Intra-bin correction and inter-bin compensation of respiratory motion in free-running five-dimensional whole-heart magnetic resonance imaging.

BACKGROUND: Free-running cardiac and respiratory motion-resolved whole-heart five-dimensional (5D) cardiovascular magnetic resonance (CMR) can reduce scan planning and provide a means of evaluating respiratory-driven changes in clinical parameters of interest. However, respiratory-resolved imaging can be limited by user-defined parameters which create trade-offs between residual artifact and motion blur. In this work, we develop and validate strategies for both correction of intra-bin and compensation of inter-bin respiratory motion to improve the quality of 5D CMR. METHODS: Each component of the reconstruction framework was systematically validated and compared to the previously established 5D approach using simulated free-running data (N = 50) and a cohort of 32 patients with congenital heart disease. The impact of intra-bin respiratory motion correction was evaluated in terms of image sharpness while inter-bin respiratory motion compensation was evaluated in terms of reconstruction error, compression of respiratory motion, and image sharpness. The full reconstruction framework (intra-acquisition correction and inter-acquisition compensation of respiratory motion [IIMC] 5D) was evaluated in terms of image sharpness and scoring of image quality by expert reviewers. RESULTS: Intra-bin motion correction provides significantly (p < 0.001) sharper images for both simulated and patient data. Inter-bin motion compensation results in significant (p < 0.001) lower reconstruction error, lower motion compression, and higher sharpness in both simulated (10/11) and patient (9/11) data. The combined framework resulted in significantly (p < 0.001) sharper IIMC 5D reconstructions (End-expiration (End-Exp): 0.45 ± 0.09, End-inspiration (End-Ins): 0.46 ± 0.10) relative to the previously established 5D implementation (End-Exp: 0.43 ± 0.08, End-Ins: 0.39 ± 0.09). Similarly, image scoring by three expert reviewers was significantly (p < 0.001) higher using IIMC 5D (End-Exp: 3.39 ± 0.44, End-Ins: 3.32 ± 0.45) relative to 5D images (End-Exp: 3.02 ± 0.54, End-Ins: 2.45 ± 0.52). CONCLUSION: The proposed IIMC reconstruction significantly improves the quality of 5D whole-heart MRI. This may be exploited for higher resolution or abbreviated scanning. Further investigation of the diagnostic impact of this framework and comparison to gold standards is needed to understand its full clinical utility, including exploration of respiratory-driven changes in physiological measurements of interest.

On the Determination of Lagrange Multipliers for a Weighted LASSO Problem Using Geometric and Convex Analysis Techniques.

Compressed Sensing (CS) encompasses a broad array of theoretical and applied techniques for recovering signals, given partial knowledge of their coefficients, cf. Candés (C. R. Acad. Sci. Paris, Ser. I 346, 589-592 (2008)), Candés et al. (IEEE Trans. Inf. Theo (2006)), Donoho (IEEE Trans. Inf. Theo. 52(4), (2006)), Donoho et al. (IEEE Trans. Inf. Theo. 52(1), (2006)). Its applications span various fields, including mathematics, physics, engineering, and several medical sciences, cf. Adcock and Hansen (Compressive Imaging: Structure, Sampling, Learning, p. 2021), Berk et al. (2019 13th International conference on Sampling Theory and Applications (SampTA) pp. 1-5. IEEE (2019)), Brady et al. (Opt. Express 17(15), 13040-13049 (2009)), Chan (Terahertz imaging with compressive sensing. Rice University, USA (2010)), Correa et al. (2014 IEEE International Conference on Acoustics, Speech and Signal Processing (ICASSP) pp. 7789-7793 (2014, May) IEEE), Gao et al. (Nature 516(7529), 74-77 (2014)), Liu and Kang (Opt. Express 18(21), 22010-22019 (2010)), McEwen and Wiaux (Mon. Notices Royal Astron. Soc. 413(2), 1318-1332 (2011)), Marim et al. (Opt. Lett. 35(6), 871-873 (2010)), Yu and Wang (Phys. Med. Biol. 54(9), 2791 (2009)), Yu and Wang (Phys. Med. Biol. 54(9), 2791 (2009)). Motivated by our interest in the mathematics behind Magnetic Resonance Imaging (MRI) and CS, we employ convex analysis techniques to analytically determine equivalents of Lagrange multipliers for optimization problems with inequality constraints, specifically a weighted LASSO with voxel-wise weighting. We investigate this problem under assumptions on the fidelity term Ax-b22, either concerning the sign of its gradient or orthogonality-like conditions of its matrix. To be more precise, we either require the sign of each coordinate of 2(Ax-b)TA to be fixed within a rectangular neighborhood of the origin, with the side lengths of the rectangle dependent on the constraints, or we assume ATA to be diagonal. The objective of this work is to explore the relationship between Lagrange multipliers and the constraints of a weighted variant of LASSO, specifically in the mentioned cases where this relationship can be computed explicitly. As they scale the regularization terms of the weighted LASSO, Lagrange multipliers serve as tuning parameters for the weighted LASSO, prompting the question of their potential effective use as tuning parameters in applications like MR image reconstruction and denoising. This work represents an initial step in this direction.

Similarity-driven multi-dimensional binning algorithm (SIMBA) for free-running motion-suppressed whole-heart MRA.

PURPOSE: Whole-heart MRA techniques typically target predetermined motion states, address cardiac and respiratory dynamics independently, and require either complex planning or computationally demanding reconstructions. In contrast, we developed a fast data-driven reconstruction algorithm with minimal physiological assumptions and compatibility with ungated free-running sequences. THEORY AND METHODS: We propose a similarity-driven multi-dimensional binning algorithm (SIMBA) that clusters continuously acquired k-space data to find a motion-consistent subset for whole-heart MRA reconstruction. Free-running 3D radial data sets from 12 non-contrast-enhanced scans of healthy volunteers and six ferumoxytol-enhanced scans of pediatric cardiac patients were reconstructed with non-motion-suppressed regridding of all the acquired data ("All Data"), with SIMBA, and with a previously published free-running framework (FRF) that uses cardiac and respiratory self-gating and compressed sensing. Images were compared for blood-myocardium sharpness and contrast ratio, visibility of coronary artery ostia, and right coronary artery sharpness. RESULTS: Both the 20-second SIMBA reconstruction and FRF provided significantly higher blood-myocardium sharpness than All Data in both patients and volunteers (P < .05). The SIMBA reconstruction provided significantly sharper blood-myocardium interfaces than FRF in volunteers (P < .001) and higher blood-myocardium contrast ratio than All Data and FRF, both in volunteers and patients (P < .05). Significantly more ostia could be visualized with both SIMBA (31 of 36) and FRF (34 of 36) than with All Data (4 of 36) (P < .001). Inferior right coronary artery sharpness using SIMBA versus FRF was observed (volunteers: SIMBA 36.1 ± 8.1%, FRF 40.4 ± 8.9%; patients: SIMBA 35.9 ± 7.7%, FRF 40.3 ± 6.1%, P = not significant). CONCLUSION: The SIMBA technique enabled a fast, data-driven reconstruction of free-running whole-heart MRA with image quality superior to All Data and similar to the more time-consuming FRF reconstruction.

Subsegmentation of the Kidney in Experimental MR Images Using Morphology-Based Regions-of-Interest or Multiple-Layer Concentric Objects.

Functional renal MRI promises access to a wide range of physiologically relevant parameters such as blood oxygenation, perfusion, tissue microstructure, pH, and sodium concentration. For quantitative comparison of results, representative values must be extracted from the parametric maps obtained with these different MRI techniques. To improve reproducibility of results this should be done based on regions-of-interest (ROIs) that are clearly and objectively defined.Semiautomated subsegmentation of the kidney in magnetic resonance images represents a simple but very valuable approach for the quantitative analysis of imaging parameters in multiple ROIs that are associated with specific anatomic locations. Thereby, it facilitates comparing MR parameters between different kidney regions, as well as tracking changes over time.Here we provide detailed step-by-step instructions for two recently developed subsegmentation techniques that are suitable for kidneys of small rodents: i) the placement of ROIs in cortex, outer and the inner medulla based on typical kidney morphology and ii) the division of the kidney into concentrically oriented layers.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers.

Radial-based acquisition strategies for pre-procedural non-contrast cardiovascular magnetic resonance angiography of the pulmonary veins.

BACKGROUND: Computed tomography angiography (CTA) or contrast-enhanced (CE) cardiovascular magnetic resonance angiography (CMRA) is often obtained in patients with atrial fibrillation undergoing evaluation prior to pulmonary vein (PV) isolation. Drawbacks of CTA include radiation exposure and potential risks from iodinated contrast agent administration. Free-breathing 3D balanced steady-state free precession (bSSFP) Non-contrast CMRA is a potential imaging option, but vascular detail can be suboptimal due to ghost artifacts and blurring that tend to occur with a Cartesian k-space trajectory or, in some cases, inconsistent respiratory gating. We therefore explored the potential utility of both breath-holding and free-breathing non-contrast CMRA, using radial k-space trajectories that are known to be less sensitive to flow and motion artifacts than Cartesian. MAIN BODY: Free-breathing 3D Cartesian and radial stack-of-stars acquisitions were compared in 6 healthy subjects. In addition, 27 patients underwent CTA and non-contrast CMRA for PV mapping. Three radial CMR acquisition strategies were tested: (1) breath-hold (BH) 2D radial bSSFP (BH-2D); (2) breath-hold, multiple thin-slab 3D stack-of-stars bSSFP (BH-SOS); and (3) navigator-gated free-breathing (FB) 3D stack-of-star bSSFP using a spatially non-selective RF excitation (FB-NS-SOS). A non-rigid registration algorithm was used to compensate for variations in breath-hold depth. In healthy subjects, image quality and vessel sharpness using a free-breathing 3D SOS acquisition was significantly better than free-breathing (FB) Cartesian 3D. In patients, diagnostic image quality was obtained using all three radial CMRA techniques, with BH-SOS and FB-NS-SOS outperforming BH-2D. There was overall good correlation for PV maximal diameter between BH-2D and CTA (ICC = 0.87/0.83 for the two readers), excellent correlation between BH-SOS and CTA (ICC = 0.90/0.91), and good to excellent correlation between FB-NS-SOS and CTA (ICC = 0.87/0.94). For PV area, there was overall good correlation between BH-2D and CTA (ICC = 0.79/0.83), good to excellent correlation between BH-SOS and CTA (ICC = 0.88/0.91) and excellent correlation between FB-NS-SOS and CTA (ICC = 0.90/0.95). CNR was significantly higher with BH-SOS (mean = 11.04) by comparison to BH-2D (mean = 6.02; P = 0.007) and FB-NS-SOS (mean = 5.29; P = 0.002). CONCLUSION: Our results suggest that a free-breathing stack-of-stars bSSFP technique is advantageous in providing accurate depiction of PV anatomy and ostial measurements without significant degradation from off-resonance artifacts, and with better image quality than Cartesian 3D. For patients in whom respiratory gating is unsuccessful, a breath-hold thin-slab stack-of-stars technique with retrospective motion correction may be a useful alternative.

Acute and Chronic Effects of SGLT2 Inhibitor Empagliflozin on Renal Oxygenation and Blood Pressure Control in Nondiabetic Normotensive Subjects: A Randomized, Placebo-Controlled Trial.

Background The sodium/glucose cotransporter 2 inhibitor empagliflozin has cardiorenal protective properties through mechanisms beyond glucose control. In this study we assessed whether empagliflozin modifies renal oxygenation as a possible mechanism of renal protection, and determined the metabolic, renal, and hemodynamic effects of empagliflozin in nondiabetic subjects. Methods and Results In this double-blind, randomized, placebo-controlled study, 45 healthy volunteers underwent blood and urine sampling, renal ultrasound, and blood-oxygenation-level-dependent magnetic resonance imaging before and 180 minutes after administration of 10 mg empagliflozin (n=30) or placebo (n=15). These examinations were repeated after 1 month of daily intake. Cortical and medullary renal oxygenation were not affected by the acute or chronic administration of empagliflozin, as determined by 148 renal blood-oxygenation-level-dependent magnetic resonance imaging examinations. Empagliflozin increased glucosuria (24-hour glucosuria at 1 month: +50.1±16.3 g). The acute decrease in proximal sodium reabsorption, as determined by endogenous fractional excretion of lithium (-34.6% versus placebo), was compensated at 1 month by a rise in plasma renin activity (+28.6%) and aldosterone (+55.7%). The 24-hour systolic and diastolic ambulatory blood pressures decreased significantly after 1 month of empagliflozin administration (-5.1 and -2.0 mm Hg, respectively). Serum uric acid levels decreased (-28.4%), hemoglobin increased (+1.7%), and erythropoietin remained the same. Conclusions Empagliflozin has a rapid and significant effect on tubular function, with sustained glucosuria and transient natriuresis in nondiabetic normotensive subjects. These effects favor blood pressure reduction. No acute or sustained changes were found in renal cortical or medullary tissue oxygenation. It remains to be determined whether this is the case in nondiabetic or diabetic patients with congestive heart failure or kidney disease. REGISTRATION: URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT03093103.

Short-term changes in dietary sodium intake influence sweat sodium concentration and muscle sodium content in healthy individuals.

OBJECTIVE: There is increasing evidence that sodium can be stored in the skin and muscles without being osmotically active, yet whether acute changes in dietary sodium intake alter sweat and muscle sodium content has not been investigated previously. METHODS: In a cross-over design, we assessed muscle sodium content by Na-MRI in 38 healthy normotensive volunteers (aged 33.5 ±â€Š11.1 years, 76.3% women) after 5 days of high-sodium diet (6 g of salt added to their normal diet) and 5 days of a low-sodium diet. In a subgroup of 18 participants (72.2% women) we conducted quantitative pilocarpine iontophoretic sweat collections and measured the sodium concentration in sweat. Plasma aldosterone and plasma renin activity levels were measured in all participants. RESULTS: Under high-sodium diet conditions urinary sodium excretion, muscle sodium content and sweat sodium concentration all increased significantly. Muscle sodium content (rm = 0.47, P = 0.03) and sodium sweat concentration (rm = 0.72, P < 0.001) correlated positively with salt intake as estimated by 24-h urine sodium excretion. Age, sex or the phase of the menstrual cycle did not influence muscle or sweat sodium concentrations or their changes. In contrast, plasma aldosterone levels were negatively associated with both muscle sodium (rs = -0.42, P = 0.0001) and sweat sodium content (rs = -0.52, P = 0.002). Plasma renin activity correlated negatively with sweat sodium (rs = -0.43, P = 0.012) and muscle sodium levels (rs = -0.42, P < 0.001). CONCLUSION: Muscle and sweat sodium concentrations are significantly higher on a high-salt intake in healthy male and female individuals, suggesting that muscle and sweat play a role in regulating sodium balance in humans.

Renal BOLD MRI in patients with chronic kidney disease: comparison of the semi-automated twelve layer concentric objects (TLCO) and manual ROI methods.

OBJECTIVE: Blood oxygenation level dependent (BOLD) MRI technique is used to evaluate changes in intra-renal oxygenation in chronic kidney disease (CKD). The purpose of this study was to evaluate if the novel twelve layer concentric objects (TLCO) method has advantages over the manually defined regions of interest (ROI) analysis. METHODS AND MATERIALS: Existing renal BOLD MRI data acquired before and after furosemide on a 3 T scanner from 41 CKD patients and 13 age matched healthy controls were analyzed using TLCO method and compared with previously reported ROI analysis. RESULTS: Regional R2* measurements were strongly correlated between the two methods, while ΔR2* was moderately correlated. Medullary R2* by ROI analysis showed higher values compared to R2*_Inner by TLCO, probably due to the contributions from the cortex to R2*_Inner. R2*_Slope and Δ(R2*_Slope), unique parameters based on the TLCO method provided the most significant differences between stage 3a CKD patients and controls and were correlated with eGFR. DISCUSSION: There was a high degree of agreement between the two methods in terms of regional R2* measurements and both methods did not show differences between moderate CKD patients and controls. However, R2*_Slope and Δ(R2*_Slope) showed the largest sensitivity in distinguishing CKD from controls.

Consensus-based technical recommendations for clinical translation of renal BOLD MRI.

Harmonization of acquisition and analysis protocols is an important step in the validation of BOLD MRI as a renal biomarker. This harmonization initiative provides technical recommendations based on a consensus report with the aim to move towards standardized protocols that facilitate clinical translation and comparison of data across sites. We used a recently published systematic review paper, which included a detailed summary of renal BOLD MRI technical parameters and areas of investigation in its supplementary material, as the starting point in developing the survey questionnaires for seeking consensus. Survey data were collected via the Delphi consensus process from 24 researchers on renal BOLD MRI exam preparation, data acquisition, data analysis, and interpretation. Consensus was defined as ≥ 75% unanimity in response. Among 31 survey questions, 14 achieved consensus resolution, 12 showed clear respondent preference (65-74% agreement), and 5 showed equal (50/50%) split in opinion among respondents. Recommendations for subject preparation, data acquisition, processing and reporting are given based on the survey results and review of the literature. These technical recommendations are aimed towards increased inter-site harmonization, a first step towards standardization of renal BOLD MRI protocols across sites. We expect this to be an iterative process updated dynamically based on progress in the field.

Exploring a new method for quantitative sodium MRI in the human upper leg with a surface coil and symmetrically arranged reference phantoms.

BACKGROUND: The aim of this study is to validate and evaluate the reproducibility of a new setup for the quantification of the tissue sodium concentration (TSC) in the human upper leg muscles with sodium MRI at 3 Tesla. This setup is making use of an emit and receive single loop surface coil together with a set of square, symmetrically arranged reference phantoms. As a second aim, the performances of two MRI protocols for the TSC quantification in the upper leg muscles are compared: one using an ultra-short echo time (UTE) 3-dimensional radial sequence (UTE-protocol), and the other one using standard gradient echo sequence (GRE-protocol). METHODS: A validation test of the quantification of sodium concentration is performed in phantoms. The bias of the method is estimated and compared between both protocols. The reproducibility of TSC quantification is assessed in phantoms by the coefficient of variation (CV) and compared between both protocols. The reproducibility is also assessed in 11 health volunteers. Signal to noise ratio (SNR) maps are acquired in phantoms with both protocols in order to compare the resulting SNR. RESULTS: The apparatus and post processing were successfully implemented. The bias of the method was smaller than 10% in phantoms (excepted for Na concentration of 10 mmol/L when using the GRE protocol). The reproducibility of the method using symmetrically arranged phantoms was high in phantoms and humans (CV <5%). The GRE-protocol leads to a better SNR than the UTE-protocol in 2D images. CONCLUSIONS: The use of symmetrically arranged reference phantoms lead to reproducible results in phantoms and humans. Sodium imaging in the human upper leg with a single loop surface coil should be performed with a standard 2-dimensional GRE protocol if an optimal SNR is needed. However, the quantification of the fast and slow decay time constants of the sodium signal, which plays a role in the TSC quantification, still has to be done with a UTE sequence. Moreover, the quantification of sodium concentration is more accurate with the UTE protocol for small sodium concentrations (<20 mmol).

Acute hyperglycemia increases renal tissue oxygenation as measured by BOLD-MRI in healthy overweight volunteers.

AIM: Animal studies have suggested that acute hyperglycemia induces transient renal hypoxia and kidney damage, yet this has not been tested in humans. Therefore, we assessed in human subjects the effect of acute hyperglycemia on renal tissue oxygenation as measured with blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI). METHODS: In this single center prospective interventional study, healthy overweight subjects were recruited. BOLD-MRI was performed before and immediately after the intravenous administration of 0.15 g/kg of glucose in a 20% solution under standard hydration and fasting conditions. R2* maps were analyzed using the twelve layer concentric objects (TLCO) technique, a semi-automatic procedure which divides the kidney parenchyma in 12 equal layers at increasing depth. R2* is a measure of local desoxyhemoglobin concentrations, with high R2* values corresponding to low oxygenation. RESULTS: Nineteen overweight subjects were enrolled (age 37 ±â€¯10 years, BMI 28.9 ±â€¯3 kg/m2, HbA1c 5.4 ±â€¯0.3%, 57.9% women): 5 were glucose intolerant, none had diabetes. The mean glycemia rose from 4.5 ±â€¯0.3 mmol/l to 9.0 ±â€¯0.9, 8.9 ±â€¯0.7, 7.7 ±â€¯0.6 and 6.8 ±â€¯0.8 mmol/l at respectively 1, 10, 20 and 30 min after IV glucose. Circulating insulin levels quadrupled. The mean R2* values decreased significantly in all kidney layers, irrespective of glucose intolerance. The lower BMI, the larger the decrease in R2*(spearman's r = 0.41, p = 0.035). CONCLUSION: These data show that acute hyperglycemia decreases the R2* signal in humans, suggesting an acute increase in renal tissue oxygenation. The precise mechanism of this observation remains unknown, and whether this phenomenon also occurs in patients with diabetes needs additional studies.

Image acquisition for intravoxel incoherent motion imaging of kidneys should be triggered at the instant of maximum blood velocity: evidence obtained with simulations and in vivo experiments.

PURPOSE: To demonstrate that diffusion-weighted images should be acquired at the instant of maximum blood velocity in kidneys to extract the perfusion fraction (PF) by the bi-exponential intravoxel incoherent motion model. METHODS: The PF values were measured in Monte-Carlo simulations corresponding to different blood velocities with a constant known PF. The distribution of the measured PF values (PF-distribution) was characterized quantitatively by 3 markers highlighting the deviation of the measurement from the true PF. Diffusion-weighted images of kidneys were acquired in 10 healthy volunteers at the instant of maximal respectively minimal blood velocity in the renal artery (Vmax versus Vmin acquisition). The PF-distributions measured from the Vmax and Vmin acquisitions were compared mutually and with simulated PF-distributions using the 3 markers. A radiologist evaluated the quality of the PF maps. RESULTS: The PF-distributions measured in the simulations were spread around the true PF value, and spreading was reduced as blood velocity increased. A comparison between simulated and in vivo PF-distributions suggests that a similar phenomenon is plausible in vivo. The quality of the PF maps of the Vmax -acquisition was scored higher by the radiologist than those of the Vmin -acquisition in 95% of cases (19 of 20). CONCLUSIONS: The PF maps are of better quality when the Vmax -acquisition is used. We show evidence supporting the hypothesis that the variation of PF along the cardiac cycle is due to oscillations between a poor estimation when the blood velocity is low, and a better estimation when blood velocity is higher.

Reduced cortical oxygenation predicts a progressive decline of renal function in patients with chronic kidney disease.

Renal tissue hypoxia is a final pathway in the development and progression of chronic kidney disease (CKD), but whether renal oxygenation predicts renal function decline in humans has not been proven. Therefore, we performed a prospective study and measured renal tissue oxygenation by blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) in 112 patients with CKD, 47 with hypertension without CKD, and 24 healthy control individuals. Images were analyzed with the twelve-layer concentric objects method that divided the renal parenchyma in 12 layers of equal thickness and reports the mean R2* value of each layer (a high R2* corresponds to low oxygenation), along with the change in R2* between layers called the R2* slope. Serum creatinine values were collected to calculate the yearly change in estimated glomerular function rate (MDRD eGFR). Follow up was three years. The change in eGFR in CKD, hypertensive and control individuals was -2.0, 0.5 and -0.2 ml/min/1.73m2/year, respectively. In multivariable regression analysis adjusted for age, sex, diabetes, RAS-blockers, eGFR, and proteinuria the yearly eGFR change correlated negatively with baseline 24 hour proteinuria and the mean R2* value of the cortical layers, and positively with the R2* slope, but not with the other covariates. Patients with CKD and high outer R2* or a flat R2* slope were three times more likely to develop an adverse renal outcome (renal replacement therapy or over a 30% increase in serum creatinine). Thus, low cortical oxygenation is an independent predictor of renal function decline. This finding should stimulate studies exploring the therapeutic impact of improving renal oxygenation on renal disease progression.

Serum calcification propensity is associated with renal tissue oxygenation and resistive index in patients with arterial hypertension or chronic kidney disease.

BACKGROUND: Arterial calcifications increase arterial stiffness and are associated with a faster decline of kidney function in patients with arterial hypertension (AH) and/or chronic kidney disease (CKD). Yet the underlying mechanisms linking arterial calcifications, vascular stiffness and renal function decline are incompletely understood. A novel in-vitro blood test evaluates the propensity of patient's serum to prevent the formation of calcifications by measuring the maturation time of calciprotein particles (CPP) [transformation time of amorphous calcium phosphate-containing primary CPP to crystalline hydroxyapatite-containing secondary CPP (T50)]. We hypothesized that a high arterial stiffness and a high propensity to calcify may be associated with high renal vascular resistance and low renal tissue oxygenation. METHODS: T50 was measured in patients with AH and a preserved renal function, in CKD patients and in healthy controls, a lower T50 indicating a higher risk of calcification. Pulse wave velocity (PWV) was assessed as a measure of arterial stiffness, and renal resistive index was measured by renal Doppler ultrasound. Renal tissue oxygenation was measured by blood oxygenation level-dependent MRI using the mean R2 values of the cortex, the medulla and layers of renal parenchyma. A high R2 value corresponds to a low tissue oxygenation. RESULTS: Mean T50 was 246 ±â€Š129 min in 58 CKD patients, 275 ±â€Š111 min in 48 AH patients and 324 ±â€Š96 min in 39 healthy controls (Panova = 0.008). In multivariable adjusted linear regression analysis, serum T50 correlated negatively with circulating calcium and phosphate levels, mean cortical and medullary R2, PWV, renal resistive index and being hypertensive. PWV was positively associated with R2 levels of outer and inner layers of renal parenchyma. CONCLUSION: The current study shows that hypertensive patients with preserved renal function as well as CKD patients have a higher risk of calcification than controls. High arterial stiffness and calcification propensity are linked to low renal tissue oxygenation and perfusion in hypertensive and CKD patients. These results provide new insights on the relationships among arterial stiffness, renal tissue oxygenation and the risk of developing CKD.

Reduction of cortical oxygenation in chronic kidney disease: evidence obtained with a new analysis method of blood oxygenation level-dependent magnetic resonance imaging.

BACKGROUND: Determinations of renal oxygenation by blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) in chronic kidney disease (CKD) patients have given heterogeneous results, possibly due to the lack of a reproducible method to analyse BOLD-MRI. It therefore remains uncertain whether patients with CKD have a reduced renal tissue oxygenation. We developed a new method to analyse BOLD-MRI signals and applied it to CKD patients and controls. METHODS: MRI was performed under standardized conditions before and 15 min after IV furosemide in 104 CKD patients, 61 hypertensives and 42 controls. MR images were analysed with the new twelve-layer concentric objects method (TLCO) that divides renal parenchyma in 12 layers of equal thickness. The mean R2* value of each layer was reported, along with the change in R2* between successive layers, as measured by the slope steepness of the relevant curve. RESULTS: Inter-observer variability was 2.3 ± 0.9%, 1.9 ± 0.8% and 3.0 ± 2.3% in, respectively, controls, moderate and severe CKD. The mean R2* of the outer (more cortical) layers was significantly higher in CKD, suggesting lower cortical oxygenation as compared with controls. In CKD patients, the response to furosemide was blunted in the inner (more medullary) layers, and the R2* slope was flatter. In multivariable regression analysis, the R2* slope correlated positively with estimated glomerular filtration rate (eGFR) in patients with an eGFR <90 mL/min/1.73 m2 (P < 0.001). CONCLUSIONS: Using the new TLCO method, we confirm the hypothesis that renal cortical oxygenation is reduced in CKD in humans, and that the level of cortical oxygenation correlates with CKD severity.

Renal tissue oxygenation in children with chronic kidney disease due to vesicoureteral reflux.

BACKGROUND: Vesicoureteral reflux (VUR) is a frequent cause of chronic kidney disease (CKD) in children. Using blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI), we measured cortical and medullary oxygenation in children with CKD due to VUR and compared the results to those obtained on healthy controls. METHOD: The study population comprised 37 children (19 with CKD due to VUR and 18 healthy age-matched controls). BOLD-MRI was performed before and after furosemide treatment. MR images were analyzed with the region-of-interest (ROI) technique to assess the mean R2* values (=1/T2*) of the cortex and medulla of each kidney and with the concentric object (CO) technique that divides renal parenchyma in 12 equal layers. RESULTS: R2* values were significantly lower (corresponding to higher oxygenation) in the cortex and medulla of kidneys of children with CKD due to VUR than in those of the healthy controls (cortex 16.4 ± 1.4 vs. 17.2 ± 1.6 s(-1) , respectively; medulla 28.4 ± 3.2 vs. 30.3 ± 1.9 s(-1) , respectively; P < 0.05), and furosemide-induced changes in medullary R2* were smaller in the former than in the latter (-5.7 ± 3.0 vs. -6.9 ± 3.4 s(-1), respectively; P < 0.05). Similar results were found with the CO technique. In children with a history of unilateral reflux (n = 9), the non-affected contralateral kidneys presented similar R2* values as the diseased kidneys, but their response to furosemide was significantly larger (-7.4 ± 3.2 vs. -5.7 ± 3.0, respectively; P = 0.05). CONCLUSIONS: Chronic kidney disease due to VUR is not associated with kidney tissue hypoxia in children. The significantly larger furosemide-induced decrease in medullary R2* levels in the healthy group and unaffected contralateral kidneys of the VUR group points towards more intense renal sodium transport in these kidneys.

Blood Oxygenation Level-Dependent MRI to Assess Renal Oxygenation in Renal Diseases: Progresses and Challenges.

BOLD-MRI (blood oxygenation-level dependent magnetic resonance imaging) allows non-invasive measurement of renal tissue oxygenation in humans, without the need for contrast products. BOLD-MRI uses the fact that magnetic properties of hemoglobin depend of its oxygenated state:: the higher local deoxyhemoglobin, the higher the so called apparent relaxation rate R2* (sec-1), and the lower local tissue oxygen content. Several factors other than deoxyhemoglobin (such as hydration status, dietary sodium intake, and susceptibility effects) influence the BOLD signal, and need to be taken into account when interpreting results. The last 5 years have witnessed important improvements in the standardization of these factors, and the appearance of new, highly reproducible analysis techniques of BOLD-images, that are reviewed in this article. Using these new BOLD-MRI analysis techniques, it has recently been shown that persons suffering from chronic kidney diseases (CKD) have lower cortical oxygenation than normotensive controls, thus confirming the chronic hypoxia hypothesis. The acute alterations in R2* after the administration of furosemide are smaller in CKD, and represent an estimate of the oxygen-dependent tubular transport of sodium. BOLD-MRI-alone or in combination with other functional MRI methods- can be used to monitor the renal effects of drugs, and is increasingly used in the preclinical setting. The near future will tell whether or not BOLD-MRI represents a new tool to predict renal function decline an adverse renal outcome.

Comparative Effect of a Renin Inhibitor and a Thiazide Diuretic on Renal Tissue Oxygenation in Hypertensive Patients.

BACKGROUND/AIMS: The purpose of the present study was to compare the direct renin inhibitor aliskiren to the diuretic hydrochlorothiazide (HCTZ) in their ability to modulate renal tissue oxygenation in hypertensive patients. METHODS: 24 patients were enrolled in this randomized prospective study and 20 completed the protocol. Patients were randomly assigned to receive either aliskiren 150-300 mg/d or HCTZ 12.5 - 25 mg/d for 8 weeks. Renal oxygenation was measured by BOLD-MRI at weeks 0 and 8. BOLD-MRI was also performed before and after an i.v. injection of 20 mg furosemide at week 0 and at week 8. BOLD-MRI data were analyzed by measuring the oxygenation in 12 computed layers of the kidney enabling to asses renal oxygenation according to the depth within the kidney and by the classical method of regions of interest (ROI). RESULTS: The classical ROI analysis of the data showed no difference between the groups at week 8. The analysis of renal oxygenation according to the 12 layers method shows no significant difference between aliskiren and HCTZ at week 8 before administration of furosemide. However, within group analyses show that aliskiren slightly but not significantly increased oxygenation in the cortex and decreased medullary oxygenation whereas HCTZ induced a significant overall decrease in renal tissue oxygenation. With the same method of analysis we observed that the response to furosemide was unchanged in the HCTZ group at week 8 but was characterized by an increase in both cortical and medullary oxygenation in aliskiren-treated patients. Patients responding to aliskiren and HCTZ by a fall in systolic blood pressure of >10 mmHg improved their renal tissue oxygenation when compared to non-responders. CONCLUSION: With the classical method of evaluation using regions no difference were found between aliskiren and HCTZ on renal tissue oxygenation after 8 weeks. In contrast, with our new method that takes into account the entire kidney, within group analyses show that aliskiren slightly increases cortical and medullary renal tissue oxygenation in hypertensive patients whereas HCTZ decreases significantly renal oxygenation at trough.

A new technique with high reproducibility to estimate renal oxygenation using BOLD-MRI in chronic kidney disease.

OBJECTIVES: To assess inter-observer variability of renal blood oxygenation level-dependent MRI (BOLD-MRI) using a new method of analysis, called the concentric objects (CO) technique, in comparison with the classical ROI (region of interest)-based technique. METHODS: MR imaging (3T) was performed before and after furosemide in 10 chronic kidney disease (CKD) patients (mean eGFR 43±24ml/min/1.73m(2)) and 10 healthy volunteers (eGFR 101±28ml/min1.73m(2)), and R2* maps were determined on four coronal slices. In the CO-technique, R2* values were based on a semi-automatic procedure that divided each kidney in six equal layers, whereas in the ROI-technique, all circles (ROIs) were placed manually in the cortex and medulla. The mean R2*values as assessed by two independent investigators were compared. RESULTS: With the CO-technique, inter-observer variability was 0.7%-1.9% across all layers in non-CKD, versus 1.6%-3.8% in CKD. With the ROI-technique, median variability for cortical and medullary R2* values was 3.6 and 6.8% in non-CKD, versus 4.7 and 12.5% in CKD; similar results were observed after furosemide. CONCLUSION: The CO-technique offers a new, investigator-independent, highly reproducible alternative to the ROI-based technique to estimate renal tissue oxygenation in CKD.