Innovations in vascular access for hemodialysis.

Background and objectives Postoperative ultrasound is commonly used to assess arteriovenous fistula (AVF) maturation for hemodialysis, but its utility for predicting unassisted AVF maturation or primary AVF patency for hemodialysis has not been well defined. This study assessed the predictive value of postoperative AVF ultrasound measurements for these clinical AVF outcomes. Design, setting, participants, & measurements We queried a prospective vascular access database to identify 246 patients on catheter-dependent hemodialysis who underwent AVF creation between 2010 and 2016 and obtained a postoperative ultrasound within 90 days. Multivariable logistic regression was used to evaluate the association of clinical characteristics and postoperative ultrasound measurements with unassisted AVF maturation. A receiver operating characteristic curve estimated the predictive value of these factors for unassisted AVF maturation. Finally, multivariable survival analysis was used to identify factors associated with primary AVF patency in patients with unassisted AVF maturation. Results Unassisted AVF maturation occurred in 121 out of 246 patients (49%), assisted maturation in 55 patients (22%), and failure to mature in 70 patients (28%). Using multivariable logistic regression, unassisted AVF maturation was associated with AVF blood flow (odds ratio [OR], 1.30; 95% confidence interval [95% CI], 1.18 to 1.45 per 100 ml/min increase; P Conclusions Unassisted AVF maturation is predicted by AVF blood flow, location, depth, and stenosis. AVF patency after unassisted maturation is predicted only by the postoperative AVF diameter.

Postoperative Ultrasound, Unassisted Maturation, and Subsequent Primary Patency of Arteriovenous Fistulas

Vascular access is the Achilles’ heel of hemodialysis. This was true for the first patient with CKD treated repeatedly by Willem Kolff in 1943, who ran out of access sites. It remains a challenge today; creation of autogenous accesses (arteriovenous fistulas [AVFs]) is characterized by high

Determinants of Arteriovenous Fistula Maturation.

The increasing prevalence of chronic and end-stage renal disease creates an increased need for reliable vascular access, and although arteriovenous fistulae (AVF) are the preferred mode of hemodialysis access, 60% fail to mature and only 50% remain patent at one year. Fistulae mature by diameter expansion and wall thickening; this outward remodeling of the venous wall in the fistula environment relies on a delicate balance of extracellular matrix (ECM) remodeling, inflammation, growth factor secretion, and cell adhesion molecule upregulation in the venous wall. AVF failure occurs via two distinct mechanisms with early failure secondary to lack of outward remodeling, that is insufficient diameter expansion or wall thickening, whereas late failure occurs with excessive wall thickening due to neointimal hyperplasia (NIH) and insufficient diameter expansion in a previously functional fistula. In recent years, the molecular basis of AVF maturation and failure are becoming understood in order to develop potential therapeutic targets to aide maturation and prevent access loss. Erythropoietin-producing hepatocellular carcinoma (Eph) receptors, along with their ligands, ephrins, determine vascular identity and are critical for vascular remodeling in the embryo. Manipulation of Eph receptor signaling in adults, as well as downstream pathways, is a potential treatment strategy to improve the rates of AVF maturation and patency. This review examines our current understanding of molecular changes occurring following fistula creation, factors predictive of fistula success, and potential areas of intervention to decrease AVF failure.

Molecular Targets for Improving Arteriovenous Fistula Maturation and Patency.

For patients with end-stage renal disease requiring hemodialysis, their vascular access is both their lifeline and their Achilles heel. Despite being recommended as primary vascular access, the arteriovenous fistula (AVF) shows sub-optimal results, with about 50% of patients needing a revision during the year following creation. After the AVF is created, the venous wall must adapt to new environment. While hemodynamic changes are responsible for the adaptation of the extracellular matrix and activation of the endothelium, surgical dissection and mobilization of the vein disrupt the vasa vasorum, causing wall ischemia and oxidative stress. As a consequence, migration and proliferation of vascular cells participate in venous wall thickening by a mechanism of neointimal hyperplasia (NH). When aggressive, NH causes stenosis and AVF dysfunction. In this review we show how hypoxia, metabolism, and flow parameters are intricate mechanisms responsible for the development of NH and stenosis during AVF maturation.

https://www.mdpi.com/1422-0067/20/21/5387/pdf

Role of Hypoxia and Metabolism in the Development of Neointimal Hyperplasia in Arteriovenous Fistulas

Creation of a hemodialysis arteriovenous fistula (AVF) causes aberrant vascular mechanics at and near the AVF anastomosis. When inadequately regulated, these aberrant mechanical factors may impede AVF lumen expansion to cause AVF maturation failure, a significant clinical problem with no effective treatments. The endothelial nitric oxide synthase (NOS3) system is crucial for vascular health and function, but its effect on AVF maturation has not been fully characterized. We hypothesize that NOS3 promotes AVF maturation by regulating local vascular mechanics following AVF creation. Here we report the first MRI-based fluid-structure interaction (FSI) study in a murine AVF model using three mouse strains: NOS3 overexpression (NOS3 OE) and knockout (NOS3-/-) on C57BL/6 background, with C57BL/6 as the wild-type control (NOS3+/+). When compared to NOS3+/+ and NOS3-/-, AVFs in the OE mice had larger lumen area. AVFs in the OE mice also had smoother blood flow streamlines, as well as lower blood shear stress at the wall, blood vorticity, inner wall circumferential stretch, and radial wall thinning at the anastomosis. Our results demonstrate that overexpression of NOS3 resulted in distinct hemodynamic and wall mechanical profiles associated with favorable AVF remodeling. Enhancing NOS3 expression may be a potential therapeutic approach for promoting AVF maturation.

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The effect of endothelial nitric oxide synthase on the hemodynamics and wall mechanics in murine arteriovenous fistulas.

Background and objectives Preoperative arterial function is associated with arteriovenous fistula (AVF) development. Because arterial pathology may correlate with its function, preexisting arterial intimal hyperplasia may be associated with AVF development. Design, setting, participants, & measurements Vascular specimens obtained from 125 patients (with minimal 2 mm arterial diameter and 2.5 mm venous diameter) undergoing AVF creation were quantified for arterial intimal hyperplasia, arterial medial fibrosis, arterial microcalcification, and venous intimal hyperplasia. A 6-week postoperative ultrasound quantified AVF diameter, blood flow, and stenosis. Clinical AVF maturation was assessed using a predefined protocol. In a prospective cohort study design, we investigated the association of preexisting arterial intimal hyperplasia with the postoperative AVF diameter, blood flow, stenosis, and clinical maturation failure, after controlling for baseline demographics, comorbidities, and preoperative vein diameter. Additional analyses evaluated whether other vascular pathologies interacted with arterial intimal hyperplasia in affecting AVF outcomes. Results The median intimal thickness of the native artery was 22.0 μ m (interquartile range, 14.8–37.1 μ m). The median postoperative AVF diameter was 4.8 (interquartile range, 3.7–6.8) mm, blood flow was 796 (interquartile range, 413–1036) ml/min, and stenosis was present in 37 out of 98 patients with ultrasound data (38%). AVF nonmaturation occurred in 37 out of 125 patients (30%). Preexisting arterial intimal thickness was not significantly associated with AVF blood flow (−12 ml/min; 95% confidence interval [95% CI], −55 to 30 ml/min), diameter (−0.04 mm; 95% CI, −0.21 to 0.14 mm), stenosis (odds ratio, 0.93; 95% CI, 0.75 to 1.14), or clinical maturation failure (odds ratio, 1.07; 95% CI, 0.90 to 1.28), all per 10 μ m increase. There was no significant interaction of preexisting arterial intimal thickness and postoperative AVF outcomes with arterial medial fibrosis, arterial microcalcification, or venous intimal hyperplasia. Conclusions Preexisting arterial intimal hyperplasia is not associated with the 6-week AVF blood flow, diameter or stenosis, or clinical maturation when the preoperative arterial diameter is ≥2 mm.

Association of Preexisting Arterial Intimal Hyperplasia with Arteriovenous Fistula Outcomes.

Hemodynamic factors, induced by pulsatile blood flow, play a crucial role in vascular health and diseases, such as the initiation and progression of atherosclerosis. Computational fluid dynamics, finite element analysis, and fluid-structure interaction simulations have been widely used to quantify detailed hemodynamic forces based on vascular images commonly obtained from computed tomography angiography, magnetic resonance imaging, ultrasound, and optical coherence tomography. In this review, we focus on methods for obtaining accurate hemodynamic factors that regulate the structure and function of vascular endothelial and smooth muscle cells. We describe the multiple steps and recent advances in a typical patient-specific simulation pipeline, including medical imaging, image processing, spatial discretization to generate computational mesh, setting up boundary conditions and solver parameters, visualization and extraction of hemodynamic factors, and statistical analysis. These steps have not been standardized and thus have unavoidable uncertainties that should be thoroughly evaluated. We also discuss the recent development of combining patient-specific models with machine-learning methods to obtain hemodynamic factors faster and cheaper than conventional methods. These critical advances widen the use of biomechanical simulation tools in the research and potential personalized care of vascular diseases.

/pdf/medical-image-based-computational-fluid-dynamics-and-fluid-1c1boehl.pdf

Ha Le

Papers

The effect of endothelial nitric oxide synthase on the hemodynamics and wall mechanics in murine arteriovenous fistulas.

Association of Preexisting Arterial Intimal Hyperplasia with Arteriovenous Fistula Outcomes.

Medical Image-Based Computational Fluid Dynamics and Fluid-Structure Interaction Analysis in Vascular Diseases