The involvement of the receptor for advanced glycation end products (RAGE)-ligand axis in liver transplantation: hepatic RAGE expression, soluble RAGE and RAGE-ligand levels

BACKGROUND. In animal testing the blockade of the receptor for advanced glycation end products (RAGE) attenuates the liver injury extent induced by RAGE-ligands. Likewise circulating truncated soluble isoforms of RAGE (sRAGE), acting as decoy of RAGE-ligands, protects by injury. AIM. The primary objective of this study was to investigate the association between tissue RAGE isoform (both full-length and truncated) mRNA expression with both recipient liver disease and early outcomes after liver transplantation. Secondarily, to evaluate trends of circulating RAGE-ligands and of protective sRAGE in the immediate period following transplantation and their association with the development of early organ dysfunction METHODS. We prospectively included 28 adult LT recipients (53±8.7 years) of primary whole-size grafts by deceased donors (62.1±17.3 years). In liver biopsies of both donor and LT recipients, we measured the transcriptional expression of full-length RAGE and its truncated isoform, the endogenous secreted RAGE (esRAGE). The RAGE-ligands — N(epsilon)-carboxymethyllysine (CML) and high-mobility group protein 1 (HMGB-1) — and the circulating sRAGE were measured in plasma specimens before LT, after graft reperfusion, 1 and 7 days after LT. RESULTS. In LT recipients the hepatic RAGE mRNA levels were higher than in healthy donors (p<0.01). In LT recipients 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 directly correlated with MELD score before LT, likewise to basal HMGB-1 plasma levels (β=0.425, p=0.043 and β=0.448, p<0.05 respectively). Basal CML levels were higher in LT recipient than donors (p=0.02), decreased after graft reperfusion (p<0.0001) but returned progressively to basal values at 7 days after LT. HMGB-1 levels increased after graft reperfusion (p<0.0001) and returned suddenly to basal values one day after LT while circulating sRAGE did not change soon after LT but decreased significantly 7 days after LT (p<0.0001). The MELD score 7 days after LT inversely correlated with graft esRAGE mRNA expression (β= -0.487, p=0.029) and tended to correlate directly with the peak values of HMGB-1 after reperfusion (β = 0.42, p = 0.07), with recipient age (β = 0.38, p = 0.07) and recipient gender (β = 0.49, p = 0.015). Multivariate analysis showed that, after adjustment for gender, donor age, recipient age, only graft esRAGE mRNA expression was a significant determinant of MELD score 7 days after LT (β= -0.788, p=0.0005). CONCLUSIONS. The inverse correlation between graft esRAGE mRNA expression and the MELD score 7 days after LT underline the importance of this protective factor for graft survival and patient outcomes. CML accumulation and rapid increase of HMGB-1 followed by remarkable decline of protective sRAGE could have deleterious consequences on graft survival and long term outcomes in LT recipients.