Distinct Complement Activation Profiles Between NELL1 ‐ and PLA2R ‐Associated Membranous Nephropathy: A Clinicopathological and Proteomic Study

AIM: Primary membranous nephropathy (MN) is classified into antigen-defined subtypes, most commonly M-type phospholipase A2 receptor (PLA2R)-associated MN and neural epidermal growth factor-like 1 (NELL1)-associated MN. Whether complement activation differs between these subtypes remains unclear. This study compared their clinicopathological features and complement-related protein expression. METHODS: We retrospectively compared PLA2R-associated MN (n = 17) and NELL1-associated MN (n = 9), including five additional NELL1-associated MN cases from an external institution. Glomerular C3 and C4d deposition were assessed by immunostaining, with quantitative C4d analysis using digital pathology. Complement-related proteins were additionally evaluated by laser microdissection-assisted data-dependent acquisition mass spectrometry in cases with available proteomic data. RESULTS: Patients with NELL1-associated MN were older and showed greater interstitial fibrosis and tubular atrophy than those with PLA2R-associated MN. Glomerular IgG4 and C3 deposition were significantly lower in NELL1-associated MN. Quantitative analysis demonstrated lower glomerular C4d deposition in NELL1-associated MN at both the glomerulus and patient levels, whereas C4d intensity was not significantly correlated with serum anti-PLA2R antibody titres. In the proteomic analysis, C3, C5 and complement factor H were numerically more abundant in PLA2R-associated MN than in NELL1-associated MN, although these differences were not statistically significant. CONCLUSION: NELL1-associated MN and PLA2R-associated MN differ not only in clinical and histological features but also in glomerular complement deposition. Reduced C3 and C4d deposition in NELL1-associated MN suggests less prominent glomerular complement activation than in PLA2R-associated MN, supporting biological heterogeneity among antigen-defined MN subtypes.