Endothelin-1 and Big-Endothelin-1 as Potential Biomarkers in Clinical Ex Vivo Lung Perfusion

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Purpose Normothermic ex vivo lung perfusion (EVLP) is a preservation technique that allows reassessment and improvement of donor lungs prior to transplantation. We hypothesized that the endothelin-1 (ET-1) axis is associated with donor lung performance during EVLP and recipient outcomes after transplantation. Methods and Materials We assessed levels of ET-1, big ET-1 and endothelin converting enzyme 1 (ECE-1) in the perfusates of donor lungs enrolled in a clinical trial EVLP. The trial included lungs from high-risk brain death donors (BDD) and lungs from donation after cardiac death (DCD). They were divided into three groups: I. Control: bilateral transplantation with good early outcomes (absence of PGD grade 3); II. PGD3: bilateral lung transplantation with PGD grade 3 whithin 72 hours; III. Declined: lungs rejected following EVLP. Single-lung transplants and patients bridged with extracorporeal life support were excluded. Results There were 25 cases in group I, 7 in group II and 16 in group III. At 1 hour of EVLP, perfusates of declined lungs had significantly higher levels of ET-1 (3.1±2.1 vs 1.8±2.3 pg/ml, p=0.01) and big ET-1 (15.8±14.2 vs 7.0±6.5, p=0.001) compared to control lungs. At the 4 hours of EVLP, declined lungs also had higher levels of ET-1 (2.7±2.2 vs 1.3±1.1 pg/ml, p=0.007) and big ET-1 (31.7±17.4 vs 19.4±9.5 pg/ml, p=0.007) compared to controls. In BDD lungs the ET-1 axis did not show significant differences between groups. However for DCD cases, groups II and III had higher ET-1 and big ET-1 levels at 4 hr perfusion when compared to group I (group II vs I: ET-1 p=0.03, big ET-1 p=0.01; group III vs I: ET-1 p=0.007, big ET-1 p=0.003). There were no differences in ECE-1 levels between groups. Conclusions In DCD lungs ET-1 and big ET-1 in perfusate predicted outcomes after lung transplantation. They were also associated with non-utilization of lungs after EVLP and thus could represent useful biomarkers to improve the accuracy of selection of donor lungs.