Another piece in the puzzle of kidney fibrosis.

Kidney fibrosis is a chronic physiomorphologic transformation of the renal parenchyma. Despite the known characteristics of the related structural and cellular changes, the mechanisms responsible for the initiation and progression of renal fibrosis are not completely understood. Development of efficient therapeutic drugs aimed at preventing the progressive loss of renal function requires an in-depth understanding of the complex phenomena associated with the pathophysiology of human diseases. The investigation of Li et al. provides novel evidence in this direction.

Diffusion magnetic resonance imaging for kidney cyst volume quantification and non-cystic tissue characterisation in ADPKD.

OBJECTIVES: Beyond total kidney and cyst volume (TCV), non-cystic tissue plays an important role in autosomal dominant polycystic kidney disease (ADPKD) progression. This study aims at presenting and preliminarily validating a diffusion MRI (DWI)-based TCV quantification method and providing evidence of DWI potential in characterising non-cystic tissue microstructure. METHODS: T2-weighted MRI and DWI scans (b = 0, 15, 50, 100, 200, 350, 500, 700, 1000; 3 directions) were acquired from 35 ADPKD patients with CKD stage 1 to 3a and 15 healthy volunteers on a 1.5 T scanner. ADPKD classification was performed using the Mayo model. DWI scans were processed by mono- and segmented bi-exponential models. TCV was quantified on T2-weighted MRI by the reference semi-automatic method and automatically computed by thresholding the pure diffusivity (D) histogram. The agreement between reference and DWI-based TCV values and the differences in DWI-based parameters between healthy and ADPKD tissue components were assessed. RESULTS: There was strong correlation between DWI-based and reference TCV (rho = 0.994, p < 0.001). Non-cystic ADPKD tissue had significantly higher D, and lower pseudo-diffusion and flowing fraction than healthy tissue (p < 0.001). Moreover, apparent diffusion coefficient and D values significantly differed by Mayo imaging class, both in the whole kidney (Wilcoxon p = 0.007 and p = 0.004) and non-cystic tissue (p = 0.024 and p = 0.007). CONCLUSIONS: DWI shows potential in ADPKD to quantify TCV and characterise non-cystic kidney tissue microstructure, indicating the presence of microcysts and peritubular interstitial fibrosis. DWI could complement existing biomarkers for non-invasively staging, monitoring, and predicting ADPKD progression and evaluating the impact of novel therapies, possibly targeting damaged non-cystic tissue besides cyst expansion. CLINICAL RELEVANCE STATEMENT: This study shows diffusion-weighted MRI (DWI) potential to quantify total cyst volume and characterise non-cystic kidney tissue microstructure in ADPKD. DWI could complement existing biomarkers for non-invasively staging, monitoring, and predicting ADPKD progression and evaluating the impact of novel therapies, possibly targeting damaged non-cystic tissue besides cyst expansion. KEY POINTS: • Diffusion magnetic resonance imaging shows potential to quantify total cyst volume in ADPKD. • Diffusion magnetic resonance imaging might allow to non-invasively characterise non-cystic kidney tissue microstructure. • Diffusion magnetic resonance imaging-based biomarkers significantly differ by Mayo imaging class, suggesting their possible prognostic value.

Basic principles and new advances in kidney imaging.

Over the past few years, clinical renal imaging has seen great advances, allowing assessments of kidney structure and morphology, perfusion, function and metabolism, and oxygenation, as well as microstructure and the interstitium. Medical imaging is becoming increasingly important in the evaluation of kidney physiology and pathophysiology, showing promise in management of patients with renal disease, in particular with regard to diagnosis, classification, and prediction of disease development and progression, monitoring response to therapy, detection of drug toxicity, and patient selection for clinical trials. A variety of imaging modalities, ranging from routine to advanced tools, are currently available to probe the kidney both spatially and temporally, particularly ultrasonography, computed tomography, positron emission tomography, renal scintigraphy, and multiparametric magnetic resonance imaging. Given that the range is broad and varied, kidney imaging techniques should be chosen based on the clinical question and the specific underlying pathologic mechanism, taking into account contraindications and possible adverse effects. Integration of various modalities providing complementary information will likely provide the greatest insight into renal pathophysiology. This review aims to highlight major recent advances in key tools that are currently available or potentially relevant for clinical kidney imaging, with a focus on non-oncological applications. The review also outlines the context of use, limitations, and advantages of various techniques, and highlights gaps to be filled with future development and clinical adoption.

COVID-19 and Italy: what next?

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already taken on pandemic proportions, affecting over 100 countries in a matter of weeks. A global response to prepare health systems worldwide is imperative. Although containment measures in China have reduced new cases by more than 90%, this reduction is not the case elsewhere, and Italy has been particularly affected. There is now grave concern regarding the Italian national health system's capacity to effectively respond to the needs of patients who are infected and require intensive care for SARS-CoV-2 pneumonia. The percentage of patients in intensive care reported daily in Italy between March 1 and March 11, 2020, has consistently been between 9% and 11% of patients who are actively infected. The number of patients infected since Feb 21 in Italy closely follows an exponential trend. If this trend continues for 1 more week, there will be 30 000 infected patients. Intensive care units will then be at maximum capacity; up to 4000 hospital beds will be needed by mid-April, 2020. Our analysis might help political leaders and health authorities to allocate enough resources, including personnel, beds, and intensive care facilities, to manage the situation in the next few days and weeks. If the Italian outbreak follows a similar trend as in Hubei province, China, the number of newly infected patients could start to decrease within 3-4 days, departing from the exponential trend. However, this cannot currently be predicted because of differences between social distancing measures and the capacity to quickly build dedicated facilities in China.

Copper-dependent biological effects of particulate matter produced by brake systems on lung alveolar cells.

Road traffic is one of the main sources of particulate emissions into the environment and has an increasing, negative impact on the release of potentially dangerous materials. Vehicle brakes release a significant amount of wear particles, and knowledge regarding their possible adverse effects is limited. One of the most dangerous elements contained in brake pads is copper (Cu), known to be toxic for human health. Therefore, our aim was to study the cell toxicity of particulate matter (PM) produced by different combinations of braking discs and pads containing different amounts of Cu. We investigated whether brake-derived microparticles have toxic effects on lung cells proportionally to their Cu content. Analyte content was measured in friction materials by XRFS and in PM2.5 captured during braking tests using SEM/EDX. The biological impact of brake-derived PM2.5 was investigated on a human epithelial alveolar cell line (A549). Cell viability, oxidative stress, mitochondrial membrane potential, apoptosis, and the pro-inflammatory response of the cells, as well as gene expression, were assessed following exposure to increasing PM2.5 concentrations (1, 10, 100, 200, and 500 µg/ml). The brake debris with the lowest Cu content did not induce significant changes in biological effects on A549 cells compared to normal controls, except for ROS production and IL6 gene expression. PM2.5 containing higher Cu quantities induced cell toxicity that correlated with Cu concentration. Our data suggest that the toxicity of PM2.5 from the brake system is mainly related to Cu content, thus confirming that eliminating Cu from brake pads will be beneficial for human health in urbanized environments.

Correction to: Phase-contrast magnetic resonance imaging to assess renal perfusion: a systematic review and statement paper.

The article Phase­contrast magnetic resonance imaging to assess renal perfusion: a systematic review and statement paper, written by Giulia Villa, Steffen Ringgaard, Ingo Hermann, Rebecca Noble, Paolo Brambilla, Dinah S. Khatir, Frank G. Zöllner, Susan T. Francis, Nicholas M. Selby, Andrea Remuzzi and Anna Caroli, was originally published electronically on the publisher's internet portal on 17 August 2019 without open access.

Phase-contrast magnetic resonance imaging to assess renal perfusion: a systematic review and statement paper.

OBJECTIVE: Phase-contrast magnetic resonance imaging (PC-MRI) is a non-invasive method used to compute blood flow velocity and volume. This systematic review aims to discuss the current status of renal PC-MRI and provide practical recommendations which could inform future clinical studies and its adoption in clinical practice. METHODOLOGY: A comprehensive search of all the PC-MRI studies in human healthy subjects or patients related to the kidneys was performed. RESULTS: A total of 39 studies were included in which PC-MRI was used to measure renal blood flow (RBF) alongside other derivative hemodynamic parameters. PC-MRI generally showed good correlation with gold standard methods of RBF measurement, both in vitro and in vivo, and good reproducibility. Despite PC-MRI not being routinely used in clinical practice, there are several clinical studies showing its potential to support diagnosis and monitoring of renal diseases, in particular renovascular disease, chronic kidney disease and autosomal dominant polycystic kidney disease. DISCUSSION: Renal PC-MRI shows promise as a non-invasive technique to reliably measure RBF, both in healthy volunteers and in patients with renal disease. Future multicentric studies are needed to provide definitive normative ranges and to demonstrate the clinical potential of PC-MRI, likely as part of a multi-parametric renal MRI protocol.

Octreotide-LAR in later-stage autosomal dominant polycystic kidney disease (ALADIN 2): A randomized, double-blind, placebo-controlled, multicenter trial.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetically determined renal disease. In affected patients, renal function may progressively decline up to end-stage renal disease (ESRD), and approximately 10% of those with ESRD are affected by ADPKD. The somatostatin analog octreotide long-acting release (octreotide-LAR) slows renal function deterioration in patients in early stages of the disease. We evaluated the renoprotective effect of octreotide-LAR in ADPKD patients at high risk of ESRD because of later-stage ADPKD. METHODS AND FINDINGS: We did an internally funded, parallel-group, double-blind, placebo-controlled phase III trial to assess octreotide-LAR in adults with ADPKD with glomerular filtration rate (GFR) 15-40 ml/min/1.73 m2. Participants were randomized to receive 2 intramuscular injections of 20 mg octreotide-LAR (n = 51) or 0.9% sodium chloride solution (placebo; n = 49) every 28 days for 3 years. Central randomization was 1:1 using a computerized list stratified by center and presence or absence of diabetes or proteinuria. Co-primary short- and long-term outcomes were 1-year total kidney volume (TKV) (computed tomography scan) growth and 3-year GFR (iohexol plasma clearance) decline. Analyses were by modified intention-to-treat. Patients were recruited from 4 Italian nephrology units between October 11, 2011, and March 20, 2014, and followed up to April 14, 2017. Baseline characteristics were similar between groups. Compared to placebo, octreotide-LAR reduced median (95% CI) TKV growth from baseline by 96.8 (10.8 to 182.7) ml at 1 year (p = 0.027) and 422.6 (150.3 to 695.0) ml at 3 years (p = 0.002). Reduction in the median (95% CI) rate of GFR decline (0.56 [-0.63 to 1.75] ml/min/1.73 m2 per year) was not significant (p = 0.295). TKV analyses were adjusted for age, sex, and baseline TKV. Over a median (IQR) 36 (24 to 37) months of follow-up, 9 patients on octreotide-LAR and 21 patients on placebo progressed to a doubling of serum creatinine or ESRD (composite endpoint) (hazard ratio [HR] [95% CI] adjusted for age, sex, baseline serum creatinine, and baseline TKV: 0.307 [0.127 to 0.742], p = 0.009). One composite endpoint was prevented for every 4 treated patients. Among 63 patients with chronic kidney disease (CKD) stage 4, 3 on octreotide-LAR and 8 on placebo progressed to ESRD (adjusted HR [95% CI]: 0.121 [0.017 to 0.866], p = 0.036). Three patients on placebo had a serious renal cyst rupture/infection and 1 patient had a serious urinary tract infection/obstruction, versus 1 patient on octreotide-LAR with a serious renal cyst infection. The main study limitation was the small sample size. CONCLUSIONS: In this study we observed that in later-stage ADPKD, octreotide-LAR slowed kidney growth and delayed progression to ESRD, in particular in CKD stage 4. TRIAL REGISTRATION: ClinicalTrials.gov NCT01377246; EudraCT: 2011-000138-12.

Toxicological evaluation of airborne particulate matter. Are cell culture technologies ready to replace animal testing?

Exposure to atmospheric particulate matter (PM) can affect human health, causing asthma, atherosclerosis, renal disease and cancer. In the last few years, outdoor air pollution has increased globally, leading to a public health emergency. Epidemiological studies have reported a correlation between the development of severe respiratory and systemic diseases and exposure to PM. To evaluate the toxic effect of PM of different origins, conventional experimental toxicological investigations have been conducted in animals; however, animal experimentation poses major ethical issues and usually differs from human conditions. As an alternative, human cell cultures are increasingly being used to investigate cellular and molecular mechanisms of PM toxicity. Although 2D cell cultures have been proven helpful, they are far from being a valid alternative to animal tests. Recently, 3D cell culture and organ-on-chip technology have provided systems that are more complex and that can be more informative for toxicity studies. In this review, the results of the 2D systems that are most frequently used for PM toxicity evaluations are summarized with a special focus on their limitations. We also examined to which extent 3D cell culture and particularly the organ-on-chip technology may overcome these limitations and represent effective tools to improve airborne PM toxicity evaluations.

Regression of Renal Disease by Angiotensin II Antagonism Is Caused by Regeneration of Kidney Vasculature.

Chronic renal insufficiency inexorably progresses in patients, such as it does after partial renal ablation in rats. However, the progression of renal diseases can be delayed by angiotensin II blockers that stabilize renal function or increase GFR, even in advanced phases of the disease. Regression of glomerulosclerosis can be induced by angiotensin II antagonism, but the effect of these treatments on the entire vascular tree is unclear. Here, using microcomputed tomography and scanning electron microscopy, we compared the size and extension of kidney blood vessels in untreated Wistar rats with those in untreated and angiotensin II antagonist-treated Munich Wistar Frömter (MWF) rats that spontaneously develop kidney disease with age. The kidney vasculature underwent progressive rarefaction in untreated MWF rats, substantially affecting intermediate and small vessels. Microarray analysis showed increased Tgf-ß and endothelin-1 gene expression with age. Notably, 10-week inhibition of the renin-angiotensin system regenerated kidney vasculature and normalized Tgf-ß and endothelin-1 gene expression in aged MWF rats. These changes were associated with reduced apoptosis, increased endothelial cell proliferation, and restoration of Nrf2 expression, suggesting mechanisms by which angiotensin II antagonism mediates regeneration of capillary segments. These results have important implications in the clinical setting of chronic renal insufficiency.

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.

The molecular mechanisms of hemodialysis vascular access failure.

The arteriovenous fistula has been used for more than 50 years to provide vascular access for patients undergoing hemodialysis. More than 1.5 million patients worldwide have end stage renal disease and this population will continue to grow. The arteriovenous fistula is the preferred vascular access for patients, but its patency rate at 1 year is only 60%. The majority of arteriovenous fistulas fail because of intimal hyperplasia. In recent years, there have been many studies investigating the molecular mechanisms responsible for intimal hyperplasia and subsequent thrombosis. These studies have identified common pathways including inflammation, uremia, hypoxia, sheer stress, and increased thrombogenicity. These cellular mechanisms lead to increased proliferation, migration, and eventually stenosis. These pathways work synergistically through shared molecular messengers. In this review, we will examine the literature concerning the molecular basis of hemodialysis vascular access malfunction.

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.

Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial.

BACKGROUND: Autosomal dominant polycystic kidney disease slowly progresses to end-stage renal disease and has no effective therapy. A pilot study suggested that the somatostatin analogue octreotide longacting release (LAR) could be nephroprotective in this context. We aimed to assess the effect of 3 years of octreotide-LAR treatment on kidney and cyst growth and renal function decline in participants with this disorder. METHODS: We did an academic, multicentre, randomised, single-blind, placebo-controlled, parallel-group trial in five hospitals in Italy. Adult (>18 years) patients with estimated glomerular filtration rate (GFR) of 40 mL/min per 1·73 m(2) or higher were randomly assigned (central allocation by phone with a computerised list, 1:1 ratio, stratified by centre, block size four and eight) to 3 year treatment with two 20 mg intramuscular injections of octreotide-LAR (n=40) or 0·9% sodium chloride solution (n=39) every 28 days. Study physicians and nurses were aware of the allocated group; participants and outcome assessors were masked to allocation. The primary endpoint was change in total kidney volume (TKV), measured by MRI, at 1 year and 3 year follow-up. Analyses were by modified intention to treat. This study is registered with ClinicalTrials.gov, NCT00309283. FINDINGS: Recruitment was between April 27, 2006, and May 12, 2008. 38 patients in the octreotide-LAR group and 37 patients in the placebo group had evaluable MRI scans at 1 year follow-up, at this timepoint, mean TKV increased significantly less in the octreotide-LAR group (46·2 mL, SE 18·2) compared with the placebo group (143·7 mL, 26·0; p=0·032). 35 patients in each group had evaluable MRI scans at 3 year follow-up, at this timepoint, mean TKV increase in the octreotide-LAR group (220·1 mL, 49·1) was numerically smaller than in the placebo group (454·3 mL, 80·8), but the difference was not significant (p=0·25). 37 (92·5%) participants in the octreotide-LAR group and 32 (82·1%) in the placebo group had at least one adverse event (p=0·16). Participants with serious adverse events were similarly distributed in the two treatment groups. However, four cases of cholelithiasis or acute cholecystitis occurred in the octreotide-LAR group and were probably treatment-related. INTERPRETATION: These findings provide the background for large randomised controlled trials to test the protective effect of somatostatin analogues against renal function loss and progression to end-stage kidney disease. FUNDING: Polycystic Kidney Disease Foundation.

Islet transplantation and insulin administration relieve long-term complications and rescue the residual endogenous pancreatic ß cells.

Islet transplantation is a poorly investigated long-term strategy for insulin replacement and for treatment of complications in patients with diabetes. We investigated whether islet transplantation and insulin treatment can relieve diabetic neuropathy and rescue the residual endogenous pancreatic ß cells. We used a multimodal approach, with five groups of Sprague-Dawley rats studied for 8 months: control rats, diabetic rats, insulin-treated diabetic rats with moderate or mild hyperglycemia, and diabetic rats transplanted with microencapsulated islets. Islet transplantation normalized glycemia and increased body and muscle weight; it was also effective in reducing proteinuria and altered liver function. Transplantation significantly improved tail nerve conduction velocity, Na(+)-K(+)-ATPase activity, and morphological alterations in the sciatic nerve as evidenced by decrease in g-ratio; it also restored thermal and ameliorated mechanical nociceptive thresholds. Morphometric analysis of pancreas indicated a significant ß-cell volume increase in transplanted rats, compared with mildly and moderately hyperglycemic rats. Thus, allogeneic islet transplantation had a positive systemic effect in diabetic rats and induced regression of the established neuropathy and restitution of the typical characteristics of the islets. These findings strongly reinforce the need for improving glycemic control, not only to reverse established diabetic complications but also to improve ß-cell status in diabetic pancreas.

Renal bioengineering with scaffolds generated from rat and pig kidneys.

BACKGROUND: Chronic kidney disease (CKD) is a global public health issue with an estimated prevalence of 8-16% worldwide. End-stage renal disease eventually develops every year in 0.15-0.2% of patients with overt CKD, and renal replacement therapy (RRT) with dialysis or transplantation is required. Although approximately 2 million people worldwide are currently on RRT to sustain life, this likely represents less than 10% of those who need it. The kidney transplant approach is also seriously impaired by limited graft survival and by the scarce availability of donors. Innovative tissue-engineering strategies have been recently proposed to overcome these challenges. It is anticipated that these novel approaches will also be cost-effective in the long term. Although the initial setup of these innovative technologies could be quite expensive, there would be a single application for each patient, with no additional costs thereafter, compared to the lifelong costs of dialysis or immunosuppressive medications required for transplantation. One of the most innovative tools currently being investigated in experimental models is based on the idea of using decellularized kidneys to engineer a new functional organ as a potential future treatment option for end-stage renal disease. SUMMARY: In the last 5 years, several interesting observations have been reported regarding the possibility of using an acellular matrix from the whole kidney and the attempt to recellularize this scaffold using stem or differentiated cells. This review provides an overview of the decellularization methods tested so far and their effects on the resulting extracellular matrix structure and composition. In addition, we also discuss methods recently described by us and others for the perfusion of kidney scaffolds for recellularization. KEY MESSAGES: Despite difficulties in achieving the import goal of kidney engineering in the laboratory, we discuss the problems with and limits of the experimental results obtained so far and point out the strategies that need to be adopted in order for this line of research to advance.

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.

Toward a physiological model of vascular wall vibrations in the arteriovenous fistula.

The mechanism behind hemodialysis arteriovenous fistula (AVF) failure remains poorly understood, despite previous efforts to correlate altered hemodynamics with vascular remodeling. We have recently demonstrated that transitional flow induces high-frequency vibrations in the AVF wall, albeit with a simplified model. This study addresses the key limitations of our original fluid-structure interaction (FSI) approach, aiming to evaluate the vibration response using a more realistic model. A 3D AVF geometry was generated from contrast-free MRI and high-fidelity FSI simulations were performed. Patient-specific inflow and pressure were incorporated, and a three-term Mooney-Rivlin model was fitted using experimental data. The viscoelastic effect of perivascular tissue was modeled with Robin boundary conditions. Prescribing pulsatile inflow and pressure resulted in a substantial increase in vein displacement ( + 400 %) and strain ( + 317 %), with a higher maximum spectral frequency becoming visible above -42 dB (from 200 to 500 Hz). Transitioning from Saint Venant-Kirchhoff to Mooney-Rivlin model led to displacement amplitudes exceeding 10 micrometers and had a substantial impact on strain ( + 116 %). Robin boundary conditions significantly damped high-frequency displacement ( - 60 %). Incorporating venous tissue properties increased vibrations by 91%, extending up to 700 Hz, with a maximum strain of 0.158. Notably, our results show localized, high levels of vibration at the inner curvature of the vein, a site known for experiencing pronounced remodeling. Our findings, consistent with experimental and clinical reports of bruits and thrills, underscore the significance of incorporating physiologically plausible modeling approaches to investigate the role of wall vibrations in AVF remodeling and failure.