Adverse Prognosis in Membranous Nephropathy with Phospholipase A2 Receptor 1 Epitope Spreading: A Prospective Study

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.