Abstract:

Objective　To investigate the clinical effect of obinutuzumab in the treatment of rituximab-resistant phospholipase A2 receptor (PLA2R) associated membranous nephropathy (MN). Methods　One hundred and forty-nine patients with rituximab-resistant PLA2R-associated MN treated at Yulin Hospital, First Hospital, Xi'an Jiaotong University from January 2021 to August 2022 were selected for the randomized controlled trial, and were divided into a control group (75 cases) and a study group (74 cases) by the random rumber table method. There were 45 males and 30 females in the control group; they were (51.89±8.24) years old; their disease course was (5.89±1.01) years. There were 38 males and 36 females in the study group; they were (53.37±7.96) years old; their disease course was (6.04±1.12) years. The control group took routine drugs and Shenyan Kangfu tablets. The study group took routine drugs, Shenyan Kangfu tablets, and obinutuzumab. The renal function (serum albumin, serum creatinine, and 24 h urinary protein), clinical efficacies, renal injury markers [N-Acetyl-β-D-Glucosaminidase (NAG), retinol-binding protein (RBP), and neutrophil gelatinase-associated lipocalin (NGAL)], immune function (CD4⁺, CD8⁺, and CD4⁺/CD8⁺), PLA2R antibody, inflammatory factors [monocyte chemoattractant protein-1 (MCP-1), platelet alpha-granule membrane protein-140 (GMP-140), and intercellular adhesion molecule-1 (ICAM-1)], and adverse drug reactions were compared between the two groups. t and χ² tests were used for the statistical analysis. Results　Before the treatment, there were no statistical differences in renal function, renal injury markers, immune function, PLA2R antibody, and inflammatory factors between the two groups (all P>0.05). After 6 months' treatment, there were statistical differences in the levels of serum albumin, serum creatinine, 24 urinary protein, NAG, RBP, NGAL, CD4⁺, CD8⁺, CD4⁺/CD8⁺, PLA2R antibody, MCP-1, GMP-140, and ICAM-1 between the study group and the control group [(42.69±6.81) g/L vs. (39.58±5.48) g/L, (66.57±8.28) μmol/L vs. (71.64±10.09) μmol/L, (2.63±0.31) g vs. (2.98±0.41) g, (16.54±2.41) U/L vs. (18.69±2.89) U/L, (1.79±0.21) mg/L vs. (2.04±0.32) mg/L, (52.01±8.23) μg/L vs. (58.64±9.84) μg/L, (43.92±4.81)% vs. (41.54±4.53)%, (21.79±3.72)% vs. (23.84±4.12)%, 1.84±0.35 vs. 1.71±0.32, (41.01±5.39) RU/ml vs. (45.98±6.54) RU/ml, (39.97±5.81) μg/L vs. (43.51±6.21) μg/L, (20.87±3.23) ng/L vs. (23.91±3.51) ng/L, and (59.01±8.21) mg/L vs. (62.84±10.14) mg/L; t=3.073, 3.350, 5.804, 4.928, 5.630, 4.458, 3.110, 3.186, 2.367, 5.058, 3.592, 5.499, and 2.532; all P<0.05]. The total treatment effective rate in the study group was higher that in the control group [91.89% (68/74) vs. 77.33% (58/75)], with a statistical difference (P<0.05). There was no statistical difference in the incidence rate of adverse reactions between the study group and the control group [10.81% (8/74) vs. 8.00% (6/75); P>0.05]. Conclusion　Obinutuzumab for patients with rituximab-resistant PLA2R-associated MN is effective and safe, and can improve their renal function and immune function, alleviate their kidney injury and inflammatory reaction, and decrease their PLA2R antibody level.

Key words:

Membranous nephropathy, Phospholipase A2 receptor, Rituximab, Ortuzumab, Shenyan Kangfu tablets, Effect, Antibody

摘要：

目的　探讨奥妥珠单抗在利妥昔单抗抵抗性磷脂酶A2受体（PLA2R）相关膜性肾病中的作用研究。方法　采用前瞻性研究，选取2021年1月至2022年8月在西安交通大学第一附属医院榆林医院治疗的149例利妥昔单抗抵抗性PLA2R相关膜性肾病患者作为研究对象，以随机数字表法分为对照组（75例）和研究组（74例）。对照组男45例、女30例，年龄（51.89±8.24）岁，膜性肾病病程（5.89±1.01）年，采用醋酸波尼松片+他克莫司胶囊+肾炎康复片治；研究组男38例、女36例，年龄（53.37±7.96）岁，膜性肾病病程（6.04±1.12）年，在对照组基础上加用奥妥珠单抗治疗。对比两组肾功能（血清白蛋白、血肌酐、24 h尿蛋白）、临床疗效、肾脏损伤标志物［N-乙酰-β-D-葡萄糖苷酶（NAG）、视黄醇结合蛋白（RBP）、中性粒细胞明胶酶相关脂质运载蛋白（NGAL）］、免疫功能（CD4⁺、CD8⁺、CD4⁺/CD8⁺）、PLA2R抗体及炎症因子［单核细胞趋化蛋白-1（MCP-1）、血小板α颗粒膜蛋白-140（GMP-140）、细胞间黏附分子-1　（ICAM-1）］、药物不良反应情况。统计学方法采用t检验、χ²检验。结果　治疗前，两组患者肾功能、肾脏损伤标志物、免疫功能、PLA2R抗体及炎症因子比较，差异均无统计学意义（均P>0.05）；治疗6个月后，研究组和对照组血清白蛋白、血肌酐、24 h尿蛋白、NAG、RBP、NGAL、CD4⁺、CD8⁺、CD4⁺/CD8⁺、PLA2R抗体、MCP-1、GMP-140、ICAM-1分别为（42.69±6.81）g/L、（66.57±8.28）μmol/L、（2.63±0.31）g、（16.54±2.41）U/L、（1.79±0.21）mg/L、（52.01±8.23）μg/L、（43.92±4.81）%、（21.79±3.72）%、1.84±0.35、（41.01±5.39）RU/ml、（39.97±5.81）μg/L、（20.87±3.23）ng/L、（59.01±8.21）mg/L和（39.58±5.48）g/L、（71.64±10.09）μmol/L、（2.98±0.41）g、（18.69±2.89）U/L、（2.04±0.32）mg/L、（58.64±9.84）μg/L、（41.54±4.53）%、（23.84±4.12）%、1.71±0.32、（45.98±6.54）RU/ml、（43.51±6.21）μg/L、（23.91±3.51）ng/L、（62.84±10.14）mg/L，两组患者上述指标比较，差异均有统计学意义（t=3.073、3.350、5.804、4.928、5.630、4.458、3.110、3.186、2.367、5.058、3.592、5.499、2.532，均P<0.05）。研究组治疗总有效率为91.89%（68/74），高于对照组的77.33%（58/75），差异有统计学意义（P<0.05）。研究组不良反应发生率为10.81%（8/74），与对照组8.00%（6/75）比较，差异无统计学意义（P>0.05）。结论　奥妥珠单抗治疗利妥昔单抗抵抗性PLA2R相关膜性肾病效果显著，可改善患者肾功能及免疫功能，减轻肾脏损伤及炎症反应，降低PLA2R抗体水平，且安全性高。

关键词:

膜性肾病, 磷脂酶A2受体, 利妥昔单抗, 奥妥珠单抗, 肾炎康复片, 效果, 抗体