Search

Background. In organ transplantation, cold ischemia is associated with sterile inflammation that subsequently conditions adaptive immunity directed against the grafts during revascularization. This inflammation is responsible for venous thrombosis, which is the main postoperative complication affecting graft function. Our aim was to investigate the modulation of immune responses and endothelial function of pancreatic grafts during cold ischemia using different preservation modalities. Methods. According to a preclinical porcine model of controlled donation after circulatory death, pancreatic grafts were preserved under hypothermic conditions for 24 h according to 4 modalities: static cold storage, hypothermic machine perfusion, hypothermic oxygenated perfusion at 21%, and 100%. Biopsies of the head and tail of the pancreas were performed during preservation. The first step involved a broad screening of the gene expression profile (84 genes) during preservation on a limited number of grafts. In the second step, a confirmation test was performed in all 4 groups. Results. Vascular endothelial growth factor gene expression showed a decrease during preservation in the hypothermic oxygenated perfusion 21% and 100% groups compared with the static cold storage group. In contrast, thrombomodulin gene expression showed an increase during preservation in the hypothermic oxygenated perfusion 21% and 100% groups compared with the static cold storage and hypothermic machine perfusion groups. Conclusions. We demonstrated that compared with static cold storage, hypothermic oxygenated perfusion is an effective modality for modulating endothelial function by increasing thrombomodulin expression and decreasing ischemia and vascular endothelial growth factor expression.

Background. Pretreating porcine kidneys with Corline Heparin Conjugate (CHC) during hypothermic machine perfusion (HMP) has been shown to reduce preservation injury and improve early kidney function. In this first-in-human phase I study, the safety and tolerability of transplanting CHC-pretreated kidneys were evaluated. Methods. CHC or placebo was added to the preservation solution during HMP of donated kidneys from deceased donors for at least 3 h before transplantation into adult patients. The primary safety endpoint was the number and severity of adverse events (AEs) and serious AEs (SAEs) during the first 30 d after transplantation. Results. In the first 30 d, 66 AEs were reported in 8 patients who received CHC-pretreated kidneys with 39 AEs in 8 patients who received placebo-pretreated kidneys (P = 0.1 in post hoc analysis). The most common AEs were hypertension (CHC, n = 5; placebo, n = 2) and anemia (CHC, n = 5; placebo, n = 2). Most AEs were assessed as mild (58%) or moderate (39%) and not related to treatment (95%). There were 2 SAEs reported in each group. One SAE, considered possibly related to CHC treatment, was a case of severe postprocedural hemorrhage that required reoperation. No patients needed dialysis. There were no observed rejections and no patient deaths. Conclusions. Pretreatment of kidneys with CHC before transplantation was considered safe and tolerable. Efficacy studies are now planned to investigate if CHC can reduce early ischemia-reperfusion injury in humans.