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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.