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.
N1 - Funding Information:
This work was supported by National Institutes of Health (NIH) 1-R01-AI110617-01A1 (PI:?Luis?Fernandez), NIH training grants T32DK007665 (Jose Reyes) and T32AI125231 (Juan Danobeitia), and the 2016 American Society of Transplant Surgeons Scientist scholarship (Juan Danobeitia). We gratefully acknowledge the veterinary and SPI staff at the WNPRC. We also thank D. Roenneburg, S. Raglin, W. Zhong, A. Mejia, H. Simmons, S. Larson, C. Boetcher, J. Rose, and T. Roehling for expert technical assistance. We thank Kristy Kraemer and Julia Shaw from the National Institutes of Health and Isabella Lussier from Alpha-Genesis for their assistance in identifying appropriate nonhuman primate pairs for our experimental design. The rhC1INH was kindly provided by Pharming Technologies BV (Leiden, The Netherlands).
Publisher Copyright:
© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons
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
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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 -