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Complement inhibitors in pediatric kidney diseases: new therapeutic opportunities

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Abstract

Historically, the complement system (classical, lectin, alternative, and terminal pathways) is known to play a crucial role in the etiopathogenesis of many kidney diseases. Direct or indirect activation in these settings is revealed by consumption of complement proteins at the serum level and kidney tissue deposition seen by immunofluorescence and electron microscopy. The advent of eculizumab has shown that complement inhibitors may improve the natural history of certain kidney diseases. Since then, the number of available therapeutic molecules and experimental studies on complement inhibition has increased exponentially. In our narrative review, we give a summary of the main complement inhibitors that have completed phase II and phase III studies or are currently used in adult and pediatric nephrology. The relevant full-text works, abstracts, and ongoing trials (clinicaltrials.gov site) are discussed. Data and key clinical features are reported for eculizumab, ravulizumab, crovalimab, avacopan, danicopan, iptacopan, pegcetacoplan, and narsoplimab. Many of these molecules have been shown to be effective in reducing proteinuria and stabilizing kidney function in different complement-mediated kidney diseases. Thanks to their efficacy and target specificity, these novel drugs may radically improve the outcome of complement-mediated kidney diseases, contributing to an improvement in our understanding of their underlying pathophysiology.

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Funding

This work was supported by the Italian Ministry of Health with “Current Research funds” and, regarding Joshua M. Thurman, by the National Institutes of Health R01 DK076690.

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Authors and Affiliations

  1. Division of Nephrology, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy

    Luca Antonucci & Marina Vivarelli

  2. Ph.D. Course in Microbiology, Immunology, Infectious Diseases, and Transplants (MIMIT), University of Rome Tor Vergata, Rome, Italy

    Luca Antonucci

  3. Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA

    Joshua M. Thurman

  4. Division of Nephrology, Laboratory of Nephrology, Bambino Gesù Children’s Hospital IRCCS, Piazza S Onofrio 4, 00165, Rome, Italy

    Marina Vivarelli

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  1. Luca Antonucci
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Correspondence to Marina Vivarelli.

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Conflict of interest

Joshua M. Thurman holds stock in and receives royalties from Q32 Bio, Inc., a company developing complement inhibitors. Marina Vivarelli receives consulting fees from Novartis, Roche, Bayer, Apellis, BioCryst, Travere, WebMD, PureSpring, and Chinook; participated in sponsored trials by Alexion, Roche, Novartis, Bayer, Chinook, Travere, and Apellis; and received speaker fees from Alexion, Glaxo, Roche, Novartis, and Vifor. These have no impact on the current publication. Luca Antonucci declares no conflicts of interest.

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1. a; 2. c; 3. c; 4. b; 5. d

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Antonucci, L., Thurman, J.M. & Vivarelli, M. Complement inhibitors in pediatric kidney diseases: new therapeutic opportunities. Pediatr Nephrol 39, 1387–1404 (2024). https://doi.org/10.1007/s00467-023-06120-8

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