Expression of Hypoxia Inducible Factor-1α, Macrophage Migration Inhibition Factor, Matrix Metalloproteinase-2 and -9, and Their Inhibitors in Hemodialysis Grafts and Arteriovenous Fistulas

Purpose: It is well recognized that arteriovenous fistulas (AVFs) used for hemodialysis access have better primary patency rates with less restenosis than polytetrafluoroethylene (PTFE) grafts; however, the mechanism responsible for this is not known. Recent data suggest that hypoxia inducible factor-1α (HIF-1α) is associated with vascular restenosis, possibly through mechanisms that increase the production of macrophage migration inhibition factor (MIF), matrix metalloproteinase-2 (MMP-2) and MMP-9, and their inhibitors (tissue inhibitor of MMPs; TIMP). The present study tested the hypothesis that there are differences in the expression patterns of HIF-1α, MIF, MMP-2, MMP-9, and TIMPs in specimens removed from patients with AVFs and PTFE grafts. Materials and Methods: Whole-vessel tissue samples were obtained from the vein distal to the vein-to-PTFE graft anastomosis and the proximal outflow vein (within 6 cm of the arteriovenous anastomosis) of AVFs from 17 patients who required a surgical revision for thrombosis and stenosis. Nonstenotic veins of four patients undergoing hemodialysis vascular access placement were used as controls. PTFE grafts (n = 6), AVFs (n = 6), and control samples (n = 3) underwent Western blot analysis and zymography. A separate group of five patients with PTFE hemodialysis grafts and one control subject were used for immunohistochemical analysis. Results: Specimens from patients with PTFE grafts had significantly higher expression of HIF-1α (P = .03), MIF (P = .02), TIMP-1 (P = .0006), pro-MMP-2 (P = .02), and pro-MMP-9 (P = .046) compared with control veins. The expression of only pro-MMP-9 was significantly higher in AVFs compared with control samples (P = .004). There was a significant increase in the expression of MIF (P = .007) and TIMP-1 (P < .0001) in PTFE graft specimens compared with AVFs. MIF and TIMP-1 were localized to the adventitia of the vein distal to the vein-to-PTFE graft anastomosis. Conclusions: There were major differences in the expression patterns of hypoxia (ie, HIF-1α) and proteins regulated by HIF-1α, including MIF, pro-MMP-2, pro-MMP-9, and TIMP-1, in specimens removed from patients with PTFE grafts and AVFs. Understanding the role of HIF-1α and these proteins in hemodialysis access failure can help improve outcomes.