Targeted Donor Complement Blockade After Brain-Death Prevents Delayed Graft Function In A Non-Human 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-Simarro Doorten, Cees Van Kooten, Ewa Jankowska-Gan, William Burlingham, Jeremy Sullivan, Arjang Djamali, Myron Pozniak, Yucel Yankol, Luis A Fernandez
American Journal of Transplantation 2020 January 10
Delayed graft function (DGF) in renal transplantation is associated with reduced graft survival and increased immunogenicity. The complement-driven inflammatory response after brain death (BD) and post-transplant reperfusion injury play significant roles in the pathogenesis of DGF. In a non-human primate model, we tested complement-blockade in BD donors to prevent DGF and improve graft survival. BD donors were maintained 20-hours, kidneys were procured and stored at 4°C for a 43-48 hours prior to implantation into ABO-compatible, non-sensitized, MHC-mismatched recipients. Animals were divided into three different donor-treatment groups: G1-Vehicle, G2-rhC1INH+heparin, and G3-heparin only. G2 donors showed significant reduction in classical complement pathway activation and decreased levels of TNFα and MCP-1. DGF was diagnosed in 4/6 (67%) G1-recipients, 3/3 (100%) of G3-recipients, and 0/6 (0%) of G2-recipients (p=0.008). In addition, G2-recipients showed superior renal function, reduced sC5b-9, and reduced urinary NGAL in the first week post-transplant. 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.

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