Thrombin inhibition during kidney ischemia-reperfusion reduces chronic graft inflammation and tubular atrophy.
BACKGROUND
Ischemia-reperfusion injury (IRI) is an unavoidable component of transplantation and correlates with delayed graft function, acute rejection, chronic fibrosis, and graft loss. Currently, new donor pools are considered to alleviate pressure on waiting lists, such as deceased after cardiac death donors (DCD) and extended criteria donors. Because these organs are particularly sensitive to IRI, there is a need for novel preservation paradigms. We assessed the effect of anticoagulation therapy during graft preservation on IRI and graft outcome.


METHODS
In a large white autotransplanted pig model, kidneys underwent warm ischemia for 60 min, mimicking DCD, then were preserved for 24 hr at 4°C, in University of Wisconsin solution. Animals were followed up 3 months, functional, histologic, and molecular parameters were assessed. In treated groups, antithrombin was added to collection and preservation protocols.


RESULTS
Treatment improved chronic graft function, reduced tubular atrophy, and substantially increased animal survival. Quantitative polymerase chain reaction analysis determined that markers of inflammation, such as interferon-[gamma], tumor necrosis factor-[alpha], interleukin (IL)-2, -1Rn, and -10, were significantly reduced in treated grafts. Histologic analysis revealed a lowering of CD3+ invasion. P selectin and C3 mRNA expressions were reduced in treated groups, indicative of lowered complement production and endothelial cell activation. Vascular endothelium growth factor protein expression was up-regulated, suggesting vascular network remodeling.


CONCLUSIONS
Inhibition of thrombin during preservation of DCD graft preserved renal integrity and function, protecting against chronic inflammation and tissue damage. Thus, coagulation seems to be a critical target for the development of therapeutic strategies to improve kidney quality for transplantation.
Thuillier
Raphael
R
Inserm U927, Ischémie-Reperfusion en Transplantation Rénale; Université de Poitiers Faculté de Medecine et de Pharmacie, Poitiers, France.
Favreau
Frederic
F
Celhay
Olivier
O
Macchi
Laurent
L
Milin
Serge
S
Hauet
Thierry
T
D000818:Animals; D000991:Antithrombins / Q000627:therapeutic use*; D002102:Cadaver; D003404:Creatinine / Q000378:metabolism; D017931:DNA Primers; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation / Q000473:pathology / Q000502:physiology*; D007684:Kidney Tubules / Q000473:pathology*; D008297:Male; D011180:Postmortem Changes; D011507:Proteinuria; D012333:RNA, Messenger / Q000235:genetics; D015427:Reperfusion Injury; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D013917:Thrombin / Q000037:antagonists & inhibitors*; D014019:Tissue Donors / Q000600:supply & distribution; D014182:Transplantation, Autologous
D000991:Antithrombins; D017931:DNA Primers; D012333:RNA, Messenger; D003404:Creatinine; D013917:Thrombin