Background: Variable graft injury severity post ischemia reperfusion injury (IRI) is observed post liver transplantation (LT). Graft function recovery and performance are linked to this initial injury severity. This study aimed to evaluate molecular profiles in association with increased graft injury determined by laboratory hepatic parameters or liver function tests (LFTs).

Patient and Methods: The study included 41 LT patients grouped in Training (n=24) and Validation (n=17) sets. Graft biopsy samples were paired collected at pre-implantation (Pre-I) and 90 min (Post-R) post-reperfusion. Laboratory data were prospectively evaluated up to 1-week of follow-up. Liver function Tests at 24 hrs post-LT were used for graft injury estimation. Transaminases elevation above 400 UI/L was used as threshold value. Study sets were sub-grouped as Low and High LTFs. Total RNA was isolated and training set samples were labeled and used for miRNA microarrays hybridization. Human miRNAs expression summaries were obtained using RMA algorithm. High LFTs vs. Low LFT comparisons at Pre-I, Post-R, and Post-R vs. Pre-I, were fit using two-sample t-test. A p-value ≤ 0.01 were considered significant. Top significant miRNAs were assessed by qPCR in the Validation set.

Results: No significant donor demographics and graft preservation differences were observed between study sets. LTFs levels were significant different at 24 hrs (ALT p=0.0002; AST p=0.003) as expected, and continued in similar trend up to 1-week follow up (ALT p=0.0006; AST p=0.009). No significant differential expressed miRNAs were observed at Pre-I. However, comparison analyses at Post-R identified 10 miRNAs (miR-3687, miR-4417, miR-4532, miR-1225, miR-4433, miR-3162, miR-4463, miR-1587, miR-4507, miR-1268, miR-4521) significantly upregulated correlated with serum LFTs elevation. A unique miRNA (miR-4521) was found up-regulated in patients with low LFTs. Post-R vs. Pre-I comparisons between High and Low LFTs groups revealed a unique common miRNA (miR-4484). More interestingly, miR-4484 expression levels at early Post-R directly correlated with post-LT elevated transaminase activity in a significant trend (p = 0.032).

Conclusion: Hepatic injury levels during the first week post-LT are associated with a specific miRNA set immediately deregulated post reperfusion. Assessment of specific miRNAs at early post reperfusion may predict increased graft injury for timely intervention.

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