TY - JOUR
T1 - Targeted donor complement blockade after brain death prevents delayed graft function in a nonhuman primate model of kidney transplantation
AU - Danobeitia, Juan S.
AU - Zens, Tiffany J.
AU - Chlebeck, Peter J.
AU - Zitur, Laura J.
AU - Reyes, Jose A.
AU - Eerhart, Michael J.
AU - Coonen, Jennifer
AU - Capuano, Saverio
AU - D’Alessandro, Anthony M.
AU - Torrealba, Jose R.
AU - Burguete, Daniel
AU - Brunner, Kevin
AU - Van Amersfoort, Edwin
AU - Ponstein, Yolanda
AU - Van Kooten, Cees
AU - Jankowska-Gan, Ewa
AU - Burlingham, William
AU - Sullivan, Jeremy
AU - Djamali, Arjang
AU - Pozniak, Myron
AU - Yankol, Yucel
AU - Fernandez, Luis A.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
KW - animal models: nonhuman primate
KW - complement biology
KW - delayed graft function (DGF)
KW - donors and donation: donation after brain death (DBD)
KW - immunosuppression/immune modulation
KW - ischemia reperfusion injury (IRI)
KW - kidney transplantation/nephrology
KW - translational research/science
UR - http://www.scopus.com/inward/record.url?scp=85079846628&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85079846628&partnerID=8YFLogxK
U2 - 10.1111/ajt.15777
DO - 10.1111/ajt.15777
M3 - Article
C2 - 31922336
AN - SCOPUS:85079846628
VL - 20
SP - 1513
EP - 1526
JO - American Journal of Transplantation
JF - American Journal of Transplantation
SN - 1600-6135
IS - 6
ER -