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 language | English (US) |
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Pages (from-to) | 1513-1526 |
Number of pages | 14 |
Journal | American Journal of Transplantation |
Volume | 20 |
Issue number | 6 |
DOIs | |
State | Published - 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)