C4d Is an Independent Predictor of the Kidney Failure in Primary IgA Nephropathy

<b>Background:</b> C4d deposits are present in a substantial proportion of patients with IgA nephropathy (IgAN), indicating the activation of the lectin pathway (LP) of the complement system. It seems that patients with activated LP have worse renal prognosis. The aim of this study was to investigate the prevalence and prognostic significance of C4d in our cohort of patients with primary IgA nephropathy (pIgAN). <b>Methods:</b> Patients with pIgAN were recruited from a hospital register of kidney biopsies of the Department of Nephrology and Dialysis, Dubrava University Hospital, Zagreb. Additional immunohistochemistry staining for C4d was performed on paraffin-embedded kidney tissue, and patients were stratified into being C4d positive or C4d negative. The clinical and histologic features of patients were analyzed and compared regarding C4d positivity. The primary outcome was defined as kidney failure (KF), and predictor variables of KF and renal survival were analyzed. <b>Results:</b> Of a total of 95 patients with pIgAN included in the study, C4d was present in 43 (45.3%). C4d-positive patients had a higher value of systolic (<i>p</i> = 0.039) and diastolic (<i>p</i> = 0.006) blood pressure at diagnosis as well as higher 24 h proteinuria (<i>p</i> = 0.018), serum urate (<i>p</i> = 0.033), and lower eGFR (<i>p</i> < 0.001). C4d-positive patients had worse renal survival (<i>p</i> < 0.001), higher rates of disease progression to KF (<i>p</i> < 0.001), and higher proteinuria (<i>p</i> < 0.001) and lower eGFR (<i>p</i> < 0.001) at the last follow-up. Glomerular C4d was an independent predictor of disease progression to KF (HR = 5.87 [0.95 CI 1.06-32.44], <i>p</i> = 0.032). <b>Conclusions:</b> C4d is an independent predictor of disease progression in patients with pIgAN. C4d may be used as an additional marker of progressive disease course in IgAN. The therapeutic implications of C4d status in IgAN, particularly in terms of complement inhibitors application, are not yet known.