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.

Public Health Relevance

The safest path for blood to flow from the patient to a dialysis machine and back, a veritable lifeline for a dialysis patient, is created by surgically connecting the patient's own artery to vein. This path is known as a native fistula, which enlarges (matures) after surgery to allow increased blood flow and has fewer long-term complications than other types of hemodialysis pathways, but, unfortunately, a majority of native fistulas do not properly mature after surgical creation. This study will examine why these conduits do not mature, and the knowledge gained should suggest new strategies to promote fistula maturation and improve the prospects of dialysis patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK088777-02
Application #
8278543
Study Section
Special Emphasis Panel (ZDK1-GRB-9 (J2))
Program Officer
Kusek, John W
Project Start
2011-07-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$609,900
Indirect Cost
$68,071
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Wilkins, Justin R; Pike, Daniel B; Gibson, Christopher C et al. (2015) The interplay of cyclic stretch and vascular endothelial growth factor in regulating the initial steps for angiogenesis. Biotechnol Prog 31:248-57
Wilkins, Justin R; Pike, Daniel B; Gibson, Christopher C et al. (2014) Differential effects of cyclic stretch on bFGF- and VEGF-induced sprouting angiogenesis. Biotechnol Prog 30:879-88
Gomez, Arnold David; Zou, Huashan; Shiu, Yan-Ting et al. (2014) Characterization of regional deformation and material properties of the intact explanted vein by microCT and computational analysis. Cardiovasc Eng Technol 5:359-370
Fitts, Michelle K; Pike, Daniel B; Anderson, Kasey et al. (2014) Hemodynamic Shear Stress and Endothelial Dysfunction in Hemodialysis Access. Open Urol Nephrol J 7:33-44
McNichols, Colton; Wilkins, Justin; Kubota, Atsutoshi et al. (2014) Investigating surface topology and cyclic-RGD peptide functionalization on vascular endothelialization. J Biomed Mater Res A 102:532-9
Manson, Roberto J; Ebner, Adrian; Gallo, Santiago et al. (2013) Arteriovenous fistula creation using the Optiflow vascular anastomosis device: a first in man pilot study. Semin Dial 26:97-9
He, Yong; Terry, Christi M; Nguyen, Cuong et al. (2013) Serial analysis of lumen geometry and hemodynamics in human arteriovenous fistula for hemodialysis using magnetic resonance imaging and computational fluid dynamics. J Biomech 46:165-9
Roy-Chaudhury, Prabir; Arnold, Perry; Seigel, Jeff et al. (2013) From basic biology to randomized clinical trial: the Beta Radiation for Arteriovenous Graft Outflow Stenosis (BRAVO II). Semin Dial 26:227-32