*Purpose: Ischemia-reperfusion injury (IRI) leading to inflammation, complement activation, cytokine release and acute kidney injury has been implicated in the mechanism for delayed graft function (DGF). We have previously demonstrated in non-human primates (NHP) that donor pre-treatment with C1 inhibitor (C1-INH) prevents DGF in kidney transplant recipients. We hypothesized that recipient treatment with C1-INH will prevent DGF in NHP kidney transplants from brain death (BD) donors by reducing inflammation and cytokine release at the time of IRI.

*Methods: BD was induced in NHP and maintained for 20 hours using conventional donor management. Recovered kidneys were cold stored for 44-hours and transplanted in ABO-compatible, fully mismatched rhesus macaques. Recipients were divided into two treatment arms: A) Vehicle (n=6) and B) C1-INH (500U/kg) plus heparin (40U/kg), which was given prior to reperfusion and repeated every 12 hours for 2 additional doses (n=8). Recipients under triple immunosuppression therapy were followed for 120 days and protocol biopsies of the allograft were performed. The main endpoints were: 1) Incidence of DGF, defined as failure of serum creatinine to fall at least 10% on 3 consecutive days in the first postoperative week and/or serum creatinine at postoperative day 7 >2.5 mg/dL and 2) Development of cellular or antibody-mediated rejection (AMR) within 120 days post-transplant.

*Results: Recipient treatment with C1-INH prevented progression to DGF. In the C1-INH arm of the study, only 14.3% (1/8) met DGF criteria, vs 66.7% (4/6) in the vehicle arm (p=0.036). Recipients in the C1-INH arm showed reduced creatinine levels in the first postoperative week (p<0.05). We observed reduced post reperfusion IL-6 and MCP-1 levels as well as reduced urine NGAL on the first postoperative day in the treatment arm when measured with LEGENDplex™ NHP Subpanel (p<0.05). Interval biopsies were graded according to the Banff 2013 criteria for rejection using C4d, donor specific antibody detection by flow cytometry and H&E stains. C1-INH prevented the development of AMR, which occurred in 3/8 animals in the C1-INH treatment arm vs 4/4 in the vehicle arm who survived the DGF period (p=0.038).

*Conclusions: Our data strongly supports the use of C1-INH as a valuable strategy for the prevention of DGF by decreasing cytokine levels and the inflammatory response associated with IRI. In addition peri-operative administration of C1-INH significantly reduced the incidence of AMR. Clinical trials are underway to prove efficacy.

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