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.

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.

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.

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.

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.

Chronic kidney disease and cardiovascular risk in six regions of the world (ISN-KDDC): a cross-sectional study.

BACKGROUND: Chronic kidney disease is an important cause of global mortality and morbidity. Data for epidemiological features of chronic kidney disease and its risk factors are limited for low-income and middle-income countries. The International Society of Nephrology's Kidney Disease Data Center (ISN-KDDC) aimed to assess the prevalence and awareness of chronic kidney disease and its risk factors, and to investigate the risk of cardiovascular disease, in countries of low and middle income. METHODS: We did a cross-sectional study in 12 countries from six world regions: Bangladesh, Bolivia, Bosnia and Herzegovina, China, Egypt, Georgia, India, Iran, Moldova, Mongolia, Nepal, and Nigeria. We analysed data from screening programmes in these countries, matching eight general and four high-risk population cohorts collected in the ISN-KDDC database. High-risk cohorts were individuals at risk of or with a diagnosis of either chronic kidney disease, hypertension, diabetes, or cardiovascular disease. Participants completed a self-report questionnaire, had their blood pressure measured, and blood and urine samples taken. We defined chronic kidney disease according to modified KDIGO (Kidney Disease: Improving Global Outcomes) criteria; risk of cardiovascular disease development was estimated with the Framingham risk score. FINDINGS: 75,058 individuals were included in the study. The prevalence of chronic kidney disease was 14·3% (95% CI 14·0-14·5) in general populations and 36·1% (34·7-37·6) in high-risk populations. Overall awareness of chronic kidney disease was low, with 409 (6%) of 6631 individuals in general populations and 150 (10%) of 1524 participants from high-risk populations aware they had chronic kidney disease. Moreover, in the general population, 5600 (44%) of 12,751 individuals with hypertension did not know they had the disorder, and 973 (31%) of 3130 people with diabetes were unaware they had that disease. The number of participants at high risk of cardiovascular disease, according to the Framingham risk score, was underestimated compared with KDIGO guidelines. For example, all individuals with chronic kidney disease should be considered at high risk of cardiovascular disease, but the Framingham risk score detects only 23% in the general population, and only 38% in high-risk cohorts. INTERPRETATION: Prevalence of chronic kidney disease was high in general and high-risk populations from countries of low and middle income. Moreover, awareness of chronic kidney disease and other non-communicable diseases was low, and a substantial number of individuals who knew they were ill did not receive treatment. Prospective programmes with repeat testing are needed to confirm the diagnosis of chronic kidney disease and its risk factors. Furthermore, in general, health-care workforces in countries of low and middle income need strengthening. FUNDING: International Society of Nephrology.

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.

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.

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.

Disturbed flow in a patient-specific arteriovenous fistula for hemodialysis: Multidirectional and reciprocating near-wall flow patterns.

Actual surgical creation of vascular access has unacceptable failure rates of which stenosis formation is a major cause. We have shown previously in idealized models of side-to-end arteriovenous fistula that disturbed flow, a near-wall hemodynamic condition characterized by low and oscillating fluid shear stress, develops in focal points that corresponds closely to the sites of future stenosis. Our present study was aimed at investigating whether disturbed flow occurs in patient-specific fistulae, too. We performed an image-based computational fluid dynamics study within a realistic model of wrist side-to-end anastomosis fistula at six weeks post-surgery, with subject-specific blood rheology and boundary conditions. We then categorized disturbed flow by means of established hemodynamic wall parameters. The numerical analysis revealed laminar flow within the arterial limbs and a complex flow field in the swing segment, featuring turbulent eddies leading to high frequency oscillation of the wall shear stress vectors. Multidirectional disturbed flow developed on the anastomosis floor and on the whole swing segment. Reciprocating disturbed flow zones were found on the distal artery near the floor and on the inner wall of the swing segment. We have found that both multidirectional and reciprocating disturbed flow develop on the inner side of the swing segment in a patient-specific side-to-end fistula used for vascular access after six weeks post-operatively. This has obvious implications for elucidating the hemodynamic forces involved in the initiation of venous wall thickening in vascular access.

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.

Novel paradigms for dialysis vascular access: upstream hemodynamics and vascular remodeling in dialysis access stenosis.

Failure of hemodialysis access is caused mostly by venous intimal hyperplasia, a fibro-muscular thickening of the vessel wall. The pathogenesis of venous neointimal hyperplasia in primary arteriovenous fistulae consists of processes that have been identified as upstream and downstream events. Upstream events are the initial events producing injury of the endothelial layer (surgical trauma, hemodynamic shear stress, vessel wall injury due to needle punctures, etc.). Downstream events are the responses of the vascular wall at the endothelial injury that consist of a cascade of processes including leukocyte adhesion, migration of smooth muscle cells from the media to the intimal layer, and proliferation. In arteriovenous fistulae, the stenoses occur in specific sites, consistently related to the local hemodynamics determined by the vessel geometry and blood flow pattern. Recent findings that the localization of these sites matches areas of disturbed flow may add new insights into the pathogenesis of neointimal hyperplasia in the venous side of vascular access after the creation of the anastomosis. The detailed study of fluid flow motion acting on the vascular wall in anastomosed vessels and in the arm vasculature at the patient-specific level may help to elucidate the role of hemodynamics in vascular remodeling and neointimal hyperplasia formation. These computational approaches may also help in surgical planning for the amelioration of clinical outcome. This review aims to discuss the role of the disturbed flow condition in acting as upstream event in the pathogenesis of venous intimal hyperplasia and in producing subsequent local vascular remodeling in autogenous arteriovenous fistulae used for hemodialysis access. The potential use of blood flow analysis in the management of vascular access is also discussed.

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.

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.

Prevalence of hypertension and diabetes and coexistence of chronic kidney disease and cardiovascular risk in the population of the republic of moldova.

In 2005, the International Society of Nephrology (ISN) established the Global Outreach Program (GO) aimed at building a capacity for detecting and managing chronic kidney disease and its complications in low- and middle-income countries. Here we report data from the 2006-2007 screening program (1025 subjects from the general population) in the Republic of Moldova aimed to determine the prevalence of hypertension, diabetes, and their coexistence with microalbuminuria. The likelihood of a serious cardiovascular (CV) event was also estimated. Hypertension and diabetes were very common among screened subjects. The prevalence of microalbuminuria was 16.9% and that of estimated GFR <60 ml/min/1.73 m(2) (decreased renal function) was 9.4%. Male gender was associated with an increased prevalence of hypertension and microalbuminuria. Hypertension and diabetes clustered in subjects with microalbuminuria and renal dysfunction. Risk factors such as preobesity/obesity, physical inactivity and smoking were relatively common, even in younger participants. The prevalence of subjects with predicted 10-year CV risk ≥10% was 10.0%. In conclusion, in the Republic of Moldova patients with hypertension and diabetes should be screened for the coexistence of renal abnormalities, with the intention of developing disease-specific health-care interventions with the primary goal to reduce CV morbidity and mortality and prevent renal disease progression to end stage renal disease.

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.

Preventing renal and cardiovascular risk by renal function assessment: insights from a cross-sectional study in low-income countries and the USA.

OBJECTIVE: To assess the prevalence of microalbuminuria and kidney dysfunction in low-income countries and in the USA. DESIGN: Cross-sectional study of screening programmes in five countries. SETTING: Screening programmes in Nepal, Bolivia, the USA (National Health and Nutrition Examination Survey (NHANES) 2005-2008) Bangladesh and Georgia. PARTICIPANTS: General population in Nepal (n=20 811), Bolivia (n=3436) and in the USA (n=4299) and high-risk subjects in Bangladesh (n=1518) and Georgia (n=1549). PRIMARY AND SECONDARY OUTCOME MEASURES: Estimated glomerular filtration rate (eGFR)<60ml/min/1.73 m(2) and microalbuminuria (defined as urinary albumin creatinine ratio values of 30-300 mg/g) were the main outcome measures. The cardiovascular (CV) risk was also evaluated on the basis of demographic, clinical and blood data. RESULTS: The prevalence of eGFR<60ml/min/1.73 m(2) was 19%, 3.2% and 7% in Nepal, Bolivia and the USA, respectively. In Nepal, 7% of subjects were microalbuminuric compared to 8.6% in the USA. The prevalence of participants with predicted 10-year CV disease (CVD) risk ≥10% was 16.9%, 9.4% and 17% in Nepal, Bolivia and in the USA, respectively. In Bangladesh and Georgia, subjects with eGFR<60 ml/min/1.73 m(2) were 8.6% and 4.9%, whereas those with microalbuminuria were 45.4% and 56.5%, respectively. Predicted 10-year CVD risk ≥10% was 25.4% and 25% in Bangladesh and Georgia, respectively. CONCLUSIONS: Renal abnormalities are common among low-income countries and in the USA. Prevention programmes, particularly focused on those with renal abnormalities, should be established worldwide to prevent CVD and progression to end-stage renal disease.

Measuring and estimating GFR and treatment effect in ADPKD patients: results and implications of a longitudinal cohort study.

Trials failed to demonstrate protective effects of investigational treatments on glomerular filtration rate (GFR) reduction in Autosomal Dominant Polycystic Kidney Disease (ADPKD). To assess whether above findings were explained by unreliable GFR estimates, in this academic study we compared GFR values centrally measured by iohexol plasma clearance with corresponding values estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) and abbreviated Modification of Diet in Renal Disease (aMDRD) formulas in ADPKD patients retrieved from four clinical trials run by a Clinical Research Center and five Nephrology Units in Italy. Measured baseline GFRs and one-year GFR changes averaged 78.6±26.7 and 8.4±10.3 mL/min/1.73 m(2) in 111 and 71 ADPKD patients, respectively. CKD-Epi significantly overestimated and aMDRD underestimated baseline GFRs. Less than half estimates deviated by <10% from measured values. One-year estimated GFR changes did not detect measured changes. Both formulas underestimated GFR changes by 50%. Less than 9% of estimates deviated <10% from measured changes. Extent of deviations even exceeded that of measured one-year GFR changes. In ADPKD, prediction formulas unreliably estimate actual GFR values and fail to detect their changes over time. Direct kidney function measurements by appropriate techniques are needed to adequately evaluate treatment effects in clinics and research.

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.