摘要：
Objective To assess the effectiveness and safety of the conversion therapy from traditional cyclosporine (CsA) triple immunosuppression therapy to sirolimus (SRL) combined with low dose CsA and prednisone (Pred) in renal transplantation recipients in a five-year follow-up period.Methods A prospective,open-label non-randomized study was performed with 46 renal allograft recipients who visited Tongji Hospital regularly for follow-up visits between January 2007 and May 2011 and were taking CsA +mycophenolate mofetil (MMF) + Pred.Conversion therapy to SRL + low dose CsA + Pred was initiated after renal transplantation.The recipients were allocated to 2 groups according to their renal function and proteinuria before the conversion:active conversion group [n =27,serum creatinine (SCr) ≤ 140 μmoL/L with no or minimal proteinuria] and passive conversion group [n =19,SCr ＞ 140 μmol/L with less than moderate proteinuria].After conversion,dosages of SRL and CsA were adjusted for trough levels of 5-7 μg/L and 20-60 μg/L,respectively.SCr and urine protein were compared before and after the conversion in five-year follow-up.Incidence of acute rejection,renal graft survival and SRL-related adverse effects of the immunosuppressive regimen were also observed.Results After conversion,an average 63％ dose reduction of CsA was achieved in all the patients.In the active conversion group,the mean SCr level was (110 ± 19) μmol/L at the time of conversion.Eight patients in this group withdrew from the study during the follow-up period for the following reasons:arthralgia (1 case),deteriorated proteinuria (2 cases),chronic diarrhea (2 cases),mild or suspicious acute rejection (2 cases),and recurrent fever (1 case).The rest patients (19/27) with a mean follow-up time of 5 years had a stable SCr level [(103 ±12) μmol/L] and a 100％ 5-year graft survival.In the passive conversion group,the mean SCr level was (205 ±45) μmol/L at the time of conversion.There were 4 patients quitting the study,2 for deteriorated proteinuria and 2 for lost to follow-up.Chronic allograft failure developed in 10 patients in this group 1-50 months after conversion,while the remaining 5 patients had a stable SCr during the 5-year follow-up period [(218 ±46) μmol/L before conversion vs (205 ± 73) μmol/L 5 years after conversion].The overall 5-year graft survival after the conversion therapy in the passive conversion group was 33.3％,significantly lower than that of the active conversion group (P ＜ 0.001).Acute rejection was observed in 2 cases in the active conversion group,while not observed in the passive conversion group.None of the patients developed leukopenia,thrombocytopenia,oral ulcer,or pneumonia in the follow-up.Conclusions The combination therapy of SRL and low dose of CsA is overall a safe and effective maintenance immunosuppressive regimen,but it is important to initiate at an appropriate stage.More favourable long-term benefits may be obtained from the conversion therapy in patients with normal or only slightly impaired renal graft function.It may offer an option of individualized immunosuppressive therapy after renal transplantation.%目的 通过5年随访,探讨肾移植术后由传统的环孢素A(CsA)三联免疫抑制治疗转换为西罗莫司(SRL)联合小剂量CsA和泼尼松(Pred)的临床有效性和安全性.方法 前瞻性、开放性非随机的临床研究,选取2007年1月至2011年5月在华中科技大学同济医学院附属同济医院器官移植研究所门诊规律随访的46例口服CsA+霉酚酸酯(MMF)+ Pred的肾移植受者,进行SRL+小剂量CsA+ Pred的转换治疗.其中主动转换组27例(转换前血肌酐≤140 μmol/L,无或仅轻微蛋白尿),被动转换组19例(血肌酐＞ 140 μmol/L,尿蛋白＜++).转换后目标谷浓度:SRL为5～7 μg/L,CsA为20 ～60 μg/L.观察转换后5年的血肌酐和尿蛋白变化,急性排斥反应发生率、移植肾存活率和SRL相关的不良反应.结果 转换后所有受者CsA平均减药63％.主动转换组转换时平均血肌酐为(110±19) μmol/L;8例退组,原因为关节痛1例、蛋白尿加重2例、慢性腹泻2例、轻度或可疑急性排斥反应2例和反复发热1例;其余19例受者平均随访5年血肌酐保持平稳,为(103±12) μmol/L,转换后5年移植肾存活率为100％.被动转换组在转换时平均血肌酐为(205±45)μmol/L,4例受者退组,原因分别为蛋白尿加重2例和人为因素2例;10例受者在转换后1～50个月移植肾失功能,其余5例受者平均随访5年血肌酐保持稳定[转换前为(218±46)μmol/L,5年随访时为(205-73)μmol/L],总体移植肾5年存活率为33.3％,显著低于主动转换组(P＜0.001).急性排斥反应在主动转换组发生2例,在被动转换组无发生.所有受者在随访期间未出现白细胞减少或血小板减少,也未观察到口腔溃疡、肺部感染等不良反应发生.结论 SRL联合小剂量CsA的免疫抑制方案是一种较为安全有效的免疫抑制维持治疗方案,但需把握合适的转换治疗时机,在移植肾功能尚正常或只有早期轻度受损时进行转换能取得较为满意的长期效果,可考虑作为临床肾移植个体化免疫抑制方案的选择之一.
