Wu Liling, Su Zhihang, Tang Bo, Chen Yuna, Hu Haofei, Cheng Yuan, Chen Jianyu, Wan Qijun
Department of Nephrology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China.
Nanjing Vazyme Medical Technology Co., Ltd, Nanjing, China.
Am J Nephrol. 2025 Mar 17:1-12. doi: 10.1159/000545133.
In primary membranous nephropathy (MN), 80% of patients harbor antibodies (Abs) against phospholipase A2 receptor 1 (PLA2R1), closely linked to disease prognosis. Prior research has validated the correlation between Abs directed toward the cysteine-rich (CysR) and C-type lectin 1, 7, and 8 (CTLD1, CTLD7, and CTLD8) domains of PLA2R1 and outcomes in MN.
In a prospective cohort of 52 patients with newly diagnosed PLA2R1-MN, with urine protein ≥ 3.5 g/24 h and estimated glomerular filtration rate ≥30 mL/min/1.73 m2, we studied epitope spreading patterns and domain-specific PLA2R1-Ab clinically using Western blot and ELISA. The primary outcome was a combination of remission at 12 months. Kaplan-Meier curves and multivariable Cox regression were employed to compare the single and multiple epitope patients.
All patients had anti-CysR-Abs. 26 (50.0%) exhibited multi-domain recognition, with 1 patient specifically recognizing the CTLD8 domain. A significant association was observed between PLA2R1-Ab and CysR-Ab (r = 0.869, p < 0.001), as well as with anti-CTLD1 Ab (r = 0.803, p < 0.001). During a median follow-up of 11 months (IQR, 6.0-17.0), 27 patients (65.9%) experienced complete or partial nephrotic syndrome remission. Notably, the multi-domain recognition exhibited a reduced remission rate compared to the single-domain (44.44% vs. 82.61%, p = 0.011, alongside higher concentrations of anti-PLA2R1-Abs. A higher baseline level of anti-CTLD1 was notably linked to a lower likelihood of remission. In a univariate analysis, multi-domain recognition decreases the probability of remission (HR, 0.38 [95% CI, 0.16-0.87], p = 0.022). After the Kaplan-Meier analysis, the multi-domain group showed lower remission rates than the single-domain group at various time points.
The PLA2R1 epitope spreading (ES) is a potent tool for monitoring disease severity and stratifying patients based on renal outcomes for prognostic purposes. Hence, we advocate evaluating ES at the baseline stage when determining early therapeutic interventions for individuals diagnosed with MN.
在原发性膜性肾病（MN）中，80%的患者体内存在针对磷脂酶A2受体1（PLA2R1）的抗体（Abs），这与疾病预后密切相关。先前的研究已证实，针对PLA2R1富含半胱氨酸（CysR）以及C型凝集素1、7和8（CTLD1、CTLD7和CTLD8）结构域的抗体与MN的预后相关。
在一个前瞻性队列中，纳入了52例新诊断为PLA2R1 - MN的患者，其尿蛋白≥3.5 g/24 h且估计肾小球滤过率≥30 mL/min/1.73 m²，我们使用蛋白质印迹法和酶联免疫吸附测定法从临床角度研究表位扩展模式和结构域特异性PLA2R1 - Ab。主要结局为12个月时缓解的综合情况。采用Kaplan - Meier曲线和多变量Cox回归来比较单表位和多表位患者。
所有患者均有抗CysR - Abs。26例（50.0%）表现出多结构域识别，其中1例患者特异性识别CTLD8结构域。观察到PLA2R1 - Ab与CysR - Ab之间存在显著相关性（r = 0.869，p < 0.001），与抗CTLD1 Ab也存在显著相关性（r = 0.803，p < 0.001）。在中位随访11个月（四分位间距，6.0 - 17.0）期间，27例患者（65.9%）经历了完全或部分肾病综合征缓解。值得注意的是，与单结构域识别相比，多结构域识别的缓解率降低（44.44%对82.61%，p = 0.011），同时抗PLA2R1 - Abs浓度更高。抗CTLD1的基线水平较高与缓解可能性较低显著相关。在单变量分析中，多结构域识别降低了缓解概率（风险比，0.38 [95%置信区间，0.16 - 0.87]，p = 0.022）。经过Kaplan - Meier分析，多结构域组在各个时间点的缓解率均低于单结构域组。
PLA2R1表位扩展（ES）是监测疾病严重程度以及基于肾脏结局对患者进行分层以用于预后评估的有效工具。因此，我们主张在为诊断为MN的个体确定早期治疗干预措施时，在基线阶段评估ES。
