利妥昔单抗治疗成人难治性原发性膜性肾病的临床分析

doi:10.3969/j.issn.1674-8115.2023.03.005

上海交通大学学报（医学版） ›› 2023, Vol. 43 ›› Issue (3): 301-307.doi: 10.3969/j.issn.1674-8115.2023.03.005

• 论著 · 临床研究 • 上一篇

利妥昔单抗治疗成人难治性原发性膜性肾病的临床分析

冯琳鸿(), 王亚琨(), 吴茜茜, 朱迎春, 白寿军()

复旦大学附属中山医院青浦分院肾内科，上海 201700

收稿日期:2022-10-26 接受日期:2023-03-10 出版日期:2023-03-28 发布日期:2023-03-28
通讯作者: 白寿军 E-mail:fenglinhonglady@163.com;baishoujun@126.com
作者简介:冯琳鸿（1992—），女，住院医师，硕士；电子信箱：fenglinhonglady@163.com
冯琳鸿（1992—），女，住院医师，硕士；电子信箱：fenglinhonglady@163.com
基金资助:
上海市青浦区卫生健康委员会科研课题(QWJ2022-19);上海市青浦区科学技术委员会软课题(R2021-07)

Clinical analysis of rituximab for adult refractory primary membranous nephropathy

FENG Linhong(), WANG Yakun(), WU Qianqian, ZHU Yingchun, BAI Shoujun()

Department of Nephrology, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai 201700, China

Received:2022-10-26 Accepted:2023-03-10 Online:2023-03-28 Published:2023-03-28
Contact: BAI Shoujun E-mail:fenglinhonglady@163.com;baishoujun@126.com
Supported by:
Scientific Research Project of Qingpu District Health Committee of Shanghai(QWJ2022-19);Soft Project of Qingpu District Science and Technology Committee of Shanghai(R2021-07)

摘要/Abstract

摘要：

目的·研究利妥昔单抗（rituximab，RTX）治疗难治性原发性膜性肾病（primary membranous nephropathy，PMN）的临床效果及安全性。方法·回顾性分析复旦大学附属中山医院青浦分院肾内科2018年7月—2022年4月收治的难治性PMN患者（经糖皮质激素联合环孢素、环磷酰胺或他克莫司等免疫抑制剂治疗1年以上仍未达到临床缓解或出现临床复发的患者），使用2剂RTX方案（RTX单次剂量为1 000 mg，2次用药间隔时间为2周；6个月后检测患者外周血B细胞数量，若外周血B细胞数量>5个/μL，则予以追加RTX 1 000 mg）。随访主要观察指标为血白蛋白、血肌酐、尿蛋白肌酐比（urinary protein/creatinine ratio，UPCR）、血磷脂酶A2（phospholipase A2 receptor，PLA2R）抗体、外周血B细胞计数、血清总IgG水平。观察患者主要指标的变化趋势及不良反应，评估治疗方案的临床疗效及安全性。结果·共纳入18例患者，平均年龄为（58.17±16.73）岁，其中男性11例。RTX治疗总剂量为（2 222.22±485.07）mg，RTX治疗后随访时间为（14.9±4.9）个月。末次随访时，血白蛋白较RTX治疗前显著升高［（36.50±5.33）g/L vs （27.61±8.59）g/L，P=0.009］，血肌酐水平稳定（P>0.05），UPCR显著下降［863.30（203.20，2 291.75）mg/g vs 2 954.00（1 458.00，7 260.75）mg/g，P=0.047］，PLA2R抗体显著下降［（44.32±33.71）RU/mL vs （168.40±88.40）RU/mL，P=0.015］，外周血B细胞计数显著下降［（37.89±12.43）个/μL vs （246.40±239.98）个/μL，P=0.009］，血清总IgG水平稳定（P>0.05）。RTX治疗后，8例患者达到完全缓解（44.4%），7例达到部分缓解（38.9%），治疗总体有效率为83.3%；仅有3例患者评估为不缓解（16.7%）。在不良反应方面，1例患者出现输注过敏反应，1例患者发生肺部感染。结论·对于经过传统免疫抑制剂治疗后持续未达到临床缓解或出现临床复发的难治性PMN患者，使用2剂RTX治疗方案可有效诱导该类患者达到临床完全或部分缓解，且安全性良好。

关键词: 利妥昔单抗, 肾小球肾炎, 原发性膜性肾病, 免疫抑制剂

Abstract:

Objective ·To evaluate clinical efficacy and safety of rituximab (RTX) in the patients with refractory primary membranous nephropathy (PMN). Methods ·A retrospective analysis was carried out on the patients with refractory PMN, who had recurred or had not achieved clinical remission after more than 1 year of treatment with glucocorticoid and cyclosporine, cyclophosphamide or tacrolimus, admitted to the Department of Nephrology, Qingpu Branch of Zhongshan Hospital, Fudan University from July 2018 to April 2022. They received 2 doses of RTX. The single dose of RTX was 1 000 mg, and the interval between the two doses was 2 weeks. After 6 months, the numbers of peripheral blood B cells of the patients were detected. If the count of peripheral blood B cells were greater than 5 cell/μL, another 1 000 mg RTX would be added. The main indicators were serum albumin, serum creatinine, urinary protein/creatinine ratio (UPCR), blood antibody against phospholipase A2 receptor (PLA2R) antibody, peripheral blood B cell count, and serum total IgG level. The clinical efficacy and safety of the treatment regimen were evaluated by observing the change of the main indicators of patients and adverse reactions. Results ·A total of 18 patients were included, with an average age of (58.17±16.73) years, including 11 males. The total dose of RTX was (2 222.22±485.07) mg, and the follow-up time after RTX treatment was (14.9±4.9) months. At the last follow-up, the serum albumin level was significantly higher than that before RTX treatment [(36.50±5.33) g/L vs (27.61±8.59) g/L, P=0.009]; the serum creatinine level was stable (P>0.05); the value of UPCR decreased significantly [863.30 (203.20, 2 291.75) mg/g vs 2 954.00 (1 458.00, 7 260.75) mg/g, P=0.047]; the PLA2R antibody decreased significantly [(44.32±33.71) RU/mL vs (168.40±88.40) RU/mL, P=0.015]; the peripheral blood B cell count decreased significantly [(37.89±12.43) cell/μL vs (246.40±239.98) cell/μL, P=0.009]; the total blood IgG level was stable (P>0.05). After RTX treatment, 8 patients achieved complete remission (44.4%), 7 patients achieved partial remission (38.9%), and the overall effective rate was 83.3%; only 3 patients were unrelieved (16.7%). In terms of adverse reactions, 1 patient had transfusion allergy reaction, and 1 patient had pulmonary infection. Conclusion ·For the patients with refractory PMN who have relapse or do not relieve after traditional immunosuppressive therapy, RTX treatment can effectively induce clinically complete remission or partial remission with good safety.

Key words: rituximab (RTX), glomerulonephritis, primary membranous nephropathy (PMN), immunosuppressant

中图分类号:

R692.6

冯琳鸿, 王亚琨, 吴茜茜, 朱迎春, 白寿军. 利妥昔单抗治疗成人难治性原发性膜性肾病的临床分析[J]. 上海交通大学学报（医学版）, 2023, 43(3): 301-307.

FENG Linhong, WANG Yakun, WU Qianqian, ZHU Yingchun, BAI Shoujun. Clinical analysis of rituximab for adult refractory primary membranous nephropathy[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(3): 301-307.

图/表 4

参考文献 38

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Indicator	Before immunosuppressant treatment	After immunosuppressant treatment	P value
Albumin/(g·L^-1)	27.94±7.56	27.61±8.59	0.846
Serum creatinine/(µmol·L^-1)	76.78±18.45	101.00±48.23	0.484
UPCR/(mg·g^-1)	2 504.50 (1 653.85, 4 414.72)	2 954.00 (1 458.00, 7 260.75)	0.031

Indicator	Before immunosuppressant treatment	After immunosuppressant treatment	P value
Albumin/(g·L^-1)	27.94±7.56	27.61±8.59	0.846
Serum creatinine/(µmol·L^-1)	76.78±18.45	101.00±48.23	0.484
UPCR/(mg·g^-1)	2 504.50 (1 653.85, 4 414.72)	2 954.00 (1 458.00, 7 260.75)	0.031

No.	Age at diagnosis/year	Gender	Time of treatment/month	Previous treatment process	Use of RAAS antagonist	Efficacy evaluation
1	30	Male	12	GC+CTX+CsA	Yes	Unrelieved
2	61	Female	60	GC+CsA+TAC	Yes	Unrelieved
3	44	Male	72	GC+CTX+TAC	No	Unrelieved
4	74	Female	114	GC+CsA+TAC	No	Recurrence
5	76	Male	57	GC+CsA+TAC	Yes	Unrelieved
6	72	Male	12	GC+CTX	Yes	Unrelieved
7	78	Female	13	GC+CsA	Yes	Recurrence
8	63	Male	20	GC+CTX+CsA	Yes	Unrelieved
9	57	Male	18	GC+CsA+TAC	No	Unrelieved
10	57	Female	90	GC+CsA	Yes	Recurrence
11	65	Female	18	GC+CsA	Yes	Recurrence
12	79	Female	48	GC+CsA+TAC	Yes	Unrelieved
13	36	Male	17	GC+CTX+TAC	Yes	Recurrence
14	70	Male	28	GC+TAC	Yes	Unrelieved
15	21	Female	36	GC+CsA	No	Recurrence
16	54	Male	12	GC+CsA	No	Unrelieved
17	60	Male	14	GC+CTX+CsA	Yes	Unrelieved
18	50	Male	12	GC+TAC	No	Recurrence

No.	Age at diagnosis/year	Gender	Time of treatment/month	Previous treatment process	Use of RAAS antagonist	Efficacy evaluation
1	30	Male	12	GC+CTX+CsA	Yes	Unrelieved
2	61	Female	60	GC+CsA+TAC	Yes	Unrelieved
3	44	Male	72	GC+CTX+TAC	No	Unrelieved
4	74	Female	114	GC+CsA+TAC	No	Recurrence
5	76	Male	57	GC+CsA+TAC	Yes	Unrelieved
6	72	Male	12	GC+CTX	Yes	Unrelieved
7	78	Female	13	GC+CsA	Yes	Recurrence
8	63	Male	20	GC+CTX+CsA	Yes	Unrelieved
9	57	Male	18	GC+CsA+TAC	No	Unrelieved
10	57	Female	90	GC+CsA	Yes	Recurrence
11	65	Female	18	GC+CsA	Yes	Recurrence
12	79	Female	48	GC+CsA+TAC	Yes	Unrelieved
13	36	Male	17	GC+CTX+TAC	Yes	Recurrence
14	70	Male	28	GC+TAC	Yes	Unrelieved
15	21	Female	36	GC+CsA	No	Recurrence
16	54	Male	12	GC+CsA	No	Unrelieved
17	60	Male	14	GC+CTX+CsA	Yes	Unrelieved
18	50	Male	12	GC+TAC	No	Recurrence

Indicator	Before RTX	1 month after RTX	3 months after RTX	6 months after RTX	Last follow-up after RTX
Albumin/(g·L^-1)	27.61±8.59	27.70±7.12	28.00±8.34	28.50±7.61	36.50±5.33^①
Serum creatinine/(µmol·L^-1)	101.00±48.23	93.63±25.44	87.03±21.09	85.33±27.24	89.39±42.08
UPCR/(mg·g^-1)	2 954.00 (1 458.00, 7 260.75)	1 780.55(989.00, 3 457.98)	1 780.00 (1 032.00, 3 357.87)	1 360.00 (870.32, 4 395.00)	863.30 (203.20, 2 291.75)^②
PLA2R antibody/(RU·mL^-1)	168.40±88.40	79.00±90.22^③	70.85±38.03^④	61.98±45.01^⑤	44.32±33.71^⑥
Peripheral blood B cell count/(cell·µL^-1)	246.40±239.98	7.10±12.15^⑦	-	69.09±52.70^⑧	37.89±12.43^①
Level of total IgG/(g·L^-1)	6.40±1.36	3.78±0.98	4.06±0.54	5.56±0.65	6.16±1.40

利妥昔单抗治疗成人难治性原发性膜性肾病的临床分析

Clinical analysis of rituximab for adult refractory primary membranous nephropathy

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Metrics

Efficacy evaluation after RTX	No.	Follow-up time after RTX/month	Time to achieve complete/partial relief/month	RTX total dose/mg
Complete relief	1	12	10	2 000
	2	14	12	2 000
	5	14	14	2 000
	7	18	17	2 000
	8	14	14	3 000
	9	11	10	2 000
	12	28	24	3 000
	18	7	7	2 000
Partial relief	3	12	12	2 000
	4	12	12	2 000
	10	14	13	2 000
	11	24	24	3 000
	14	15	13	2 000
	16	13	12	3 000
	17	12	12	2 000
Unrelieved	6	20	-	3 000
	13	12	-	2 000
	15	17	-	3 000

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