimus in appropriate patient populations, close monitoring of proteinuria and renal function, use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers if proteinuria occurs and withdrawal if needed. Further long-term analysis of renal allograft studies using sirolimus as de novo immunosuppression along with clinical and laboratory studies will refine these issues in the future.
西罗莫司是一种新型免疫抑制剂，通过抑制含raptor的哺乳动物雷帕霉素靶蛋白激酶而具有强大的抗增殖作用。西罗莫司在预防急性肾移植排斥反应和慢性移植肾肾病方面代表了一项重大的治疗进展。其在肾小球肾炎、自身免疫性疾病、囊性肾病和肾癌治疗中的作用正在研究中。由于西罗莫司不具有钙调神经磷酸酶抑制剂所表现出的肾血管运动不良反应，它被指定为“非肾毒性药物”。然而，临床报告表明，在某些情况下，西罗莫司与蛋白尿和急性肾功能障碍有关。一个常见的危险因素似乎是存在预先存在的慢性肾损害。西罗莫司相关蛋白尿的机制是多因素的，可能是由于停用钙调神经磷酸酶抑制剂后肾小球毛细血管压力增加所致。也有人提出西罗莫司直接导致肾小球通透性增加/损伤，但目前这一机制的证据尚无定论。与西罗莫司相关的急性肾功能障碍（如移植肾功能延迟）可能是由于代偿性肾细胞增殖以及存活/修复过程受到抑制。尽管这些不良反应在一些患者中出现，但通过了解西罗莫司对肾脏的分子作用、在合适的患者群体中使用西罗莫司、密切监测蛋白尿和肾功能、如果出现蛋白尿则使用血管紧张素转换酶抑制剂或血管紧张素II受体阻滞剂以及必要时停药，其发生可以降至最低。未来，对使用西罗莫司作为初始免疫抑制的肾移植研究进行进一步的长期分析以及临床和实验室研究将完善这些问题。
