ATG-F单次大剂量与多次低剂量给药应用于肾移植诱导治疗的有效性和安全性

Efficacy and safety of single high-dose versus multiple low-dose ATG-Fresenius induction in de novo renaltransplantation

目的 对比抗人T细胞兔免疫球蛋白（ATG-F）单次大剂量与多次低剂量给药在肾移植受者中的有效性和安全性.方法 采用前瞻性、开放性、随机对照研究,在19家移植中心入组280例首次肾移植受者随机分为2组：（1）单次大剂量给药组（SD组）：138例,术中移植肾恢复血流灌注前,单次静脉输注ATG-F 7～9 mg/kg;（2）多次低剂量给药组（MD组）：142例,术中移植肾恢复血流灌注前、术后1～4 d,静脉输注ATG-F 2 mg· kg-1·d-1.除ATG-F诱导之外,所有受者均采用他克莫司缓释胶囊、吗替麦考酚酯及激素的免疫抑制方案.受者访视点分别为术后第1、3、7、14、30、90、180、270、365天.根据治疗失败率对两种治疗方案进行非劣效性评价.主要疗效指标为术后12个月的治疗失败率,次要疗效指标为三种亚型急性排斥反应（AR）和移植肾功能恢复延迟（DGF）发生率,受者和移植物存活率,以及各时点血肌酐（SCr）水平.安全性评价指标为血液学检查变化和不良反应发生率.结果 SD组和MD组治疗失败率分别为17.24％和23.08％,非劣效检验证实SD组治疗失败率不劣于MD组.AR是导致治疗失败的主要原因,SD组AR发生率非劣于MD组（12.07％和21.37％）.SD组和MD组术后1年DGF发生率分别为12.07％和6.84％,差异无统计学意义（P=0.1721）;两组受者存活率分别为96.55％和98.29％（P=0.6714）,移植肾存活率分别为94.83％和98.29％（P=0.2750）,以及两组间各时点SCr水平的差异均无统计学意义.两组总体不良反应发生率的差异无统计学意义.所有关注的不良反应中以感染最为多见,其次为血液学检查异常、肝肾功能异常、胃肠道反应.SD组和MD组外周血淋巴细胞在术后1d大量减少,分别在术后1和3个月恢复至给药前水平,未见严重粒细胞减少症、红细胞减少症和血小板减少症.结论 ATC-F单次大剂量给药的有效性不劣于多次低剂量给药方式,且两组安全性相当.单次大剂量用药更方便、更经济.

Objective To evaluate the efficacy and safety of single bolus high dose （SD group） ATG-Fresenius induction therapy in kidney transplantation vs.multiple low dose （MD group） administration.Methods A multiple center,prospective,randomized and controlled clinical study was performed on 280 de novo renal transplant recipients from 19 centers.Patients were randomized into 2 groups as follows：SD group,a single high dose （7-9 mg/kg） of ATG-F infused as an induction agent before the vessel anastomoses;MD group,2 mg/kg of ATG-F daily administrated in postoperative 4 days.All the patients accepted maintenance immunosuppressive protocol including tacrolimus,mycophenolate and prednisone.Patients were assessed and data were collected at regular schedule clinic visits on the day 1,3,7,14,30,90,180,270 and 365.The primary end point of efficacy was therapeutic failure rate [the number of death,grafts loss and acute rejection （AR）].The event first occurred should be used in the classification of patients.The non-inferiority evaluation of the two treatment regimens was done based on treatment failure rate.The secondary end points of efficacy were the incidence of AR,delayed graft function （DGF）,1-year survival rate of patients and grafts,and serum creatinine at each visiting point.The indicators for safety evaluation included hemotologic variation and incidence of adverse events.Results The therapeutic failure rate in SD group was non-inferior to the MD group （17.24% vs.23.08%）.AR was the major cause of therapeutic failure and there was similar incidence of AR between SD gronp and MD group （12.07% vs.21.37%）.There was no significant difference in the incidence of DGF between SD group and MD group （12.07% vs.6.84%,P =0.1721）.The 1-year patient＇s survival rate and 1-year graft survival rate in SD group and MD group showed no significant difference （96.55% vs.98.29%,P =0.6714;94.83% vs 98.29%,P =0.2750）.The serum creatinine level showed no significant differences between two groups at each visit point.There was also no significant difference in total incidence of adverse events between the two groups.In addition,there was also no statistically significant difference in the incidence of concerned and drug-related adverse events between the two groups,including infection,hemotologic abnormality,liver or renal dysfunction,gastrointestinal disorder,etc.After ATG-F administration,peripheral blood lymphocytes in the SD and the MD group immediately decreased but nearly restored to the normal level on the postoperative day 30 and 90 respectively.No severe granulocytopenia,erythropenia or thrombocytopenia occurred in both two groups.Conclusion The efficacy and safety of single high dose of ATG-F induction are non-inferior to multiple low dose ATG-F induction,moreover,single high dose of ATG-F induction is administered more conveniently and economically.