Clinical use of computational modeling for surgical planning of arteriovenous fistula for hemodialysis.

BACKGROUND: Autogenous arteriovenous fistula (AVF) is the best vascular access (VA) for hemodialysis, but its creation is still a critical procedure. Physical examination, vascular mapping and doppler ultrasound (DUS) evaluation are recommended for AVF planning, but they can not provide direct indication on AVF outcome. We recently developed and validated in a clinical trial a patient-specific computational model to predict pre-operatively the blood flow volume (BFV) in AVF for different surgical configuration on the basis of demographic, clinical and DUS data. In the present investigation we tested power of prediction and usability of the computational model in routine clinical setting. METHODS: We developed a web-based system (AVF.SIM) that integrates the computational model in a single procedure, including data collection and transfer, simulation management and data storage. A usability test on observational data was designed to compare predicted vs. measured BFV and evaluate the acceptance of the system in the clinical setting. Six Italian nephrology units were involved in the evaluation for a 6-month period that included all incident dialysis patients with indication for AVF surgery. RESULTS: Out of the 74 patients, complete data from 60 patients were included in the final dataset. Predicted brachial BFV at 40 days after surgery showed a good correlation with measured values (in average 787 ± 306 vs. 751 ± 267 mL/min, R = 0.81, p < 0.001). For distal AVFs the mean difference (±SD) between predicted vs. measured BFV was -2.0 ± 20.9%, with 50% of predicted values in the range of 86-121% of measured BFV. Feedbacks provided by clinicians indicate that AVF.SIM is easy to use and well accepted in clinical routine, with limited additional workload. CONCLUSIONS: Clinical use of computational modeling for AVF surgical planning can help the surgeon to select the best surgical strategy, reducing AVF early failures and complications. This approach allows individualization of VA care, with the aim to reduce the costs associated with VA dysfunction, and to improve AVF clinical outcome.

Flow-induced high frequency vascular wall vibrations in an arteriovenous fistula: a specific stimulus for stenosis development?

Hemodialysis is the lifeline for nearly three million end stage renal disease patients worldwide. Native arteriovenous fistula (AVF) is the preferred vascular access, but 40% fail within 1 year. We recently demonstrated that AVFs harbour transitional flows and the goal of the present study was to investigate whether the associated high-frequency pressure fluctuations could promote vibrations within the vascular wall. We acquired MRI images and flow rates immediately after surgery in one patient and generated a 3D patient-specific model. High-fidelity fluid structure interaction simulations revealed the presence of wall vibrations in distinct frequency bands up to 200 Hz and amplitude of 200 µm. A sensitivity analysis to assess the impact of flow rates, and vascular wall stiffness and thickness, changes that typically occur during AVF maturation, confirmed the robustness of the results. Interestingly, the vibrations were always predominant at the anastomosis floor and on the inner venous side, which correlates with typical stenotic regions. As studies seeking to correlate aberrant stresses and vascular remodelling have been largely inconclusive, the focal colocalization between vibrations and stenosis may suggest an unknown mechanobiological process between high-frequency mechanical stresses within the vascular wall and adverse vascular remodelling.

Surgical planning of arteriovenous fistulae in routine clinical practice: A machine learning predictive tool.

BACKGROUND: Arteriovenous fistula (AVF) is the preferred vascular access (VA) for hemodialysis, but it is associated with high non-maturation and failure rates. Predicting patient-specific AVF maturation and postoperative changes in blood flow volumes (BFVs) and vessel diameters is of fundamental importance to support the choice of optimal AVF location and improve VA survival. The goal of this study was to employ machine learning (ML) in order to give physicians a fast and easy-to-use tool that provides accurate patient-specific predictions, useful to make AVF surgical planning decisions. METHODS: We applied a set of ML approaches on a dataset of 156 patients. Both parametric and non-parametric ML approaches, taking preoperative data as input, were exploited to predict maturation, postoperative BFVs, and diameters. The best approach associated with lowest cross-validation errors between predictions and real measurements was then chosen to provide estimates and quantify prediction errors. RESULTS: The k-NN was the best approach to predict brachial BFV, AVF maturation, and other VA variables, and it was also associated with the least computational effort. With this approach, the confusion matrices proved the high accuracy of the prediction for AVF maturation (96.8%) and the low absolute error distribution for the continuous BFV and diameter variables. CONCLUSIONS: Our data-based approach provided accurate patient-specific predictions for different AVF configurations, requiring short computational time as compared to a physical model we previously developed. By supporting VA surgical planning, this fast computing approach could allow AVF surgical planning and help reducing the rate of non-maturation, which might ultimately have a broad impact on the management of hemodialysis patients.

Hemodynamics in AVF over time: A protective role of vascular remodeling toward flow stabilization.

The mechanisms underlying vascular stenosis formation in the arteriovenous fistula (AVF) for hemodialysis (HD) remain mostly unknown. Several computational fluid dynamics (CFD) studies have suggested a potential role for unsteady flow in inducing intimal hyperplasia and AVF stenosis, but the majority of these observations have been limited to a single time point after surgical creation. The aim of the present study was to investigate the relation between hemodynamic conditions and AVF vascular remodeling through a CFD longitudinal study. Non contrast-enhanced MR images and Doppler Ultrasound (US) examinations were acquired at 3 days, 40 days, 6 months, 1 year, and 1.5 years after surgery in a 72-year male referred for native radio-cephalic AVF. Three-dimensional AVF models were generated and high fidelity CFD simulations were performed using pimpleFoam, setting patient-specific boundary conditions derived from US. Morphological and hemodynamic changes over time were then analyzed. Analysis of vessel morphology and hemodynamics during follow-up showed that the AVF had a successful maturation process, characterized by a massive arterial and venous dilatation within the 6 months after surgery, a corresponding increase in blood flow volume and important flow instabilities. Between 6 months and 1 year, a stenosis developed in the juxta-anastomotic vein and caused AVF failure at 1.5 years. The development of stenosis was paralleled by the regularization of blood flow velocity pattern and consequent decrease in the near-wall disturbed flow metrics. These results suggest that development of intimal hyperplasia and vessel stenosis, triggered by unsteady flow, could be the result of vascular inward remodeling toward regularization of turbulent-like flow.

Velocity vector comparison between vector flow imaging and computational fluid dynamics in the carotid bifurcation.

It has been largely documented that local hemodynamic conditions, characterized by low and oscillating wall shear stresses, play a key role in the initiation and progression of vascular atherosclerotic lesions. Thus, investigation of the flow field in the carotid bifurcation can lead to early identification of vulnerable plaques. In this scenario, the development of novel non-invasive imaging tools that can be used in routine clinical practice to identify disturbed and recirculating blood flow becomes crucial. In this context, Vector Flow Imaging is becoming a relevant tool as it provides an angle independent assessment of blood flow velocity and multidimensional flow vector visualization. The purpose of the present study was to validate, in several locations of the carotid bifurcation, the high-frame rate vector flow imaging (HiFR-VFI) technique by comparing with computational fluid dynamic simulations (CFD). In all eight carotid bifurcations, HiFR-VFI accurately detected regions of laminar flow as well as recirculation and unsteady flow areas. An accurate and statistically significant agreement was observed between velocity vectors obtained by HiFR-VFI and those computed by CFD, both for vector magnitude (R = 0.85) and direction (R = 0.74). Our study demonstrated that HiFR-VFI is a valid technique for rapid and advanced visual representation of velocity field in large arteries. Thus, it has a great potential in research-based clinical practice for the identification of flow recirculation, low and oscillating velocity gradients near vessel wall. The use of HiFR-VFI may provide a great improvement in the investigation of the role of local hemodynamics in vascular pathologies, as well in the assessment of the effect of pharmacological treatments.

The use of AVF.SIM system for the surgical planning of arteriovenous fistulae in routine clinical practice.

BACKGROUND: The number of patients treated with hemodialysis (HD) in Europe is more than half a million and this number increases annually. The arteriovenous fistula (AVF) is the vascular access (VA) of first choice, but the clinical outcome is still poor. A consistent number of AVFs fails to reach the desired blood flow rate for HD treatment, while some have too high flow and risk for cardiac complications. Despite the skill of the surgeons and the possibility to use Ultrasound investigation for mapping arm vasculature, it is still not possible to predict the blood flow volume that will be obtained after AVF maturation. METHODS: We evaluated the potential of using a computational model (AVF.SIM) to predict the blood flow volume that will be achieved after AVF maturation, within a multicenter international clinical investigation aimed at assessing AVF.SIM predictive power. The study population included 231 patients, with data on AVF maturation in 124 patients, and on long-term primary patency in 180 patients. RESULTS: At 1 year of follow-up, about 60% of AVFs were still patent, with comparable primary patency in proximal and distal anastomosis. The correlation between predicted and measured blood flow volume in the brachial artery at 40 days after surgery was statistically significant, with an overall correlation coefficient of 0.58 (p < 0.001). The percent difference between measured and predicted brachial blood flow 40 days after surgery was less than 30% in 72% of patients investigated. CONCLUSIONS: The results indicate that the use of the AVF.SIM system allowed to predict with a good accuracy the blood flow volume achievable after VA maturation, for a given location and type of anastomosis. This information may help in AVF surgical planning, reducing the AVFs with too low or too high blood flow, thus improving AVF patency rate and clinical outcome of renal replacement therapy.

Arteriovenous fistula creation with VasQTM device: A feasibility study to reveal hemodynamic implications.

BACKGROUND: Arteriovenous fistula (AVF) is the preferred vascular access (VA) for hemodialysis, but it is still affected by high non-maturation and early failure rates due to stenosis development. Increasing evidence suggests that the presence of turbulent-like flow may play a key role, therefore, to stabilize the flow in the venous segment, an external support device (VasQTM) has been designed. The aim of this study was to provide preliminary evidence of VasQTM impact on AVF hemodynamics as compared to AVFs created with conventional surgery. METHODS: In this pilot single-center prospective randomized study six patients were enrolled, three in the VasQ group and three in the control group. Contrast-free magnetic resonance imaging (MRI) scans were acquired at 3 days, 3 months and 1 year after AVF surgery and were used to generate 3D patient-specific models. Computational fluid dynamic (CFD) simulations were performed using pimpleFoam, imposing patient-specific flow waveforms derived from ultrasound (US) examinations at the inlet of the proximal and distal artery, and a traction-free condition at the venous outflow. Morphologic and hemodynamic changes occurring over time were compared between VasQ and control AVFs. RESULTS: Our MRI protocol provided high-quality images suitable for reliable segmentation and reconstruction of patient-specific 3D models of AVFs at all three timepoints in four out of six patients. The VasQTM device maintained the angle between the artery and the vein almost unchanged over time, with a more stable flow in the AVFs supported by the device. In contrast, one of the AVFs of the control group evolved to an extreme dilatation of the vein and highly disturbed flow, while the other developed a stenosis in the juxta-anastomotic region. CONCLUSIONS: This study demonstrated the feasibility of characterizing the morphological and hemodynamic changes occurring over time in AVFs created using the VasQTM device and provided preliminary evidence of the potential hemodynamic benefits of its use.

Toward longitudinal studies of hemodynamically induced vessel wall remodeling.

INTRODUCTION:: Autogenous arteriovenous fistula is the preferred vascular access for hemodialysis, but it has high rates of non-maturation and early failure due to vascular stenosis. Convincing evidence supports a key role of local hemodynamics in vascular remodeling, suggesting that unsteady and disturbed flow conditions may be related to stenosis formation in arteriovenous fistula. The purpose of our study was to explore the feasibility of coupling contrast-free magnetic resonance imaging and computational fluid dynamics in longitudinal studies to identify the role of local hemodynamic changes over time in inducing vessel wall remodeling in arteriovenous fistula. METHODS:: We acquired contrast-free magnetic resonance imaging of arm vasculature at 1 week and 6 weeks after arteriovenous fistula creation in a 72-year-old patient. We then generated three-dimensional models and evaluated lumen cross-sectional area of arteriovenous fistula limbs. We performed high-resolution computational fluid dynamics to evaluate changes in local hemodynamics over time. RESULTS:: Our contrast-free magnetic resonance imaging protocol provided good quality images in a short scan duration. We observed a homogeneous dilatation in the proximal artery, while there was a more pronounced lumen dilatation in the venous outflow as compared to a limited dilatation in the juxta-anastomotic vein. Furthermore, we observed a slight stabilization of the flow pattern over time, suggesting that vascular outward remodeling accommodates the flow to a more helicoidally phenotype. CONCLUSION:: Coupling contrast-free magnetic resonance imaging and high-resolution computational fluid dynamics represents a promising approach to shed more light in the mechanisms of vascular remodeling and can be used for prospective clinical investigations aimed at identifying critical hemodynamic factors contributing to arteriovenous fistula failure.

Biological and Physical Factors Involved in the Maturation of Arteriovenous Fistula for Hemodialysis.

One of the most important limitations of hemodialysis (HD) treatment is the vascular access (VA) that is used to connect the patient's blood vessels to the extracorporeal circulation. The arteriovenous fistula (AVF) obtained with native vessels is the VA of choice for the low incidence of infections and the long-term patency, but it is affected by high incidence of non-maturation or primary failure. Before use for cannulation, AVF must undergo vascular remodeling, with progressive increase in vessel diameter, to accommodate the increase in blood flow. A growing body of evidence indicates that AVF maturation is related to the response of endothelial cells to changes in blood flow and wall shear stress. In the present report we examine the experimental and clinical evidences on the mechanisms that play a role in vascular remodeling during AVF maturation. The physical and biological factors that develop upon arteriovenous surgical connection affect endothelial and smooth muscle cell function, as well as extracellular matrix remodeling. They can explain to a great extent the process of vascular remodeling and put more light on cellular mechanisms of vessel wall adaptation. The understanding of these phenomena, besides indicating the reasons for non-maturation and primary failure, may be fundamental in the future to ameliorate clinical outcomes of AVF creation, with a great impact on the clinical management of HD patients and their quality of life.

Is shear stress the key factor for AVF maturation?

Autologous arteriovenous fistula (AVF) is the preferred choice for providing vascular access to hemodialysis (HD) patients, but it is still affected by high incidence of non-maturation or early failure. After creation, AVF must undergo vascular remodeling, a process characterized by an increase in blood vessel diameter and wall thickness, to allow efficient and adequate HD. A growing body of evidence indicates that AVF maturation is related to the response of endothelial cells (ECs) to changes in wall shear stress (WSS), and in particular, to changes of its peak value. The reasons why important number of AVFs are affected by non-maturation or early failure still remain to be elucidated, but it has been suggested that local hemodynamic conditions with highly disturbed flow patterns may play an important role. In the present contribution, we addressed the role of WSS on AVF maturation, clarifying mechanisms that affect the clinical outcome of AVF creation. We also pointed out the need of non-invasive longitudinal studies, with repeated observations of hemodynamic parameters and structural changes during time, to obtain evidence of a cause-and-effect relationship between the presence of disturbed flow and AVF maturation failure. This understanding may be fundamental in the future to ameliorate clinical outcome of AVF creation, with a great impact on the clinical management of HD patients and their quality of life.

Kidney volume measurement methods for clinical studies on autosomal dominant polycystic kidney disease.

BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD), total kidney volume (TKV) is regarded as an important biomarker of disease progression and different methods are available to assess kidney volume. The purpose of this study was to identify the most efficient kidney volume computation method to be used in clinical studies evaluating the effectiveness of treatments on ADPKD progression. METHODS AND FINDINGS: We measured single kidney volume (SKV) on two series of MR and CT images from clinical studies on ADPKD (experimental dataset) by two independent operators (expert and beginner), twice, using all of the available methods: polyline manual tracing (reference method), free-hand manual tracing, semi-automatic tracing, Stereology, Mid-slice and Ellipsoid method. Additionally, the expert operator also measured the kidney length. We compared different methods for reproducibility, accuracy, precision, and time required. In addition, we performed a validation study to evaluate the sensitivity of these methods to detect the between-treatment group difference in TKV change over one year, using MR images from a previous clinical study. Reproducibility was higher on CT than MR for all methods, being highest for manual and semiautomatic contouring methods (planimetry). On MR, planimetry showed highest accuracy and precision, while on CT accuracy and precision of both planimetry and Stereology methods were comparable. Mid-slice and Ellipsoid method, as well as kidney length were fast but provided only a rough estimate of kidney volume. The results of the validation study indicated that planimetry and Stereology allow using an importantly lower number of patients to detect changes in kidney volume induced by drug treatment as compared to other methods. CONCLUSIONS: Planimetry should be preferred over fast and simplified methods for accurately monitoring ADPKD progression and assessing drug treatment effects. Expert operators, especially on MR images, are required for performing reliable estimation of kidney volume. The use of efficient TKV quantification methods considerably reduces the number of patients to enrol in clinical investigations, making them more feasible and significant.

Transitional Flow in the Venous Side of Patient-Specific Arteriovenous Fistulae for Hemodialysis.

Arteriovenous fistula (AVF) is the first choice for providing vascular access for hemodialysis patients, but maintaining its patency is challenging. AVF failure is primarily due to development of neointimal hyperplasia (NH) and subsequent stenosis. Using idealized models of AVF we previously suggested that reciprocating hemodynamic wall shear is implicated in vessel stenosis. The aim of the present study was to investigate local hemodynamics in patient-specific side-to-end AVF. We reconstructed realistic geometrical models of four AVFs from magnetic resonance images acquired in a previous clinical study. High-resolution computational fluid dynamics simulations using patient-specific blood rheology and flow boundary conditions were performed. We then characterized the flow field and categorized disturbed flow areas by means of established hemodynamic wall parameters. In all AVF, either in upper or lower arm location, we consistently observed transitional laminar to turbulent-like flow developing in the juxta-anastomotic vein and damping towards the venous outflow, but not in the proximal artery. High-frequency fluctuations of the velocity vectors in these areas result in eddies that induce similar oscillations of wall shear stress vector. This condition may importantly impair the physiological response of endothelial cells to blood flow and be responsible for NH formation in newly created AVF.