Recombinant C1INH Reduces Ischemia Reperfusion-Induced Immune Response and Improves Kidney Graft Outcome.

Abstract

Ischemia reperfusion (IR) induced immune response is a critical issue in transplantation (Tx). Complement and contact system activation are two of its key mechanisms. 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 in which the transplanted kidney was subjected to 60min warm ischemia prior to 24h static preservation in University of Wisconsin solution to maximize damage. This preclinical model (with contralateral nephrectomy after Tx) permits us to obtain clinically relevant functional and histological data on both the acute response and the chronic outcomes during a 3 months-follow up period. ELISA and immunohistofluorescent analyses revealed an inhibition of both C5 and MASP2 in treated animals, indicating full inhibition of the complement system. Treated animals recovered kidney function quickly (Fig1), as measured by serum creatinine, reaching pretransplant levels by Day 11 while Vehicle animals could never recover proper kidney function (p<0.05 AUC comparison). Urinary NGal measurements showed elevated levels that did not differ between groups, indicating that the treatment did not influence IR-mediated tubular cell necrosis. With regards to chronic graft outcome (Fig2), rhC1INH treatment prevented fibrosis development compared to vehicle (p<0.05), in association with improved function at months 1 and 3 (p<0.05). Immunohistochemistry analyses showed a decreased number of invading macrophages within the graft and a reduction of epithelial to mesenchymal transition activation. In this preclinical model of kidney transplantation, while tubular necrosis was similar between the groups the inhibition of complement activation by rhC1INH at reperfusion permitted the limitation of immune system activation, preserving graft integrity on the short and long term and significantly improving outcomes.Figure: No Caption available.Figure: No Caption available.DISCLOSURE:van Amersfoort, E.: Employee, Pharming BV. Oortwijn, B.: Employee, Pharming BV.