美国移植协会2008年会议上的Spare-the Nephron（STN）试验报告指出，肾移植受体在术后避免长期使用钙调神经磷酸酶抑制因子（CNIs）有利于改善术后一年的肾功能。
本研究的领导研究者、美国佐治亚州亚特兰大埃默里大学医学院、埃默里移植中心肾移植主任、外科教授Thomas Pearson表示，“本研究证明了CNIs有剧烈的、长期的肾毒性，它的机械动力学基础是血流流经肾脏过滤单位时造成的血管收缩。”
在一项开放式、前瞻性、多中心的研究中，首先对患者使用霉酚酸酯（MMF）和包括一种CNIs（他克莫司或环孢霉素），然后在肾移植术后30天至180天随机对患者维持原治疗方案或将CNI换成西罗莫司（SRL）。患者每日服用两次MMF，剂量为1至1.5 g，SRL的剂量为2至10 mg。研究人员指出，“至少2 mg/day，5-10 ng/ml。”
加拿大和美国共计35个移植中心参与了此项研究，每个移植中心都在本中心自行完成抗体诱导和/或皮质类固醇的准入。
根据测量得到的肾小球过滤率（GFR）的平均百分比变化可以看出主要的结果是改善了肾功能，次要结果包括切片检查证明的急性排斥（BPAR）、移植物失功能和移植术后12个月后患者死亡等。
Pearson教授指出，这项对患者进行2年术后随访的研究并未让患者立即使用西罗莫司（sirolimus）来减少与药物相关不良反应，如伤口愈合不佳。
Pearson医师解释说，“如果你能在移植术后早期避免这些副作用，让伤口愈合，然后让患者转而使用以西罗莫司为基础的治疗方案，那么你就能取得最佳疗效。你会在术后早期获得钙调神经磷酸酶强有力的抑制作用，长期使用西罗莫司能够降低肾毒性。”
共有305名单器官肾移植受体参与了此项研究，其中298名受体随机接受持续MMF/CNI疗法（n = 150）或接受新的MMF/SRL治疗（n = 148）。患者的年龄范围在13岁至75岁之间，平均年龄为48.7岁。三分之二的患者为男性。各治疗组患者的基线特征（包括GFR）相似。
148名将治疗方案换为MMF/SRL疗法的患者中，112名患者停用他克莫司，26名患者停用环孢素。在150名接受MMF/CNI疗法的患者中，119名患者（81%）接受他克莫司，31名患者（19%）接受环孢素。
在两个研究组中，患者的次要结果如BPAR、移植物失功能、术后12个月死亡等没有出现显著的统计学差异。而且，与停药有关的不良反应也没有出现显著的统计学差异：21 MMF/SRL（14%）vs10 MMF/CNI（7%）。MMF/SRL组没有出现患者死亡事件，MMF/CNI组中3名患者死亡。
在MMF/SRL组患者中，口腔溃疡和蛋白尿是与停药相关的主要不良反应；而在MMF/CNI组患者中，腹泻则是主要由停药引起的。
在测量基线GFR总体变化百分比时，研究者在两组患者中没有发现明显的统计学差异：MMF/SRL组为27.9%，MMF/CNI组为11.0%（P = .052）。而在MMF/CNI组91名接受他克莫司的患者中，平均GFR变化百分比确实存在显著的统计学差异，分别为MMF/SRL组27.9% vs MMF/CNI组6.1%（P = .0247）。
威斯康星医学院医学教授、肾脏科主任Sundaram Hariharan医生表示，目前的资料还不足以提倡对肾移植受体停用CNI。
Hariharan医生是此研究的发言人之一，他说：“这是一项很重要的试验，因为我们向避免和停止对肾移植受体使用钙调神经磷酸酶抑制因子以保护患者的肾功能方面又迈进了一步。”
“我希望看到更多关于肾功能的细节，而不是仅仅看看GFR的改变百分比。另外还需要了解更多关于西罗莫司剂量的问题。了解是使用高剂量还是低剂量的西罗莫对未来将研究成果转化为临床治疗方案会很有帮助。”
Avoidance of Calcineurin Inhibitors Improves Kidney Function in Renal Transplant Patients
A postoperative regimen that avoids long-term use of calcineurin inhibitors (CNIs) in renal transplant patients improves kidney function at 1 year, according to results of the Spare-the Nephron (STN) trial presented here at the American Transplant Congress 2008.
"It is well documented that the CNIs are acutely and in the long term nephrotoxic," said lead investigator Thomas Pearson, MD, PhD, the Livingston professor of surgery and chief of renal transplantation at Emory Transplant Center, Emory University School of Medicine in Atlanta, Georgia. "The mechanistic basis of that is the vasoconstriction of the blood flow into the filtering units of the kidney."
In an open-label, prospective, multicenter fashion, patients were first treated with mycophenolate mofetil (MMF) and a CNI, consisting of either tacrolimus or cyclosporine, and then randomized after 30 to 180 days following kidney transplantation to maintaining that same regimen or to switch CNI therapy to sirolimus (SRL). Patients received 1 to 1.5 g of MMF twice daily, with 2 to 10 mg of SRL, "followed by at least 2 mg/day; trough 5-10 ng/ml," according to the investigators.
A total of 35 centers in Canada and the United States participated in the study, with each center implementing its own practice of antibody induction and/or administration of corticosteroids.
The primary outcome was improved renal function as measured by mean percentage change in measured glomerular filtration rate (GFR), with secondary outcomes including biopsy-proven acute rejection (BPAR), graft loss, and death at 12 months of follow-up.
"If you can avoid those side effects in the early posttransplant period, get the wounds healed, and then convert patients to sirolimus-based therapy, you may get the best of both worlds," Dr. Pearson told Medscape Transplantation. "You get the potent inhibition of the calcineurin inhibitors early posttransplant and the lack of nephrotoxicity with the calcineurin inhibitors in the long term with sirolimus."
A total of 305 single-organ renal allograft recipients initially participated in the study, with 298 randomized to either continue MMF/CNI therapy (n = 150) or to begin a new regimen of MMF/SRL (n = 148).
Patients ranged in age from 13 to 75 years with the mean age of 48.7 years. Two thirds of the patients were men. Other baseline characteristics, including GFR, were similar between the treatment groups.
Of the 148 patients who were switched to MMF/SRL therapy, 122 were withdrawn from tacrolimus, and 26 were withdrawn from cyclosporine. Of the 150 patients receiving MMF/CNI therapy, 119 (81%) received tacrolimus, and 31 (19%) received cyclosporine.
There were no statistically significant differences in secondary outcomes such as BPAR, graft loss, or death at 12 months between the 2 study groups. In addition, there was no statistically significant difference in withdrawal due to adverse events: 21MMF/SRL (14%) vs 10 MMF/CNI (7%). No deaths occurred in the MMF/SRL group, and 3 patients died in the MMF/CNI group.
Mouth ulcers and proteinuria were the main adverse events responsible for withdrawal from the study among patients who received MMF/SRL, while diarrhea was mainly responsible for withdrawal among patients who received MMF/CNI.
In measuring the overall percentage change from baseline GFR, investigators found no statistically significant difference between the 2 arms: 27.9% for the MMF/SRL group and 11.0% for the MMF/CNI group (P = .052). In looking at a subset of 91 MMF/CNI patients who received tacrolimus, they did conclude there was a statistically significant difference in the mean GFR percentage change between the MMF/SRL group and the MMF/CNI subset: 27.9% vs. 6.1% (P = .0247).
Sundaram Hariharan, MD, a professor of medicine and chief of nephrology at the Medical College of Wisconsin in Milwaukee, said the data are too premature to advocate CNI withdrawal in renal transplant patients.
"This is a very important trial as we are moving toward calcineurin inhibitor avoidance and withdrawal in renal transplant recipients to preserve renal function," said Dr. Hariharan, who was one of the moderators of the oral session at which the research was presented.
"I would like to see more details about renal function, rather than just seeing the percent change in GFR," he told Medscape Transplantation. "The other question is to know more about the dose of sirolimus that was used. It would be useful to know if they used a very high dose or low dose and translate that practice into patient care."
The study was funded by Roche. Dr. Pearson has received grants from and has sat on advisory boards for Roche. Dr. Hariharan disclosed no relevant financial relationships.
American Transplant Congress 2008: Abstract 129. Presented June 1, 2008.
[责任编辑:刘聪]
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