Targeted donor complement blockade after brain death prevents delayed graft function in a nonhuman primate model of kidney transplantation
| Autor: | Tiffany Zens, Anthony M. D’Alessandro, Michael J. Eerhart, Peter J. Chlebeck, Jose A. Reyes, Saverio Capuano, Daniel Burguete, Yucel Yankol, Yolanda Ponstein, Luis A. Fernandez, Jose R. Torrealba, Jennifer Coonen, William J. Burlingham, Kevin Brunner, Laura J. Zitur, Edwin Van Amersfoort, Myron A. Pozniak, Jeremy A. Sullivan, Juan S. Danobeitia, Arjang Djamali, Ewa Jankowska-Gan, Cees van Kooten |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Primates
medicine.medical_specialty Brain Death donors and donation Urinary system delayed graft function (DGF) Urology nephrology Delayed Graft Function kidney transplantation nonhuman primate 030230 surgery complement biology 03 medical and health sciences Classical complement pathway 0302 clinical medicine Risk Factors medicine Immunology and Allergy Animals Humans Pharmacology (medical) Kidney transplantation science donation after brain death (DBD) Transplantation immunosuppression immune modulation business.industry Graft Survival Heparin medicine.disease Tissue Donors animal models Complement system Blockade ischemia reperfusion injury (IRI) translational research business Reperfusion injury medicine.drug |
| Zdroj: | American Journal of Transplantation, 20(6), 1513-1526. WILEY |
| Popis: | 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 degrees 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 alpha 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. |
| Databáze: | OpenAIRE |
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