西罗莫司对肾移植受者的转换治疗

Conversion treatment with sirolimus in renal transplant recipients

背景:新一代的强效免疫抑制剂西罗莫司具有肾毒性少、抗增殖、抗肿瘤等作用,能够减少肾移植受者的肝肾毒性和严重感染等不良反应。目的:验证以神经钙蛋白抑制剂为主要免疫抑制方案出现一种或多种危险因素时,应用西罗莫司转换治疗方案的有效性及其安全性。设计、时间和地点:回顾性病例分析,于2003-06/2006-12在解放军南京军区南京总医院解放军肾脏病研究所完成。对象:肾移植后转换以西罗莫司为主的免疫抑制剂治疗的患者93例,男59例,女34例,年龄(38±11)岁。神经钙蛋白抑制剂肾中毒者13例、神经钙蛋白抑制剂肝毒性者26例、移植后糖尿病11例、慢性移植肾肾病33例、移植后并发肿瘤10例。方法:所有患者治疗方案都采用快速转换法,即2周内撤除神经钙蛋白抑制剂,口服环孢素A或他克莫司后4h,口服西罗莫司,单次首剂负荷剂量6mg,之后维持剂量1.0～2.0mg/d。在服用第1剂西罗莫司后的5～7d检测第1次西罗莫司浓度,目标质量浓度6～10μg/L。主要观察指标:动态观察西罗莫司转换后的血肌酐水平、急性排斥反应发生率、移植肾的丢失率、肺部感染和死亡率等。结果:西罗莫司转换治疗后,神经钙蛋白抑制剂肾毒性和肝毒性患者症状明显好转,血浓度维持在(5.1±1.2)μg/L,血肌酐由(297.72±150.28)μmol/L降至(123.76±44.2)μmol/L,转换后肝功能恢复(24例,92.3%)。高糖血症患者9例恢复正常,2例改善;17例血肌酐下降大于原肌酐水平的25%,有效率为51.5%;10例肿瘤发生于肾移植后6～43个月,8例稳定无复发,2例死亡。西罗莫司转换治疗6个月内发生急性排斥反应3例。并发症主要包括高脂血症和蛋白尿。3例死亡,6例返回透析治疗,2例移植肾摘除。转换治疗3年人肾存活率分别为90.9%和75.8%。结论:使用神经钙蛋白抑制剂的肾移植受者时出现一种或多种危险因素时,切换成西罗莫司和霉酚酸酯免疫抑制方案后不良反应减少。

BACKGROUND： Sirolimus is a new generation of immunosuppressive agent with little renal toxicity, as well as effects of anti-proliferation and anti-tumor, which can decrease the occurrence of adverse reaction such as hepatic and renal toxicity, as well as serious infection in renal transplant recipients. OBJECTIVE： To verify the efficacy and safety of conversion treatment with sirolimus in renal transplant recipients using the calcineurin inhibitor （CNI） with one or more risk factors. DESIGN, TIME AND SETTING： A retrospective analysis on cases was performed in the Research Institute of Nephrology, Nanjing General Hospital of Nanjing Military Command from June 2003 to December 2006. PARTICIPANTS： A total of 93 patients performed conversion treatment with sirolimus after renal transplantation. They consisted of 59 males and 34 females, with an average age of （38.2±11.1 ） years. Among them, CNI induced renal toxicity were in 13 （13.9%） cases, CNI induced hepatic toxicity were in 26 （28.0%） cases, post-transplantation diabetes mellitus were in 11 （11.8%） cases, chronic allograft nephropathy were in 33 （35.5%） cases, and post-transplantation tumor were in 10 （10.8%） cases. METHODS： Rapid conversion with sirolimus was performed in all patients. The CNI withdrawal was in 2 weeks. At 4 hours after oral administration of cyclosporin A or Tacrolimus, the patients took sirolimus. Initial dose of sirolimus was 6 rag, and repeated maintenance dose is 1.0 2.0 mg/d. The first concentration of sirolimus was detected at 5-7 days after first oral administration, and the target concentration was 6 10 μg/L. MAIN OUTCOME MEASURES： Serum creatinine levels, incidence of acute rejection, loss rate of grafts, pulmonary infection, and mortality rates were dynamically observed after conversion with sirolimus. RESULTS： The symptoms were markedly improved in patients with CNI induced renal toxicity and CNI induced liver toxicity, and the concentration of sirolimus were maintained at （5.1±1.2） pg/L. Serum creatinine levels decreased from （297：72±150.28） μmol/L to （123.76±44：2） μmol/L, and the liver function were recovery in 24 （92.3%） patients. 9 patients with high glucose returned to normal, and 2 patients were improved. Serum creatinine levels decreased more than 25% of primary level in 17 patients, and the effective rate was 51.5%. 10 patients with tumor were appeared 6-43 months after renal transplantation, no recurrence was found in 8 of them and 2 patients were dead. Acute rejections were occurred in 3 patients at 6 months after conversion treatment. The complications were included hyperlipidemia and proteinuria. 3 patients were dead, 6 patients returned to dialysis treatment, and 2 patients were removal of grafts. At 3 years after conversion treatment, the survival rates of patients and grafts were 90.9% and 75.8%, respectively. CONCLUSION： The conversion treatment with SRL and MMF may be a better option for the renal transplant recipients using the CNI with risk factors appeared.