Combined Evaluation of Glomerular Phospholipase A2 Receptor and IgG Subclass Staining Predicts Overall Survival in Membranous Nephropathy

Background: Phospholipase A2 receptor (PLA2R) is a key antigen in membranous nephropathy (MN) and widely used in diagnosis. IgG subclass staining in kidney biopsies also helps differentiate primary from secondary MN. While serum anti-PLA2R antibodies correlate with proteinuria remission, the prognostic value of glomerular PLA2R and IgG subclasses for survival remains unclear. We previously showed that combining PLA2R and IgG subclass staining improves remission prediction. As MN often affects older individuals, evaluating life prognosis is important. This study examined whether glomerular PLA2R and IgG subclass staining are associated with overall survival in MN. Methods: We retrospectively analyzed 183 MN patients diagnosed by kidney biopsy from 1998 to 2018 at six centers. Biopsies were stained for glomerular PLA2R and IgG subclasses. Survival was assessed using Kaplan–Meier analysis, log-rank testing, and Cox models adjusted for age and sex. Results: Median age at biopsy was 66; 57.4% were male. PLA2R was positive in 127 cases (69.4%) and negative in 56 (30.6%). Kidney function and proteinuria showed no significant differences. Over a median follow-up of 5.6 years, 19 patients (10.4%) died: 7 from cancer, 6 infections, and 6 cardiovascular causes, including 4 sudden deaths. PLA2R-negative patients had higher mortality than positives (P < 0.05), remaining significant after adjustment (HR 3.32; 95% CI 1.32–8.36). Among PLA2R-positive patients, IgG3 positivity was linked to worse survival (P < 0.05). Of 9 deaths in PLA2R-positive cases, 5 were due to cancer and 4 to infection. Among 10 PLA2R-negative deaths, 2 were from cancer, 2 from infection, and 6 from cardiovascular causes, including all 4 sudden deaths. Conclusion: PLA2R-negative MN is linked to worse survival, with increased risk of sudden death. IgG3 positivity in PLA2R-positive patients may also indicate higher mortality. Combined evaluation of glomerular PLA2R and IgG subclass staining in kidney biopsy specimens provides valuable prognostic information.