High-Resolution Computational Fluid Dynamic Simulation of Haemodialysis Cannulation in a Patient-Specific Arteriovenous Fistula.

Arteriovenous fistulae (AVF) are the preferred choice of vascular access in hemodialysis patients; however, complications such as stenosis can lead to access failure or recirculation, which reduces dialysis efficiency. This study utilized computational fluid dynamics on a patient-specific radiocephalic fistula under hemodialysis treatment to determine the dynamics of access recirculation and identify the presence of disturbed flow. Metrics of transverse wall shear stress (transWSS) and oscillatory shear index (OSI) were used to characterize the disturbed flow acting on the blood vessel wall, while a power spectral density (PSD) analysis was used to calculate the any turbulence within the access. Results showed that turbulence is generated at the anastomosis and continues through the swing segment. The arterial needle dampens the flow as blood is extracted to the dialyzer, while the venous needle reintroduces turbulence due to the presence of jet flows. Adverse shear stresses are present throughout the vascular access and coincide with these complex flow fields. The position of the needles had no effect in minimizing these forces. However, improved blood extraction may occur when the arterial needle is placed further from the anastomosis, minimizing the effects of residual turbulent structures generated at the anastomosis. Furthermore, the arterial and venous needle may be placed in close proximity to each other without increasing the risk of access recirculation, in a healthy mature fistula, due to the relatively stable blood flow in this region. This may negate the need for a long cannulation segment and aid clinicians in optimizing needle placement for hemodialysis.

Endothelial cell activation by hemodynamic shear stress derived from arteriovenous fistula for hemodialysis access.

Intimal hyperplasia (IH) is the first cause of failure of an arteriovenous fistula (AVF). The aim of the present study was to investigate the effects on endothelial cells (ECs) of shear stress waveforms derived from AVF areas prone to develop IH. We used a cone-and-plate device to obtain real-time control of shear stress acting on EC cultures. We exposed human umbilical vein ECs for 48 h to different shear stimulations calculated in a side-to-end AVF model. Pulsatile unidirectional flow, representative of low-risk stenosis areas, induced alignment of ECs and actin fiber orientation with flow. Shear stress patterns of reciprocating flow, derived from high-risk stenosis areas, did not affect EC shape or cytoskeleton organization, which remained similar to static cultures. We also evaluated flow-induced EC expression of genes known to be involved in cytoskeletal remodeling and expression of cell adhesion molecules. Unidirectional flow induced a significant increase in Kruppel-like factor 2 mRNA expression, whereas it significantly reduced phospholipase D1, α4-integrin, and Ras p21 protein activator 1 mRNA expression. Reciprocating flow did not increase Kruppel-like factor 2 mRNA expression compared with static controls but significantly increased mRNA expression of phospholipase D1, α4-integrin, and Ras p21 protein activator 1. Reciprocating flow selectively increased monocyte chemoattractant protein-1 and IL-8 production. Furthermore, culture medium conditioned by ECs exposed to reciprocating flows selectively increased smooth muscle cell proliferation compared with unidirectional flow. Our results indicate that protective vascular effects induced in ECs by unidirectional pulsatile flow are not induced by reciprocating shear forces, suggesting a mechanism by which oscillating flow conditions may induce the development of IH in AVF and vascular access dysfunction.

Rituximab in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome.

The outcome of steroid-dependent or frequently relapsing nephrotic syndrome of minimal change disease (MCD), mesangial proliferative GN (MesGN), or FSGS may be poor and with major treatment toxicity. This academic, multicenter, off-on trial (ClinicalTrials.gov #NCT00981838) primarily evaluated the effects of rituximab therapy followed by immunosuppression withdrawal on disease recurrence in 10 children and 20 adults with MCD/MesGN (n=22) or FSGS who had suffered ≥2 recurrences over the previous year and were in steroid-induced remission for ≥1 month. Participants received one dose (n=28) or two doses of rituximab (375 mg/m(2) intravenously). At 1 year, all patients were in remission: 18 were treatment-free and 15 never relapsed. Compared with the year before rituximab treatment, total relapses decreased from 88 to 22 and the per-patient median number of relapses decreased from 2.5 (interquartile range [IQR], 2-4) to 0.5 (IQR, 0-1; P<0.001) during 1 year of follow-up. Reduction was significant across subgroups (children, adults, MCD/MesGN, and FSGS; P<0.01). After rituximab, the per-patient steroid maintenance median dose decreased from 0.27 mg/kg (IQR, 0.19-0.60) to 0 mg/kg (IQR, 0-0.23) (P<0.001), and the median cumulative dose to achieve relapse remission decreased from 19.5 mg/kg (IQR, 13.0-29.2) to 0.5 mg/kg (IQR, 0-9.4) (P<0.001). Furthermore, the mean estimated GFR increased from 111.3±25.7 to 121.8±29.2 ml/min per 1.73 m(2) (P=0.01), with the largest increases in children and in FSGS subgroups. The mean height z score slope stabilized in children (P<0.01). Treatment was well tolerated. Rituximab effectively and safely prevented recurrences and reduced the need for immunosuppression in steroid-dependent or frequently relapsing nephrotic syndrome, and halted disease-associated growth deficit in children.

Validation of a patient-specific hemodynamic computational model for surgical planning of vascular access in hemodialysis patients.

Vascular access dysfunction is one of the main causes of morbidity and hospitalization in hemodialysis patients. This major clinical problem points out the need for prediction of hemodynamic changes induced by vascular access surgery. Here we reviewed the potential of a patient-specific computational vascular network model that includes vessel wall remodeling to predict blood flow change within 6 weeks after surgery for different arteriovenous fistula configurations. For model validation, we performed a multicenter, prospective clinical study to collect longitudinal data on arm vasculature before and after surgery. Sixty-three patients with newly created arteriovenous fistula were included in the validation data set and divided into four groups based on fistula configuration. Predicted brachial artery blood flow volumes 40 days after surgery had a significantly high correlation with measured values. Deviation of predicted from measured brachial artery blood flow averaged 3% with a root mean squared error of 19.5%, showing that the computational tool reliably predicted patient-specific blood flow increase resulting from vascular access surgery and subsequent vascular adaptation. This innovative approach may help the surgeon to plan the most appropriate fistula configuration to optimize access blood flow for hemodialysis, potentially reducing the incidence of vascular access dysfunctions and the need of patient hospitalization.

Effect of anastomosis angle on the localization of disturbed flow in 'side-to-end' fistulae for haemodialysis access.

BACKGROUND: Early failure of the vascular access for haemodialysis (HD) after the surgical creation of a radial-cephalic arteriovenous fistula (AVF) occurs mainly due to a juxta-anastomotic stenosis. Even if elevated blood flow induces high wall shear stress, we have recently shown that disturbed flow, characterized by low and reciprocating flow, may develop in zones of the AVF where it can provide a good indication of the sites of future stenoses. The present study was aimed at investigating whether the anastomosis angle influences disturbed flow in radial-cephalic 'side-to-end' AVF. METHODS: By means of a parametric AVF model we created four equivalent meshes with anastomosis angles of 30°, 45°, 60° and 90°, respectively. We then performed transient, non-Newtonian computational fluid dynamics simulations using, as boundary conditions, previously measured blood volume flow and division ratio in subjects requiring primary access. The relative residence time (RRT), a robust indicator of disturbed flow, was calculated for the overall wall surface and disturbed flow was localized as areas having RRT > 1. Quantitative characterization and statistical tests were employed to assess the difference in RRT medians between the four anastomosis angle cases. RESULTS: Disturbed flow was located in all AVF models in the same areas where flow recirculation and stagnation occurred, on the inner wall of the swing segment (SS) and on the arterial wall at the anastomosis floor (AF). A smaller angle AVF had smaller disturbed flow areas with lower RRT peak values, either on the venous or the arterial limb. There were significant differences in the RRT medians on the SS and on the AF between sharper (30° and 45°) and wider (60° or 90°) angles. CONCLUSIONS: We have found that in 'side-to-end' radial-cephalic AVFs for HD, the anastomosis angle does impact on the local disturbed flow patterns. Among the four geometries we considered in this study, the smaller angle (30°) would be the preferred choice that minimizes the development of neointima. Clinicians should consider this at the time of AVF creation because the anastomosis angle is in part amenable to surgical manipulation.

Hypertension and kidney function in an adult population of West Bengal, India: role of body weight, waist circumference, proteinuria and rural area living.

AIM: Hypertension (HTN) and chronic kidney disease (CKD) are important emerging problems in low-income countries, with an increasing number of patients dying from their consequences. METHODS: A project for investigating these issues was carried out in West Bengal, India, in 2536 adult subjects. Body mass index (BMI) was classified using traditional and new cut-offs identified by the World Health Organization for Asian populations. HTN was classified according to the Joint National Committee 7 and CKD according to presence of estimated glomerular filtration rate (eGFR) of less than 60 mL/min per 1.73 m(2) . RESULTS: Normal BMI (Asian reference) was found in 41.5% of subjects, while 33.4% were underweight, 19.3% overweight and 5.8% obese. Prevalence of stage 1 and 2 HTN was 39.4%. Proteinuria (urine dipstick >1+) was present in 7.7% of the sample. In a subsample of 1526 subjects, eGFR of less than 60 mL/min per 1.73 m(2) was found in 4.2%. At multivariate analysis, factors associated with HTN were weight classes (P<0.001), presence of proteinuria (P<0.001) and family history of HTN (P=0.028), while living in rural areas was associated with lower risk for HTN (P=0.003). eGFR was inversely related to BMI (P=0.03), the presence of proteinuria (P<0.001) and HTN (P<0.003), and directly related to living in rural areas (P=0.003). CONCLUSION: High prevalence of HTN was found in subjects with very limited access to health care in West Bengal. HTN was more common in overweight individuals, but also affected normal weight and underweight subjects in a significant part of the tested population. Preventive medicine should be a strong priority in this setting.

Measurable urinary albumin predicts cardiovascular risk among normoalbuminuric patients with type 2 diabetes.

Micro- or macroalbuminuria is associated with increased cardiovascular risk factors among patients with type 2 diabetes, but whether albuminuria within the normal range predicts long-term cardiovascular risk is unknown. We evaluated the relationships between albuminuria and cardiovascular events in 1208 hypertensive, normoalbuminuric patients with type 2 diabetes from the BErgamo NEphrologic Diabetes Complication Trial (BENEDICT), all of whom received angiotensin-converting enzyme inhibitor (ACEI) therapy at the end of the trial and were followed for a median of 9.2 years. The main outcome was time to the first of fatal or nonfatal myocardial infarction; stroke; coronary, carotid, or peripheral artery revascularization; or hospitalization for heart failure. Overall, 189 (15.6%) of the patients experienced a main outcome event (2.14 events/100 patient-years); 24 events were fatal. Albuminuria independently predicted events (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.02-1.08). Second-degree polynomial multivariable analysis showed a continuous nonlinear relationship between albuminuria and events without thresholds. Considering the entire study population, even albuminuria at 1-2 µg/min was significantly associated with increased risk compared with albuminuria <1 µg/min (HR, 1.04; 95% CI, 1.02-1.07). This relationship was similar in the subgroup originally randomly assigned to non-ACEI therapy. Among those originally receiving ACEI therapy, however, the event rate was uniformly low and was not significantly associated with albuminuria. Taken together, among normoalbuminuric patients with type 2 diabetes, any degree of measurable albuminuria bears significant cardiovascular risk. The association with risk is continuous but is lost with early ACEI therapy.

Disturbed flow in radial-cephalic arteriovenous fistulae for haemodialysis: low and oscillating shear stress locates the sites of stenosis.

BACKGROUND: Despite recent clinical and technological advancements, the vascular access (VA) for haemodialysis still has significant early failure rates after arteriovenous fistula (AVF) creation. VA failure is mainly related to the haemodynamic conditions that trigger the phenomena of vascular wall disease such as intimal hyperplasia (IH) or atherosclerosis. METHODS: We performed transient computational fluid dynamics simulations within idealized three-dimensional models of 'end-to-side' and 'end-to-end' radio-cephalic anastomosis, using non-Newtonian blood and previously measured flows and division ratio in subjects requiring primary access procedure as boundary conditions. RESULTS: The numerical simulations allowed full characterization of blood flow inside the AVF and of patterns of haemodynamic shear stress, known to be the major determinant of vascular remodelling and disease. Wall shear stress was low and oscillating in zones where flow stagnation occurs on the artery floor and on the inner wall of the juxta-anastomotic vein. CONCLUSIONS: Zones of low and oscillatory shear stress were located in the same sites where luminal reduction was documented in previous experimental studies on sites stenosis distribution in AVF. We conclude that even when exposed to high flow rates, there are spot regions along the AVF exposed to athero-prone shear stress that favour vessel stenosis by triggering IH.

Sirolimus therapy to halt the progression of ADPKD.

Activation of mammalian target of rapamycin (mTOR) pathways may contribute to uncontrolled cell proliferation and secondary cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). To assess the effects of mTOR inhibition on disease progression, we performed a randomized, crossover study (The SIRENA Study) comparing a 6-month treatment with sirolimus or conventional therapy alone on the growth of kidney volume and its compartments in 21 patients with ADPKD and GFR>or=40 ml/min per 1.73 m2. In 10 of the 15 patients who completed the study, aphthous stomatitis complicated sirolimus treatment but was effectively controlled by topical therapy. Compared with pretreatment, posttreatment mean total kidney volume increased less on sirolimus (46+/-81 ml; P=0.047) than on conventional therapy (70+/-72 ml; P=0.002), but we did not detect a difference between the two treatments (P=0.45). Cyst volume was stable on sirolimus and increased by 55+/-75 ml (P=0.013) on conventional therapy, whereas parenchymal volume increased by 26+/-30 ml (P=0.005) on sirolimus and was stable on conventional therapy. Percentage changes in cyst and parenchyma volumes were significantly different between the two treatment periods. Sirolimus had no appreciable effects on intermediate volume and GFR. Albuminuria and proteinuria marginally but significantly increased during sirolimus treatment. In summary, sirolimus halted cyst growth and increased parenchymal volume in patients with ADPKD. Whether these effects translate into improved long-term outcomes requires further investigation.

Characterization of the Microflow Through 3D Synthetic Niche Microenvironments Hosted in a Millifluidic Bioreactor.

Background: Development of new medicines is a lengthy process with high risk of failure since drug efficacy measured in vitro is difficult to confirm in vivo. Intended to add a new tool aiding drug discovery, the MOAB-NICHOID device was developed: a miniaturized optically accessible bioreactor (MOAB) housing the 3D engineered scaffold NICHOID. The aim of our study was to characterize the microflow through the 3D nichoid microenvironment hosted in the MOAB-NICHOID device. Methods: We used computational fluid dynamics (CFD) simulations to compute the flow field inside a very fine grid resembling the scaffold microenvironment. Results: The microflow inside the multi-array of nichoid blocks is fed and locally influenced by the mainstream flow developed in the perfusion chamber of the device. Here we have revealed a low velocity, complex flow field with secondary, backward, or local recirculation micro-flows induced by the intricate architecture of the nichoid scaffold. Conclusion: Knowledge of the microenvironment inside the 3D nichoids allows planning of cell experiments, to regulate the transport of cells towards the scaffold substrate during seeding or the spatial delivery of nutrients and oxygen which affects cell growth and viability.

Burden of CKD, proteinuria, and cardiovascular risk among Chinese, Mongolian, and Nepalese participants in the International Society of Nephrology screening programs.

BACKGROUND: In 2007, the International Society of Nephrology funded the Kidney Disease Data Center database to house data from sponsored programs aimed at preventing chronic kidney disease and its complications in developing nations. This study compares baseline characteristics and burden of illness among participants from centers in China, Mongolia, and Nepal. An important secondary objective is to show the feasibility of screening for chronic kidney disease and its major risk factors in a diverse group of lower income settings. STUDY DESIGN: Cross-sectional screening study. SETTING & PARTICIPANTS: Participants from Nepal (n = 8,398), China (n = 1,999), and Mongolia (n = 997). Screening was open to the public for participants in China and Nepal; referral from a general practitioner was required for participants in Mongolia. OUTCOMES: Estimated glomerular filtration rate (eGFR), proteinuria, hypertension, diabetes, obesity, cardiovascular risk. MEASUREMENT: Demographic and clinical data were collected prospectively using a standard format. Blood and urine specimens were provided according to local protocol. RESULTS: Of 11,394 participants, decreased eGFR (<60 mL/min/1.73 m(2)) was present in 7.3%-14% of participants across centers; proteinuria (≥1+) on dipstick (2.4%-10%), hypertension (26%-36%), diabetes (3%-8%), and obesity (body mass index ≥30 kg/m(2); 2%-20%) were all common. Predicted 5-year cardiovascular risk ≥10% ranged from 20%-89%. Numbers needed to screen to detect a new case of eGFR <60 mL/min/1.73 m(2), hypertension, or diabetes were 2.6 (95% CI, 2.5-2.7), 3.4 (95% CI, 3.1-3.7), and 4.7 (95% CI, 3.3-8.0) for Nepal, China, and Mongolia, respectively. LIMITATIONS: May not be representative of the general population. CONCLUSIONS: The acceptable diagnostic yield of abnormalities across these 3 diverse settings suggests that trials of targeted screening and intervention are feasible and warranted in such countries.

Role of ultrastructural determinants of glomerular permeability in ultrafiltration function loss.

The epithelial filtration slit is a crucial component of the glomerular capillary membrane, which is essential for maintaining glomerular filtration function. Though chronic kidney diseases are an immense clinical problem, the mechanisms through which structural alterations reduce glomerular water filtration have not yet been understood completely. To investigate the mechanisms underlying filtration function loss, we studied rats with spontaneously occurring progressive kidney disease, either treated with angiotensin II antagonist or untreated, combining high-resolution electron microscopy of the glomerular capillary wall with theoretical water filtration modeling. Under pathological conditions, epithelial filtration pores and the extension of the subpodocyte space were larger than in normal controls. Numerical analyses indicated that these ultrastructural changes increased hydraulic resistance of the glomerular capillary wall by extending coverage of the filtration barrier by the subpodocyte space, with the changes in hydrodynamic forces acting on podocytes likely being responsible for their detachment. Angiotensin II inhibition normalized the subpodocyte space's hydraulic resistance, restored mechanical podocyte load, and preserved CD151-α3 integrin complex assembly, improving podocyte adherence and survival. Our results show that ultrastructural changes in podocytes are major determinants of the hydraulic resistance of the glomerular capillary wall and highlight the mechanism of podocyte loss in kidney disease progression, as well as the mechanisms underlying angiotensin II inhibition.

Developing regulatory-compliant electronic case report forms for clinical trials: experience with the demand trial.

The use of electronic case report forms (CRF) to gather data in randomized clinical trials has grown to progressively replace paper-based forms. Computerized form designs must ensure the same data quality expected of paper CRF, by following Good Clinical Practice rules. Electronic data capture (EDC) tools must also comply with applicable statutory and regulatory requirements. Here the authors focus on the development of computerized systems for clinical trials implementing FDA and EU recommendations and regulations, and describe a laptop-based electronic CRF used in a randomized, multicenter clinical trial.

Cerebrovascular reactivity and autonomic drive following traumatic brain injury.

INTRODUCTION: The autonomic nervous system exerts tonic control on cerebral vessels, which in turn determine the autoregulation of cerebral blood flow. We hypothesize that the impairment of cerebral autoregulation following traumatic brain injury might be related to the acute failure of the autonomic system. METHODS: This prospective, observational study included patients with severe traumatic brain injury requiring mechanical ventilation and invasive monitoring of intracranial pressure (ICP) and arterial blood pressure (ABP). Pressure reactivity index (PRx), a validated index of cerebrovascular reactivity, was continuously monitored using bedside computers. Autonomic drive was assessed by means of heart rate variability (HRV) using frequency domain analysis. FINDINGS: Eighteen TBI patients were included in the study. Cerebrovascular reactivity impairment (PRx above 0.2) and autonomic failure (low spectral power of HRV) are significantly and independently associated with fatal outcome (P = 0.032 and P < 0.001, respectively). We observed a significant correlation between PRx and HRV spectral power (P < 0.001). The high frequency component of HRV (HF, 0.15-0.4Hz) can be used to predict impaired autoregulation (PRx > 0.2), although sensitivity and specificity are low (ROC AUC = 0.67; P = 0.001). CONCLUSION: Following traumatic brain injury, autonomic failure and cerebrovascular autoregulation impairment are both associated with fatal outcome. Impairment of cerebrovascular autoregulation and autonomic drive are interdependent phenomena. With some refinements, HRV might become a tool for screening patients at risk for cerebral autoregulation derangement following TBI.

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.

Preventing microalbuminuria in type 2 diabetes.

BACKGROUND: The multicenter double-blind, randomized Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) was designed to assess whether angiotensin-converting-enzyme inhibitors and non-dihydropyridine calcium-channel blockers, alone or in combination, prevent microalbuminuria in subjects with hypertension, type 2 diabetes mellitus, and normal urinary albumin excretion. METHODS: We studied 1204 subjects, who were randomly assigned to receive at least three years of treatment with trandolapril (at a dose of 2 mg per day) plus verapamil (sustained-release formulation, 180 mg per day), trandolapril alone (2 mg per day), verapamil alone (sustained-release formulation, 240 mg per day), or placebo. The target blood pressure was 120/80 mm Hg. The primary end point was the development of persistent microalbuminuria (overnight albumin excretion, > or =20 microg per minute at two consecutive visits). RESULTS: The primary outcome was reached in 5.7 percent of the subjects receiving trandolapril plus verapamil, 6.0 percent of the subjects receiving trandolapril, 11.9 percent of the subjects receiving verapamil, and 10.0 percent of control subjects receiving placebo. The estimated acceleration factor (which quantifies the effect of one treatment relative to another in accelerating or slowing disease progression) adjusted for predefined baseline characteristics was 0.39 for the comparison between verapamil plus trandolapril and placebo (P=0.01), 0.47 for the comparison between trandolapril and placebo (P=0.01), and 0.83 for the comparison between verapamil and placebo (P=0.54). Trandolapril plus verapamil and trandolapril alone delayed the onset of microalbuminuria by factors of 2.6 and 2.1, respectively. Serious adverse events were similar in all treatment groups. CONCLUSIONS: In subjects with type 2 diabetes and hypertension but with normoalbuminuria, the use of trandolapril plus verapamil and trandolapril alone decreased the incidence of microalbuminuria to a similar extent. The effect of verapamil alone was similar to that of placebo.

Blood Flow in Idealized Vascular Access for Hemodialysis: A Review of Computational Studies.

Although our understanding of the failure mechanism of vascular access for hemodialysis has increased substantially, this knowledge has not translated into successful therapies. Despite advances in technology, it is recognized that vascular access is difficult to maintain, due to complications such as intimal hyperplasia. Computational studies have been used to estimate hemodynamic changes induced by vascular access creation. Due to the heterogeneity of patient-specific geometries, and difficulties with obtaining reliable models of access vessels, idealized models were often employed. In this review we analyze the knowledge gained with the use of computational such simplified models. A review of the literature was conducted, considering studies employing a computational fluid dynamics approach to gain insights into the flow field phenotype that develops in idealized models of vascular access. Several important discoveries have originated from idealized model studies, including the detrimental role of disturbed flow and turbulent flow, and the beneficial role of spiral flow in intimal hyperplasia. The general flow phenotype was consistent among studies, but findings were not treated homogeneously since they paralleled achievements in cardiovascular biomechanics which spanned over the last two decades. Computational studies in idealized models are important for studying local blood flow features and evaluating new concepts that may improve the patency of vascular access for hemodialysis. For future studies we strongly recommend numerical modelling targeted at accurately characterizing turbulent flows and multidirectional wall shear disturbances.

Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial.

BACKGROUND: In chronic nephropathies, inhibition of angiotensin-converting enzyme (ACE) is renoprotective, but can further renoprotection be achieved by reduction of blood pressure to lower than usual targets? We aimed to assess the effect of intensified versus conventional blood-pressure control on progression to end-stage renal disease. METHODS: We undertook a multicentre, randomised controlled trial of patients with non-diabetic proteinuric nephropathies receiving background treatment with the ACE inhibitor ramipril (2.5-5 mg/day). We randomly assigned participants either conventional (diastolic <90 mm Hg; n=169) or intensified (systolic/diastolic <130/80 mm Hg; n=169) blood-pressure control. To achieve the intensified blood-pressure level, patients received add-on therapy with the dihydropyridine calcium-channel blocker felodipine (5-10 mg/day). The primary outcome measure was time to end-stage renal disease over 36 months' follow-up, and analysis was by intention to treat. FINDINGS: Of 338 patients who were randomised, three (two assigned intensified and one allocated conventional blood-pressure control) never took study drugs and they were excluded. Over a median follow-up of 19 months (IQR 12-35), 38/167 (23%) patients assigned to intensified blood-pressure control and 34/168 (20%) allocated conventional control progressed to end-stage renal disease (hazard ratio 1.00 [95% CI 0.61-1.64]; p=0.99). INTERPRETATION: In patients with non-diabetic proteinuric nephropathies receiving background ACE-inhibitor therapy, no additional benefit from further blood-pressure reduction by felodipine could be shown.

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.

Design of a cone-and-plate device for controlled realistic shear stress stimulation on endothelial cell monolayers.

Endothelial cells are constantly exposed to blood flow and the resulting frictional force, the wall shear stress, varies in magnitude and direction with time, depending on vasculature geometry. Previous studies have shown that the structure and function of endothelial cells, and ultimately of the vessel wall, are deeply affected by the nature of wall shear stress waveforms. To investigate the in vitro effects of these stimuli, we developed a compact, programmable, real-time operated system based on cone-and-plate geometry, that can be used within a standard cell incubator. To verify the capability to replicate realistic shear stress waveforms, we calculated both analytically and numerically to what extent the system is able to correctly deliver the stimuli defined by the user at plate level. Our results indicate that for radii greater than 25 mm, the shear stress is almost uniform and directly proportional to cone rotation velocity. We further established that using a threshold of 10 Hz of wall shear stress waveform frequency components, oscillating flow conditions can be reproduced on cell monolayer surface. Finally, we verified the capability of the system to perform long-term flow exposure experiments ensuring sterility and cell culture viability on human umbilical vein endothelial cells exposed to unidirectional and oscillating shear stress. In conclusion, the system we developed is a highly dynamic, easy to handle, and able to generate pulsatile and unsteady oscillating wall shear stress waveforms. This system can be used to investigate the effects of realistic stimulations on endothelial cells, similar to those exerted in vivo by blood flow.