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Tesi etd-03052013-185850

Thesis type
Tesi di dottorato di ricerca
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
Settore scientifico disciplinare
Corso di studi
tutor Dott. Basta, Giuseppina
Parole chiave
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Data inizio appello
Riassunto analitico
BACKGROUND. In animal testing the blockade of the receptor for advanced glycation<br>end products (RAGE) attenuates the liver injury extent induced by RAGE-ligands.<br>Likewise circulating truncated soluble isoforms of RAGE (sRAGE), acting as decoy of<br>RAGE-ligands, protects by injury.<br>AIM. The primary objective of this study was to investigate the association between<br>tissue RAGE isoform (both full-length and truncated) mRNA expression with both<br>recipient liver disease and early outcomes after liver transplantation. Secondarily, to<br>evaluate trends of circulating RAGE-ligands and of protective sRAGE in the immediate<br>period following transplantation and their association with the development of early<br>organ dysfunction<br>METHODS. We prospectively included 28 adult LT recipients (53±8.7 years) of<br>primary whole-size grafts by deceased donors (62.1±17.3 years). In liver biopsies of<br>both donor and LT recipients, we measured the transcriptional expression of full-length<br>RAGE and its truncated isoform, the endogenous secreted RAGE (esRAGE). The<br>RAGE-ligands — N(epsilon)-carboxymethyllysine (CML) and high-mobility group<br>protein 1 (HMGB-1) — and the circulating sRAGE were measured in plasma<br>specimens before LT, after graft reperfusion, 1 and 7 days after LT.<br>RESULTS. In LT recipients the hepatic RAGE mRNA levels were higher than in<br>healthy donors (p&lt;0.01). In LT recipients the tissue full-length RAGE inversely<br>correlated with antithrombin III (β= -0.58, p = 0.013) and cholinesterase plasma levels<br>(β= -0.717, p= 0.0018) and directly correlated with MELD score before LT, likewise to<br>basal HMGB-1 plasma levels (β=0.425, p=0.043 and β=0.448, p&lt;0.05 respectively).<br>Basal CML levels were higher in LT recipient than donors (p=0.02), decreased after<br>graft reperfusion (p&lt;0.0001) but returned progressively to basal values at 7 days after<br>LT. HMGB-1 levels increased after graft reperfusion (p&lt;0.0001) and returned suddenly<br>to basal values one day after LT while circulating sRAGE did not change soon after LT<br>but decreased significantly 7 days after LT (p&lt;0.0001). The MELD score 7 days after<br>LT inversely correlated with graft esRAGE mRNA expression (β= -0.487, p=0.029) and<br>tended to correlate directly with the peak values of HMGB-1 after reperfusion (β = 0.42,<br>p = 0.07), with recipient age (β = 0.38, p = 0.07) and recipient gender (β = 0.49, p =<br>0.015). Multivariate analysis showed that, after adjustment for gender, donor age,<br>recipient age, only graft esRAGE mRNA expression was a significant determinant of<br>MELD score 7 days after LT (β= -0.788, p=0.0005).<br>CONCLUSIONS. The inverse correlation between graft esRAGE mRNA expression<br>and the MELD score 7 days after LT underline the importance of this protective factor<br>for graft survival and patient outcomes. CML accumulation and rapid increase of<br>HMGB-1 followed by remarkable decline of protective sRAGE could have deleterious<br>consequences on graft survival and long term outcomes in LT recipients.