Objective: To investigate the efficacy and safety of rapamycin in children with tuberous sclerosis complex (TSC) associated renal disease. Methods: A prospective self-control study was conducted. The clinical data of 92 children diagnosed with tuberous sclerosis complex associated kidney disease at the People's Liberation Army General Hospital from January 2011 to January 2019 were collected. The long-term rapamycin treatment for all patients initiated at 1 mg/(m(2)·d), which was gradually adjusted to reach a blood concentration of 5-10 μg/L. The changes of the maximum diameter of renal lesions in children after rapamycin treatment were observed and analyzed with Wilcoxon test. Results: Ninety-two children, including 52 males and 40 females, who met the criteria were analyzed. Sixty patients had only renal angiomyolipoma(RAML), while 24 patients had only multiple renal cysts(MRC), and 8 patients had both lesions. The age of TSC diagnosis was 16.0 (7.0, 42.0) months, and the age of initial treatment with rapamycin was 63.5 (21.0, 103.0) months. The follow-up lasted for 12.0 (4.0, 23.0) months. Sequencing of TSC1 and TSC2 genes was performed in 54 children with TSC, including 3 patients (6%) with mutations in TSC1 gene and 51 patients (94%) with mutations in TSC2 gene. The maximum RAML diameter before treatment was 7.0 (4.0, 9.0) mm. The best effect reached at 3 months of treatment, with the diameter of 4.0 (0,7.0) mm. The maximum diameters at 6 months, 1 year and 1-2 years were 5.0 (0,9.8) mm, 5.0 (1.5, 8.5) mm, 5.5 (3.0, 9.0) mm, respectively, and were significantly different from the baseline (Z=-2.404,-2.350,-2.750,P=0.016,0.019,0.006, respectively). The maximum diameter after 2-3 years, and ≥3 years were 5.0 (3.9,7.0) mm and 6.0 (1.0, 11.0) mm, without significant difference from the baseline (Z=-0.856,-0.102,P=0.393,0.919, respectively).The maximum diameters of MRC after 3 months, 6 months, 1 year,1-2 years, 2-3 years, and ≥3 years were 11.0 (5.0, 14.0) mm,3.0 (0.0,11.0) mm,5.0 (0,21.0) mm,0 (0,14.0) mm,0 (0,10.0) mm, and 0 (0,18.3) mm, respectively, but were not significantly different rom the baseline (7.0 (5.0, 15.7) mm)(Z=-0.944,-1.214,-1.035,-1.896,-1.603,-1.214,P=0.345,0.225,0.301,0.058,0.109,0.225, respectively).Twenty-nine patients (32%) had oral ulcers during the entire treatment period, and no serious adverse reactions were observed. Conclusions: Rapamycin could decrease the diameter of TSC-related RAML, but could not inhibit the growth of cysts. It is well tolerated in the treatment of renal diseases associated with tuberous sclerosis complex.
目的： 探讨雷帕霉素治疗结节性硬化症(TSC)相关肾脏疾病患儿的疗效和安全性。 方法： 采用前瞻性自身对照研究。收集2011年1月至2019年1月在解放军总医院诊断为TSC相关肾脏疾病的患儿92例。入组患儿均长期规律接受雷帕霉素治疗，起始剂量1 mg/(m(2)·d)，逐渐调整到血药浓度5~10 μg/L。观察雷帕霉素治疗后患儿肾脏病变最大径的变化情况。治疗前后病变最大径的比较采用Wilcoxon检验。 结果： 入组的92例患儿男52例、女40例。60例只患有肾血管平滑肌脂肪瘤（RAML）；24例只患有多发肾囊肿（MRC），8例同时患有上述两种病变。92例患儿TSC确诊年龄16.0（7.0，42.0）月龄，开始接受雷帕霉素治疗年龄63.5（21.0，103.0）月龄，随访时间12.0（4.0，23.0）个月。共有54例患儿行基因检测，均检测出基因异常，3例（6%）TSC1基因变异，51例（94%）TSC2基因变异。RAML治疗前(基线)最大径为7.0(4.0，9.0)mm。治疗3个月时RAML肿瘤最大径最小，为4.0(0，7.0)mm，与基线相比，差异有统计学意义（Z=-3.343，P=0.001），治疗6个月、1年、1~<2年肿瘤最大径分别为5.0(0，9.8)、5.0(1.5，8.5)、5.5(3.0，9.0)mm，与基线相比差异均有统计学意义（Z=-2.404、-2.350、-2.750,P=0.016、0.019、0.006)。2~<3年及≥3年随访期间最大径分别为5.0(3.9，7.0)、6.0(1.0，11.0)mm，与基线比差异均无统计学意义（Z=-0.856、-0.102,P=0.393、0.919）。MRC肿瘤最大径治疗3个月、6个月、1年、1~<2年、2~<3年、≥3年分别为11.0（5.0，14.0），3.0(0，11.0)、5.0（0，21.0）、0(0，14.0)、0（0，10）、0（0，18.3）mm，与治疗前（基线）[7.0（5.0，15.7）mm]相比，差异均无统计学意义（Z=-0.944、-1.214、-1.035、-1.896、-1.603、-1.214,P=0.345、0.225、0.301、0.058、0.109、0.225）。29例（32%）患儿在整个治疗过程中曾经出现过一次口腔溃疡，没有严重的不良反应报告。 结论： 雷帕霉素可以减少TSC相关RAML的直径，可以延缓MRC的增大，但并不能抑制囊肿的增长。具有良好的安全性。.
Keywords: Angiomyolipoma; Child; Renal cyst; Sirolimus; Tuberous sclerosis.