Abstract
Background: Complement activation contributes to the pathogenesis of immunoglobulin A nephropathy (IgAN), and glomerular C4d deposition is a tissue marker of lectin and classical pathway activation. Whether C4d deposition and its intraglomerular localization are associated with longitudinal kidney outcomes independently of baseline disease severity remains uncertain. Methods: This retrospective single-center cohort included 77 adults with biopsy-proven primary IgAN. C4d was assessed immunohistochemically and considered positive when present in >25% of non-sclerotic glomeruli; positive biopsies were classified according to mesangial or glomerular capillary localization, and staining confined to sclerotic segments or Bowman’s capsule was not considered positive. eGFR and proteinuria measured from baseline to 48 months were analyzed using linear mixed-effects models, with adjustment for baseline proteinuria, Oxford S1, and corticosteroid treatment. Kidney failure, defined as sustained eGFR < 15 mL/min/1.73 m2, maintenance dialysis, or kidney transplantation, was analyzed using Kaplan–Meier and Cox regression analyses. Results: Glomerular C4d deposition was present in 32 patients (41.6%), with mesangial and glomerular capillary deposition in 15 (19.5%) and 17 (22.1%), respectively. Baseline proteinuria, S1 frequency, and serum C3 and C4 levels did not differ significantly according to C4d status. Mesangial C4d deposition was associated with S1 lesions (80.0% vs. 51.6%; p = 0.046). C4d-positive patients had persistently higher proteinuria during follow-up (p = 0.002), and this association remained after adjustment (geometric mean ratio 1.67, 95% CI 1.07–2.61; p = 0.026). The eGFR trajectory did not differ according to C4d status (p = 0.808). Kidney failure occurred in 11 patients (14.3%) and was not associated with C4d positivity after adjustment for baseline eGFR (HR 0.96, 95% CI 0.23–4.09). Neither localization was independently associated with longitudinal outcomes. Conclusions: In IgAN, glomerular C4d deposition was associated with persistently higher proteinuria after adjustment for baseline proteinuria, Oxford S1 status, and corticosteroid treatment, but was not significantly associated with longitudinal eGFR changes or kidney failure. The clinical relevance of C4d localization requires further evaluation in larger cohorts with longer follow-up.