A single-center retrospective cohort study of rituximab combined with glucocorticoids in the treatment of high-risk primary membranous nephropathy

doi:10.3969/j.issn.1674-8115.2025.08.007

Abstract

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)

CLC Number:

R459.1

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.

Figures/Tables 7

TrendMD

References 18

[1]	RONCO P, BECK L, DEBIEC H, et al. Membranous nephropathy[J]. Nat Rev Dis Primers, 2021, 7(1): 69.
[2]	GAUCKLER P, SHIN J I, ALBERICI F, et al. Rituximab in membranous nephropathy[J]. Kidney Int Rep, 2021, 6(4): 881-893.
[3]	KANIGICHERLA D A K, KEHAGIA A A, JAMSHIDI B, et al. Prospective study of the effect of rituximab on kidney function in membranous nephropathy[J]. Clin Kidney J, 2024, 17(8): sfae179.
[4]	Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 clinical practice guideline for the management of glomerular diseases[J]. Kidney Int, 2021, 100(4S): S1-S276.
[5]	FERVENZA F C, APPEL G B, BARBOUR S J, et al. Rituximab or cyclosporine in the treatment of membranous nephropathy[J]. N Engl J Med, 2019, 381(1): 36-46.
[6]	FERNÁNDEZ-JUÁREZ G, ROJAS-RIVERA J, VAN DE LOGT A E, et al. The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy[J]. Kidney Int, 2021, 99(4): 986-998.
[7]	WALDMAN M, BECK L H, BRAUN M, et al. Membranous nephropathy: pilot study of a novel regimen combining cyclosporine and rituximab[J]. Kidney Int Rep, 2016, 1(2): 73-84.
[8]	CHEN X, JIAO S M, LI S M, et al. Combination of rituximab and low-dose tacrolimus in the treatment of refractory membranous nephropathy: a retrospective cohort study[J]. Balkan Med J, 2023, 40(4): 287-293.
[9]	DONG L J, YAN L, LI Y, et al. The monitoring of B lymphocytes in non-lymphoma patients following rituximab treatment[J]. Front Immunol, 2024, 15: 1513303.
[10]	HOGAN S L, MULLER K E, JENNETTE J C, et al. A review of therapeutic studies of idiopathic membranous glomerulopathy[J]. Am J Kidney Dis, 1995, 25(6): 862-875.
[11]	FLAMMER J R, ROGATSKY I. Minireview: glucocorticoids in autoimmunity: unexpected targets and mechanisms[J]. Mol Endocrinol, 2011, 25(7): 1075-1086.
[12]	SHIMBA A, IKUTA K. Control of immunity by glucocorticoids in health and disease[J]. Semin Immunopathol, 2020, 42(6): 669-680.
[13]	KAMBUROVA E G, KOENEN H J P M, BORGMAN K J E, et al. A single dose of rituximab does not deplete B cells in secondary lymphoid organs but alters phenotype and function[J]. Am J Transplant, 2013, 13(6): 1503-1511.
[14]	ROCAMORA-REVERTE L, VILLUNGER A, JAN WIEGERS G. Cell-specific immune regulation by glucocorticoids in murine models of infection and inflammation[J]. Cells, 2022, 11(14): 2126.
[15]	LI Y H, GAO Z Q, ZHU J H, et al. Comparison of dosage of glucocorticoid in idiopathic membranous nephropathy: a systematic review and network meta-analysis[J]. Cureus, 2024, 16(1): e51936.
[16]	MA Q Q, LI M N, XU G S. Combination of rituximab and short-term glucocorticoids in the treatment of anti-phospholipase A₂ receptor antibody positive idiopathic membranous nephropathy[J]. Clin Exp Med, 2023, 23(8): 5337-5343.
[17]	ZONOZI R, LALIBERTE K, HUIZENGA N R, et al. Combination of rituximab, low-dose cyclophosphamide, and prednisone for primary membranous nephropathy: a case series with extended follow up[J]. Am J Kidney Dis, 2021, 78(6): 793-803.
[18]	VINK C H, WETZELS J F M, LOGT A V. Combination therapy with rituximab and low-dose cyclophosphamide and prednisone in membranous nephropathy[J]. Kidney Int Rep, 2024, 9(12): 3439-3445.

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