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Digital archive of theses discussed at the University of Pisa


Thesis etd-03052013-185850

Thesis type
Tesi di dottorato di ricerca
Thesis title
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
Academic discipline
Course of study
tutor Dott. Basta, Giuseppina
  • Nessuna parola chiave trovata
Graduation session start date
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.