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

ABSTRACT 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.