Targeted donor complement blockade after brain death prevents delayed graft function in a nonhuman primate model of kidney transplantation.

Autor: Danobeitia JS; Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA., Zens TJ; Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA., Chlebeck PJ; Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA., Zitur LJ; Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA., Reyes JA; Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA., Eerhart MJ; Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA., Coonen J; Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA., Capuano S; Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA., D'Alessandro AM; Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA., Torrealba JR; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA., Burguete D; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA., Brunner K; Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA., Van Amersfoort E; Pharming Technologies B.V., Leiden, the Netherlands., Ponstein Y; Pharming Technologies B.V., Leiden, the Netherlands., Van Kooten C; Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands., Jankowska-Gan E; Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA., Burlingham W; Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA., Sullivan J; Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA., Djamali A; Department of Medicine, Division of Nephrology, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA., Pozniak M; Department of Radiology, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA., Yankol Y; Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA., Fernandez LA; Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA.
Jazyk: angličtina
Zdroj: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons [Am J Transplant] 2020 Jun; Vol. 20 (6), pp. 1513-1526. Date of Electronic Publication: 2020 Feb 20.
DOI: 10.1111/ajt.15777
Abstrakt: 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.
(© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)
Databáze: MEDLINE
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