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.

Determinants of renal tissue oxygenation as measured with BOLD-MRI in chronic kidney disease and hypertension in humans.

Experimentally renal tissue hypoxia appears to play an important role in the pathogenesis of chronic kidney disease (CKD) and arterial hypertension (AHT). In this study we measured renal tissue oxygenation and its determinants in humans using blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) under standardized hydration conditions. Four coronal slices were selected, and a multi gradient echo sequence was used to acquire T2* weighted images. The mean cortical and medullary R2* values ( = 1/T2*) were calculated before and after administration of IV furosemide, a low R2* indicating a high tissue oxygenation. We studied 195 subjects (95 CKD, 58 treated AHT, and 42 healthy controls). Mean cortical R2 and medullary R2* were not significantly different between the groups at baseline. In stimulated conditions (furosemide injection), the decrease in R2* was significantly blunted in patients with CKD and AHT. In multivariate linear regression analyses, neither cortical nor medullary R2* were associated with eGFR or blood pressure, but cortical R2* correlated positively with male gender, blood glucose and uric acid levels. In conclusion, our data show that kidney oxygenation is tightly regulated in CKD and hypertensive patients at rest. However, the metabolic response to acute changes in sodium transport is altered in CKD and in AHT, despite preserved renal function in the latter group. This suggests the presence of early renal metabolic alterations in hypertension. The correlations between cortical R2* values, male gender, glycemia and uric acid levels suggest that these factors interfere with the regulation of renal tissue oxygenation.

Effect of dark chocolate on renal tissue oxygenation as measured by BOLD-MRI in healthy volunteers.

BACKGROUND: Cocoa is rich in flavonoids, has anti-oxidative properties and increases the bioavailability of nitric oxide (NO). Adequate renal tissue oxygenation is crucial for the maintenance of renal function. The goal of this study was to investigate the effect of cocoa-rich dark chocolate (DC) on renal tissue oxygenation in humans, as compared to flavonoid-poor white chocolate (WC). METHODS: Ten healthy volunteers with preserved kidney function (mean age ± SD 35 ± 12 years, 70% women, BMI 21 ± 3 kg/m2) underwent blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) before and 2 hours after the ingestion of 1 g/kg of DC (70% cocoa). Renal tissue oxygenation was determined by the measurement of R2* maps on 4 coronal slices covering both kidneys. The mean R2* (= 1/T2*) values in the medulla and cortex were calculated, a low R2* indicating high tissue oxygenation. Eight participants also underwent BOLD-MRI at least 1 week later, before and 2 hours after the intake of 1 g/kg WC. RESULTS: The mean medullary R2* was lower after DC intake compared to baseline (28.2 ± 1.3 s-1 vs. 29.6 ± 1.3 s-1, p = 0.04), whereas cortical and medullary R2* values did not change after WC intake. The change in medullary R2* correlated with the level of circulating (epi)catechines, metabolites of flavonoids (r = 0.74, p = 0.037), and was independent of plasma renin activity. CONCLUSION: This study suggests for the first time an increase of renal medullary oxygenation after intake of dark chocolate. Whether this is linked to flavonoid-induced changes in renal perfusion or oxygen consumption, and whether cocoa has potentially renoprotective properties, merits further study.

Renal tissue oxygenation in essential hypertension and chronic kidney disease.

Animal studies suggest that renal tissue hypoxia plays an important role in the development of renal damage in hypertension and renal diseases, yet human data were scarce due to the lack of noninvasive methods. Over the last decade, blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI), detecting deoxyhemoglobin in hypoxic renal tissue, has become a powerful tool to assess kidney oxygenation noninvasively in humans. This paper provides an overview of BOLD-MRI studies performed in patients suffering from essential hypertension or chronic kidney disease (CKD). In line with animal studies, acute changes in cortical and medullary oxygenation have been observed after the administration of medication (furosemide, blockers of the renin-angiotensin system) or alterations in sodium intake in these patient groups, underlining the important role of renal sodium handling in kidney oxygenation. In contrast, no BOLD-MRI studies have convincingly demonstrated that renal oxygenation is chronically reduced in essential hypertension or in CKD or chronically altered after long-term medication intake. More studies are required to clarify this discrepancy and to further unravel the role of renal oxygenation in the development and progression of essential hypertension and CKD in humans.

Blockade of the renin-angiotensin system and renal tissue oxygenation as measured with BOLD-MRI in patients with type 2 diabetes.

AIM: To assess whether blockade of the renin-angiotensin system (RAS), a recognized strategy to prevent the progression of diabetic nephropathy, affects renal tissue oxygenation in type 2 diabetes mellitus (T2DM) patients. METHODS: Prospective randomized 2-way cross over study; T2DM patients with (micro)albuminuria and/or hypertension underwent blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) at baseline, after one month of enalapril (20 mgqd), and after one month of candesartan (16 mgqd). Each BOLD-MRI was performed before and after the administration of furosemide. The mean R2* (=1/T2*) values in the medulla and cortex were calculated, a low R2* indicating high tissue oxygenation. RESULTS: Twelve patients (mean age: 60 ± 11 years, eGFR: 62 ± 22 ml/min/1.73 m(2)) completed the study. Neither chronic enalapril nor candesartan intake modified renal cortical or medullary R2* levels. Furosemide significantly decreased cortical and medullary R2* levels suggesting a transient increase in renal oxygenation. Medullary R2* levels correlated positively with urinary sodium excretion and systemic blood pressure, suggesting lower renal oxygenation at higher dietary sodium intake and blood pressure; cortical R2* levels correlated positively with glycemia and HbA1c. CONCLUSION: RAS blockade does not seem to increase renal tissue oxygenation in T2DM hypertensive patients. The response to furosemide and the association with 24 h urinary sodium excretion emphasize the crucial role of renal sodium handling as one of the main determinants of renal tissue oxygenation.

Renal perfusion evaluation with contrast-enhanced ultrasonography.

BACKGROUND: Contrast-enhanced ultrasonography (CEUS) is a novel imaging technique that is safe and applicable on the bedside. Recent developments seem to enable CEUS to quantify organ perfusion. We performed an exploratory study to determine the ability of CEUS to detect changes in renal perfusion and to correlate them with effective renal plasma flow. METHODS: CEUS with destruction-refilling sequences was studied in 10 healthy subjects, at baseline and during infusion of angiotensin II (AngII) at low (1 ng/kg/min) and high dose (3 ng/kg/min) and 1 h after oral captopril (50 mg). Perfusion index (PI) was obtained and compared with the effective renal plasma flow (ERPF) obtained by parallel para-aminohippurate (PAH) clearance. RESULTS: Median PI decreased from 188.6 (baseline) to 100.4 with low-dose AngII (-47%; P < 0.02) and to 66.1 with high-dose AngII (-65%; P < 0.01) but increased to 254.7 with captopril (+35%; P > 0.2). These changes parallelled those observed with ERPF, which changed from a median of 672.1 mL/min (baseline) to 572.3 (low-dose AngII, -15%, P < 0.05) and to 427.2 (high-dose AngII, -36%, P < 0.001) and finally 697.1 (captopril, +4%, P < 0.02). CONCLUSIONS: This study demonstrates that CEUS is able to detect changes in human renal cortical microcirculation as induced by AngII infusion and/or captopril administration. The changes in perfusion indices parallel those in ERPF as obtained by PAH clearance.

Effect of sodium loading/depletion on renal oxygenation in young normotensive and hypertensive men.

The goal of this study was to investigate the effect of sodium intake on renal tissue oxygenation in humans. To this purpose, we measured renal hemodynamics, renal sodium handling, and renal oxygenation in normotensive (NT) and hypertensive (HT) subjects after 1 week of a high-sodium and 1 week of a low-sodium diet. Renal oxygenation was measured using blood oxygen level-dependent magnetic resonance. Tissue oxygenation was determined by the measurement of R2* maps on 4 coronal slices covering both kidneys. The mean R2* values in the medulla and cortex were calculated, with a low R2* indicating a high tissue oxygenation. Ten male NT (mean age: 26.5+/-7.4 years) and 8 matched HT subjects (mean age: 28.8+/-5.7 years) were studied. Cortical R2* was not different under the 2 conditions of salt intake. Medullary R2* was significantly lower under low sodium than high sodium in both NT and HT subjects (28.1+/-0.8 versus 31.3+/-0.6 s(-1); P<0.05 in NT; and 27.9+/-1.5 versus 30.3+/-0.8 s(-1); P<0.05, in HT), indicating higher medullary oxygenation under low-sodium conditions. In NT subjects, medullary oxygenation was positively correlated with proximal reabsorption of sodium and negatively with absolute distal sodium reabsorption, but not with renal plasma flow. In HT subjects, medullary oxygenation correlated with the 24-hour sodium excretion but not with proximal or with the distal handling of sodium. These data demonstrate that dietary sodium intake influences renal tissue oxygenation, low sodium intake leading to an increased renal medullary oxygenation both in normotensive and young hypertensive subjects.

Functional evaluation of transplanted kidneys with diffusion-weighted and BOLD MR imaging: initial experience.

PURPOSE: To prospectively evaluate feasibility and reproducibility of diffusion-weighted (DW) and blood oxygenation level-dependent (BOLD) magnetic resonance (MR) imaging in patients with renal allografts, as compared with these features in healthy volunteers with native kidneys. MATERIALS AND METHODS: The local ethics committee approved the study protocol; patients provided written informed consent. Fifteen patients with a renal allograft and in stable condition (nine men, six women; age range, 20-67 years) and 15 age- and sex-matched healthy volunteers underwent DW and BOLD MR imaging. Seven patients with renal allografts were examined twice to assess reproducibility of results. DW MR imaging yielded a total apparent diffusion coefficient including diffusion and microperfusion (ADC(tot)), as well as an ADC reflecting predominantly pure diffusion (ADC(D)) and the perfusion fraction. R2* of BOLD MR imaging enabled the estimation of renal oxygenation. Statistical analysis was performed, and analysis of variance was used for repeated measurements. Coefficients of variation between and within subjects were calculated to assess reproducibility. RESULTS: In patients, ADC(tot), ADC(D), and perfusion fraction were similar in the cortex and medulla. In volunteers, values in the medulla were similar to those in the cortex and medulla of patients; however, values in the cortex were higher than those in the medulla (P < .05). Medullary R2* was higher than cortical R2* in patients (12.9 sec(-1) +/- 2.1 [standard deviation] vs 11.0 sec(-1) +/- 0.6, P < .007) and volunteers (15.3 sec(-1) +/- 1.1 vs 11.5 sec(-1) +/- 0.5, P < .0001). However, medullary R2* was lower in patients than in volunteers (P < .004). Increased medullary R2* was paralleled by decreased diffusion in patients with allografts. A low coefficient of variation in the cortex and medulla within subjects was obtained for ADC(tot), ADC(D), and R2* (<5.2%), while coefficient of variation within subjects was higher for perfusion fraction (medulla, 15.1%; cortex, 8.6%). Diffusion and perfusion indexes correlated significantly with serum creatinine concentrations. CONCLUSION: DW and BOLD MR imaging are feasible and reproducible in patients with renal allografts.

Non-invasive monitoring of renal oxygenation using BOLD-MRI: a reproducibility study.

Blood oxygenation level-dependent (BOLD) MRI was shown to allow non-invasive observation of renal oxygenation in humans. However, clinical applications of this type of functional MRI of the kidney are still limited, most likely because of difficulties in obtaining reproducible and reliable information. The aim of this study was to evaluate the reproducibility and robustness of a BOLD method applied to the kidneys and to identify systematic physiological changes potentially influencing the renal oxygenation of healthy volunteers. To measure the BOLD effect, a modified multi-echo data image combination (MEDIC) sequence was used to acquire 12 T2*-weighted images within a single breath-hold. Three identical measurements were performed on three axial and three coronal slices of right and left kidneys in 18 volunteers. The mean R2* (1/T2*) values determined in medulla and cortex showed no significant differences over three repetitions and low intra-subject coefficients of variation (CV) (3 and 4% in medulla and cortex, respectively). The average R2* values were higher in the medulla (16.15 +/- 0.11) than in the cortex (11.69 +/- 0.18) (P < 0.001). Only a minor influence of slice orientation was observed. Mean R2* values were slightly higher (3%) in the left than in the right kidney (P < 0.001). Differences between volunteers were identified (P < 0.001). Part of these differences was attributable to age-dependent R2* values, since these values increased with age when medulla (P < 0.001, r = 0.67) or cortex (P < 0.020, r = 0.42) were considered. Thus, BOLD measurements in the kidney are highly reproducible and robust. The results allow one to identify the known cortico-medullary gradient of oxygenation evidenced by the gradient of R2* values and suggest that medulla is more hypoxic in older than younger individuals. BOLD-MRI is therefore a useful tool to study sequentially and non-invasively regional oxygenation of human kidneys.

Integrated data acquisition and processing to determine metabolite contents, relaxation times, and macromolecule baseline in single examinations of individual subjects.

Absolute quantitation of clinical (1)H-MR spectra is virtually always incomplete for single subjects because the separate determination of spectrum, baseline, and transverse and longitudinal relaxation times in single subjects is prohibitively long. Integrated Processing and Acquisition of Data (IPAD) based on a combined 2-dimensional experimental and fitting strategy is suggested to substantially improve the information content from a given measurement time. A series of localized saturation-recovery spectra was recorded and combined with 2-dimensional prior-knowledge fitting to simultaneously determine metabolite T(1) (from analysis of the saturation-recovery time course), metabolite T(2) (from lineshape analysis based on metabolite and water peak shapes), macromolecular baseline (based on T(1) differences and analysis of the saturation-recovery time course), and metabolite concentrations (using prior knowledge fitting and conventional procedures of absolute standardization). The procedure was tested on metabolite solutions and applied in 25 subjects (15-78 years old). Metabolite content was comparable to previously found values. Interindividual variation was larger than intraindividual variation in repeated spectra for metabolite content as well as for some relaxation times. Relaxation times were different for various metabolite groups. Parts of the interindividual variation could be explained by significant age dependence of relaxation times.

Observation and identification of metabolites emerging during postmortem decomposition of brain tissue by means of in situ 1H-magnetic resonance spectroscopy.

Postmortem decomposition of brain tissue was investigated by (1)H-magnetic resonance spectroscopy (MRS) in a sheep head model and selected human cases. Aiming at the eventual estimation of postmortem intervals in forensic medicine, this study focuses on the characterization and identification of newly observed metabolites. In situ single-voxel (1)H-MRS at 1.5 T was complemented by multidimensional homo- and heteronuclear high-resolution NMR spectroscopy of an extract of sheep brain tissue. The inclusion of spectra of model solutions in the program LC Model confirmed the assignments in situ. The first postmortem phase was characterized mainly by changes in the concentrations of metabolites usually observed in vivo and by the appearance of previously reported decay products. About 3 days postmortem, new metabolites, including free trimethylammonium, propionate, butyrate, and iso-butyrate, started to appear in situ. Since the observed metabolites and the time course is comparable in sheep and human brain tissue, the model system seems to be appropriate.