利妥昔单抗联合糖皮质激素治疗高危原发性膜性肾病的单中心回顾性队列研究

doi:10.3969/j.issn.1674-8115.2025.08.007

摘要/Abstract

摘要：

目的·评估并比较利妥昔单抗（rituximab，RTX）单药与RTX联合糖皮质激素治疗高危原发性膜性肾病（primary membranous nephropathy，PMN）的临床疗效及安全性。方法·采用回顾性队列研究设计，纳入2018年12月—2024年2月上海交通大学医学院附属新华医院接受RTX治疗的87例高危PMN患者。根据治疗方案将患者分为RTX单药组和RTX联合糖皮质激素组（激素联合组）。采用倾向性评分匹配调整混杂因素后，分别进行意向性（intention-to-treat，ITT）分析和方案依从性（per-protocol，PP）分析以评估主要疗效结局。结果·倾向性评分匹配后共纳入58例患者，RTX单药组和激素联合组各29例。治疗开始后的第12个月，ITT分析显示，RTX单药组的复合缓解率和完全缓解率分别为72.41%和20.69%，激素联合组分别为79.31%和55.17%，其中2组间完全缓解率差异具有统计学意义（P=0.007）；2组间血清肌酐、尿素氮及估算的肾小球滤过率差异均无统计学意义，但激素联合组24 h尿蛋白显著低于RTX单药组（P=0.024）。PP分析显示，激素联合组的完全缓解率同样显著高于RTX单药组（P=0.026）。随访期间，2组患者血清肌酐水平和估算的肾小球滤过率均保持稳定。2组不良事件发生率相似，未见明显差异。结论·与RTX单药治疗相比，RTX联合糖皮质激素治疗可显著改善高危PMN患者的完全缓解率，同时未明显增加不良事件的发生率。RTX联合糖皮质激素作为高危PMN患者的有效治疗方案，未来仍需进一步行大规模前瞻性研究以验证其长期疗效与安全性。

关键词: 膜性肾病, 利妥昔单抗, 糖皮质激素, 完全缓解

Abstract:

Objective ·To evaluate and compare the clinical efficacy and safety of rituximab (RTX) monotherapy and RTX combined with glucocorticoids in the treatment of high-risk primary membranous nephropathy (PMN). Methods ·A retrospective cohort study was conducted to include 87 high-risk PMN patients who received RTX treatment in Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, between December 2018 and February 2024. Patients were divided into RTX monotherapy group and RTX combined with glucocorticoid group (combination therapy group) according to their treatment regimens. After adjusting for confounding factors using propensity score matching (PSM), intention-to-treat (ITT) and per-protocol (PP) analyses were performed to evaluate the primary efficacy outcomes. Results ·A total of 58 patients were included after PSM, with 29 in each group. At 12 months after treatment, ITT analysis showed that the overall remission and complete remission (CR) of RTX monotherapy were 72.41% and 20.69% respectively, compared to 79.31% and 55.17% in the combination therapy group. The difference in CR rates between the two groups was statistically significant (P=0.007). The differences in serum creatinine, blood urea nitrogen, and estimated glomerular filtration rate (eGFR) were not statistically significant. However, the 24-hour urinary protein levels in the combination therapy group were significantly lower than those in the RTX monotherapy group (P=0.024). PP analysis showed that the CR rate of the combination therapy group was also significantly higher than that of the RTX monotherapy group (P=0.026). During follow-up, serum creatinine levels and eGFR remained stable in both groups. The incidence of adverse events was comparable between the two groups, with no statistically significant differences. Conclusion ·Compared with RTX monotherapy, RTX combined with glucocorticoids significantly improves the CR rate in high-risk PMN patients without increasing the incidence of adverse events. This combination regimen appears to be an effective treatment strategy, though its long-term efficacy and safety warrant further confirmation through large-scale prospective studies.

Key words: membranous nephropathy, rituximab, glucocorticoid, complete remission (CR)

中图分类号:

R459.1

赵可可, 李惠, 张翀. 利妥昔单抗联合糖皮质激素治疗高危原发性膜性肾病的单中心回顾性队列研究[J]. 上海交通大学学报（医学版）, 2025, 45(8): 1001-1008.

ZHAO Keke, LI Hui, ZHANG Chong. A single-center retrospective cohort study of rituximab combined with glucocorticoids in the treatment of high-risk primary membranous nephropathy[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(8): 1001-1008.

图/表 7

参考文献 18

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Characteristic	Before PSM				After PSM
Characteristic	RTX monotherapy group (n=48)	Combination therapy group (n=39)	χ²/Z/t value	P value	RTX monotherapy group (n=29)	Combination therapy group (n=29)	χ²/Z/t value	P value
Age/year	65.50 (54.75, 73.00)	66.00 (50.50, 71.00)	-0.76	0.445	65.00 (54.00, 72.00)	59.00 (41.00, 72.00)	-0.83	0.405
Gender (male)/n(%)	32 (66.67)	29 (74.36)	0.61	0.436	20 (68.97)	22 (75.86)	0.35	0.557
Diabetes/n(%)	14 (29.17)	6 (15.38)	2.31	0.129	5 (17.24)	5 (17.24)	0.00	>0.999
Hypertension/n(%)	32 (66.67)	26 (66.67)	0.00	>0.999	18 (62.07)	18 (62.07)	0.00	>0.999
BMI/(kg·m^-2)	24.25 (23.02, 26.17)	24.22 (22.65, 25.31)	-1.05	0.296	24.28 (23.14, 26.45)	24.22 (22.47, 25.16)	-1.09	0.276
White blood cell/(×10⁹·L^-1)	6.19 (4.92, 7.15)	7.07 (5.71, 9.44)	-2.10	0.036	6.99±2.32	6.93±2.05	0.10	0.922
Hemoglobin/(g·L^-1)	124.92±20.57	118.23±21.64	1.47	0.145	124.34±22.83	120.72±21.73	0.62	0.539
Platelet/(×10¹²·L^-1)	232.60±66.38	248.62±66.18	-1.12	0.266	240.00 (200.00, 253.00)	247.00 (196.00, 284.00)	-0.27	0.785
Urinary protein/[mg·(24 h)^-1]	5 550.50 (4 560.69, 7 459.99)	6 349.98 (5 072.83, 9 487.98)	-1.82	0.068	5 973.11 (4 840.58, 8 465.80)	6 312.40 (4 928.22, 9 036.11)	-0.51	0.610
Albumin/(g·L^-1)	25.26±5.16	22.84±5.44	2.12	0.037	24.92±5.33	22.61±6.08	1.54	0.129
Blood urea nitrogen/(mg·dL^-1)	7.21 (5.43, 8.35)	8.00 (7.00, 11.34)	-2.52	0.012	7.51 (5.62, 8.39)	8.00 (7.00, 10.74)	-1.29	0.197
Serum creatinine/(μmol·L^-1)	74.00 (60.00, 100.75)	100.00 (67.50, 120.60)	2.03	0.043	85.00 (66.00, 118.00)	96.00 (65.00, 111.00)	-0.05	0.963
eGFR/[mL·(min·1.73 m²)^-1]	81.97±28.49	71.42±28.97	1.70	0.092	76.14±27.98	78.53±26.94	-0.33	0.742
eGFR<60 mL·(min·1.73 m²)^-1/n(%)	13 (27.08)	14 (35.90)	0.78	0.377	10 (34.48)	7 (24.14)	0.75	0.387
Fasting blood glucose/(mmol·L^-1)	5.15 (4.64, 5.56)	4.80 (4.66, 5.20)	-1.35	0.177	4.91 (4.59, 5.40)	4.81 (4.71, 5.21)	-0.07	0.943
HbA1c/%	5.90 (5.38, 6.30)	6.00 (5.40, 6.10)	-0.23	0.816	5.89±0.75	5.84±0.69	0.24	0.809
PLA2R antibody-associated PMN/n(%)	35 (72.92)	30 (76.92)	0.18	0.669	21 (72.41)	23 (79.31)	0.38	0.539
PLA2R antibody/(RU·mL^-1)	65.41 (6.81, 175.96)	45.41 (9.21, 191.62)	-0.06	0.949	73.23 (6.45, 183.00)	43.93 (9.27, 167.93)	-0.04	0.969
CD19^＋ B cell/μL^-1	223.78 (114.60, 379.77)	160.38 (106.22, 312.25)	-0.85	0.394	209.28 (90.51, 378.50)	149.78 (113.01, 266.82)	-0.57	0.569
CD20^＋ B cell/μL^-1	210.54 (111.68, 376.24)	158.24 (98.82, 284.31)	-0.90	0.368	201.45 (88.99, 372.83)	146.13 (108.59, 245.85)	-0.70	0.482
Initial therapy/n(%)	22 (45.83)	23 (58.97)	1.49	0.223	15 (51.72)	14 (48.28)	0.07	0.793
RTX initial treatment regimen/n(%)	36 (75.00)	19 (48.72)	6.39	0.011	22 (75.86)	16 (55.17)	2.75	0.097
RTX total dose/g	2.00 (2.00, 2.40)	2.40 (2.00, 3.00)	-2.33	0.020	2.00 (2.00, 2.30)	2.00 (2.00, 3.00)	-1.71	0.088
Re-RTX/n(%)	12 (25.00)	13 (33.33)	0.73	0.393	5 (17.24)	8 (27.59)	0.89	0.345
RASi/n(%)	21 (43.75)	19 (48.72)	0.21	0.644	11 (37.93)	13 (44.83)	0.28	0.594
SGLT2i/n(%)	21 (43.75)	20 (51.28)	0.49	0.484	12 (41.38)	16 (55.17)	1.10	0.293
Anticoagulant/n(%)	26 (54.17)	29 (74.36)	3.77	0.052	17 (58.62)	22 (75.86)	1.96	0.162

Characteristic	Before PSM				After PSM
Characteristic	RTX monotherapy group (n=48)	Combination therapy group (n=39)	χ²/Z/t value	P value	RTX monotherapy group (n=29)	Combination therapy group (n=29)	χ²/Z/t value	P value
Age/year	65.50 (54.75, 73.00)	66.00 (50.50, 71.00)	-0.76	0.445	65.00 (54.00, 72.00)	59.00 (41.00, 72.00)	-0.83	0.405
Gender (male)/n(%)	32 (66.67)	29 (74.36)	0.61	0.436	20 (68.97)	22 (75.86)	0.35	0.557
Diabetes/n(%)	14 (29.17)	6 (15.38)	2.31	0.129	5 (17.24)	5 (17.24)	0.00	>0.999
Hypertension/n(%)	32 (66.67)	26 (66.67)	0.00	>0.999	18 (62.07)	18 (62.07)	0.00	>0.999
BMI/(kg·m^-2)	24.25 (23.02, 26.17)	24.22 (22.65, 25.31)	-1.05	0.296	24.28 (23.14, 26.45)	24.22 (22.47, 25.16)	-1.09	0.276
White blood cell/(×10⁹·L^-1)	6.19 (4.92, 7.15)	7.07 (5.71, 9.44)	-2.10	0.036	6.99±2.32	6.93±2.05	0.10	0.922
Hemoglobin/(g·L^-1)	124.92±20.57	118.23±21.64	1.47	0.145	124.34±22.83	120.72±21.73	0.62	0.539
Platelet/(×10¹²·L^-1)	232.60±66.38	248.62±66.18	-1.12	0.266	240.00 (200.00, 253.00)	247.00 (196.00, 284.00)	-0.27	0.785
Urinary protein/[mg·(24 h)^-1]	5 550.50 (4 560.69, 7 459.99)	6 349.98 (5 072.83, 9 487.98)	-1.82	0.068	5 973.11 (4 840.58, 8 465.80)	6 312.40 (4 928.22, 9 036.11)	-0.51	0.610
Albumin/(g·L^-1)	25.26±5.16	22.84±5.44	2.12	0.037	24.92±5.33	22.61±6.08	1.54	0.129
Blood urea nitrogen/(mg·dL^-1)	7.21 (5.43, 8.35)	8.00 (7.00, 11.34)	-2.52	0.012	7.51 (5.62, 8.39)	8.00 (7.00, 10.74)	-1.29	0.197
Serum creatinine/(μmol·L^-1)	74.00 (60.00, 100.75)	100.00 (67.50, 120.60)	2.03	0.043	85.00 (66.00, 118.00)	96.00 (65.00, 111.00)	-0.05	0.963
eGFR/[mL·(min·1.73 m²)^-1]	81.97±28.49	71.42±28.97	1.70	0.092	76.14±27.98	78.53±26.94	-0.33	0.742
eGFR<60 mL·(min·1.73 m²)^-1/n(%)	13 (27.08)	14 (35.90)	0.78	0.377	10 (34.48)	7 (24.14)	0.75	0.387
Fasting blood glucose/(mmol·L^-1)	5.15 (4.64, 5.56)	4.80 (4.66, 5.20)	-1.35	0.177	4.91 (4.59, 5.40)	4.81 (4.71, 5.21)	-0.07	0.943
HbA1c/%	5.90 (5.38, 6.30)	6.00 (5.40, 6.10)	-0.23	0.816	5.89±0.75	5.84±0.69	0.24	0.809
PLA2R antibody-associated PMN/n(%)	35 (72.92)	30 (76.92)	0.18	0.669	21 (72.41)	23 (79.31)	0.38	0.539
PLA2R antibody/(RU·mL^-1)	65.41 (6.81, 175.96)	45.41 (9.21, 191.62)	-0.06	0.949	73.23 (6.45, 183.00)	43.93 (9.27, 167.93)	-0.04	0.969
CD19^＋ B cell/μL^-1	223.78 (114.60, 379.77)	160.38 (106.22, 312.25)	-0.85	0.394	209.28 (90.51, 378.50)	149.78 (113.01, 266.82)	-0.57	0.569
CD20^＋ B cell/μL^-1	210.54 (111.68, 376.24)	158.24 (98.82, 284.31)	-0.90	0.368	201.45 (88.99, 372.83)	146.13 (108.59, 245.85)	-0.70	0.482
Initial therapy/n(%)	22 (45.83)	23 (58.97)	1.49	0.223	15 (51.72)	14 (48.28)	0.07	0.793
RTX initial treatment regimen/n(%)	36 (75.00)	19 (48.72)	6.39	0.011	22 (75.86)	16 (55.17)	2.75	0.097
RTX total dose/g	2.00 (2.00, 2.40)	2.40 (2.00, 3.00)	-2.33	0.020	2.00 (2.00, 2.30)	2.00 (2.00, 3.00)	-1.71	0.088
Re-RTX/n(%)	12 (25.00)	13 (33.33)	0.73	0.393	5 (17.24)	8 (27.59)	0.89	0.345
RASi/n(%)	21 (43.75)	19 (48.72)	0.21	0.644	11 (37.93)	13 (44.83)	0.28	0.594
SGLT2i/n(%)	21 (43.75)	20 (51.28)	0.49	0.484	12 (41.38)	16 (55.17)	1.10	0.293
Anticoagulant/n(%)	26 (54.17)	29 (74.36)	3.77	0.052	17 (58.62)	22 (75.86)	1.96	0.162

Characteristic	ITT				PP
Characteristic	RTX monotherapy group (n=29)	Combination therapy group (n=29)	X²/Z/t value	P value	RTX monotherapy group (n=23)	Combination therapy group (n=28)	X²/Z/t value	P value
Overall remission/n(%)
6 months	14 (48.28)	20 (68.97)	2.56	0.110	13 (56.52)	20 (71.43)	1.23	0.268
12 months	21 (72.41)	23 (79.31)	0.38	0.539	18 (78.26)	23 (82.14)	0.12	0.728
CR/n(%)
6 months	5 (17.24)	14 (48.28)	6.34	0.012	5 (21.74)	14 (50.00)	4.31	0.038
12 months	6 (20.69)	16 (55.17)	7.32	0.007	6 (26.09)	16 (57.14)	4.97	0.026
CR time/month	6.50 (6.00, 7.75)	5.50 (5.00, 8.25)	-1.27	0.204	6.50 (6.00, 7.75)	5.50 (5.00, 8.25)	-1.27	0.204

Characteristic	ITT				PP
Characteristic	RTX monotherapy group (n=29)	Combination therapy group (n=29)	X²/Z/t value	P value	RTX monotherapy group (n=23)	Combination therapy group (n=28)	X²/Z/t value	P value
Overall remission/n(%)
6 months	14 (48.28)	20 (68.97)	2.56	0.110	13 (56.52)	20 (71.43)	1.23	0.268
12 months	21 (72.41)	23 (79.31)	0.38	0.539	18 (78.26)	23 (82.14)	0.12	0.728
CR/n(%)
6 months	5 (17.24)	14 (48.28)	6.34	0.012	5 (21.74)	14 (50.00)	4.31	0.038
12 months	6 (20.69)	16 (55.17)	7.32	0.007	6 (26.09)	16 (57.14)	4.97	0.026
CR time/month	6.50 (6.00, 7.75)	5.50 (5.00, 8.25)	-1.27	0.204	6.50 (6.00, 7.75)	5.50 (5.00, 8.25)	-1.27	0.204

Characteristic	ITT				PP
Characteristic	RTX monotherapy group (n=29)	Combination therapy group (n=29)	χ²/Z/t value	P value	RTX monotherapy group (n=23)	Combination therapy group (n=28)	χ²/Z/t value	P value
Urinary protein/[mg·(24 h)^-1]	1 855.68 (514.38, 3 042.58)^①	290.57 (114.44, 1 614.40)^①	-2.26	0.024	1 509.86 (221.80, 2 631.64)^①	296.50 (69.60, 1 398.60)^①	-1.80	0.072
Albumin/(g·L^-1)	37.80 (33.22, 40.40)^①	39.95 (33.08, 42.88)^①	-1.11	0.266	38.70 (35.00, 40.50)^①	40.20 (32.80, 42.75)^①	-0.42	0.677
Blood urea nitrogen/(mg·dL^-1)	6.94 (5.49, 8.36)	7.00 (6.33, 9.99)	-1.45	0.148	6.94 (5.81, 8.22)	6.66 (6.10, 10.40)	-1.22	0.221
Serum creatinine/(μmol·L^-1)	78.00 (62.50, 104.00)	80.50 (64.50, 80.50)	-0.65	0.514	75.00 (62.00, 98.00)	81.00 (70.00, 99.00)	-1.04	0.299
eGFR/[mL·(min·1.73 m²)^-1]	95.02 (54.67, 100.99)	89.25 (64.03, 105.30)	-0.10	0.919	93.77 (54.31, 99.14)	85.36 (66.73, 105.54)	-0.05	0.961
Fasting blood glucose/(mmol·L^-1)	5.02 (4.73, 5.64)	4.75 (4.52, 5.17)	-1.60	0.109	5.12 (4.79, 5.68)	4.75 (4.52, 5.17)	-1.92	0.055
HbA1c/%	5.59±0.41	5.50±0.40	0.67	0.507	5.70±0.48	5.50±0.40	1.45	0.156
PLA2R antibody/(RU·mL^-1)	0 (0, 3.63)^①	0 (0, 0)^①	-0.70	0.484	0 (0, 3.16)^①	0 (0, 0)^①	-0.22	0.830