一项随机2×2析因试验，第1部分：单剂量兔抗胸腺细胞球蛋白诱导治疗可能改善肾移植结局。
A randomized 2×2 factorial trial, part 1: single-dose rabbit antithymocyte globulin induction may improve renal transplantation outcomes.
作者信息
Stevens R Brian, Foster Kirk W, Miles Clifford D, Lane James T, Kalil Andre C, Florescu Diana F, Sandoz John P, Rigley Theodore H, Nielsen Kathleen J, Skorupa Jill Y, Kellogg Anna M, Malik Tamer, Wrenshall Lucile E
机构信息
1 Department of Surgery, Wright State University Boonshoft School of Medicine, Dayton, OH. 2 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE. 3 Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE. 4 Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK. 5 Sigma Analytics, Inc., Anthem, AZ. 6 Department of Surgery, Methodist Hospital, Houston, TX.
出版信息
Transplantation. 2015 Jan;99(1):197-209. doi: 10.1097/TP.0000000000000250.
BACKGROUND
We conducted a randomized and unblinded 2 × 2 sequential-factorial trial, composed of an induction arm (part 1) comparing single-dose (SD) versus divided-dose rabbit antithymocyte globulin (rATG), and a maintenance arm (part 2) comparing tacrolimus minimization versus withdrawal. We report the long-term safety and efficacy of SD-rATG induction in the context of early steroid withdrawal and tacrolimus minimization or withdrawal.
METHODS
Patients (n=180) received 6 mg/kg rATG, SD or four alternate-day doses (1.5 mg/kg/dose), with early steroid withdrawal and tacrolimus or sirolimus maintenance. After 6 months targeted maintenance levels were tacrolimus, 2 to 4 ng/mL and sirolimus, 4 to 6 ng/mL or, if calcineurin inhibitor-withdrawn, sirolimus 8 to 12 ng/mL with mycophenolate mofetil 2 g two times per day. Primary endpoints were renal function (abbreviated modification of diet in renal disease) and chronic graft histopathology (Banff). Secondary endpoints included patient survival, graft survival, biopsy-proven rejection, and infectious or noninfectious complications.
RESULTS
Follow-up averaged longer than 4 years. Tacrolimus or sirolimus and mycophenolate mofetil exposure was identical between groups. The SD-rATG associated with improved renal function (2-36 months; P<0.001) in deceased donor recipients. The SD-rATG associated with quicker lymphocyte, CD4 T cell, and CD4-CD8 recovery and fewer infections. Cox multivariate hazard modeling showed divided-dose-rATG (P=0.019), deceased donor (P=0.003), serious infection (P=0.0.018), and lower lymphocyte count (P=0.001) associated with increased mortality. Patients with all four covariates showed a 27-fold increased likelihood of death (P=0.00002). Chronic graft histopathology, rejection rates, and death-censored graft survival were not significantly different between groups.
CONCLUSION
The SD-rATG induction improves the 3-year renal function in recipients of deceased donor kidneys. This benefit, along with possibly improved patient survival and fewer infections suggest that how rATG is administered may impact its efficacy and safety.
背景
我们进行了一项随机、非盲的2×2序贯析因试验，包括一个诱导组（第1部分），比较单剂量（SD）与分剂量兔抗胸腺细胞球蛋白（rATG），以及一个维持组（第2部分），比较他克莫司最小化与停用。我们报告了在早期停用类固醇以及他克莫司最小化或停用的情况下，SD-rATG诱导的长期安全性和有效性。
方法
180例患者接受6mg/kg的rATG，单剂量或分4天给药（1.5mg/kg/剂量），同时早期停用类固醇，并使用他克莫司或西罗莫司维持治疗。6个月后，目标维持水平为他克莫司2至4ng/mL，西罗莫司4至6ng/mL；或者，如果停用钙调神经磷酸酶抑制剂，则西罗莫司8至12ng/mL，霉酚酸酯2g，每日2次。主要终点为肾功能（简化的肾脏病饮食改良法）和慢性移植肾组织病理学（班夫分类法）。次要终点包括患者生存率、移植肾生存率、活检证实的排斥反应以及感染性或非感染性并发症。
结果
随访平均超过4年。两组间他克莫司或西罗莫司以及霉酚酸酯的暴露情况相同。在死亡供体肾移植受者中，SD-rATG与改善肾功能相关（2至36个月；P<0.001）。SD-rATG与淋巴细胞、CD4 T细胞和CD4-CD8恢复更快以及感染更少相关。Cox多变量风险模型显示，分剂量rATG（P=0.019）、死亡供体（P=0.003）、严重感染（P=0.018）以及较低的淋巴细胞计数（P=0.001）与死亡率增加相关。具有所有这四个协变量的患者死亡可能性增加27倍（P=0.00002）。两组间慢性移植肾组织病理学、排斥反应率以及死亡校正后的移植肾生存率无显著差异。
结论
SD-rATG诱导可改善死亡供体肾移植受者的3年肾功能。这一益处，连同可能改善的患者生存率和更少的感染，提示rATG的给药方式可能会影响其疗效和安全性。
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