Brain-death (BD) induces an innate immune response that increases the risk of delayed graft function (DGF) and leads to reduced graft survival and increased immunogenicity compared to living donors. In this study, we evaluated the role of donor pretreatment targeting systemic complement activation using recombinant human C1 inhibitor (rhC1INH) in the prevention of DGF. We created a novel DGF model using kidneys recovered from BD non-human primates and subjected to 40 h of cold ischemia. Kidneys were then transplanted into ABO compatible, MHC mismatched recipients. Donors were divided into two groups: Group 1 (G1) – Vehicle treatment (n=2) or Group 2 (G2) – rhC1INH treatment (n=5) at 0.5, 3 and 6 h after BD induction. The two end points of the study were: A) DGF incidence within 7 days of transplantation and B) 30-day survival without dialysis. Donor treatment with rhC1INH prevented DGF in 60% of G2 kidney recipients. In addition, 2/5 animals survived and maintained normal renal function throughout the 30 day trial and overall mean survival of 19 days for G2 recipients. In contrast, 100% (2/2) of G1 recipients developed DGF and mean survival was 4.5 days (p=0.03). Recipients of G2 kidneys showed significantly lower serum creatinine (p<0.001), BUN (p=0.02) and markedly superior urinary output (p=0.004) in the first week post-transplant compared to recipients in G1. Significant reductions in classical and mannose-binding lectin pathways of complement activation in G2 donors were also documented. Furthermore, recipients of G2 kidneys expressed lower TNFΑ and MCP-1 mRNA levels and markedly reduced urinary IL-18 level, a marker of DGF. Recipients of kidneys from G1 showed histological signs of severe acute tubular injury with greater leukocytic graft infiltration at day 5, compared to minimal changes observed in biopsies from recipients of G2 kidneys. In conclusion, donor management targeting complement activation resulted in a profound anti-inflammatory effect limiting pre-transplant innate immune activation and preventing progression to DGF. These results suggest a pivotal role for complement activation in BD-induced renal injury and represent a new paradigm in the management of BD donors. RhC1INH constitutes a promising strategy for the prevention of DGF after transplantation using marginal kidneys.

Van Amersfoort, E.: Employee, Pharming Group NV. Oortwijn, B.: Employee, Pharming Group NV. Fernandez, L.: Grant/Research Support, Pharming Group NV.

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