Targeted donor complement blockade after brain death prevents delayed graft function in a nonhuman primate model of kidney transplantation
American Journal of Transplantation, vol. 20, pp. 1513–1526
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.
Authors 22
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University of Wisconsin–Madison
Affiliation as printed
Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA
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University of Wisconsin–Madison
Affiliation as printed
Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA
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University of Wisconsin–Madison
Affiliation as printed
Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA
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University of Wisconsin–Madison
Affiliation as printed
Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA
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University of Wisconsin–Madison
Affiliation as printed
Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA
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University of Wisconsin–Madison
Affiliation as printed
Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA
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University of Wisconsin–Madison
Affiliation as printed
Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
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University of Wisconsin–Madison
Affiliation as printed
Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
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University of Wisconsin–Madison
Affiliation as printed
Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA
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The University of Texas Southwestern Medical Center
Affiliation as printed
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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The University of Texas Southwestern Medical Center
Affiliation as printed
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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University of Wisconsin–Madison
Affiliation as printed
Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
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Affiliation as printed
Pharming Technologies B.V., Leiden, the Netherlands
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Affiliation as printed
Pharming Technologies B.V., Leiden, the Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands
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University of Wisconsin–Madison
Affiliation as printed
Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA
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University of Wisconsin–Madison
Affiliation as printed
Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA
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University of Wisconsin–Madison
Affiliation as printed
Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA
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University of Wisconsin–Madison
Affiliation as printed
Department of Medicine, Division of Nephrology, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA
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University of Wisconsin–Madison
Affiliation as printed
Department of Radiology, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA
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University of Wisconsin–Madison
Affiliation as printed
Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA
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Luis A. Fernandez corresponding
University of Wisconsin–Madison
Affiliation as printed
Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA