Inflammation, Oxidation and Venous Neointimal Hyperplasia Precede Vascular Injury from AVF Creation in CKD Patients

Abstract

Purpose Intimal hyperplasia (IH), a well-recognized cause of dialysis vascular access failure, is generally believed to be an acquired pathologic lesion. Recent data suggests that IH is present prior to AVF creation. We sought to determine whether pre-existing inflammation and oxidation co-exist with IH prior to their incorporation into an AVF conduit, as their presence may predispose the AVF to further IH following AVF creation. Methods At the time of first AV access surgery, vein segments were collected from ten Stage 4 and 5 CKD patients undergoing AVF creation 6-12 months prior to anticipated dialysis initiation. Morphometry and immunohistochemistry was performed to detect inflammatory markers IL-6, TGF-β1, and TNFa, and markers of DNA oxidative damage (8-Hydroxy-2′-deoxyguanosine [HNE]) and lipid peroxidation (4-Hydroxy-2-Nonenal [8OHdG]). Results The degree of IH severity was variable. IL-6, TGF-β1, and TNFa co-localized with a-smooth muscle actin prominently within the venous intima and media. Although more diffuse, HNE and 8OHdG were intensely expressed in parallel with the inflammatory markers. In spite of these findings, however, neither extant IH nor the intensity of inflammatory or oxidative markers were associated with primary or secondary AVF failure at 12 month follow-up. Conclusions Not only does venous IH pre-exist, but inflammation and oxidation markers are present within veins used for the AVF conduit prior to its creation in CKD patients as early as one year before dialysis is commenced. Nevertheless, short and long-term AVF outcomes were not associated with the inflammatory or oxidative burden, suggesting the complexity of AVF dysfunction in humans with CKD.

Arteriovenous Fistula Placement in the Elderly

“…One potential explanation is that, in patients with comorbidities that may lead to endothelial dysfunction and vascular wall abnormalities, the hemodynamic shear stress of an AVF might cause increased neointimal hyperplasia with a lack of vascular dilation. 29 Because a significant degree of neointimal hyperplasia has been found at the site of the vascular access placement in patients with CKD before AVF creation, 30,31 placing an AVF too early in patients with CHF or diabetes may increase the exposure time to neointimal hyperplasia and thereby, AVF failure.…”

Preoperative Venous Intimal Hyperplasia, Postoperative Arteriovenous Fistula Stenosis, and Clinical Fistula Outcomes

“…More recently, preexisting intimal hyperplasia has been observed in the native veins used to create an AVF in CKD patients (10,11). It is possible that preexisting venous intimal hyperplasia predisposes those patients to more aggressive venous neointimal hyperplasia after AVF creation, thereby contributing to AVF stenosis and presumably, AVF nonmaturation and inferior long-term AVF outcomes.…”

Novel Paradigms for Dialysis Vascular Access

“…Consequently, it also results in significant endothelial and medial smooth muscle cell damage, and the vessel wall invariably responds with an increased cellular proliferation within the neointima and, subsequently, a more aggressive neointimal hyperplasia development (13). Although most of the data on angioplasty-induced neointimal hyperplasia come from studying arterial models (14,15), it is also very likely that there is a deleterious injury from angioplasty to the venous system, especially because the venous tissue has intrinsically high baseline levels of inflammation and oxidative stress (16,17) from the uremic milieu.…”

“…Recently, several studies have demonstrated that neointimal hyperplasia is present in the majority of patient veins at the time of surgical creation (16)(17)(18) (Figure 1B), suggesting that the health of the vein at the time of AVF creation may also play an important role in AVF nonmaturation. Moreover, initial results from the multicenter National Institutes of Health Fistula Maturation Study have reported that 87.8% of vein samples examined to date (n5204; total planned enrollment, 600 participants) have neointimal hyperplasia (19).…”