Oxidative stress and increased expression of growth factors in lesions of failed hemodialysis access

Abstract

The pathological role of oxidative stress in patients treated by hemodialysis has gained increasing recognition inrecent years. Because complications related to vascular access are a major source of morbidity, lmmunohistochemical evidence of oxidative stress and activation of growth factors were examined in native arteriovenous (AV) fistulae (n = 11) and expanded polytetrafluoroethylene (ePTFE) grafts (n = 15) recovered from hemodialysis patients at the time of surgical revision or resection. To show the presence of oxidative stress in tissues, three markers were chosen: NE(carboxymethyl)lysine, a structurally identified advanced glycation end product; 4-hydroxy-2,3-nonenol, a lipid peroxidation product; and redox-active transition metals bound to proteins, a source of Fenton chemistry-generated free radicals. Markers of cell growth and proliferation were endothelin-1 (ET-1), a potent mitogenic peptide Implicated In the formation of intimal hyperplasia; transforming growth factor-β (TGF-β), a stimulus to vascular cell growth and matrix production; and platelet-derived growth factor (PDGF), a mediator of intimal hyperplasia. All specimens studied showed significant intimal hyperplasia. In general, the neointima close to the vascular lumen of the AV fistula and the pseudointima close to the lumen of the ePTFE graft were positive for oxidative stress markers. At sites of injury, especially in the presence of histological evidence of inflammation and healing, expression of oxidative markers was particularly intense. Prominent staining of PDGF was shown at sites of anastomotic hyperplasia and in neovasculature. TGF-β was associated with proliferation or repair in both AV fistulae and ePTFE grafts. ET-1 staining was most intense in the neointima and pseudointima. This study showed histochemical colocalization of markers of oxidative stress with growth factors known to contribute to intimal hyperplasia.