*Purpose: The ischemia and reperfusion injury contributs to grafts deterioration and adverse post-transplant outcomes. The aim of the present study was to evaluate the safety and protective effects of a natural antioxidant named α-lipoic acid (ALA) in patients undergoing liver transplantation.

*Methods: A double-blind randomized controlled trial was performed. 38 patients were preconditioned with 600 mg of ALA administered to the donor portal vein immediately before the cold ischemia time and another 600 mg of ALA 15 min prior to the reperfusion (ALA-treated group). 34 patients received placebo (control group). Hepatic biopsy was performed 2 hours post-reperfusion to perform qPCR analysis to assess genes involved in the response to hypoxia and tissue damage protection. The follow up was 6 months. Blood samples were also collected.

*Results: 72 patients (58 ± 10.7 years of age) were included and 38 patients were treated with ALA. There were no statistically significant differences between the ALA-treated and untreated group in recipient and donor age and gender, MELD, Child-Pugh score, pre-transplant serum creatinine, bilirubin, alanine aminotransferase (ALT), warm and cold ischemia time. 25 livers out of 72 belonged to marginal donors (12 and 13 in the untreated and ALA-treated group, respectively). Notably, 19 of 72 patients developed post-reperfusion syndrome (PRS), but only 5 of them belonged to the ALA-treated group. There was no difference between the untreated and ALA-treated group in the serum levels of bilirubin, ALT and creatinine on day 1, 3, 7 and 30 after the surgery. Other variables analyzed were rejection episodes, the need for dialysis and patient survival. 12 patients needed dialysis during the first week of transplantation (8 from untreated and 4 from ALA-treated group). Rejection episodes were observed in 6 patients in each group at 30 days. 9 patients died at six month post-transplant; 6 from the untreated and 3 from ALA-treated group of patient. Of the group of patients who received an optimal donor, those who obtained the greatest benefit from the use of ALA were patients > 58 years and with MELD score > 22. Furthermore, the analysis on marginal donors showed that ALA reduced PRS, rejections episodes, dialysis and death (7 vs 1 for PRS; 3 vs none for rejection; 4 vs 2 for dialysis and 4 vs 2 for death, in ALA-treated vs untreated patients). There was a decrease in PHD2 and an increase in HIF-1α and Birc2 transcript levels in the biopsies from the ALA-treated vs the control group of patients. Additionally, plasma levels of alarmins were lower in ALA-treated patients than control patients.

*Conclusions: These results showed that ALA is safe for use in liver transplantation and reduces the appearance of PRS, mainly in patient with high MELD score.

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