Fibrosis Progression According to Epithelial-Mesenchymal Transition Profile: A Randomized Trial of Everolimus Versus CsA
Fibrosis Progression According to Epithelial-Mesenchymal Transition Profile: A Randomized Trial of Everolimus Versus CsA
复制标题
DOI：
10.1111/ajt.13132
复制
发表时间：
2015-05-01
影响因子：
8.8
通讯作者：
Rondeau, E.
中科院分区：
文献类型：
--
作者：
Rostaing, L.;Hertig, A.;Rondeau, E.
上皮-间质转化（EMT）标志物可以识别移植物纤维化高风险患者，这些患者可以从早期钙调磷酸酶抑制剂（CNI）撤药中获益。在一项随机、开放标签、12个月的试验中，初治肾移植患者接受环孢菌素、肠溶麦考酚酸钠（EC-MPS）和类固醇治疗至第3个月。根据第3个月的活检结果，将患者分层为EMT+或EMT-，然后随机分配至开始依维莫司治疗时使用半剂量EC-MPS（720 mg/天）和停用环孢素（无CNI）或继续使用环孢素和标准EC-MPS（CNI）。主要终点是EMT+患者移植物纤维化的进展（3-12个月间质纤维化/肾小管萎缩[IF/TA]等级增加>= 1）。194例患者随机分组（96例无CNI，98例CNI）; 153例（69例无CNI，84例CNI）纳入组织学分析。46.2%（12/26）无CNI EMT+患者与51.6%（16/31）CNI EMT+患者发生纤维化进展（p = 0.68）。活检证实的急性排斥反应（BPAR，包括亚临床事件）分别发生在无CNI和CNI患者的25.0%和5.1%（p < 0.001）。总之，早期停用CNI并开始使用依维莫司不能预防间质性纤维化。使用这种无CNI的方案，其中依维莫司暴露相对较低，并给予半剂量EC-MPS，无CNI的患者绝大多数免疫抑制不足，并发生BPAR的风险增加。
Markers of epithelial-mesenchymal transition (EMT) may identify patients at high risk of graft fibrogenesis who could benefit from early calcineurin inhibitor (CNI) withdrawal. In a randomized, open-label, 12-month trial, de novo kidney transplant patients received cyclosporine, enteric-coated mycophenolate sodium (EC-MPS) and steroids to month 3. Patients were stratified as EMT+ or EMT- based on month 3 biopsy, then randomized to start everolimus with half-dose EC-MPS (720 mg/day) and cyclosporine withdrawal (CNI-free) or continue cyclosporine with standard EC-MPS (CNI). The primary endpoint was progression of graft fibrosis (interstitial fibrosis/tubular atrophy [IF/TA] grade increase >= 1 between months 3-12) in EMT+ patients. 194 patients were randomized (96 CNI-free, 98 CNI); 153 (69 CNI-free, 84 CNI) were included in histological analyses. Fibrosis progression occurred in 46.2% (12/26) CNI-free EMT+patients versus 51.6% (16/31) CNI EMT+ patients (p = 0.68). Biopsy-proven acute rejection (BPAR, including subclinical events) occurred in 25.0% and 5.1% of CNI-free and CNI patients, respectively (p < 0.001). In conclusion, early CNI withdrawal with everolimus initiation does not prevent interstitial fibrosis. Using this CNI-free protocol, in which everolimus exposure was relatively low and administered with half-dose EC-MPS, CNI-free patients were overwhelmingly under-immunosuppressed and experienced an increased risk of BPAR.