Inhibition of complement improves graft outcome in a pig model of kidney autotransplantation.
BACKGROUND
Ischemia reperfusion injury (IRI) induced immune response is a critical issue in transplantation. Complement and contact system activation are among its key mechanisms.


METHODS
We investigated the benefits of pre-reperfusion treatment with recombinant human C1INH (rhC1INH), inhibitor of both complement and contact activation, in a pig model of kidney autotransplantation, subjecting the organ to 60 min warm ischemia prior to 24 h static preservation to maximize damage.


RESULTS
Serum creatinine measurement showed that treated animals recovered glomerular function quicker than the Vehicle group. However, no difference was observed in tubular function recovery, and elevated level of urinary NGal (Neutrophil gelatinase-associated lipocalin) and plasma AST (Aspartate Aminotransferase) were detected, indicating that treatment did not influence IRI-mediated tubular cell necrosis. Regarding chronic graft outcome, rhC1INH significantly prevented fibrosis development and improved function. Immunohistochemistry and western blot showed decreased invasion by macrophages and T lymphocytes, and reduction of epithelial to mesenchymal transition. We determined the effect of treatment on complement activation with immunofluorescence analyses at 30 min post reperfusion, showing an inhibition of C4d deposition and MBL staining in treated animals.


CONCLUSIONS
In this model, the inhibition of complement activation by rhC1INH at reperfusion, while not completely counteracting IRI, limited immune system activation, significantly improving graft outcome on the short and long term.
Département d'Urologie, CHU de Poitiers, 86000, Poitiers, France.|Inserm U1082, 86000, Poitiers, France.
Pierre-Olivier
PO
Delpech
Inserm U1082, 86000, Poitiers, France.|Service de Biochimie, CHU Poitiers, 86000, Poitiers, France.|Faculté de Médecine et de Pharmacie, Université de Poitiers, 86000, Poitiers, France.|Fédération Hospitalo-Universitaire SUPORT, 86000, Poitiers, France.
Raphael
R
Thuillier
Département D'urologie, CH D'Angoulème, 16000, Angoulème, France.
Thibault
T
SaintYves
Service de Chirurgie Viscérale, CHU de Poitiers, 86000, Poitiers, France.
Jerome
J
Danion
Inserm U1082, 86000, Poitiers, France.|Faculté de Médecine et de Pharmacie, Université de Poitiers, 86000, Poitiers, France.
Sylvain
S
Le Pape
Pharming Technologies BV, NL-2333CR, Leiden, The Netherlands.
Edwin S
ES
van Amersfoort
Pharming Technologies BV, NL-2333CR, Leiden, The Netherlands.
Beatrijs
B
Oortwijn
Institut de Transplantation Urologie et Néphrologie (ITUN), CHU de Nantes, Faculté de Médecine et des Techniques Médicales de Nantes, Université de Nantes, Inserm U1064, 44000, Nantes, France.
Gilles
G
Blancho
Inserm U1082, 86000, Poitiers, France. thierry.hauet@chu-poitiers.fr.|Service de Biochimie, CHU Poitiers, 86000, Poitiers, France. thierry.hauet@chu-poitiers.fr.|Faculté de Médecine et de Pharmacie, Université de Poitiers, 86000, Poitiers, France. thierry.hauet@chu-poitiers.fr.|Fédération Hospitalo-Universitaire SUPORT, 86000, Poitiers, France. thierry.hauet@chu-poitiers.fr.|Institut National de La Recherche Agronomique, Unité Expérimentale Génétique, Expérimentations et Systèmes Innovants, Domaine Expérimental Du Magneraud, Plateforme IBiSA 'MOPICT', 17700, Surgères, France. thierry.hauet@chu-poitiers.fr.|INSERM U1082, CHU de Poitiers, 2 Rue de La Miletrie, 86021, Poitiers Cedex, France. thierry.hauet@chu-poitiers.fr.
Thierry
T
Hauet
Complement system proteins; Drug evaluation; Ischemia; Kidney transplantation; Preclinical; Reperfusion injury
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