Arteriovenous fistula stenosis in hemodialysis patients is characterized by an increased adventitial fibrosis

作者：Simone, Simona; Loverre, Antonia; Cariello, Marica; Divella, Chiara; Castellano, Giuseppe; Gesualdo, Loreto; Pertosa, Giovanni; Grandaliano, Giuseppe^*

来源：Journal of Nephrology, 2014, 27(5): 555-562.

DOI：10.1007/s40620-014-0050-7

• Arteriovenous fistula stenosis
• Adventitial fibrosis
• Myofibroblast
• Platelet derived growth factor

Background Arteriovenous fistula (AVF) stenosis is the major cause of vascular access failure in hemodialysis. Adventitial remodeling has been suggested to play a role in the pathogenesis of AVF stenosis. This study aimed to evaluate adventitial fibrosis in stenotic AVF and investigate the underlying molecular mechanisms.
Methods Forty-four patients undergoing surgery for AVF creation were examined; ten presented AVF failure, with histological-proven AVF stenosis.
Results In stenotic AVF we observed a significant increase of adventitia extracellular matrix deposition and alpha-smooth muscle actin (alpha-SMA)(+) cell numbers; most of these cells were myofibroblast (alpha-SMA(+)/vimentin(+)). Phosphorylated platelet-derived growth factor beta receptor (p-PDGFR beta) was significantly increased within the adventitia of stenotic compared to native AVF, along with a marked increase in the phosphorylation of Akt and ERK, two key kinases in PDGFR beta signalling. Myofibroblasts were the main cell type associated with the activation of p-PDGFR beta. At the same time, we observed a significant adventitial vessels rarefaction in stenotic AVF, as demonstrated by a reduced CD34 expression. This event was associated with a marked reduction in the expression of KDR/fetal liver kinase-1, the main vascular endothelial growth factor receptor. The degree of adventitial fibrosis was directly correlated with the extent of adventitial alpha-SMA and inversely associated with adventitial CD34 expression. Finally, we observed an increase in CD34(+)/alpha-SMA(+) cells within the adventitia of failed AVF.
Conclusion This study suggests that AVF failure is associated with an increased adventitial fibrosis, myofibroblast activation and capillary rarefaction, potentially linked with endothelial-to-mesenchymal transition. In this scenario, our data suggest that PDGF may play a pathogenic role.

• 出版日期2014-10