Dynamics of Circulating Ligands and Soluble Receptor for Advanced Glycation End-Product in Liver Transplantation

Abstract

Background and aim: The ligand-receptor for advanced glycation end products (RAGE) pathway is involved in liver injury and animal testing have highlighted that the RAGE blockade attenuates the extent of the liver injury. A truncated isoform of the RAGE (endogenous secreted RAGE, esRAGE), consisting of the extracellular ligand-binding domain only, is detectable as circulating soluble form (sRAGE) in the blood. These latter, acting as decoy, can contribute to the removal of circulating RAGE- ligands. Objective of this study is understand the hepatic expression of both RAGE isoforms (full-length and truncated), and kinetics of the RAGE-ligands and sRAGE plasma levels in patients undergoing liver transplantation (LT) and compared them with healthy donors. Methods: We prospectively included twenty four adult LT recipients (52.7 ± 9.2 years) of primary whole-size grafts by deceased donors (60.4 ± 17.9 years). On both LT recipients and donors, we measured the transcriptional expression of hepatic tissue RAGE and esRAGE, the plasma levels of the RAGE-ligands - N(epsilon)-carboxymethyllysine (CML) and high-mobility group protein 1 (HMGB-1) - and circulating sRAGE. In LT recipient CML, HMGB-1 and sRAGE plasma levels were measured before LT, after graft reperfusion, 1, 7, 30 and 90 days after LT. Results: In LT recipients the hepatic RAGE and esRAGE mRNA levels were higher than in healthy donors (p< 0.01 and p=0.02 respectively). The tissue full-length RAGE inversely correlated with antithrombin III (β= - 0.58, p = 0.013) and cholinesterase plasma levels (β= -0.717, p= 0.0018) and tended to directly correlate with MELD score (β= 0.422, p= 0.063). Basal plasma levels CML, but not sRAGE and HMGB-1, were higher in LT recipients than in healthy donors (p< 0.05). At follow-up CML levels decreased after graft reperfusion (p = 0.0001) while returned progressively to basal values during the follow-p. Instead, HMGB-1, increased after graft reperfusion (p = 0.0001) and returned suddenly to basal values one day after LT. The basal HMGB-1 correlated directly with MELD score (β= 0.448, p= 0.05). The plasma levels of sRAGE did not change significantly soon after LT while decreased seven days after LT (p = 0.0001) and remained constantly low during follow-up. Conclusions: The high levels of RAGE and esRAGE tissue expression in the end-stage liver failure highlight the involvement of the RAGEligand axis in liver injury. The circulating CML accumulation and the rapid increase of HMGB-1 followed by a dramatic decline of the protective sRAGE could have deleterious consequences on graft survival and long term outcomes in LT recipients.