Bogdan Ene-Iordache

An image-based modeling framework for patient-specific computational hemodynamics

We present a modeling framework designed for patient-specific computational hemodynamics to be performed in the context of large-scale studies. The framework takes advantage of the integration of image processing, geometric analysis and mesh generation techniques, with an accent on full automation and high-level interaction. Image segmentation is performed using implicit deformable models taking advantage of a novel approach for selective initialization of vascular branches, as well as of a strategy for the segmentation of small vessels. A robust definition of centerlines provides objective geometric criteria for the automation of surface editing and mesh generation. The framework is available as part of an open-source effort, the Vascular Modeling Toolkit, a first step towards the sharing of tools and data which will be necessary for computational hemodynamics to play a role in evidence-based medicine.

Computational geometry for patient-specific reconstruction and meshing of blood vessels from MR and CT angiography

Investigation of three-dimensional (3-D) geometry and fluid-dynamics in human arteries is an important issue in vascular disease characterization and assessment. Thanks to recent advances in magnetic resonance (MR) and computed tomography (CT), it is now possible to address the problem of patient-specific modeling of blood vessels, in order to take into account interindividual anatomic variability of vasculature. Generation of models suitable for computational fluid dynamics is still commonly performed by semiautomatic procedures, in general based on operator-dependent tasks, which cannot be easily extended to a significant number of clinical cases. In this paper, we overcome these limitations making use of computational geometry techniques. In particular, 3-D modeling was carried out by means of 3-D level sets approach. Model editing was also implemented ensuring harmonic mean curvature vectors distribution on the surface, and model geometric analysis was performed with a novel approach, based on solving Eikonal equation on Voronoi diagram. This approach provides calculation of central paths, maximum inscribed sphere estimation and geometric characterization of the surface. Generation of adaptive-thickness boundary layer finite elements is finally presented. The use of the techniques presented here makes it possible to introduce patient-specific modeling of blood vessels at clinical level.

Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial

BACKGROUND Mycophenolate mofetil has replaced azathioprine in immunosuppression regimens worldwide to prevent graft rejection. However, evidence that its antirejection activity is better than that of azathioprine has been provided only by registration trials with an old formulation of ciclosporin and steroid. We aimed to compare the antirejection activity of these two drugs with a new formulation of ciclosporin. METHODS The mycophenolate steroids sparing multicentre, prospective, randomised, parallel-group trial compared acute rejections and adverse events in recipients of cadaver-kidney transplants over 6-month treatment with mycophenolate mofetil or azathioprine along with ciclosporin microemulsion (Neoral) and steroids (phase A), and over 15 more months without steroids (phase B). The primary endpoint was occurrence of acute rejection episodes. Analysis was by intention to treat. FINDINGS 168 patients per group entered phase A. 56 (34%) assigned mycophenolate mofetil and 58 (35%) assigned azathioprine had clinical rejections (risk reduction [RR] on mycophenolate mofetil compared with azathioprine 13.7% [95% CI -25.7% to 40.7%], p=0.44). 88 patients in the mycophenolate mofetil group and 89 in the azathioprine group entered phase B. 14 (16%) taking mycophenolate mofetil and 11 (12%) taking azathioprine had clinical rejections (RR -16.2%, [-157.5% to 47.5%], p=0.71). Average per-patient costs of mycophenolate mofetil treatment greatly exceeded those of azathioprine (phase A 2665 Euros [SD 586] vs Euros 184 [62]; phase B 5095 Euros [2658] vs 322 Euros [170], p<0.0001 for both). INTERPRETATION In recipients of cadaver kidney-transplants given ciclosporin microemulsion, mycophenolate mofetil offers no advantages over azathioprine in preventing acute rejections and is about 15 times more expensive. Standard immunosuppression regimens for transplantation should perhaps include azathioprine rather than mycophenolate mofetil, at least for kidney grafts.

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.

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.

Mycophenolate Mofetil versus Azathioprine for Prevention of Chronic Allograft Dysfunction in Renal Transplantation: The MYSS Follow-Up Randomized, Controlled Clinical Trial

The Mycophenolate Steroids Sparing (MYSS) study found that in renal transplant recipients who were on immunosuppressive therapy with the cyclosporine microemulsion Neoral, mycophenolate mofetil (MMF) was not better than azathioprine in preventing acute rejection at 21 mo after transplantation and was 15 times more expensive. The MYSS Follow-up Study, an extension of MYSS, was aimed at comparing long-term outcome of 248 MYSS patients according to their original randomization to MMF (1 g twice daily) or azathioprine (75 to 100 mg/d). Primary outcome was estimated GFR at 5 yr after transplantation. Mean 5-yr GFR difference between azathioprine and mycophenolate was 4.67 ml/min per 1.73 m(2) (95% confidence interval [CI] -0.43 to 9.77 ml/min per 1.73 m(2); P = 0.07). GFR from month 6 (mean +/- SEM: 54.3 +/- 1.6 versus 53.9 +/- 1.5 ml/min per 1.73 m(2); P = 0.83) to month 72 after transplantation (49.5 +/- 2.2 versus 47.3 +/- 2.4 ml/min per 1.73 m(2); P = 0.50); GFR slopes (mean +/- SEM: -1.10 +/- 0.56 versus -1.23 +/- 0.31 ml/min per 1.73 m(2) per year; P = 0.83); and 72-mo patient mortality (4.0 versus 4.0% [P = 0.95]; HR 0.96; 95% CI 0.28 to 3.31; P = 0.95), graft loss (6.8 versus 6.1% [P = 0.82]; HR 0.89; 95% CI 0.32 to 2.46; P = 0.83), incidence of persistent proteinuria (25.0 versus 27.4%; P = 0.72), late (>6 mo after transplantation) rejections (25.3 versus 21.2%; P = 0.53), and adverse events were similar on azathioprine (n = 124) and MMF (n = 124), respectively. Outcomes in the two groups were comparable also among patients with or without steroid therapy, considered separately. In kidney transplantation, the long-term risk/benefit profile of MMF and azathioprine therapy in combination with cyclosporine Neoral is similar. In view of the cost, standard immunosuppression regimens for kidney transplantation should perhaps include azathioprine rather than MMF.

Geometric reconstruction for computational mesh generation of arterial bifurcations from CT angiography

A methodology for patient-specific model reconstruction and computational mesh generation of arterial bifurcations from angio-CT scans is presented. Three-dimensional models were reconstructed with a level set technique, analyzed with a skeletoning algorithm and automatically decomposed into branches. Cooper scheme was then employed to generate high quality hexahedral mesh. We successfully applied our technique to the carotid bifurcations of two patients affected by severe atherosclerotic plaques. The proposed technique is fast, accurate and reproducible, and can be a useful tool for the evaluation of arterial fluid dynamics within conventional computed tomography investigations.

Radial Artery Remodeling in Response to Shear Stress Increase within Arteriovenous Fistula for Hemodialysis Access

It is known that changes in blood flow induce vascular remodeling and that shear stress, the tractive force acting on the vessel wall due to blood flowing, influences endothelial cell function. The aim of the present study was to investigate the relation between changes in pulsatile shear forces and arterial remodeling in response to chronic elevation in blood flow within the radial artery. The authors studied vessel diameter, flow rate, and shear stress in the radial artery of uremic patients before and after surgical creation of a native arteriovenous fistula for hemodialysis access. For this purpose, the authors used echo-color-Doppler ultrasound to perform diameter and blood velocity measurements. Time-function blood flow rate and wall shear stress were calculated based on arterial diameter, center-line velocity wave-form, and blood viscosity, using a numerical method developed according to Womersleys theory for unsteady flow in tubes. The results confirmed that the radial artery diameter increases in response to a chronic increase in blood flow in uremic patients. Moreover, it seems that the radial artery dilates in such a way as to maintain the peak wall shear stress constant, suggesting that endothelial cells sense the maximum rather than the time-averaged wall shear stress. This finding may lead to further understanding of the mechanisms responsible for endothelial response to physical stimulation by flowing blood.

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.

Impact of Blood Pressure Control and Angiotensin-Converting Enzyme Inhibitor Therapy on New-Onset Microalbuminuria in Type 2 Diabetes: A Post Hoc Analysis of the BENEDICT Trial

For assessment of the independent renoprotective effect of BP control and angiotensin-converting enzyme inhibitor (ACEi) therapy, the relationships of baseline BP, BP reduction, and follow-up BP with the incidence of persistent microalbuminuria were evaluated in 1204 hypertensive patients who had type 2 diabetes and normoalbuminuria and were included in the BErgamo Nephrologic Diabetic Complications Trial (BENEDICT) study and were randomly assigned to 3.6 yr of treatment with the ACEi trandolapril (2 mg/d), the nondihydropyridine calcium channel blocker (ndCCB) verapamil SR (240 mg/d), their fixed combination Veratran (trandolapril 2 mg/d plus verapamil SR 180 mg/d), or placebo, plus other antihypertensive medications targeted at systolic/diastolic BP <130/80 mmHg. Follow-up (from month 3 to study end) systolic, diastolic, mean, and pulse BP and their reductions versus baseline--but not baseline BP--independently predicted (P < 0.001) the risk for microalbuminuria. In patients with follow-up BP above medians, ACEi significantly reduced the risk for microalbuminuria to levels that were observed among patients with BP below medians, regardless of ACEi treatment. The same trend was observed among patients with BP reductions below medians. ndCCB therapy did not independently affect microalbuminuria. Patients who were on Veratran had lower BP and less frequently received diuretics, beta blockers, or dihydropyridine dCCB. In hypertensive, normoalbuminuric patients with type 2 diabetes, BP reduction and ACEi therapy both independently may prevent microalbuminuria. ACEi therapy is particularly effective when BP is poorly controlled, whereas ndCCB therapy is ineffective at any level of achieved BP. As compared with trandolapril, Veratran may help with achievement of target BP with less need for concomitant antihypertensive medications.