Status: Not yet recruiting
Keywords: Hemodialysis , Fistula maturation , dialysis access , hemodynamics , wall shear stress , magnetic resonance imaging
IRB Number: 00049099
Specialty: Vascular Surgery
A functional arteriovenous 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. The parent HFM cohort study has been approved (IRB_00037892)
We propose an HFM ancillary study, at three HFM Clinical Centers (the University of Utah, the University of Florida and the University of Cincinnati) and the Data Coordinating Center (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 within 1 week, 6 weeks, and 6 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 within 1 week and 6 weeks after AVF creation with subsequent changes in AVF lumen cross-sectional area and blood flow rate at 6 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.
SPECIFIC AIMS The parent NIDDK-sponsored Hemodialysis Fistula Maturation (HFM) cohort study will study the relationships of a broad range of clinical, physiological, and process-of-care variables with maturation and usability for dialysis of newly-placed arteriovenous fistulas (AVF). We propose a highly synergistic ancillary study to obtain mechanistic insights into the pathobiology of AVF failure by examining the interplay of hemodynamic wall shear stress (WSS) in the AVF with pre-existing vascular properties, in influencing AVF maturation. Hypotheses (1) Hemodynamic WSS at the venous wall is a crucial determinant of AVF development (specifically, lumen cross-sectional area and blood flow rate). (2) The effect of WSS on wall remodeling is modulated by local pre-existing endothelial functionality, vein wall morphometry, and venous biomechanics. Specific Aim 1: To monitor the lumen geometry and blood flow rate of newly-created AVFs over time, and delineate WSS profiles from these structural and flow rate data. Approach: Magnetic resonance imaging (MRI) will be performed at 2 days, 6 weeks, 6 months and 18 months post-operatively. At each time point, the entire lumen geometry and the blood flow rates at strategic locations will be obtained by contrast-free MRI, and WSS profiles in the AVF will be derived from these MRI data using computational fluid dynamic (CFD) modeling. Specific Aim 2: To describe the relationships of local WSS parameters soon after AVF creation (e.g., 2 days, 6 weeks) to changes in AVF lumen cross-sectional area and blood flow rate in the succeeding periods. Approach: A panel of local WSS parameters (time-averaged WSS, peak WSS, spatial WSS gradient and oscillatory shear index (OSI)) will be derived from CFD modeling at increments along the length of the AVF. The associations of 2-day WSS parameters with subsequent changes in lumen area and blood flow rate at the same location at 6 weeks will be examined. Analogously, the associations of 6-week WSS parameters with subsequent changes in lumen area and blood flow rate will also be studied. Specific Aim 3: To assess pre-existing endothelial functionality, vein wall morphometry and venous biomechanics as additional predictors, confounders, or especially modifiers of the relationships between WSS parameters and subsequent changes in AVF lumen area and blood flow rate studied in Aim 2. Approach: Results of the following standardized testing in the parent study will be used: (a) pre-operative brachial artery flow-mediated dilation (FMD); (b) pre-operative forearm venous plethysmography (VP); and (c) morphometry from a vein segment collected intra-operatively. Statistical models will be used to study the interrelationships among these variables in predicting subsequent changes in AVF lumen cross-sectional area and blood flow rate, with particular attention to altered relationships of WSS parameters with subsequent maturation, as a result of FMD, venous plethysmography, or vein morphometry abnormalities in the patients. The proposed studies will effectively exploit the unique data collection effort in the parent HFM study (“Vascular Wall Biology” in Fig. 1), add significant mechanistic insight into the physiology and pathophysiology of AVF development, and increase the understanding of the role of hemodynamic factors in determining the substantial heterogeneity in AVF maturation. We anticipate that non-physiological venous flow (e.g., very high and very low WSS, high spatial WSS gradient, and high oscillatory shear index) at an earlier time point will be associated with a failure of the AVF to mature. Specifically, we postulate that vein wall that experiences non-physiological flow patterns will have a lack of outward wall remodeling and undergo the development of neointimal hyperplasia and stenosis at those regions at a later time point, limiting the blood flow rate and lumen dilation of the AVF. Clinically, these results will provide important insights that can be used to optimize anatomical configuration and surgical techniques used in AVF creation, and contribute to earlier post-operative identification of AVFs that are prone to maturation failure.