他克莫司联合小剂量西罗莫司治疗儿童激素耐药型肾病综合征的临床疗效与安全性研究
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摘要
目的探讨他克莫司联合小剂量西罗莫司治疗儿童激素耐药型肾病综合征的临床疗效与安全性。方法纳入武汉市第三医院2013年10月至2016年10月确诊的激素耐药型肾病综合征患儿,纳入标准采用2001年中华医学会儿科学分会肾脏病学组制订的诊断标准。采用随机数表将入选患者随机分为A组(27例)与B组(27例)。A组采用他克莫司+小剂量糖皮质激素治疗;B组使用小剂量西罗莫司+他克莫司+小剂量糖皮质激素治疗。比较各组白介素(IL)-2、IL-13、干扰素(INF)-γ改变,以及血尿常规、肝肾功能、血脂、24 h尿蛋白、血糖、血药浓度等生化指标,分析临床疗效与不良反应。结果两组经过治疗3个月、6个月后总胆固醇、血肌酐、肾小球滤过率、白蛋白及24 h尿蛋白较治疗前均显著改善,差异具有统计学意义(P<0.05);且治疗后B组前述指标的改善情况显著优于A组(P<0.05)。两组经过治疗后IL-2、INF-γ较治疗前均显著下降,而IL-13显著升高,差异具有统计学意义(P<0.05);且治疗后B组前述指标的改善情况显著优于A组(P<0.05)。治疗后B组他克莫司血药浓度略低于A组,差异有统计学意义(P<0.05);虽然B组总缓解率略高于A组,但差异无统计学意义(P>0.05)。B组不良反应发生率和疾病复发率均显著低于A组,差异均有统计学意义(P<0.05)。结论他克莫司+小剂量糖皮质激素+小剂量西罗莫司的三联治疗方案较他克莫司+小剂量糖皮质激素治疗更加安全有效,能更好的改善胆固醇、血肌酐、肾小球滤过率、白蛋白及24 h尿蛋白等生化指标,同时降低不良反应与疾病复发的发生。
Objective To investigate the clinical efficacy and safety of tacrolimus combined with low-dose sirolimus for pediatric steroid-resistant nephrotic syndrome. Methods Children with steroid-resistant nephrotic syndrome diagnosed in our hospital from October 2013 to October 2016 were included in the study. The inclusion criteria met the diagnostic criteria formulated by the Nephrology Group of the Society of Pediatrics, Chinese Medical Association in 2001. They were randomly divided into group A(27 cases) and group B(27 cases) using a random number table. Group A was treated with tacrolimus + low dose glucocorticoid; group B was treated with tacrolimus + low-dose sirolimus + low-dose glucocorticoid tacrolimus. The changes of interleukin-2, interleukin-13, interferon-gamma(INF-γ), blood routine test results, liver and kidney function test results, blood lipid, 24-hour urinary protein, blood sugar, blood-drug concentration and other biochemical indicators were compared, and the clinical efficacy and adverse reactions were analyzed. Results The total cholesterol, serum creatinine, glomerular filtration rate, albumin and 24-hour urinary protein in the two groups were significantly improved at 3 months and 6 months after treatment(P<0.05). Compared with group A, the total cholesterol, serum creatinine, glomerular filtration rate, albumin and 24-hour urinary protein in group B were significantly improved at 3 months and 6 months after treatment.(P<0.05). After treatment, the levels of IL-2 and INF-gamma in two groups were significantly lower than those before treatment, while the levels of IL-13 were significantly higher, with difference of statistical significance(P<0.05); compared with group A, the levels of IL-2 and INF-gamma in group B were significantly lower than those in group A at 3 months and 6 months after treatment, while the levels of IL-13 were significantly higher than those in group A, with difference of statistical significance(P<0.05). After treatment, the blood concentration of tacrolimus in group B was slightly lower than that in group A, with difference of statistical significance(P<0.05); although the total remission rate in group B was slightly higher than that in group A, there was no statistically significant difference(P>0.05). The incidence of adverse reactions and recurrence rates in group B were significantly lower than those in group A, with difference of statistical significance(P<0.05). Conclusions The triplet regime of tacrolimus + low dose glucocorticoid combined with low-dose sirolimus has higher safety and effectiveness than tacrolimus alone, which can better improve biochemical indicators such as cholesterol, serum creatinine, glomerular filtration rate, albumin and 24-hour urinary protein, and reduce occurrence of recurrence and adverse reactions.
Objective To investigate the clinical efficacy and safety of tacrolimus combined with low-dose sirolimus for pediatric steroid-resistant nephrotic syndrome. Methods Children with steroid-resistant nephrotic syndrome diagnosed in our hospital from October 2013 to October 2016 were included in the study. The inclusion criteria met the diagnostic criteria formulated by the Nephrology Group of the Society of Pediatrics, Chinese Medical Association in 2001. They were randomly divided into group A(27 cases) and group B(27 cases) using a random number table. Group A was treated with tacrolimus + low dose glucocorticoid; group B was treated with tacrolimus + low-dose sirolimus + low-dose glucocorticoid tacrolimus. The changes of interleukin-2, interleukin-13, interferon-gamma(INF-γ), blood routine test results, liver and kidney function test results, blood lipid, 24-hour urinary protein, blood sugar, blood-drug concentration and other biochemical indicators were compared, and the clinical efficacy and adverse reactions were analyzed. Results The total cholesterol, serum creatinine, glomerular filtration rate, albumin and 24-hour urinary protein in the two groups were significantly improved at 3 months and 6 months after treatment(P<0.05). Compared with group A, the total cholesterol, serum creatinine, glomerular filtration rate, albumin and 24-hour urinary protein in group B were significantly improved at 3 months and 6 months after treatment.(P<0.05). After treatment, the levels of IL-2 and INF-gamma in two groups were significantly lower than those before treatment, while the levels of IL-13 were significantly higher, with difference of statistical significance(P<0.05); compared with group A, the levels of IL-2 and INF-gamma in group B were significantly lower than those in group A at 3 months and 6 months after treatment, while the levels of IL-13 were significantly higher than those in group A, with difference of statistical significance(P<0.05). After treatment, the blood concentration of tacrolimus in group B was slightly lower than that in group A, with difference of statistical significance(P<0.05); although the total remission rate in group B was slightly higher than that in group A, there was no statistically significant difference(P>0.05). The incidence of adverse reactions and recurrence rates in group B were significantly lower than those in group A, with difference of statistical significance(P<0.05). Conclusions The triplet regime of tacrolimus + low dose glucocorticoid combined with low-dose sirolimus has higher safety and effectiveness than tacrolimus alone, which can better improve biochemical indicators such as cholesterol, serum creatinine, glomerular filtration rate, albumin and 24-hour urinary protein, and reduce occurrence of recurrence and adverse reactions.
引文
[1] 余自华.儿童激素耐药型肾病综合征的诊疗现状[J].中华实用儿科临床杂志,2013,28(5):321-323.
[2] Lee S,Kim CD,Huh K,et al.Low-dose mycophenolate mofetil in tablet form or capsule form combined with tacrolimus in the early period after kidney transplantation:a prospective randomized trial[J].Clin Nephrol,2016,86(12):319-327.
[3] Manuel O,Venetz JP,Fellay J,et al.Efficacy and safety of universal valganciclovir prophylaxis combined with a tacrolimus/mycophenolate-based regimen in kidney transplantation[J].Swiss Med Wkly,2007,137(47-48):669-676.
[4] 王倩涵,史长松.环磷酰胺与他克莫司治疗儿童激素耐药型肾病综合征的疗效对比[J].临床医药文献电子杂志,2016,3(31):6273-6274.
[5] 李月兰.他克莫司治疗儿童激素依赖型和耐药型肾病综合征的疗效比较[J].实用临床医药杂志,2016,20(7):109-112.
[6] 张艳敏,宋晓翔,王丽峰,等.他克莫司治疗50例儿童激素耐药型肾病综合征的临床研究[J].中华临床医师杂志,电子版,2016,10(23):3526-3529.
[7] Zhang Y,Luo J,Hu B,et al.Efficacy and safety of tacrolimus combined with glucocorticoid treatment for IgA nephropathy:a meta-analysis[J].J Int Med Res,2018,46(8):3236-3250.
[8] 周优丽,沈增晖,姚云,等.他克莫司联合激素对儿童激素耐药难治性肾病综合征的疗效研究[J].儿科药学杂志,2016,22(3):21-23.
[9] Tada M,Shimohata T,Tada M,et al.Long-term therapeutic efficacy and safety of low-dose tacrolimus (FK506) for myasthenia gravis[J].J Neurol Sci,2006,247(1):17-20.
[10] Lee YH,Lee HS,Choi SJ,et al.Efficacy and safety of tacrolimus therapy for lupus nephritis:a systematic review of clinical trials[J].Lupus,2011,20(6):636-640.
[11] Yu K,Wang Y,Wan T,et al.Tacrolimus nanoparticles based on chitosan combined with nicotinamide:enhancing percutaneous delivery and treatment efficacy for atopic dermatitis and reducing dose[J].Int J Nanomedicine,2018,13:129-142.
[12] 杨剑辉,孟丽丽,刘增波,等.小剂量西罗莫司治疗难治性肾病综合征的疗效和安全性[J].中华内科杂志,2010,49(9):789-790.
[13] 王娜,刘超,郑舒婷.西罗莫司联合激素治疗增殖性狼疮性肾炎疗效观察[J].临床合理用药杂志,2012,5(19):54-56.
[14] Baldan N,Rigotti P,Furian L,et al.Co-administration of sirolimus alters tacrolimus pharmacokinetics in a dose-dependent manner in adult renal transplant recipients[J].Pharmacol Res,2006,54(3):181-185.
[15] 毛建华,傅海东,方澄清,等.西罗莫司治疗儿童难治性肾病综合征的初步体会:2例报道[C].浙江省中医药学会肾病分会学术年会暨国家级中医药继续教育项目"慢性肾脏病临床实践与新进展"学习班暨慢性肾脏病中医临床路径学术研讨会文集,2011.
[16] 张胜志.他克莫司对激素抵抗型肾病综合征患者Th1/Th2平衡失调及机体自身免疫的影响[J].中国实用医刊,2017,44(11):101-104.
[17] 招玉龙,王云霞,吴春.他克莫司治疗老年激素抵抗型肾病综合征的临床疗效[J].中国老年学杂志,2013,33(6):1266-1268.
[18] 赵晶莹.IL-21和INF-γ在肾病综合征发病机制中的作用[J].国际儿科学杂志,2017,44(5):309-315.
[2] Lee S,Kim CD,Huh K,et al.Low-dose mycophenolate mofetil in tablet form or capsule form combined with tacrolimus in the early period after kidney transplantation:a prospective randomized trial[J].Clin Nephrol,2016,86(12):319-327.
[3] Manuel O,Venetz JP,Fellay J,et al.Efficacy and safety of universal valganciclovir prophylaxis combined with a tacrolimus/mycophenolate-based regimen in kidney transplantation[J].Swiss Med Wkly,2007,137(47-48):669-676.
[4] 王倩涵,史长松.环磷酰胺与他克莫司治疗儿童激素耐药型肾病综合征的疗效对比[J].临床医药文献电子杂志,2016,3(31):6273-6274.
[5] 李月兰.他克莫司治疗儿童激素依赖型和耐药型肾病综合征的疗效比较[J].实用临床医药杂志,2016,20(7):109-112.
[6] 张艳敏,宋晓翔,王丽峰,等.他克莫司治疗50例儿童激素耐药型肾病综合征的临床研究[J].中华临床医师杂志,电子版,2016,10(23):3526-3529.
[7] Zhang Y,Luo J,Hu B,et al.Efficacy and safety of tacrolimus combined with glucocorticoid treatment for IgA nephropathy:a meta-analysis[J].J Int Med Res,2018,46(8):3236-3250.
[8] 周优丽,沈增晖,姚云,等.他克莫司联合激素对儿童激素耐药难治性肾病综合征的疗效研究[J].儿科药学杂志,2016,22(3):21-23.
[9] Tada M,Shimohata T,Tada M,et al.Long-term therapeutic efficacy and safety of low-dose tacrolimus (FK506) for myasthenia gravis[J].J Neurol Sci,2006,247(1):17-20.
[10] Lee YH,Lee HS,Choi SJ,et al.Efficacy and safety of tacrolimus therapy for lupus nephritis:a systematic review of clinical trials[J].Lupus,2011,20(6):636-640.
[11] Yu K,Wang Y,Wan T,et al.Tacrolimus nanoparticles based on chitosan combined with nicotinamide:enhancing percutaneous delivery and treatment efficacy for atopic dermatitis and reducing dose[J].Int J Nanomedicine,2018,13:129-142.
[12] 杨剑辉,孟丽丽,刘增波,等.小剂量西罗莫司治疗难治性肾病综合征的疗效和安全性[J].中华内科杂志,2010,49(9):789-790.
[13] 王娜,刘超,郑舒婷.西罗莫司联合激素治疗增殖性狼疮性肾炎疗效观察[J].临床合理用药杂志,2012,5(19):54-56.
[14] Baldan N,Rigotti P,Furian L,et al.Co-administration of sirolimus alters tacrolimus pharmacokinetics in a dose-dependent manner in adult renal transplant recipients[J].Pharmacol Res,2006,54(3):181-185.
[15] 毛建华,傅海东,方澄清,等.西罗莫司治疗儿童难治性肾病综合征的初步体会:2例报道[C].浙江省中医药学会肾病分会学术年会暨国家级中医药继续教育项目"慢性肾脏病临床实践与新进展"学习班暨慢性肾脏病中医临床路径学术研讨会文集,2011.
[16] 张胜志.他克莫司对激素抵抗型肾病综合征患者Th1/Th2平衡失调及机体自身免疫的影响[J].中国实用医刊,2017,44(11):101-104.
[17] 招玉龙,王云霞,吴春.他克莫司治疗老年激素抵抗型肾病综合征的临床疗效[J].中国老年学杂志,2013,33(6):1266-1268.
[18] 赵晶莹.IL-21和INF-γ在肾病综合征发病机制中的作用[J].国际儿科学杂志,2017,44(5):309-315.