Glomerular Capillary C4d Staining in Native Kidney Biopsies: Associations with Proteinuric Phenotype and Reduced Likelihood of Early Proteinuria Remission

Background/Objectives: This study investigated the prevalence and clinical significance of glomerular capillary C4d staining in native kidney biopsies and its association with renal outcomes in patients with biopsy-proven glomerular diseases. Methods: This single-center, retrospective study reviewed adult native kidney biopsy cases performed between November 2022 and November 2024 and included 173 patients with biopsy-proven glomerular disease who underwent immunohistochemical C4d staining. Results: C4d positivity was detected in 38.2% of biopsies, most frequently in membranous nephropathy (74.2%), followed by AA amyloidosis (63.6%) and lupus nephritis (63.6%). General characteristics were similar between C4d-negative and C4d-positive patients; however, the C4d-positive group had higher baseline LDL and proteinuria levels and lower albumin levels. At 6 months, the proportion of patients who achieved proteinuria levels <1 g/day and <0.5 g/day was significantly lower in the C4d-positive group compared to the C4d-negative group. The two groups did not differ regarding glomerular filtration rate and the need for renal replacement therapy. Older age and C4d positivity were independently associated with a lower likelihood of achieving proteinuria <0.5 g/day at 6 months. Conclusions: Glomerular capillary C4d positivity was associated with a more pronounced proteinuric phenotype and a reduced likelihood of early proteinuria remission. These findings support the clinical relevance of glomerular capillary C4d staining in relation to early proteinuria remission; however, larger prospective studies incorporating standardized semiquantitative C4d assessment and long-term follow-up are required before C4d can be considered a validated prognostic biomarker.