Complement Mediated Renal Inflammation Induced by Donor Brain Death: Role of Renal C5a-C5aR Interaction

Authors

  • M. B. van Werkhoven,

    Corresponding author
    • Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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  • J. Damman,

    1. Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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  • M. C. R. F. van Dijk,

    1. Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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  • M. R. Daha,

    1. Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
    2. Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands
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  • I. J. de Jong,

    1. Department of Urology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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  • A. Leliveld,

    1. Department of Urology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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  • C. Krikke,

    1. Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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  • H. G. Leuvenink,

    1. Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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  • H. van Goor,

    1. Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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  • W. J. van Son,

    1. Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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  • P. Olinga,

    1. Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen Research Institute of Pharmacy, Groningen, the Netherlands
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  • J.-L. Hillebrands,

    1. Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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  • M. A. J. Seelen

    1. Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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Maaike B. van Werkhoven,

m.b.van.werkhoven@umcg.nl

Abstract

Kidneys retrieved from brain-dead donors have impaired allograft function after transplantation compared to kidneys from living donors. Donor brain death (BD) triggers inflammatory responses, including both systemic and local complement activation. The mechanism by which systemic activated complement contributes to allograft injury remains to be elucidated. The aim of this study was to investigate systemic C5a release after BD in human donors and direct effects of C5a on human renal tissue. C5a levels were measured in plasma from living and brain-dead donors. Renal C5aR gene and protein expression in living and brain-dead donors was investigated in renal pretransplantation biopsies. The direct effect of C5a on human renal tissue was investigated by stimulating human kidney slices with C5a using a newly developed precision-cut method. Elevated C5a levels were found in plasma from brain-dead donors in concert with induced C5aR expression in donor kidney biopsies. Exposure of precision-cut human kidney slices to C5a induced gene expression of pro-inflammatory cytokines IL-1 beta, IL-6 and IL-8. In conclusion, these findings suggest that systemic generation of C5a mediates renal inflammation in brain-dead donor grafts via tubular C5a-C5aR interaction. This study also introduces a novel in vitro technique to analyze renal cells in their biological environment.

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