Cardiovascular Department, University of Bologna, Academic Hospital S. Orsola-Malpighi, via Massarenti 9, Bologna, Italy.
J Heart Lung Transplant. 2012 Jun;31(6):565-70. doi: 10.1016/j.healun.2012.01.002. Epub 2012 Feb 15.
Cyclosporine nephrotoxicity negatively impacts long-term outcome after heart transplantation (HT). We previously reported 1-year results from a randomized study showing that cyclosporine-lowering strategies based on everolimus or mycophenolate mofetil (MMF) are equally effective for reducing progression of renal dysfunction. It is unknown whether this efficacy could be maintained over the long term.
Thirty-four recipients 1 to 4 years after HT and with 25 to 60 ml/min of creatinine clearance (CrCl) were randomized to everolimus with a very low dose (C(0): 50 to 90 ng/ml, n = 17) or MMF with low dose of cyclosporine (C(0): 100 to 150 ng/ml, n = 17). Follow-up was prolonged up to 3 years, and calculated CrCl was the main efficacy measure.
Cyclosporine was maintained at 70% and 30% lower than baseline in the everolimus and MMF arms, respectively, throughout the 3-year study period. CrCl remained stable in the everolimus patients (+7% from baseline; p = 0.7), but improved in the MMF patients (+20% from baseline; p < 0.01), with a trend toward improved values compared with everolimus patients (46 ± 12 vs 56 ± 15 ml/min; p = 0.06). Subgroup analysis revealed that baseline proteinuria markedly influenced the renal function response to everolimus: whereas in patients with baseline proteinuria CrCl significantly worsened (-20%; p = 0.04), it improved in those without (+15%; p = 0.03). Safety was comparable between the two study arms.
Cyclosporine nephrotoxicity improved after a prolonged dose reduction in patients receiving MMF. The everolimus-based strategy provided a similar benefit only to patients without baseline proteinuria. While raising caution against the universal use of everolimus for kidney protection, our long-term results support the need for customized approaches in the management of drug toxicities in maintenance HT recipients.
环孢素肾毒性会对心脏移植（HT）后的长期预后产生负面影响。我们之前报告了一项随机研究的 1 年结果，该研究表明，基于依维莫司或吗替麦考酚酯（MMF）的环孢素降阶策略在降低肾功能障碍进展方面同样有效。目前尚不清楚这种疗效是否能长期维持。
34 例 HT 后 1 至 4 年、肌酐清除率（CrCl）为 25 至 60 ml/min 的受者被随机分为依维莫司低剂量组（C（0）：50 至 90ng/ml，n=17）或 MMF 低剂量环孢素组（C（0）：100 至 150ng/ml，n=17）。随访时间延长至 3 年，计算的 CrCl 是主要疗效指标。
在整个 3 年研究期间，依维莫司组和 MMF 组的环孢素分别维持在基线水平的 70%和 30%以下。依维莫司组的 CrCl 保持稳定（与基线相比增加 7%；p=0.7），而 MMF 组则有所改善（与基线相比增加 20%；p<0.01），与依维莫司组相比有改善的趋势（46±12 与 56±15ml/min；p=0.06）。亚组分析显示，基线蛋白尿显著影响依维莫司的肾功能反应：基线蛋白尿患者的 CrCl 显著恶化（-20%；p=0.04），而无蛋白尿患者则改善（+15%；p=0.03）。两组研究之间的安全性相当。
在接受 MMF 的患者中，长时间减少环孢素剂量后，环孢素肾毒性得到改善。依维莫司为基础的策略仅对无基线蛋白尿的患者提供了类似的益处。虽然对普遍使用依维莫司进行肾脏保护持谨慎态度，但我们的长期结果支持在维持性 HT 受者药物毒性管理中采用个体化方法的必要性。
