Targeted donor complement blockade after brain death prevents delayed graft function in a nonhuman primate model of kidney transplantation

Juan S. Danobeitia, Tiffany J. Zens, Peter J. Chlebeck, Laura J. Zitur, Jose A. Reyes, Michael J. Eerhart, Jennifer Coonen, Saverio Capuano, Anthony M. D’Alessandro, Jose R. Torrealba, Daniel Burguete, Kevin Brunner, Edwin Van Amersfoort, Yolanda Ponstein, Cees Van Kooten, Ewa Jankowska-Gan, William Burlingham, Jeremy Sullivan, Arjang Djamali, Myron PozniakYucel Yankol, Luis A. Fernandez

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Delayed graft function (DGF) in renal transplant is associated with reduced graft survival and increased immunogenicity. The complement-driven inflammatory response after brain death (BD) and posttransplant reperfusion injury play significant roles in the pathogenesis of DGF. In a nonhuman primate model, we tested complement-blockade in BD donors to prevent DGF and improve graft survival. BD donors were maintained for 20 hours; kidneys were procured and stored at 4°C for 43-48 hours prior to implantation into ABO-compatible, nonsensitized, MHC-mismatched recipients. Animals were divided into 3 donor-treatment groups: G1 - vehicle, G2 - rhC1INH+heparin, and G3 - heparin. G2 donors showed significant reduction in classical complement pathway activation and decreased levels of tumor necrosis factor α and monocyte chemoattractant protein 1. DGF was diagnosed in 4/6 (67%) G1 recipients, 3/3 (100%) G3 recipients, and 0/6 (0%) G2 recipients (P =.008). In addition, G2 recipients showed superior renal function, reduced sC5b-9, and reduced urinary neutrophil gelatinase–associated lipocalin in the first week posttransplant. We observed no differences in incidence or severity of graft rejection between groups. Collectively, the data indicate that donor-management targeting complement activation prevents the development of DGF. Our results suggest a pivotal role for complement activation in BD-induced renal injury and postulate complement blockade as a promising strategy for the prevention of DGF after transplantation.

Original languageEnglish (US)
Pages (from-to)1513-1526
Number of pages14
JournalAmerican Journal of Transplantation
Volume20
Issue number6
DOIs
StatePublished - Jun 1 2020

Keywords

  • animal models: nonhuman primate
  • complement biology
  • delayed graft function (DGF)
  • donors and donation: donation after brain death (DBD)
  • immunosuppression/immune modulation
  • ischemia reperfusion injury (IRI)
  • kidney transplantation/nephrology
  • translational research/science

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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    Danobeitia, J. S., Zens, T. J., Chlebeck, P. J., Zitur, L. J., Reyes, J. A., Eerhart, M. J., Coonen, J., Capuano, S., D’Alessandro, A. M., Torrealba, J. R., Burguete, D., Brunner, K., Van Amersfoort, E., Ponstein, Y., Van Kooten, C., Jankowska-Gan, E., Burlingham, W., Sullivan, J., Djamali, A., ... Fernandez, L. A. (2020). Targeted donor complement blockade after brain death prevents delayed graft function in a nonhuman primate model of kidney transplantation. American Journal of Transplantation, 20(6), 1513-1526. https://doi.org/10.1111/ajt.15777