Hemodynamics and Vascular Wall Biology Determine Arteriovenous Fistula Maturation

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DESCRIPTION (provided by applicant): A functional rteriovenous fistula (AVF) is the preferred form of vascular access for chronic hemodialysis. However, up to 60% of AVFs never mature, i.e., achieve sufficient lumen dilation to allow adequate blood flow rate for chronic dialysis. The NIDDK has recently established the Hemodialysis Fistula Maturation (HFM) Consortium to investigate this problem through a 600-patient cohort study at six Clinical Centers, a Data Coordinating Center (DCC) and Core Laboratories. The HFM cohort study will identify predictors of AVF maturation failure, and collect indirect evidence about mechanistic hypotheses. However, its broad scope inevitably limits more direct and extensive investigations of specific mechanisms. We propose an HFM ancillary study, at three HFM Clinical Centers and the DCC, to examine the role of aberrant hemodynamics in the pathogenesis of AVF maturation failure. While alterations in hemodynamic wall shear stress (WSS) are known to modulate vascular remodeling and neointimal hyperplasia formation, the spatial distribution profile of WSS in the developing AVF, and the relationship between this WSS profile and AVF maturation, are currently unclear. In addition, the impact of WSS on the AVF lumen is likely modulated by the pre-existing properties of the vascular wall before AVF creation. Previous studies on WSS in AVF have been small, and have not examined the relationships among WSS, pre-existing vascular wall properties, and AVF outcomes. This ancillary study will collect WSS data in developing AVFs over time using state-of-the art magnetic resonance imaging (MRI) and computational fluid dynamic (CFD) modeling techniques, and link this information with vascular wall property data collected in the parent HFM study. Through this linkage, we will be able to examine the interplay among WSS, vascular wall properties, and AVF maturation over time. In Specific Aim 1, we will enroll 40 patients in each of the three Clinical Centers, for a total of 120 patients, who are already enrolled in the parent HFM cohort study. We will obtain luminal geometry and blood flow data in the AVF by MRI at 2 days, 6 weeks, 6 months and 18 months after AVF creation, and derive WSS profiles from the MRI data using CFD modeling. In Specific Aim 2, we will analyze the relationships between local WSS at 2 days and 6 weeks after AVF creation with subsequent changes in AVF lumen cross-sectional area and blood flow rate at 6 and 18 months. In Specific Aim 3, we will assess whether pre-existing endothelial functionality, venous biomechanics and vein wall morphometry are additional predictors, confounders, or especially modifiers, of the relationships described under Specific Aim 2. Illuminating the interplay of hemodynamics and pre-existing vascular wall properties with the AVF outcomes should lead to novel predictors of AVF maturation, elucidate critical pathways to AVF failure, and point towards innovative therapies supporting successful maturation by targeting these pathways.