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Targeted donor complement blockade after brain death prevents delayed graft function in a nonhuman primate model of kidney transplantation
Author(s) -
Danobeitia Juan S.,
Zens Tiffany J.,
Chlebeck Peter J.,
Zitur Laura J.,
Reyes Jose A.,
Eerhart Michael J.,
Coonen Jennifer,
Capuano Saverio,
D’Alessandro Anthony M.,
Torrealba Jose R.,
Burguete Daniel,
Brunner Kevin,
Van Amersfoort Edwin,
Ponstein Yolanda,
Van Kooten Cees,
JankowskaGan Ewa,
Burlingham William,
Sullivan Jeremy,
Djamali Arjang,
Pozniak Myron,
Yankol Yucel,
Fernandez Luis A.
Publication year - 2020
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.15777
Subject(s) - medicine , blockade , transplantation , complement system , immunogenicity , kidney transplantation , kidney , complement factor i , alternative complement pathway , immunology , immune system , receptor
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.