AUTHOR=Andrulli Simeone , Manenti Lucio , Reggiani Francesco , Pisani Isabella , Giannese Domenico , Vischini Gisella , Valsecchi Giovanni , Godeas Giulia , Gigliotti Giuseppe , Esposito Pasquale , De Giovanni Paola , Murtas Corrado , Casuscelli Chiara , Caruso Sabrina , Rossini Michele , Andrulli Giovanni , Quaglia Marco , Aucella Filippo , Buscaroli Andrea , Rossi Giovanni Maria , Mattozzi Francesca , Di Renzo Brigida , Zanchelli Fulvia , Bruno Francesca , Sciri Raffaela , Manes Massimo , Torres Diletta Domenica , Garozzo Maurizio , Lazzarin Roberta , Corbani Valentina , Fontana Francesco , Calatroni Marta , Incerti Monia , Bini Claudia , Infante Barbara , D’Angio’ Pierluigi , Di Martino Margherita , Rigotti Angelo , Gesualdo Loreto 

TITLE=Isolated C3 hypocomplementemia as an early predictor of chronic kidney disease in lupus nephritis

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1655825

DOI=10.3389/fimmu.2025.1655825

ISSN=1664-3224

ABSTRACT=ObjectiveThe role of complement in the long-term renal survival of patients with lupus nephritis (LN) remains poorly understood. Recent studies suggest its potential impact; however, long-term data are lacking.MethodsThis multicenter, observational, retrospective study aimed at investigating the influence of complement levels on long-term renal outcomes in LN patients. We evaluated whether isolated C3 hypocomplementemia (i-LowC3), defined as serum low C3 (≤80 mg/dL) and normal C4 (>10 mg/dL) six months after kidney biopsy is associated with subsequent risk of chronic kidney disease (CKD), End Stage Kidney Disease (ESKD) or death.Results445 patients with LN were studied (median follow-up 4.9 years). Based on six-month C3/C4 levels, patients were categorized into i-LowC3 (91 patients) and controls (354 patients). Over the first six months, serum C3 and C4 levels increased by a median of 20 mg/dL and 5 mg/dL, respectively. i-LowC3 was significantly associated with twice the risk of a poor outcome, including CKD, ESKD, composite outcome of CKD or death and ESKD or death, with lower survival rates for all these outcomes compared to controls (P < 0.001). Multivariate Cox regression analysis revealed a lower risk of CKD and CKD or death with increases in C3 levels during the first six months, while i-LowC3 was associated with an independent higher risk for these outcomes.ConclusionThe trajectory of serum C3 levels within the first six months appears to predict long-term renal prognosis of LN patients. These findings support the use of i-LowC3 as a low-cost, readily available biomarker to guide early treatment of LN patients.