上海交通大学学报（医学版）

上海交通大学学报（医学版） ›› 2022, Vol. 42 ›› Issue (12): 1685-1692.doi: 10.3969/j.issn.1674-8115.2022.12.005

• 论著 · 临床研究 • 上一篇    

单用他克莫司治疗特发性膜性肾病的效果及安全性评估

胡宁宁(), 张丹, 邹军, 张翀, 林芙君(), 蒋更如()   

  1. 上海交通大学医学院附属新华医院肾脏风湿免疫科，上海 200092
  • 收稿日期:2022-06-30 接受日期:2022-11-05 出版日期:2022-12-28 发布日期:2022-12-28
  • 通讯作者: 林芙君,蒋更如 E-mail:nnh1234@sjtu.edu.cn;linfujun@xinhuamed.com.cn;jianggeng-ru@hotmail.com
  • 作者简介:胡宁宁（1995—），女，博士生；电子信箱：nnh1234@sjtu.edu.cn。
  • 基金资助:
    国家自然科学基金(82070697);上海市卫生健康委员会卫生行业临床研究专项(201940255);上海申康医院发展中心临床研究培育项目(SHDC12018X07);上海交通大学医学院多中心临床研究项目(DLY201806);解放军总医院国家慢性肾病临床医学研究中心开放课题(kfkt202015)

Efficacy and safety evaluation of tacrolimus monotherapy in the treatment of idiopathic membranous nephropathy

HU Ningning(), ZHANG Dan, ZOU Jun, ZHANG Chong, LIN Fujun(), JIANG Gengru()   

  1. Department of Renal Rheumatology and Immunology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
  • Received:2022-06-30 Accepted:2022-11-05 Online:2022-12-28 Published:2022-12-28
  • Contact: LIN Fujun,JIANG Gengru E-mail:nnh1234@sjtu.edu.cn;linfujun@xinhuamed.com.cn;jianggeng-ru@hotmail.com
  • Supported by:
    National Natural Science Foundation of China(82070697);Shanghai Municipal Health Commission Health Industry Clinical Research Project(201940255);Clinical Research Cultivation Project of Shanghai Hospital Development Center(SHDC12018X07);Multicenter Clinical Research Project of Shanghai Jiao Tong University School of Medicine(DLY201806);Opening Foundation of National Clinical Research Center for Chronic Kidney Disease, PLA General Hospital(kfkt202015)

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摘要：

目的·探讨单独使用他克莫司（tacrolimus，TAC）治疗特发性膜性肾病（idiopathic membranous nephropathy，IMN）的效果是否不劣于TAC联合糖皮质激素（glucocorticoids，GC），并对其使用安全性进行评估。方法·该研究为一项预试验研究，纳入2017年11月—2021年3月于上海交通大学医学院附属新华医院肾脏风湿免疫科就诊并经肾穿刺活检确诊的高风险IMN患者，将其随机分为2组。其中，TAC单药组仅接受TAC治疗［起始剂量0.050~0.075 mg/（kg·d），维持血药谷浓度5~10 ng/mL］，TAC联合GC组（TAC+GC组）接受TAC（同TAC单药组）联合泼尼松［起始剂量0.5 mg/（kg·d），8~12周后逐渐减量直至停用］治疗。收集2组患者的基线资料，并于访视时观察、记录患者的疗效指标及安全性指标。研究的主要终点为治疗24周时的蛋白尿总缓解率和完全缓解率，次要终点包括疗效指标（治疗24周时的24 h尿蛋白定量、血清白蛋白水平、估算肾小球滤过率水平）及不良反应（血糖升高、血栓、感染）的发生率。采用非劣效检验比较2组患者的蛋白尿总缓解率，非劣效界值设定为-10%。采用Fisher确切概率检验比较2组患者的总缓解率、完全缓解率、不良反应发生率。采用非参数检验比较患者在治疗24周时的疗效指标相对于基线水平的变化百分比的组间差异。结果·共纳入36例IMN患者，TAC单药组、TAC+GC组各18例，且2组患者的基线资料间差异均无统计学意义。治疗期间，TAC单药组失访1例，TAC+GC组失访3例。最终，共36例患者纳入全分析集（full analysis set，FAS），32例纳入符合方案分析集（per protocol set，PPS），36例纳入安全集。非劣效检验的结果显示，未观察到TAC单药治疗效果不劣于TAC联合GC治疗，2组患者蛋白尿总缓解率的风险差为0（95%CI -31.9~31.9，P=0.269），下限低于非劣效性界值-10%。在FAS、PPS中，治疗24周时2组患者的完全缓解率、总缓解率的差异均无统计学意义；将治疗24周时的患者疗效指标相对于其基线水平的变化百分比进行比较，结果发现该3个指标的组间差异亦均无统计学意义。治疗期间有10例患者（TAC单药组4例，TAC+GC组6例）发生血糖升高，组间差异无统计学意义；1例患者（TAC+GC组）出现右上肢贵要静脉血栓。结论·该预试验发现治疗24周时2组患者的总缓解率和完全缓解率相当，TAC单药组的不良反应发生频数低于TAC联合GC用药组，但现有数据尚无法确定单独使用TAC治疗IMN的效果不劣于TAC联合GC治疗。

关键词: 特发性膜性肾病, 他克莫司, 糖皮质激素, 疗效, 安全性

Abstract:

Objective ·To investigate whether the efficacy of tacrolimus (TAC) monotherapy is non-inferior to TAC combined with glucocorticoids (TAC+GC) in the treatment of idiopathic membranous nephropathy (IMN), and evaluate its safety. Methods ·This pilot study was conducted by the Department of Renal Rheumatology and Immunology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine from November 2017 to March 2021. High-risk patients with biopsy-proven IMN were recruited and randomly divided into two groups: TAC monotherapy group only received TAC treatment [an initial dose of 0.050?0.075 mg/(kg·d), maintaining trough blood concentration of 5?10 ng/mL]; TAC combined with GC group (TAC+GC group) received TAC (the same as TAC monotherapy group) combined with prednisone [an initial dose of 0.5 mg/(kg·d) for 8?12 weeks, then tapered until complete withdrawal]. The baseline data of the two groups of patients were collected, and the efficacy indicators and safety indicators of the patients were observed and recorded during the visit. The primary end points of the study were the total remission rate and complete remission rate of proteinuria at 24 weeks of treatment. The secondary end points included the efficacy indicators [24 h urinary protein quantification, serum albumin level and estimated glomerular filtration rate level at 24 weeks of treatment] and the incidence of adverse events (elevated blood glucose, thrombosis and infection). Non-inferiority test was used to compare the total remission rate of proteinuria in the two groups, and the non-inferiority margin was set as -10%. Fisher's precision probability test was used to compare the total remission rate, complete remission rate and adverse events rate of the two groups of patients. Non parametric tests were used to compare the differences of the percentage changes of the efficacy indicators from baseline values after treatment between the two groups. Results ·A total of 36 IMN patients were enrolled, with 18 in TAC monotherapy group and 18 in TAC+GC group. There was no statistically significant difference between the baseline data of the two groups. During the treatment, 1 case was lost in TAC monotherapy group and 3 cases in TAC+GC group. Finally, 36 patients were included in the full analysis set (FAS), 32 patients were included in the per protocol set (PPS), and 36 patients were included in the safety set. The results of non-inferiority test showed that it was not observed that the efficacy of TAC monotherapy was not inferior to that of TAC combined with GC. The risk difference of total remission rate of proteinuria in the two groups was 0 (95%CI -31.9?31.9, P=0.269), and the lower limit was below the non-inferiority margin. In FAS and PPS, there was no significant difference in complete remission rate and total remission rate between the two groups at 24 weeks of treatment, and no significant difference in the percentage changes of the efficacy indicators from baseline values after treatment between the two groups. Ten patients (4 cases in TAC monotherapy group, and 6 cases in TAC+GC group) developed elevated blood glucose over the period of treatment, with no significant difference between the two groups; one patient (TAC+GC group) developed right upper extremity venous thrombosis. Conclusion ·This pilot study finds that the total remission rate and complete remission rate of the two groups are similar at 24 weeks of treatment. The frequency of adverse events in TAC monotherapy group is relatively lower than that in TAC combined with GC group. However, the available data cannot prove that the efficacy of TAC monotherapy is non-inferior to that of TAC combined with GC in the treatment of IMN.

Key words: idiopathic membranous nephropathy (IMN), tacrolimus (TAC), glucocorticoids (GC), efficacy, safety

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