Prognostic Value of C4d and Anti-PLA2R1 Immunoexpression (Intensity) in Primary Membranous Nephropathy: An Immunohistochemical Study.

Background: Membranous nephropathy (MN) is an immune-mediated disease characterized by subepithelial immune complex deposition within capillary walls. This study evaluates the prognostic value of C4d and anti-PLA2R1 immunoexpression intensities in primary MN, correlating these with histopathological features and clinical outcomes. Methods: A retrospective cohort study was conducted at Path Lab, Egypt, from June 2022 to June 2024, using archival kidney biopsy diagnosed as primary anti-PLA2R1–associated MN. Inclusion required biopsy-proven primary MN with positive anti-PLA2R1 expression; secondary causes were excluded. Immunohistochemistry for C4d (clone SP91, 1:100, Abcam, UK) and anti-PLA2R1 (polyclonal, 1:200, Sigma, USA) was scored semi-quantitatively (0–3+) by two blinded pathologists. Proteinuria was assessed via 24-hour urine collection, and eGFR was calculated using the CKD-EPI formula. Outcomes were evaluated at 12 and 24 months. Statistical analyses included chi-square, Spearman correlation, and multivariate regression. Results: Fifty patients (60% male, mean age 45 ± 12 years) were included. C4d expression was positive in 80% (3+ in 50%, 2+ in 20%, 1+ in 10%), and anti-PLA2R1 was positive in 90% (3+ in 60%, 2+ in 20%, 1+ in 10%). Strong C4d and anti-PLA2R1 staining correlated with higher proteinuria (r = 0.48, p < 0.01) and worse eGFR at 12 months (r = –0.45, p = 0.01). C4d intensity independently predicted renal function decline (β = 0.34, 95% CI 0.08–0.60, p = 0.02). Conclusion: C4d and anti-PLA2R1 immunoexpression intensities are valuable prognostic markers in primary MN, with strong staining indicating worse outcomes, aiding risk stratification and management. Keywords: Membranous Nephropathy; PLA2R1; C4d; Immunohistochemistry; Prognosis