Objective  To investigate the optimal blood concentration range of tacrolimus (TAC) for the treatment of nephrotic syndrome (NS) in children.

Methods  Children with NS admitted to the Department of Nephrology and Immunology of Hebei Children's Hospital from January 2021 to December 2023 were retrospectively selected as study subjects. They were divided into the effective group and the ineffective group according to whether the treatment was effective or not, and the TAC threshold for effective treatment was determined by using the receiver operator characteristic (ROC) curve. The children with NS were divided into a low concentration group (<3 ng/mL), a medium concentration group (3-5 ng/mL) and a target concentration group (5-10 ng/mL) according to the TAC concentration, and the relationships between the TAC concentration and the clinical efficacy and adverse reactions was analyzed.

Results  A total of 160 children were enrolled in the study. The numbers of complete remission (CR), partial remission (PR), and null remission (NR) cases of NS children were 91, 37, and 32, respectively, and the treatment was effective in 128 cases (80%). The ROC curve analysis results showed that the area under the ROC curve (95%CI), sensitivity, specificity, and threshold of the mean trough concentration of TAC for predicting the efficacy of the treatment were 0.779 (0.704, 0.853), 62.5%, 84.45%, and 3.33 ng/mL, respectively. In terms of clinical efficacy, CR and PR were lower and NR was higher in the low concentration group compared with the target concentration group (P<0.05); whereas, CR was lower and PR was higher in the medium concentration group (P<0.05), and the difference in NR was not statistically significant (P>0.05). In terms of different hormone-responsive phenotypes of NS, the CR of the low concentration group was lower (P<0.05), while there was no significant difference in CR and PR between the medium concentration group and the target concentration group (P>0.05). As for the different pathological types of NS, CR was lower in the low concentration group when compared with the target concentration group or medium concentration group (P<0.05); while the differences in CR and PR between the medium concentration group and the target concentration group were not statistically significant (P>0.05). Regarding adverse reactions, the incidence of limb tremor and abnormal blood glucose was significantly higher in the target concentration group than in the other two groups (P<0.05). In addition, the differences in serious infections and hypertension among the three groups were not statistically significant (P>0.05).

Conclusion  When TAC is used to treat NS in children, the recommended TAC concentration range is 3-5 ng/mL.

1.朱会玲, 高瑛子, 王光, 等. 激素治疗基础加服他克莫司或环磷酰胺对肾病综合征患者肾功能、炎症水平及免疫功能影响[J]. 数理医药学杂志, 2022, 35(9): 1318-1321. [Zhu HL, Gao YZ, Wang G, et al. Effects of hormone therapy combined with tacrolimus or cyclophosphamide on renal function, inflammatory level and immune function in patients with nephrotic syndrome[J]. Journal of Mathematical Medicine, 2022, 35(9): 1318-1321.] DOI: 10.3969/j.issn.1004-4337.2022.09.018.

2.郭嘉鸿, 魏华, 梁照志, 等. 腹膜透析辅助治疗重症肾病综合征合并急性肾损伤临床分析[J]. 数理医药学杂志, 2022, 35(3): 362-365. [Guo JH, Wei H, Liang  ZZ, et al. Clinical analysis of peritoneal dialysis-assisted treatment for severe nephrotic syndrome complicated with acute kidney injury[J]. Journal of Mathematical Medicine, 2022, 35(3): 362-365.] DOI: 10.3969/j.issn.1004-4337. 2022.03.016.

3.涂娟, 陈朝英, 耿海云, 等. 中等剂量糖皮质激素治疗激素敏感肾病综合征复发患儿的前瞻性随机对照研究[J]. 中国当代儿科杂志, 2022, 24(5): 466-471. [Tu J, Chen CY, Geng HY, et al. Prospective randomized controlled study on the treatment of recurrent steroid-sensitive nephrotic syndrome in children with moderate doses of glucocorticoids[J]. Chinese Journal of Contemporary Pediatrics, 2022, 24(5): 466-471.] DOI: 10.7499/j.issn.1008-8830.2111133.

4.Basu B, Sander A, Roy B, et al. Efficacy of rituximab vs tacrolimus in pediatric corticosteroid-dependent nephrotic syndrome: a randomized clinical trial[J]. JAMA Pediatr, 2018, 172(8): 757-764. DOI: 10.1001/jamapediatrics. 2018.1323.

5.陆晓玲, 陈冰. 机器学习在移植患者他克莫司个体化精准用药中的应用概述[J]. 药物流行病学杂志, 2023, 32(1): 82-88. [Lu XL, Chen B. Overview of the application of machine learning in the individualized and precise medication of tacrolimus in transplant patients[J]. Chinese Journal of Pharmacoepidemiology, 2023, 32(1): 82-88.] DOI: 10.19960/j.issn.1005-0698.202301011.

6.徐世希, 林杰, 李洁, 等. 不同给药途径下质子泵抑制药对肾移植患者免疫抑制药血药浓度的影响[J]. 中国药师, 2022, 25(11): 1980-1983. [Xu SX, Lin  J, Li J, et al. The effect of proton pump inhibitors on the blood concentration of immunosuppressive drugs in renal transplant patients under different administration routes[J]. China Pharmacist, 2022, 25(11): 1980-1983.] DOI: 10.19962/j.cnki.issn1008-049X.2022.11.018.

7.孙蕾, 匡新宇, 康郁林, 等. 环孢霉素A与他克莫司治疗儿童难治性肾病综合征疗效及安全性对照研究 [J]. 中国实用儿科杂志, 2022, 37(8): 625-631. [Sun  L, Kuang XY, Kang YL, et al. A comparative study on the efficacy and safety of cyclosporine A and tacrolimus in the treatment of refractory nephrotic syndrome in children[J]. Chinese Journal of Practical Pediatrics, 2022, 37(8): 625-631.] DOI: 10.19538/j.ek2022080612.

8.宋艳, 成璐, 贾淼鑫, 等. 肾病综合征患者他克莫司血药浓度监测的回顾性分析与评价[J]. 中国医院药学杂志, 2017, 37(7): 654-658. [Song Y, Cheng L, Jia MX, et al. Retrospective analysis and evaluation of blood concentration monitoring of tacrolimus in patients with nephrotic syndrome[J]. Chinese Journal of Hospital Pharmacy, 2017, 37(7): 654-658.] DOI: 10.13286/j.cnki.chinhosppharmacyj.2017.07.21.

9.Pennesi M, Gagliardo A, Minisini S. Effective tacrolimus treatment in a child suffering from severe nephrotic syndrome[J]. Pediatr Nephrol, 2003, 18(5): 477-478. DOI: 10.1007/s00467-003-1098-0.

10.Eckardt KU, Kasiske BL. KDIGO Clinical Practice Guideline for Glomerulonephritis Foreword[J]. Kidney Int Suppl, 2012, 2(2): 140. DOI: 10.1038/kisup.2012.10.

11.Jahan A, Prabha R, Chaturvedi S, et al. Clinical efficacy and pharmacokinetics of tacrolimus in children with steroid-resistant nephrotic syndrome[J]. Pediatr Nephrol, 2015, 30(11): 1961-1967. DOI: 10.1007/s00467-015-3133-3.

12.中华医学会儿科学分会肾脏学组. 激素耐药型肾病综合征诊治循证指南(2016)[J]. 中华儿科杂志, 2017, 55(11): 805-809. DOI: 10.3760/cma.j.issn.0578-1310.2017.11. 002.

13.高萍, 关鑫磊, 刘炘, 等. 他克莫司治疗儿童肾病综合征的最佳血药浓度范围研究[J]. 中国医院药学杂志, 2020, 40(1): 59-64. [Gao P, Guan XL, Liu X, et al. Study on the optimal blood concentration range of tacrolimus in the treatment of nephrotic syndrome in children[J]. Chinese Journal of Hospital Pharmacy, 2020, 40(1): 59-64.] DOI: 10.13286/j.1001-5213.2020.01.08.

14.Supavekin S, Surapaitoolkorn W, Kurupong T, et al. Tacrolimus in steroid resistant and steroid dependent childhood nephrotic syndrome[J]. J Med Assoc Thai, 2013, 96(1): 33-40. https://pubmed.ncbi.nlm.nih.gov/23720975/.

15.Sinha A, Gupta A, Kalaivani M, et al. Mycophenolate mofetil is inferior to tacrolimus in sustaining remission in children with idiopathic steroid-resistant nephrotic syndrome[J]. Kidney Int, 2017, 92(1): 248-257. DOI: 10.1016/j.kint.2017.01.019.

16.胡宁宁. 他克莫司对肾移植受者及肾病患者免疫指标的影响及其全血稳态谷浓度范围的优化[D]. 石家庄: 河北医科大学, 2016. DOI: 10.7666/d.D844600.

17.Shah SS, Hafeez F, Akhtar N. Tacrolimus drug level and response to treatment in idiopathic childhood steroid resistant nephrotic syndrome[J]. J Ayub Med Coll Abbottabad, 2015, 27(4): 784-787. https://pubmed.ncbi.nlm.nih.gov/27004322/.

18.Yang EM, Lee ST, Choi HJ, et al. Tacrolimus for children with refractory nephrotic syndrome: a one-year prospective, multicenter, and open-label study of tacrobell, a generic formula[J]. World J Pediatr, 2016, 12(1): 60-65. DOI: 10.1007/s12519-015-0062-y.

19.叶超, 李昕, 刘丽华, 等. 基于文献病例的他克莫司致急性胰腺炎临床特征分析[J]. 药物流行病学杂志, 2023, 32(11): 1285-1295. [Ye C, Li X, Liu LH, et al. Analysis of clinical characteristics of acute pancreatitis caused by tacrolimus based on literature cases[J]. Chinese Journal of Pharmacoepidemiology, 2023, 32(11): 1285-1295.] DOI: 10.19960/j.issn.1005-0698.202311012.

20.廖敏辉, 陈芳昭, 韩信, 等. 他克莫司与环孢素A对肾移植后糖尿病发病率影响的系统评价[J]. 药物流行病学杂志, 2023, 32(6): 689-697. [Liao MH, Chen  FZ, Han X, et al. Systematic evaluation of the effect of tacrolimus and cyclosporine A on the incidence of diabetes after kidney transplantation[J]. Chinese Journal of Pharmacoepidemiology, 2023, 32(6): 689-697.] DOI: 10.19960/j.issn.1005-0698.202306011.

21.Zhang X, Men T, Liu H, et al. Genetic risk factors for post-transplantation diabetes mellitus in Chinese Han renal allograft recipients treated with tacrolimus[J]. Transpl Immunol, 2018, 49: 39-42. DOI: 10.1016/j.trim.2018.04.001.

22.刘相端, 曲青山, 蒋欣, 等. 肾移植后血他克莫司浓度与血脂和空腹血糖水平的相关性分析[J]. 中华器官移植杂志, 2013, 34(4): 227-230. [Liu XD, Qu QS, Jiang X, et al. Correlation analysis of blood tacrolimus concentration and blood lipid and fasting blood glucose levels after kidney transplantation[J]. Chinese Journal of Organ Transplantation, 2013, 34(4): 227-230.] DOI: 10.3760/cma.j.issn. 0254-1785.2013.04.009.

23.杨琳. 原发性肾病综合征患者他克莫司剂量优化及预测模型研究[D]. 长沙: 中南大学, 2024. DOI: 10.27661/d.cnki.gzhnu.2022.004209.