雷帕霉素联合小剂量环孢素在肾移植受者转换治疗后的2年临床观察

Efficacy and safety of the conversion therapy with the combination of Sirolimus with low dose Cyclosporine in renal transplant patients:two-year Results

目的探讨肾移植术后由经典环孢素(CsA)三联免疫抑制治疗转换为雷帕霉素(SRL)联合小剂量CsA和强的松(Pred)的临床有效性和安全性。方法对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Scr<140μmol/L,无或仅轻微蛋白尿),被动转换组19例(Scr>140μmol/L,蛋白尿<2+)。转换后目标谷浓度SRL 4～7 ng/ml,CsA 20～50 ng/ml。观察转换后2年的Scr、eGFR和尿蛋白变化,并动态监测PRA水平,急性排斥反应发生率以及雷帕霉素相关的不良反应。结果转换后所有受者CsA平均减药量超过60%。转换后3月时,主动转换组Scr由转换前平均(109±27)μmol/L下降至(97±19)μmol/L(P<0.01),eGFR由平均63±11上升至(71±12)ml/min/1.73 m2(P<0.01),并在平均随访2年期间保持平稳,尿蛋白仅1例出现明显加重。被动转换组中共10例在随访期间退组,其中8例退组原因为发展至肾功能不全或蛋白尿加重,其余组内受者Scr由转换前平均(195±43)μmol/L下降至(165±39)μmol/L(转换后3月,P<0.05),eGFR由平均33±8上升至(41±15)ml/min/1.73 m2(转换后3月,P<0.05),并一直维持平稳。两组病例中,基础PRA阴性的受者中95%保持阴性,基础PRA阳性的受者中60%在转换后的随访期间明显下降,其余40%的PRA无增加。2年随访期内无1例急性排斥反应发生。绝大多数病例未见明显的雷帕霉素副作用。结论 SRL联合小剂量CsA的转换治疗在平均2年的临床观察期内能总体改善移植肾功能、有效预防急性排斥反应,可能是一种既能显著减轻CsA肾毒性又经济实用的较理想免疫抑制方案。但需把握好转换的适应症,对已有明显蛋白尿或慢性肾功能不全受者需谨慎转换。

Objective To study the efficacy and safety of the conversion therapy from traditional cyclosporine（CsA） triple therapy to a novel regimen of sirolimus（SRL） combined with low dose CsA in renal transplant patients.Methods Conversion therapy from CsA＋Mycophenolate mofetil（MMF）＋Prednisone（Pred） to SRL＋ low dose CsA＋Pred was conducted in 46 renal allograft recipients after transplantation.These recipients were allocated to the following 2 groups according to their renal function and proteinuria at the time of the conversion： ①active conversion group（n=27）,serum creatinine（Scr）140 μmol/L with no or minimal proteinuria before the conversion;②passive conversion group（n=19）,Scr140 μmol/L with less than moderate proteinuria before the conversion.After conversion,dosages of SRL and CsA were adjusted for trough levels of 4~7 ng/ml and 20~50 ng/ml,respectively.Renal allograft function evaluated by Scr and MDRD eGFR were compared before and after the conversion.Flow PRA was performed to estimate alloantibody levels.Allograft rejection episodes and adverse effects of SRL were also observed.Results At 3 months after conversion,average more than 60% dose reduction of daily CsA was achieved in all patients.In active conversion group,the mean Scr levels significantly reduced from（109±27） μmol/L to（97±19） μmol/L（P0.01） and the mean eGFR was markedly increased from 63±11 to（71±12） ml/min/1.73 m2（P0.01）.The improvement of renal function was maintained very well during the 2-year follow-up period.Only 1 patient had significantly deteriorated proteinuria in this group.In passive conversion group,there were 10 patients quitted the observation during the follow-up period,and 8 of them were due to the chronic renal allograft failure and serious proteinuria.The rest of patients in this group had significantly improved renal function（the mean SCr levels reduced from（195±43） μmol/L to（165±39） μmol/L and the mean eGFR was increased from 33±8 to（41±15） ml/min/1.73 m2 at 3 months after conversion and kept stable afterwards（P0.05）.Flow PRA remained less than 10% in 95% of patients with negative PRA before the conversion therapy.For patients with positive PRA before the conversion,60% of them had significantly reduced PRA levels during the follow-up period and the rest 40% kept stable.There was no episodes of acute rejection in all cases and no significant side-effects due to SRL in most cases during the 2-year follow-up period.Conclusions Conversion from traditional CsA triple therapy to a combination of SRL and low dose of CsA markedly improved renal graft function without increasing the risk of rejection in a 2-year period of follow-up.This immunosuppressive regimen may represent an optimal way to minimize CsA toxicity and also reduce the maintaining costs in renal transplant patients.However,it should be very cautiously to perform this conversion therapy for those patients with preexisted chronic renal allograft injury and obvious proteinuria.