Abstract
BackgroundIschemia reperfusion injury (IRI) induced immune response is a critical issue in transplantation. Complement and contact system activation are among its key mechanisms.Study designWe 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.ResultsSerum 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.ConclusionsIn 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1013-7) contains supplementary material, which is available to authorized users.
Highlights
Ischemia reperfusion injury (IRI) induced immune response is a critical issue in transplantation
Tubular injury marker urinary Neutrophil gelatinase-associated lipocalin (Ngal) levels were high at day 3, with ~10,000 pg/mL in both groups, while the baseline in Large White pigs is ~700 pg/mL
There was no difference between groups, suggesting that recombinant human C1INH (rhC1INH) does not directly affect tubular ischemia reperfusion (IR) lesions (Additional file 2: Fig. 1)
Summary
Ischemia reperfusion injury (IRI) induced immune response is a critical issue in transplantation. Only one quarter of patients on waiting lists have access to an organ. This led to the extension of donor criteria and the acceptation of marginal donors [1], donors aged over 60, Delpech et al J Transl Med (2016) 14:277. The complement cascade is a key feature of the immune response, capable of inducing both innate and adaptive responses as well as lead to cell death [5]. The complement system is activated immediately following reperfusion, continuing through the multiple stages of graft survival [6], from the early response to chronic fibrosis development [7]. Complement is already involved at the donor level, playing for instance a key role in the tissue damage occurring during brain death [8]
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