利妥昔单抗治疗PLA2R阴性的原发性膜性肾病患者疗效预测相关指标的研究

doi:10.16150/j.1671-2870.2025.03.006

摘要/Abstract

摘要：

目的：观察临床表现为肾病综合征的磷脂酶A2受体（phospholipase A2 receptor，PLA2R）阴性的原发性膜性肾病（primary membranous nephropathy，PMN）患者使用利妥昔单抗（rituximab，RTX）的临床疗效，并分析疗效预测相关指标。方法：回顾性收集上海交通大学附属瑞金医院2020年3月至2024年3月间，经肾活检确诊为PLA2R阴性且临床表现为肾病综合征的19例PMN患者，所有患者均使用RTX治疗；同时匹配PLA2R阳性且临床表现为肾病综合征，并使用RTX治疗的38例PMN患者作为对照。最少随访6个月（中位12个月），观察这2组患者使用RTX的临床疗效，并分析可预测RTX治疗PLA2R阴性MN患者疗效的相关指标。结果：PLA2R阴性的PMN患者，采用RTX治疗12个月时，与基线相比，总体24 h尿蛋白定量从（9.8±4.3）g/d下降至（2.6±2.6）g/d，总体血清白蛋白从（20.3±4.3）g/L上升至（36.4±7.1）g/L（P<0.05），总体估算肾小球滤过率变化无统计学意义[（90.7±30.0）mL·min^-1·1.73m^-2比（84.4±22.19）mL·min^-1·1.73m^-2]（P>0.05）。PLA2R阴性组总体缓解率在治疗3个月（57.89%）、6个月（57.89%）、12个月（85.71%）时与PLA2R阳性组相当（P>0.05）。治疗3个月及6个月时，PLA2R阴性组的完全缓解率高于PLA2R抗体阳性组（3个月时，21.5%比0，P=0.009 8；6个月时36.84%比10.53%，P=0.030 5），差异有统计学意义。单因素logistic回归分析显示，影响PLA2R阴性PMN患者RTX治疗12个月时临床缓解的变量包括，3个月时24 h尿蛋白定量（OR=0.993，P=0.047 1）及3个月时血清白蛋白（OR=1.309，P=0.048 8）。结论：RTX治疗PLA2R阴性的PMN有效，与PLA2R阳性组相比，治疗12个月时总缓解率相当，治疗3个月时完全缓解率略胜一筹。RTX治疗3个月时24 h尿蛋白定量及血清白蛋白水平可能作为PLA2R阴性PMN患者12个月时临床缓解情况的预测指标。

关键词: 原发性膜性肾病, 磷脂酶A2受体, 利妥昔单抗, 缓解率, 预测因素

Abstract:

Objective To evaluate the clinical efficacy of rituximab (RTX) in patients with phospholipase A2 receptor (PLA2R)-negative primary membranous nephropathy (PMN) presenting as nephrotic syndrome, and to identify predictors for treatment efficacy. Methods This retrospective cohort study included 19 biopsy-proven PLA2R-negative PMN patients with nephrotic syndrome who received RTX at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine between March 2020 and March 2024. Additionally, 38 PLA2R-positive PMN patients with nephrotic syndrome who received RTX were matched as controls. All patients were followed for at least 6 months (median = 12 months) to evaluate the clinical efficacy of RTX in both groups and to analyze potential predictors of treatment efficacy in PLA2R-negative MN patients. Results In PLA2R-negative PMN patients treated with RTX for 12 months, the 24-hour proteinuria significantly decreased from (9.8±4.3) g/d to (2.6±2.6) g/d and serum albumin increased from (20.3±4.3) g/L to (36.4±7.1) g/L (P<0.05). The overall change in estimated glomerular filtration rate showed no statistical significance [(90.7±30.0) mL·min^-1·1.73 m^-2 vs. (84.4±22.19) mL·min^-1·1.73 m^-2] (P>0.05). Overall remission rates in the PLA2R-negative group at 3 months (57.89%), 6 months (57.89%), 12 months (85.71%) were comparable to those in the PLA2R-positive group (P>0.05). However, the complete remission rate was significantly higher in the PLA2R-negative group at 3 months (21.5% vs. 0%, P=0.009 8) and 6 months (36.84% vs. 10.53%, P=0.030 5), indicating statistical significance. The univariate logistic regression analysis showed that factors influencing clinical remission at 12 months of RTX treatment in PLA2R-negative PMN patients were 3-month 24-hour proteinuria (OR=0.993, P=0.047 1) and 3-month serum albumin (OR=1.309, P=0.048 8). Conclusion RTX treatment is effective in treating PLA2R-negative PMN. Compared with the PLA2R-positive group, the overall remission rate at 12 months was comparable, with a slightly higher complete remission rate at 3 months. The 3-month 24-hour proteinuria and 3-month serum albumin levels may serve as potential predictors for clinical remission at 12 months in PLA2R-negative PMN patients.

Key words: Primary membranous nephropathy, Phospholipase A2 receptor, Rituximab, Remission rate, Predictor

中图分类号:

R692

徐丽梨, 胡晓帆, 李灏, 王伟铭. 利妥昔单抗治疗PLA2R阴性的原发性膜性肾病患者疗效预测相关指标的研究[J]. 诊断学理论与实践, 2025, 24(03): 279-285.

XU Lili, HU Xiaofan, LI Hao, WANG Weiming. Study on predictors for treatment efficacy of rituximab in patients with PLA2R-negative primary membranous nephropathy[J]. Journal of Diagnostics Concepts & Practice, 2025, 24(03): 279-285.

图/表 4

表1

图1

表2

表3

参考文献 19

[1]	PAN X, XU J, REN H, et al. Changing spectrum of biopsy-proven primary glomerular diseases over the past 15 years: a single-center study in China[J]. Contrib Nephrol, 2013,181:22-30.
[2]	XU X, NING Y, SHANG W, et al. Analysis of 4931 renal biopsy data in central China from 1994 to 2014[J]. Ren Fail, 2016, 38(7):1021-1030. doi: 10.1080/0886022X.2016.1183443 pmid: 27193055
[3]	DEBIEC H, RONCO P. PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy[J]. N Engl J Med, 2011, 364(7):689-690.
[4]	ROSENZWAJG M, LANGUILLE E, DEBIEC H, et al. B- and T-cell subpopulations in patients with severe idiopathic membranous nephropathy may predict an early response to rituximab[J]. Kidney Int, 2017, 92(1):227-237. doi: S0085-2538(17)30039-X pmid: 28318628
[5]	Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 clinical practice guideline for the management of glomerular di-seases[J]. Kidney Int, 2021, 100(4S):S1-S276.
[6]	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.
[7]	CARAVACA-FONTÁN F, FERNÁNDEZ-JUÁREZ G M, FLOEGE J, et al. The management of membranous nephropathy-an update[J]. Nephrol Dial Transplant, 2022, 37(6):1033-1042.
[8]	TOMAS N M, BECK L H JR, MEYER-SCHWESINGER C, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy[J]. N Engl J Med, 2014, 371(24):2277-2287.
[9]	SETHI S, DEBIEC H, MADDEN B, et al. Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy[J]. Kidney Int, 2020, 97(1):163-174.
[10]	CAZA T N, STOREY A J, HASSEN S I, et al. Discovery of seven novel putative antigens in membranous nephropathy and membranous lupus nephritis identified by mass spectrometry[J]. Kidney Int, 2023, 103(3):593-606. doi: 10.1016/j.kint.2023.01.001 pmid: 36638888
[11]	SETHI S, BECK L H JR, GLASSOCK R J, et al. Mayo Clinic consensus report on membranous nephropathy: proposal for a novel classification[J]. Kidney Int, 2023, 104(6):1092-1102. doi: 10.1016/j.kint.2023.06.032 pmid: 37795587
[12]	HU X, WANG X, YU X, et al. The role of renal PLA2R staining combined with serum PLA2R antibody in membranous nephropathy risk stratification[J]. J Clin Med. 2023; 13(1):68.
[13]	BECK LH JR, BONEGIO R G, LAMBEAU G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy[J]. N Engl J Med, 2009, 361(1):11-21.
[14]	DAHAN K, DEBIEC H, PLAISIER E, et al. Rituximab for severe membranous nephropathy: a 6-month trial with extended follow-up[J]. J Am Soc Nephrol, 2017, 28(1):348-358. doi: 10.1681/ASN.2016040449 pmid: 27352623
[15]	SCOLARI F, DELBARBA E, SANTORO D, et al. Ritu-ximab or cyclophosphamide in the treatment of membranous nephropathy: the RI-CYCLO randomized trial[J]. J Am Soc Nephrol, 2021, 32(4):972-982.
[16]	GUO H, YAO Y, ZHOU J, et al. The cutoff value and prognosis of anti-PLA2R antibody for idiopathic membranous nephropathy: a single-center retrospective study in China[J]. Ren Fail, 2023, 45(2):2253922.
[17]	LIU Y, LI X, MA C, et al. Serum anti-PLA2R antibody as a diagnostic biomarker of idiopathic membranous nephropathy: The optimal cut-off value for Chinese patients[J]. Clin Chim Acta, 2018,476:9-14.
[18]	ZHOU Z, ZOU Y, KE B, et al. How to choose treatment regimens for idiopathic membranous nephropathy patients with PLA2R-negative: a single-center retrospective cohort study[J]. Immunotargets Ther, 2025,14:515-522.
[19]	BARBOUR S J, FERVENZA F C, INDURUWAGE D, et al. Anti-PLA2R antibody levels and clinical risk factors for treatment nonresponse in membranous nephropathy[J]. Clin J Am Soc Nephrol, 2023, 18(10):1283-1293.

Items	PLA2R-Negative (N=19)	PLA2R-Positive(N=38)	P value
Age (years)	61(28-75)	61.5(23-76)	0.902 4
Male [n (%)]	8（42.11%）	18（47.37%）	0.782 4
Treatment-naïve [n (%)]	16(84.21%)	30（78.95%）	0.734 9
Follow-up(months)	15（9-19）	12(11-24）	0.280 3
Hypertension [n (%)]	9（47.37%）	19（50.0%）	>0.999 9
Diabetes mellitus [n (%)]	1(5.26%)	10(26.32%)	0.079 2
ARB/ACEI [n(%)]	12（63.16%）	28（71.79%）	0.554 3
Infection [n(%)]	4（21.05%）	7（18.42%）	>0.999 9
BMI(kg/m²)	24.54±2.58	24.55±3.07	0.986 2
Anti-PLA2R antibody(RU/mL)	1.76±0.12	96.50±110.80	0.000 7
Serum creatinine(μmol/L)	77.16±28.46	87.89±47.55	0.498 8
eGFR(mL·min^-1·1.73m^-²)	90.70±30.03	83.07±25.89	0.324 8
Triglycerides(mmol/L)	2.69±1.78	2.36±1.44	0.459 4
Cholesterol (mmol/L)	8.08±3.79	7.50±2.61	0.505 2
Hemoglobin (g/L)	122.10±17.77	118.50±16.33	0.455 3
Serum albumin (g/L)	20.26±4.37	20.87±4.43	0.627 2
Serum IgG(g/L)	6.06±2.02	5.14±2.28	0.142 8
Serum IgA(g/L)	2.67±0.81	2.03±0.85	0.009 5
Serum IgM(g/L)	1.08±0.45	0.93±0.58	0.349 0
24 h urine protein(mg/d)	9 772±4 269	8 946±3 990	0.474 6
24 h urine IgG(mg/d)	585.5±603.6	508.2±370.2	0.772 5
24 h urine albumin(mg/d)	6 808±3 194	5 938±2 869	0.314 1
24 h urine α1-microglobulin(mg/d)	49.45±21.07	59.52±45.23	0.953 6
24 h urine transferrin(mg/d)	570.0±217.9	515.4±273.8	0.462 6
NLR	2.184±1.230	2.083±1.172	0.765 6
Fibrinogen(g/L)	4.884±1.610	4.190±1.040	0.089 6
D-dimer(mg/L)	0.710 0±0.703 3	1.011 0±1.067 0	0.270 6
CD19 count(cells/μL)	235.2±77.2	255.2±150.7	0.885 4
CD3 count(cells/μL)	1 249.0±492.8	1 502.0±717.9	0.175 9
CD4 count(cells/μL)	824.9±293.3	944.3±430.6	0.284 9
CD8 count(cells/μL)	401.4±217.8	499.3±326.7	0.246 2

Items	PLA2R-Negative(N=19)	PLA2R-Positive(N=38)	P value
3-month
CR	4(21.5%)	0(0%)	0.0098
CR+PR	11(57.89%)	18(47.37%)	0.5765
6-month
CR	7(36.84%)	4(10.53%)	0.0305
CR+PR	11(57.89%)	23(60.53%)	>0.9999
12-month
CR	7/14(50%)	14/29(48.28%)	>0.9999
CR+PR	12/14(85.71%)	26/29 (89.66%)	>0.9999

Items	CR+PR
Items	OR	P
Age	1.030(0.951-1.119)	0.4482
Male [n(%)]	0.222(0.010-2.214)	0.2360
Follow-up time(months)	1.448(1.085-2.420)	0.0534
Treatment-naïve [n(%)]	2.167(0.084-31.87)	0.5759
Comorbid infection [n(%)]	0.154(0.011-1.851)	0.1361
BMI(kg/m²)	1.300(0.804-2.321)	0.3108
Serum creatinine(μmol/L)	0.991(0.957-1.031)	0.6292
eGFR(mL·min^-1·1.73m^-²)	0.999(0.962-1.038)	0.9544
Serum albumin(g/L)	0.989(0.757-1.286)	0.9298
Serum IgG(g/L)	0.580(0.278-1.027)	0.0854
24-hour urine protein(mg/day)	1.000(0.9998-1.000)	0.5131
24-hour urine IgG(mg/day)	1.000(0.9985-1.003)	0.7910
NLR	2.976(0.901-57.63)	0.2867
Fibrinogen(g/L)	1.660(0.774-4.516)	0.2416
CD19 count(cells/μL)	0.986(0.962-1.004)	0.1709
3-month 24-hour urine protein(mg/day)	0.993(0.998-0.999)	0.0471
3-month serum albumin(g/L)	1.309(1.043-1.945)	0.0488
3-month eGFR(mL·min^-1·1.73m^-²)	1.190(0.990-1.675)	0.1675
3-month CD19 count(cells/μL)	0	-