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M-type phospholipase A2 receptor(PLA2R) is a major auto-antigen of primary membranous nephropathy(PMN) and anti-PLA2R antibody levels are closely associated with disease severity and therapeutic effectiveness.With the investigation of the immunological epitopes of the PLA2R antigen,the knowledge of the immunological pathogenesis of PMN has been deepened.As the analysis of epitope reactivity may have a predictive value greater than that of PLA2R-antibody level,our study aimed to discover the relationship between domain specific antibody levels and clinical outcome of patients with 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, a significant difference in immunological remission in the PLA2R-IgG4 between the RTX and CTX groups (21.43% vs. 61.90%, P=0.019) was observed. 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. The 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 have a better predict value at remission of proteinuria at the 6th month than that of total PLA2R-IgG.