Malvezzi Paolo, Rostaing Lionel
a 1 Clinique Universitaire de Néphrologie, CHU Grenoble , Grenoble, France.
b 2 Department of Nephrology and Organ Transplantation, CHU Rangueil , TSA 50032, 31059 Toulouse Cedex 9, France +33 5 61 32 23 35 ; +33 5 61 32 39 89 ;
Expert Opin Drug Saf. 2015 Oct;14(10):1531-46. doi: 10.1517/14740338.2015.1083974. Epub 2015 Sep 2.
Cyclosporine-A and tacrolimus are the cornerstones in modern immunosuppression after organ transplantation. They are potent inhibitors of calcineurin, that is, so-called calcineurin-inhibitors (CNIs). However, because these drugs have narrow therapeutic windows, they are associated with many side-effects, with some being dose related.
The most frequent side-effect of CNIs is nephrotoxicity, which in the long term can contribute, to allograft deterioration. Other frequent side-effects include metabolic disorders (new onset of diabetes, dyslipidemia), neurotoxicity, or promoting of de novo cancers.
In kidney transplantation, many strategies have been developed to minimize nephrotoxicity while maintaining efficacy of immunosuppression: for example, the minimization of CNI in addition to either full-dose mycophenolic acid or low doses of m-TOR inhibitors, mainly everolimus (EVR). Attempts made to eliminate CNIs by replacing them with m-TOR inhibitors have been unsuccessful because of occurrence of de novo donor-specific alloantibodies in a substantial number of patients, associated with antibody-mediated rejection. Conversely, CNI-avoidance by replacing them by Belatacept is feasible with very good renal function in the long term despite a significant increase in acute cellular rejections within the first-year posttransplantation. Other side-effects of CNIs, such as neurologic disorders, diabetes, dyslipidemia, viral infections, and cancer, seem to be less frequent in low-dose or CNI-free immunosuppressive regimens. Thus, although CNIs remain the major immunosuppressive treatment, their dosage should be minimized by using them with either full-dose MPA or reduced-dose EVR.
环孢素A和他克莫司是器官移植后现代免疫抑制治疗的基石。它们是钙调神经磷酸酶的强效抑制剂，即所谓的钙调神经磷酸酶抑制剂（CNIs）。然而，由于这些药物的治疗窗较窄，它们会引发许多副作用，其中一些与剂量相关。
CNIs最常见的副作用是肾毒性，从长期来看，这可能会导致移植器官恶化。其他常见副作用包括代谢紊乱（新发糖尿病、血脂异常）、神经毒性或促进新发癌症。
在肾移植中，已经制定了许多策略来在维持免疫抑制效果的同时尽量减少肾毒性：例如，除了全剂量霉酚酸或低剂量的m-TOR抑制剂（主要是依维莫司（EVR））外，尽量减少CNI的使用。试图用m-TOR抑制剂替代CNIs以消除CNIs的尝试并未成功，因为大量患者出现了新发供体特异性同种抗体，并伴有抗体介导的排斥反应。相反，对于肾功能非常好的患者，用贝拉西普替代CNIs以避免使用CNIs在长期来看是可行的，尽管移植后第一年急性细胞排斥反应显著增加。在低剂量或无CNI的免疫抑制方案中，CNIs的其他副作用，如神经紊乱、糖尿病、血脂异常、病毒感染和癌症，似乎不太常见。因此，尽管CNIs仍然是主要的免疫抑制治疗药物，但应通过将其与全剂量MPA或减量EVR联合使用来尽量减少其剂量。
