Autophagy and Arteriovenous Fistula Maturation

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The vascular access is the lifeline for the hemodialysis patient and the single most important component of the hemodialysis procedure. The most common etiology of vascular access dysfunction in hemodialysis patients is failure of an arteriovenous fistula (AVF) to mature successfully for dialysis use (AVF maturation failure). At present, there remains a very high rate of AVF maturation failure in the United States and there are no effective treatments to enhance AVF maturation. On a radiologic level, AVF maturation failure is most commonly characterized by a stenosis at the venous anastomosis, and at a histological level it is characterized by a combination of aggressive intimal hyperplasia and poor outward remodeling. The poor outcomes following AVF creation reflect our limited understanding of the mechanisms leading to AVF maturation failure; and the lack of therapies to treat this clinical problem represent an unmet clinical need. The objective of this proposal is to investigate a new paradigm, the role of autophagy in AVF maturation. Our proposal is novel and supported by strong preliminary work from our research team pointing to a causal role for repressed endothelial cell (EC) autophagy in AVF maturation failure, in response to a unique setting of disturbed hemodynamics in the AVF and chronic kidney disease (CKD) milieu. Based on these preliminary studies, the central hypothesis of this proposal is that disturbed flow and CKD repress endothelial autophagy, leading to AVF maturation failure. Using a combination of in vitro, in vivo, and, human studies, we will test our central hypothesis with three specific aims: (1) Identify steps of EC autophagy repression in the setting of disturbed flow and CKD milieu, (2) Define how repressed EC autophagy contributes to AVF remodeling, and (3) Determine the role of autophagy in AVF maturation in hemodialysis patients. We believe our proposed research is significant because: (1) it addressed a very important clinical problem in hemodialysis patients, AVF maturation failure, where there are presently no effective therapies; and (2) examine a new paradigm in AVF development, autophagy. Successful completion of these aims will identify important targets for developing innovative therapies that aim to modify autophagy in order to enhance AVF maturation.