The Critical Role of Endothelial Inflammation in Arteriovenous Fistula Failure

About This Grant

Abstract The number of Americans living with end-stage renal disease (ESRD) who will eventually need a functional vascular access to receive hemodialysis and extend their lives is increasing. The arteriovenous (AV) fistula created by anastomosing an arm vein to a nearby artery is the preferred vascular access because, if it matures, it poses fewer complications than central venous catheters and arteriovenous grafts. AV fistulas fail because postoperative venous stenosis (narrowing) frequently compromises blood flow, demanding additional endovascular and surgical interventions to extend the life of the access. The failure of this vascular access is one of the most important causes of morbidity and hospitalization in the hemodialysis (HD) population. This highlights the need for in-depth research initiatives to investigate the cellular and molecular mechanisms leading to venous stenosis after anastomosis. This retro translational research (from clinical to basic science) finds preliminary premises supporting the association of type VIII collagen accumulation by endothelial cells (EC) with non-maturation of AV fistulas in hemodialysis patients. Our fundamental hypothesis is that IL-1b mediated endothelial inflammation promotes type VIII collagen biosynthesis to enhance monocyte recruitment and exacerbates the proliferative and pro-fibrotic vascular response that leads to failure. We will challenge the hypothesis with an integrated molecular/cellular approach, encompassing in vivo and in vitro models. In Aim 1, we will demonstrate the causality of endothelial type VIII collagen in fistula remodeling. In Aim 2, we will dissect the mechanisms controlling the transcriptional activation of COL8A1 in EC after AV anastomosis. We will reveal the first spatial transcriptomic cellular atlas of human stenotic and nearby non-stenotic venous segments obtained at the time of transposition. In line with the NIH-NCATS drug repurposing initiative, in Aim 3 we will demonstrate the clinical potential of IL-1b signaling inhibitors in a preclinical model of AV fistula failure in swine. We expect to demonstrate that we can improve AV fistula maturation by targeting the harmful effects of endothelial type VIII collagen after surgery.