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目的:探讨利妥昔单抗（rituximab，RTX）治疗M型磷脂酶A2受体（M-type phospholipase A2 receptor，PLA2R）相关特发性膜性肾病（idiopathic membranous，IMN）的疗效及预后。方法:该研究为回顾性队列研究。收集2018年9月至2023年3月深圳市第二人民医院使用RTX治疗的PLA2R相关IMN患者的临床资料。按照蛋白尿缓解情况将患者分为蛋白尿缓解组（24 h尿蛋白量<3.5 g）和蛋白尿未缓解组（24 h尿蛋白量≥3.5 g），比较两组临床资料的差异。按照基线24 h尿蛋白量和估算肾小球滤过率（eGFR）将患者分为疾病进展高风险组［24 h尿蛋白量≥ 8 g或eGFR<60 ml·min -1·（1.73 m 2） -1］和非疾病进展高风险组［24 h尿蛋白量<8 g或eGFR≥60 ml·min -1·（1.73 m 2） -1］。采用Kaplan-Meier生存曲线法比较两组患者蛋白尿缓解率及肾脏复合终点事件［eGFR下降≥基线值30%或进入终末期肾病］生存率的差异。多因素Cox回归分析法分析蛋白尿缓解及肾脏复合终点事件发生的影响因素。 结果:该研究纳入46例PLA2R相关IMN患者，男性31例（67.4%），基线eGFR为（78.4±34.1）ml·min -1·（1.73 m 2） -1，24 h尿蛋白量为8.33（6.04，12.85）g。随访时间为14.95（7.44，22.15）个月，RTX治疗后蛋白尿缓解29例（63.0%），缓解时间为6.0（5.0，9.0）个月；其中6例（20.7%）复发，复发时间为17.25（11.75，18.28）个月。与蛋白尿未缓解组比较，蛋白尿缓解组患者CD20较低（ Z=2.270， P=0.023）。发生肾脏复合终点事件11例（23.9%），发生时间为16.07（7.87，29.63）个月。Kaplan-Meier生存分析结果显示，基线24 h尿蛋白量<8 g组和24 h尿蛋白量≥8 g组、基线eGFR≥60 ml·min -1·（1.73 m 2） -1组和eGFR<60 ml·min -1·（1.73 m 2） -1组患者RTX治疗后蛋白尿缓解率（Log-rank χ 2=0.26， P=0.612；Log-rank χ2=0.77， P=0.381）及肾脏复合终点事件生存率（Log-rank χ2=0.25， P=0.619；Log-rank χ2=1.41， P=0.236）的差异均无统计学意义。多因素Cox回归分析结果显示，合并高血压（ HR=0.16，95% CI 0.05~0.55）、有免疫抑制剂用药史（ HR=0.08，95% CI 0.01~0.50）、基线eGFR<60 ml·min -1·（1.73 m 2） -1（ HR=0.21，95% CI 0.05~0.92）、基线PLA2R抗体滴度≥100 RU/ml（ HR=0.20，95% CI 0.06~0.69）、治疗距首诊时间较长（ HR=1.33，95% CI 1.12~1.57）、基线三酰甘油较高（ HR=1.46，95% CI 1.02~2.08）及基线24 h尿蛋白量≥8 g（ HR=8.54，95% CI 2.08~35.12）是RTX治疗后蛋白尿缓解的独立影响因素，基线PLA2R抗体滴度≥100 RU/ml是RTX治疗后发生肾脏复合终点事件的独立影响因素（ HR=7.31，95% CI 1.23~43.62）。 结论:RTX治疗PLA2R相关IMN的蛋白尿缓解率为63.0%，复发率为20.7%，肾脏复合终点事件发生率为23.9%。合并高血压、有免疫抑制剂用药史、基线eGFR<60 ml·min -1·（1.73 m 2） -1、基线PLA2R≥100 RU/ml、治疗距首诊时间较长、基线三酰甘油较高及基线24 h尿蛋白量≥8 g是蛋白尿缓解的独立影响因素。基线PLA2R≥100 RU/ml是肾脏预后不良的独立危险因素。

Objective:To investigate the efficacy and prognosis of rituximab (RTX) in the treatment of M-type phospholipase A2 receptor (PLA2R)-associated idiopathic membranous nephropathy (IMN).Methods:It was a retrospective cohort study. The clinical data of PLA2R-associated IMN patients who received RTX treatment in the Shenzhen Second People's Hospital from September 2018 to March 2023 were collected. According to remission status of proteinuria, the patients were divided into proteinuria remission group (24-hour urinary protein quantity < 3.5 g) and non-proteinuria remission group (24-hour urinary protein quantity ≥ 3.5 g), and the clinical data between the two groups were compared. According to baseline 24-hour urinary protein quantity and estimated glomerular filtration rate (eGFR), the patients were divided into high-risk disease progression group [24-hour urinary protein quantity ≥ 8 g or eGFR < 60 ml·min -1·(1.73 m 2) -1] and non-high-risk disease progression group [24-hour urinary protein quantity < 8 g or eGFR ≥ 60 ml·min -1·(1.73 m 2) -1]. Kaplan-Meier survival curve was utilized to compare the differences of proteinuria remission rates and renal composite endpoint event survival rates between the two groups. Multivariate Cox regression analysis was utilized to identify the influencing factors of proteinuria remission and renal composite endpoint event. Results:This study included 46 PLA2R-associated IMN patients, with 31 males (67.4%). The baseline eGFR was (78.4±34.1) ml·min -1·(1.73 m 2) -1. The 24-hour urinary protein quantity was 8.33 (6.04, 12.85) g. After 14.95 (7.44, 22.15) months of follow-up, 29 patients (63.0%) achieved proteinuria remission, with remission time of 6.0 (5.0, 9.0) months. Six (20.7%) patients relapsed, with relapsed time of 17.25 (11.75, 18.28) months. CD20 in the proteinuria remission group was lower than that in the non-proteinuria remission group ( Z=2.270, P=0.023). Eleven (23.9%) patients experienced renal composite endpoint events wtih occurrence time of 16.07 (7.87, 29.63) months. Kaplan-Meier survival curve analysis indicated that there was no statistically significant difference in proteinuria remission rates (log-rank χ2=0.26, P=0.612) and renal composite endpoint event survival rates (log-rank χ2=0.25, P=0.619) between baseline 24-hour urinary protein quantity ≥ 8 g and < 8 g groups. There was no statistically significant difference in proteinuria remission rates after RTX treatment (log-rank χ2=0.77, P=0.381) and renal composite endpoint event survival rates (log-rank χ2=1.41, P=0.236) between eGFR ≥ 60 ml·min -1·(1.73 m 2) -1 and < 60 ml·min -1·(1.73 m 2) -1 groups. Multivariate Cox regression analysis showed that hypertension history ( HR=0.16, 95% CI 0.05-0.55), immunosuppressive therapy history ( HR=0.08, 95% CI 0.01-0.50), baseline eGFR < 60 ml·min -1·(1.73 m 2) -1 ( HR=0.21, 95% CI 0.05-0.92), baseline PLA2R antibody titer ≥ 100 RU/ml ( HR=0.20, 95% CI 0.06-0.69), long time between treatment and first diagnosis ( HR=1.33, 95% CI 1.12-1.57), high baseline triglyceride ( HR=1.46, 95% CI 1.02-2.08), and baseline 24-hour urinary protein quantity ≥ 8 g ( HR=8.54, 95% CI 2.08-35.12) were independent influencing factors of proteinuria remission after RTX treatment. The baseline PLA2R antibody titer ≥ 100 RU/ml was an independent influencing factor of reaching the renal composite endpoint event ( HR=7.31, 95% CI 1.23-43.62). Conclusions:The proteinuria remission rate after RTX treatment of PLA2R-associated IMN is 63.0% and the recurrence rate is 20.7%. The incidence rate of renal composite endpoint event is 23.9%. The hypertension history, immunosuppressant medication history, baseline eGFR < 60 ml·min -1·(1.73 m 2) -1, baseline PLA2R antibody titer ≥ 100 RU/ml, long time between treatment and first diagnosis, high baseline triglyceride, and baseline 24-hour urinary protein quantity ≥ 8 g are independent influencing factors of proteinuria remission, and baseline PLA2R antibody titer ≥ 100 RU/ml is an independent risk factor of renal poor prognosis in PLA2R-associated IMN patients.