Alberú J
National Institute of Medical Sciences and Nutrition, Salvador Zubirán, Mexico.
Transplant Proc. 2010 Nov;42(9 Suppl):S36-40. doi: 10.1016/j.transproceed.2010.07.006.
The long-term fate of renal transplant recipients has remained relatively unchanged over the last 15 years. The cumulative, chronic effects of immunosuppression contribute, to a great extent, to the higher, premature mortality rates linked to cardiovascular disease and malignancy observed in this patient population. Immunosuppression disrupts both antitumor surveillance and antiviral activities, and oncogenic viruses predispose to specific malignancies. Further, some drugs promote carcinogenesis by mechanisms independent of their immunosuppressive effects. In vitro studies have shown that calcineurin inhibitors (CNIs) promote tumor progression by a transforming growth factor-β-dependent mechanism. In contrast, in vivo mouse models have demonstrated that mammalian target of rapamycin (mTOR) inhibitors inhibit metastatic tumor growth and angiogenesis. The association between mTOR-inhibitor and reduced malignancy has been demonstrated in several studies. United Network for Organ Sharing registry data demonstrate that an mTOR-inhibitor either with or without a CNI, is associated with a reduced incidence of tumors compared to regimens that do not utilize mTOR-inhibitor Five years after renal transplantation, patients in the Rapamune Maintenance Regimen study who received sirolimus (SRL)-based CNI-free therapy after cyclosporine (CsA) withdrawal at 3 months showed a reduced incidence of malignancy compared with those who continued a regimen including (CsA) In the CONVERT study, patients who converted to SRL displayed a significantly lower malignancy rate (3.8%) at 24 months compared with those who continued CNI based therapy (11%; P < .001). A randomized, prospective study to evaluate the effect of conversion to SRL from a CNI, compared with continued CNI, showed that SRL was associated with a lower rate of nonmelanoma skin cancer (NMSC) and a longer time to first biopsy-confirmed new NMSC. An mTOR-inhibitor CNI-free regimen should be considered for transplant recipients at high risk for cancer development and for those who develop malignancies over the posttransplant course.
在过去15年里，肾移植受者的长期预后相对没有变化。免疫抑制的累积慢性影响在很大程度上导致了该患者群体中与心血管疾病和恶性肿瘤相关的较高过早死亡率。免疫抑制会破坏抗肿瘤监测和抗病毒活性，致癌病毒易引发特定恶性肿瘤。此外，一些药物通过与其免疫抑制作用无关的机制促进致癌作用。体外研究表明，钙调神经磷酸酶抑制剂（CNIs）通过一种依赖转化生长因子-β的机制促进肿瘤进展。相比之下，体内小鼠模型已证明雷帕霉素靶蛋白（mTOR）抑制剂可抑制转移性肿瘤生长和血管生成。多项研究已证实mTOR抑制剂与恶性肿瘤减少之间的关联。器官共享联合网络登记数据表明，与未使用mTOR抑制剂的方案相比，使用或未使用CNI的mTOR抑制剂与肿瘤发生率降低相关。肾移植后5年，在雷帕霉素维持治疗方案研究中，在3个月时停用环孢素（CsA）后接受基于西罗莫司（SRL）的无CNI治疗的患者，与继续使用包括（CsA）的方案的患者相比，恶性肿瘤发生率降低。在CONVERT研究中，转换为SRL的患者在24个月时的恶性肿瘤发生率（3.8%）显著低于继续接受基于CNI治疗的患者（11%；P<0.001）。一项评估从CNI转换为SRL与继续使用CNI相比的效果的随机前瞻性研究表明，SRL与较低的非黑色素瘤皮肤癌（NMSC）发生率以及首次活检确诊新NMSC的时间延长相关。对于癌症发生风险高的移植受者以及在移植后过程中发生恶性肿瘤的患者，应考虑使用无CNI的mTOR抑制剂方案。
