【摘要】 目的他克莫司(Tacrolimus,FK506)和环孢素(CsA)都是很强的钙神经蛋白酶抑制剂,能有效地抑制淋巴细胞活化,防治早期急性排斥反应。文中对使用CsA的慢性移植肾肾病(chronic allograft nephropathy,CAN)患者转换为FK506后的临床和病理进行对照观察,旨在探讨该方法的有效性及其安全性。方法选择61例首次接受尸肾移植1年以上、肾功能异常、经移植肾活检诊断为CAN的患者,对符合入选条件的病例随机分为2组:CsA组(n=30):采用原治疗方案CsA+霉酚酸酯(Mycophenolate mofetil,MMF)+泼尼松;FK506组(n=31):由CsA转换至FK506+MMF+泼尼松方案治疗。至少随访12个月,以血肌酐(Scr)值倒数为纵坐标,时间为横坐标作图,通过曲线回归分析计算转换前后肾功能的下降率。治疗有效的定义为肾功能改善或稳定。肾功能改善:血肌酐斜率<-5%;肾功能稳定:血肌酐斜率介于-5%和5%之间;肾功能恶化:血肌酐斜率>5%。结果随访12个月时,FK506组平均总胆固醇(total cholesterol,TC)、三酰甘油(total triglyceride,TG)、低密度脂蛋白(low density lipoprotein,LDL)水平均明显降低,分别为(5.14±1.02)mmol/Lvs(6.61±1.37)mmol/L,P<0.001;(2.01±0.91)mmol/Lvs(2.44±1.35)mmol/L,P<0.05;(2.03±0.99)mmol/Lvs(4.11±1.21)mmol/L,P<0.01;而CsA组血TC、TG、LDL水平无明显改变,甚至呈上升趋势,分别为(7.10±1.13)mmol/Lvs(6.60±1.22)mmol/L,P<0.05;(2.49±1.32)mmol/Lvs(2.47±1.48)mmol/L,P=NS;(5.11±1.21)mmol/Lvs(4.01±0.99)mmol/L,P<0.05。2组之间的肾功能改善率(64.5%vs23.3%,P<0.01)、肾功能稳定率(12.9%vs33.3%,P<0.01)和肾功能恶化率(22.6%vs43.3%,P<0.01)均存在明显的差异。FK506转换治疗后病理上也得到明显改善:肾小管萎缩(58.1%vs46.2%,P<0.05)、间质纤维化(51.6%vs30.8%,P<0.01)和动脉透明变性(54.8%vs38.5%,P<0.01)。随访期间无一例死亡。FK506组移植肾失功率低于CsA组,分别为6.5%和23.3%,P<0.01;移植肾1年存活率分别为93.5%和76.7%,P<0.01。FK506组患者高血压、多毛症、齿龈增生、肝功能异常和肺部巨细胞病毒感染的发生率均显著低于CsA组,分别为63.8%vs84.6%(P<0.01)、22.4%vs53.8%(P<0.01)、8.6%vs51.3%(P<0.01)、6.5%vs16.7%(P<0.01)和6.5%vs10.0%(P<0.05)。胃肠道反应的发生率与CsA组无显著差异。结论 CsA转换至FK506治疗CAN患者是安全有效的,不仅能改善CAN患者的脂质异代谢,而且能有效地改善移植肾功能,延缓CAN患者慢性移植肾功能减退的进展。更多还原

【Abstract】 Objective This study evaluated the efficacy and safety of tacrolimus(FK506) as secondary intervention in cyclosporine A(CsA) treated renal transplantation patients with chronic allograft nephropathy(CAN).Methods Sixty-one patients who received a cadeveric renal transplantation in our unit more than 12 months prior to study enrollment and who were being treated with CsA-based immunosuppressive treatment were included,all patients received allograft biopsy and were diagnosed as CAN according to Banff criteria.Patients were differentiated according to following regimen.Patients were either converted to FK506 group(n=31) or remained on their initial CsA-based immunosuppression(CsA group,n=30).An important effectiveness index is the rate of decline of renal function before and after the FK506 conversion,calculated by curve fitting and regression analysis with reciprocal SCr as Y-axis and time as X-axis.Therapeutic effectiveness is defined as improvement or stabilization of renal function.Improvement: slope of serum creatinine less than-5%;Stabilization: slope of serum creatinine between <-5% and 5%;Deterioration of renal function: slope of serum creatinine larger than 5%.Results Trough TC,TG and LDL levels remained unchanged in CsA group while statistically reduced in FK506 group.Renal function was markedly improved in FK506 group.Among the twenty-four patients with improvement in the rate of decline of renal function,twenty patients(64.5%) had their regression lines become positive and four patients(12.9%) had their regression lines become less negative.Seven patients(22.6%) had increased rate of decline in renal function with their regression lines becoming more negative.The clinical efficiency after the FK506 conversion for 31 patients was compared with the pathological degree of allograft nephropathy before the conversion,and the lighter the pathological degree was,the higher the improvement rate of renal function was,and vice versa.Graft survival rate was significantly increased in FK506 group(93.5% vs 76.7%,P<0.01) follow-up one year.The incidence rates of hypertension,hypertrichosis,gum hypertrophy,liver disfunction,and CMV pneumonia in FK506 group were markedly lower than those in CsA group,63.8% vs 84.6%(P<0.01),22.4% vs 53.8%(P<0.01),8.6% vs 51.3%(P<0.01),6.5% vs 16.7%(P<0.01) and 6.5% vs 10.0%(P<0.05),respectively.Conclusion FK506 treatment markedly improved abnormality in lipid profile and graft renal function post-transplantation.Conversion from a CsA-based regimen to a tacrolimus-based regimen was an effective alterative for salvage of patients with abnormal graft renal function induced by CAN.更多还原