神经钙蛋白阻滞剂减量联合西罗莫司治疗慢性移植肾肾病

Reducing calcineurin inhibitor and adding Sirolimus to treat chronic allograft nephropathy

背景:西罗莫司具有明确的抗增殖特性而无肾毒性,可能在慢性移植肾肾病的防治方面发挥作用,但以其为基础的免疫抑制方案治疗慢性移植肾肾病尚无统一标准。目的:探讨神经钙蛋白阻滞剂减量联合西罗莫司治疗慢性移植肾肾病的效果。设计、时间及地点:回顾性病例分析,于2005-05/2007-05在解放军第三军医大学大坪医院野战外科研究所完成。对象:选取同期收治的经病理学检测证实的慢性移植肾肾病患者69例,免疫抑制剂方案为他克莫司+霉酚酸脂+强地松19例,环孢素+霉酚酸脂+强地松43例,环孢素+硫唑嘌呤+强地松7例,其中他克莫司用量1.0～4.0mg/d,环孢素用量100～325mg/d,霉酚酸脂用量500～1500mg/d,强地松用量2.5～15mg/d。西罗莫司为美国惠氏制药公司产品,批号H20050066。神经钙蛋白阻滞剂他克莫司为日本藤泽药品工业株式会社产品,批号X980596;环孢素为杭州中美华东制药有限公司产品,批号H10960122。方法:将他克莫司或环孢素剂量减少2/3,加用西罗莫司2mg/d,根据血药浓度监测调整西罗莫司用量达到常规目标谷浓度的1/2,其余免疫抑制剂霉酚酸脂、硫唑嘌呤及醋酸泼尼松用量维持不变,随访6个月。主要观察指标:24h尿量、血清肌酐、内生肌酐清除率、24h尿蛋白的变化;部分患者移植肾再次活检病理学表现。结果:与使用前比较,69例患者使用西罗莫司6个月后24h尿量、内生肌酐清除率明显升高(P<0.05或0.01),血清肌酐值、24h尿蛋白含量显著下降(P<0.01)。使用西罗莫司6个月后4例患者接受再次穿刺活检,病理学上可见以间质炎性细胞浸润为特点的排斥反应减轻,而以微动脉管壁增厚和玻璃样变性为特点的神经钙蛋白阻滞剂肾毒性反应变化不大。结论:神经钙蛋白阻滞剂减量联合西罗莫司治疗慢性移植肾肾病是一种安全有效的方法,其原因可能与两者联合应用后产生的协同性免疫抑制作用及减少神经钙蛋白阻滞剂肾毒性有关。

BACKGROUND： Sirolimus exhibits strong anti-proliferative property but no renal toxicity. It may play a role in prevention of chronic allograft nephropathy. However, there are no uniform criteria. OBJECTIVE： To investigate the effect of the treatment of chronic allograft nephropathy by reducing calcineurin inhibitor combining Sirolimus. DESIGN, TIME AND SETTING： Retrospective case analysis. The experiment was performed at the Daping Hospital and Institute of Surgery, Third Military Medical University of Chinese PLA between May 2005 and May 2007. PARTICIPANTS： Sixty-nine patients with chronic allograft nephropathy which was confirmed by pathology were selected. Immunosuppressant regimens included tacrolimus＋mycophenolate mofetil （MMF）＋ prednisone acetate in 19 cases, cyclosporine A （CsA）＋ MMF＋prednisone acetate in 43 cases, and CsA＋azathioprine＋ prednisone acetate in 7 cases. Dose of tacrolimus （FK506） was 1.0-4.0 mg/d, CsA 100-325 mg/d, MMF 500-1 500 mg/d, and methylprednisolone 2.5-15 mg/d. Sirolimus was provided by Wyeth USA, No. H20050066; calcineurin inhibitor FK506 by Fujisawa, Japan, No. X980596, and CsA was product of Huadong Medicine, No. H10960122. METHODS： The dose of calcineurin inhibitor （CsA or FK506） was reduced to 1/3 of their original doses, and Sirolimus was added with dose of 2 mg per day, which was adjusted to half of the aim density, but the original doses of MMF, azathioprine and Pred were kept. All patients were followed up for 6 months. MAIN OUTCOME MEASURES： 24 h urinary volume, creatinine clearance, serum creatinine and 24 h urine protein changes were observed. Some of the patients accepted second biopsy to observe the pathological changes. RESULTS： After using Sirolimus for 6 months, 24 h urinary volume and creatinine clearance were significantly increased in 69 patients （P 〈 0.05 or 0.01）, while serum creatinine and 24 h urine protein significantly decreased （P 〈 0.01）. Four patients accepted second biopsy, and from pathology we found the relief of renal interstitium inflammatory cell infiltration, but the thickening and glassy degeneration of arteriole tubal wall had no obvious change. CONCLUSION： Reducing calcineurin inhibitor and adding Sirolimus is an efficient and safe method to treat chronic allograft nephropathy. The cooperative immunosuppressive action and the reducing of calcineurin inhibitor relative nephrotoxicity may both produce a marked effect.