Predictive value of the domain specific PLA2R antibodies for clinical remission in patients with primary membranous nephropathy: A retrospective study

• Published in: PloS one Vol. 19; no. 5; p. e0302100
• Main Authors: Zhou, Kezhi, Zhou, Junyi, Zhou, Leting, Xue, Jing, Liu, Bin, Zhang, Zhijian, Zhang, Xiran, Cai, Ting, Shao, Sijia, Huang, Biao, Zhang, Yi, Hu, Zhigang, Wang, Liang, Liu, Xiaobin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08-05-2024; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Analysis; Antibodies; Antigen-antibody reactions; Antigenic determinants; Antigens; Autoantibodies - blood; Autoantibodies - immunology; Biology and Life Sciences; Biomarkers; Care and treatment; Comparative analysis; Confidence intervals; Creatinine; Cyclophosphamide; Cyclophosphamide - therapeutic use; Demographic aspects; Diagnosis; Disease; Dosage and administration; Effectiveness; Epitopes; Female; Glomerulonephritis, Membranous - blood; Glomerulonephritis, Membranous - drug therapy; Glomerulonephritis, Membranous - immunology; Health aspects; Health services; Humans; IgG antibody; Immunoassays; Immunoglobulin G; Immunoglobulin G - blood; Immunoglobulin G - immunology; Immunology; Kidney diseases; Male; Medicine and Health Sciences; Membranous nephropathy; Middle Aged; Multivariate analysis; Nephropathy; Nephrotic syndrome; Nomograms; Normal distribution; Patients; Performance evaluation; Phospholipase A2; Physical Sciences; Prediction models; Proteins; Proteinuria; Receptors, Phospholipase A2 - immunology; Regression analysis; Remission; Remission (Medicine); Remission Induction; Research and Analysis Methods; Retrospective Studies; Risk factors; Rituximab; Rituximab - therapeutic use; ROC Curve; Software; Statistical analysis; Testing; Treatment Outcome; China; Taiwan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0302100

M-type phospholipase A2 receptor (PLA2R) is a major auto-antigen of primary membranous nephropathy(PMN). Anti-PLA2R antibody levels are closely associated with disease severity and therapeutic effectiveness. Analysis of PLA2R antigen epitope reactivity may have a greater predictive value for remission compared with total PLA2R-antibody level. This study aims to elucidate the relationship between domain-specific antibody levels and clinical outcomes of PMN.
This retrospective analysis included 87 patients with PLA2R-associated PMN. Among them, 40 and 47 were treated with rituximab (RTX) and cyclophosphamide (CTX) regimen, respectively. The quantitative detection of -immunoglobulin G (IgG)/-IgG4 targeting PLA2R and its epitope levels in the serum of patients with PMN were obtained through time-resolved fluorescence immunoassays and served as biomarkers in evaluating the treatment effectiveness. A predictive PMN remission possibility nomogram was developed using multivariate logistic regression analysis. Discrimination in the prediction model was assessed using the area under the receiver operating characteristic curve (AUC-ROC).Bootstrap ROC was used to evaluate the performance of the prediction model.
After a 6-month treatment period, the remission rates of proteinuria, including complete remission and partial remission in the RTX and CTX groups, were 70% and 70.21% (P = 0.983), respectively. However, there was a significant difference in immunological remission in the PLA2R-IgG4 between the RTX and CTX groups (21.43% vs. 61.90%, P = 0.019). Furthermore, we found differences in PLA2R-CysR-IgG4(P = 0.030), PLA2R-CTLD1-IgG4(P = 0.005), PLA2R-CTLD678-IgG4(P = 0.003), and epitope spreading (P = 0.023) between responders and non-responders in the CTX group. Multivariate logistic analysis showed that higher levels of urinary protein (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.26-0.95; P = 0.035) and higher levels of PLA2R-CTLD1-IgG4 (OR, 0.79; 95%CI,0.62-0.99; P = 0.041) were independent risk factors for early remission. A multivariate model for estimating the possibility of early remission in patients with PMN is presented as a nomogram. The AUC-ROC of our model was 0.721 (95%CI, 0.601-0.840), in consistency with the results obtained with internal validation, for which the AUC-ROC was 0.711 (95%CI, 0.587-0.824), thus, demonstrating robustness.
Cyclophosphamide can induce immunological remission earlier than rituximab at the span of 6 months. The PLA2R-CTLD1-IgG4 has a better predict value than total PLA2R-IgG for remission of proteinuria at the 6th month.