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Targeting Complement Pathways During Cold Ischemia and Reperfusion Prevents Delayed Graft Function
Author(s) -
Yu Z. X.,
Qi S.,
Lasaro M. A.,
Bouchard K.,
Dow C.,
Moore K.,
Wu Z.,
Barama A.,
Xu J.,
Johnson K.,
Marozsan A. J.,
Wang Y.
Publication year - 2016
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.13797
Subject(s) - medicine , cold ischemia , ischemia , reperfusion injury , complement system , warm ischemia , complement (music) , immunology , cardiology , immune system , phenotype , biochemistry , complementation , gene , chemistry
The complement system plays a critical role in ischemia–reperfusion injury ( IRI )–mediated delayed graft function ( DGF ). To better understand the roles of complement activation pathways in IRI in kidney transplantation, donor kidneys were treated ex vivo with terminal complement pathway ( TP ) inhibitor, anti‐rat C5 mA b 18A10, or complement alternative pathway ( AP ) inhibitor TT 30 for 28 h at 4°C pretransplantation in a syngeneic kidney transplantation rat model. All 18A10‐ and 67% of TT 30‐pretreated grafts, but only 16.7% of isotype control‐pretreated grafts, survived beyond day 21 (p < 0.01). Inhibitor treatment in the final 45 min of 28‐h cold ischemia ( CI ) similarly improved graft survival. Systemic posttransplant treatment with 18A10 resulted in 60% increased graft survival beyond day 21 (p < 0.01), while no TT 30‐treated rat survived > 6 days. Our results demonstrate that AP plays a prominent role during CI and that blocking either the AP or, more effectively the TP prevents ischemic injury and subsequent DGF . Multiple complement pathways may be activated and contribute to reperfusion injury; blocking the TP , but not the AP , posttransplant is effective in preventing reperfusion injury and increasing graft survival. These results demonstrate the feasibility of using complement inhibitors for prevention of DGF in humans.