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Observational Study
. 2025 Sep 12:16:1655825.
doi: 10.3389/fimmu.2025.1655825. eCollection 2025.

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

Simeone Andrulli  1 , Lucio Manenti  2 , Francesco Reggiani  3 , Isabella Pisani  4 , Domenico Giannese  5 , Gisella Vischini  6 , Giovanni Valsecchi  1 , Giulia Godeas  7 , Giuseppe Gigliotti  8 , Pasquale Esposito  9 , Paola De Giovanni  10 , Corrado Murtas  11 , Chiara Casuscelli  12 , Sabrina Caruso  13 , Michele Rossini  14 , Giovanni Andrulli  15 , Marco Quaglia  16 , Filippo Aucella  17 , Andrea Buscaroli  18 , Giovanni Maria Rossi  4 , Francesca Mattozzi  19 , Brigida Di Renzo  20 , Fulvia Zanchelli  21 , Francesca Bruno  22 , Raffaela Sciri  23 , Massimo Manes  24 , Diletta Domenica Torres  25 , Maurizio Garozzo  26 , Roberta Lazzarin  27 , Valentina Corbani  28 , Francesco Fontana  29 , Marta Calatroni  3 , Monia Incerti  4 , Claudia Bini  6 , Barbara Infante  7 , Pierluigi D'Angio'  8 , Margherita Di Martino  9 , Angelo Rigotti  10 , Loreto Gesualdo  14
Affiliations
Observational Study

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

Simeone Andrulli et al. Front Immunol. .

Abstract

Objective: The 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.

Methods: This 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.

Results: 445 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.

Conclusion: The 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.

Keywords: CKD; ESKD; complement; immunosuppression; lupus; proteinuria.

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Conflict of interest statement

LM received consulting fees from Vifor CSL, GSK, Alexion and payment or honoraria for lectures and presentations from Vifor CSL, GSK, Alexion and Astra Zeneca. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Kaplan-Meier long-term survival curves for CKD (A), CKD or Death (B), ESKD (C) and ESKD or Death (D), grouped, at six month follow up, by levels of C3 <= 80 mg/dL and C4 > 10 mg/dL (i-LowC3 group). In all cases, survival was lower in the i-LowC3 group compared with Controls.
See this image and copyright information in PMC

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