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Background: Individuals with chronic kidney disease (CKD) have a high burden of cardiovascular disease (CVD). Abnormalities in cardiac structure and function represent subclinical CVD and can be assessed by cardiac magnetic resonance imaging (cMRI). Methods: We investigated differences in cMRI parameters in 140 individuals with CKD stages 3b-4 who participated in the CKD Optimal Management with BInders and NicotinamidE (COMBINE) trial and in 24 age-and sex matched healthy volunteers. Among COMBINE participants, we examined the associations of estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), phosphate, fibroblast growth factor 23 (FGF23), and parathyroid hormone (PTH) with baseline (N=140) and 12-month change (N=112) in cMRI parameters. Results: Mean (standard deviation [SD]) age of the COMBINE participants and healthy volunteers were 64.9 (11.9) and 60.4 (7.3) years. The mean (SD) baseline eGFR in COMBINE participants was 32.1 (8.0) and 85.9 (16.0) ml/ min/1.73m2 in healthy volunteers. The median (interquartile range [IQR]) UACR in COMBINE participants was 154 (20.3 - 540.0) mg/g. Individuals with CKD had lower mitral valve E/A ratio compared to healthy volunteers (β estimate -0.13 CKD vs. non-CKD, 95% confidence interval [CI] -0.24, -0.012). Among COMBINE participants, multivariable linear regression analyses showed that higher UACR was significantly associated with lower mitral valve E/A ratio (β-estimate per 1 unit increase in natural log UACR -0.06, 95% CI -0.09, -0.03). This finding was preserved among individuals without baseline CVD. UACR was not associated with 12-month change in any cMRI parameter. eGFR, phosphate, FGF23, and PTH were not associated with any cMRI parameter in cross-sectional or change analyses. Conclusions: Individuals with CKD stages 3b-4 have evidence of cMRI abnormalities. Albuminuria was independently associated with diastolic dysfunction assessed by mitral valve E/A ratio in individuals with CKD with and without clinical CVD, but was not associated with change in any cMRI parameter.

Background and objectives Kidney functional magnetic resonance imaging (MRI) requires further investigation to enhance the noninvasive identification of patients at high risk of CKD progression. Design, setting, participants, & measurements In this exploratory study, we obtained baseline diffusion-weighted and blood oxygen level–dependent MRI in 122 participants of the CKD Optimal Management with Binders and Nicotinamide trial, which was a multicenter, randomized, double-blinded, 12-month, four-group parallel trial of nicotinamide and lanthanum carbonate versus placebo conducted in individuals with eGFR 20–45 ml/min per 1.73 m2. Lower values of apparent diffusion coefficient (ADC) on diffusion-weighted MRI may indicate increased fibrosis, and higher values of relaxation rate (R2*) on blood oxygen level–dependent MRI may represent decreased oxygenation. Because there was no effect of active treatment on eGFR over 12 months, we tested whether baseline kidney functional MRI biomarkers were associated with eGFR decline in all 122 participants. In a subset of 87 participants with 12-month follow-up MRI data, we evaluated whether kidney functional MRI biomarkers change over time. Results Mean baseline eGFR was 32±9 ml/min per 1.73 m2, and mean annual eGFR slope was −2.3 (95% confidence interval [95% CI], −3.4 to −1.1) ml/min per 1.73 m2 per year. After adjustment for baseline covariates, baseline ADC was associated with change in eGFR over time (difference in annual eGFR slope per 1 SD increase in ADC: 1.3 [95% CI, 0.1 to 2.5] ml/min per 1.73 m2 per year, ADC×time interaction P=0.04). This association was no longer significant after further adjustment for albuminuria (difference in annual eGFR slope per 1 SD increase in ADC: 1.0 (95% CI, −0.1 to 2.2) ml/min per 1.73 m2 per year, ADC×time interaction P=0.08). There was no significant association between baseline R2* and change in eGFR over time. In 87 participants with follow-up functional MRI, ADC and R2* values remained stable over 12 months (intraclass correlation: 0.71 and 0.68, respectively). Conclusions Baseline cortical ADC was associated with change in eGFR over time, but this association was not independent of albuminuria. Kidney functional MRI biomarkers remained stable over 1 year. Clinical Trial registry name and registration number CKD Optimal Management with Binders and Nicotinamide (COMBINE), NCT02258074.

OBJECTIVES The aim of this study was to determine a robust (sensitive and objective) method for analyzing renal blood oxygenation level-dependent magnetic resonance imaging data. MATERIALS AND METHODS Forty-seven subjects (30 with chronic kidney disease [CKD] and 17 controls) were imaged at baseline and after furosemide with a multiecho gradient recalled echo sequence. Conventional analysis consisted of regional segmentation (small cortex, large cortex, and medulla), followed by computing the mean of each region. In addition, we segmented the entire parenchyma and computed the mean (μ1) plus higher moments (μ2, μ3, and μ4). Two raters performed each of the segmentation steps, and agreement was assessed with intraclass correlation coefficients (ICCs). We used a measure of effect size (Cohen's d value), in addition to the usual measure of statistical significance, P values, for determining significant results. RESULTS The mean of the renal parenchyma showed the highest agreement between raters (ICC, 0.99), and the higher parenchyma moments were on par with large cortical region of interest (ROI) ICC. The renal parenchymal mean also exhibited significant sensitivity to changes after furosemide administration in healthy subjects (P = 0.002, d = 0.84), in agreement with medullary ROIs (P = 0.002, d = 1.59). When comparing controls and subjects with CKD at baseline, cortical ROI showed a significant difference (P = 0.015, d = -0.69), whereas the parenchyma ROI did not (P = 0.152, d = 0.39). Post-furosemide data in all regions resulted in a significant difference (large cortex: P = 0.026, d = -0.51; medulla: P = 0.019, d = -0.61) with the renal parenchyma ROI resulting in the largest effect size (P = 0.003, d = -0.75). Higher moments of the renal parenchyma showed similar significant differences as well. CONCLUSIONS Overall, our data support the use of the entire parenchyma to evaluate changes in the medulla after administration of furosemide, a widely used pharmacological maneuver. Changes in higher moments indicate that there is more than just a shift in the mean renal R2* and may provide clinically relevant information without the need for subjective regional segmentation. For evaluating differences between controls and subjects with CKD at baseline; large cortical ROI provided the highest sensitivity and objectivity. A combination of renal parenchyma assessment and large cortical ROI may provide the most robust method of evaluating renal blood oxygenation level-dependent magnetic resonance imaging data.

Objectives The objective of this study was to assess whether streptozotocin (STZ)-induced diabetic rats develop iodinated contrast-induced acute kidney injury. The intrarenal R2* (=1/T2*) was evaluated continuously before, during, and after contrast administration. Renal injury was confirmed using urinary neutrophil gelatinase-associated lipocalin measurements. Materials and methods Six Sprague-Dawley rats were administered with STZ to induce diabetes (group 1). R2* was measured before, during, and after administration of iodixanol. R2* readings were sampled from 4 renal regions: inner medulla, inner stripe of outer medulla (ISOM), outer stripe of outer medulla, and cortex. Peak R2* and initial upslope of R2* increase after iodinated contrast were calculated. Data from 12 nondiabetic rats pretreated with nitric oxide synthase and prostaglandin inhibitors to induce susceptibility to contrast-induced acute kidney injury (pretreatment model) from a previous study were reanalyzed for peak R2* and initial upslope of R2* increase after contrast. Six of these animals received saline (group 2), and the other 6 received furosemide (group 3) before iodixanol. Results Peak R2* and initial upslope of R2* increase were used as blood-oxygenation-level-dependent response parameters. R2* in ISOM was comparable in all 3 groups before administration of furosemide/saline. Except for the furosemide group, ISOM showed a rapid increase in R2* immediately after contrast administration. Unlike the L-NAME- and indomethacin-treated groups, the diabetic group showed a quick reversal of R2* toward baseline measurements after contrast administration. Urinary neutrophil gelatinase-associated lipocalin indicated significant increase in diabetic rats 4 hours after contrast administration. The observed trends with peak R2* and initial upslope of R2* increase in renal ISOM were in agreement with those of urinary neutrophil gelatinase-associated lipocalin. Conclusions The STZ-induced diabetic rat may be suitable for studying the effects of iodinated contrast on renal oxygenation status and may mimic human condition closer than the pretreatment model described before. The peak R2* value and initial upslope of R2* in ISOM appear to be effective magnetic resonance imaging markers to predict renal injury after administration of an iodinated contrast agent.

The renal medulla operates at low oxygenation levels (renal medullary hypoxia) making it more susceptible to mild reductions in blood flow.1–3 Renal medullary hypoxia is thought to play a role in the pathogenesis and/or progression of acute renal failure,4–6 hypertension,7,8 and diabetic nephropathy.9,10 Blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) has been used to evaluate intrarenal oxygenation levels noninvasively in humans under normal conditions and during physiological and pharmacologic maneuvers at field strengths of 1.5 T10–14 and most recently at 3.0 T.15 To date, all BOLD MRI applied to the human kidney for functional evaluation have used single-shot echo planar (EPI)13 or 2-dimensional (2-D) breathhold multiple gradient-recalled echo (mGRE) techniques.14 Despite the advantage of faster acquisition times, the single-shot EPI technique suffers from limitations such as having high sensitivity to susceptibility differences, which can lead to signal loss, image distortions, and increased blurring resulting from T2* decay during data acquisition.14 The 2-D mGRE technique, although efficacious in terms of R2* mapping, requires multiple acquisitions to achieve adequate spatial coverage, typically a breathhold for each slice acquisition. In this study, we validated the quantitation of R2* and ΔR2* using a 3-D implementation of mGRE to perform intrarenal oxygenation studies. R2* measurements obtained by the 3-D technique were compared with measurements acquired with the 2-D sequence used in previous studies. Changes in R2* (ΔR2*) after administration of furosemide were also compared against previous reports. Furosemide is a loop diuretic that has been shown to improve medullary oxygenation, presumably because it selectively decreases oxygen consumption by blocking active transport in the thick ascending limbs.1,16 We hypothesized that the relatively fast acquisitions afforded by the 3-D implementation method would allow us to monitor the temporal response after administration of furosemide without sacrificing spatial coverage.

Background The countercurrent arrangement of capillary blood flow in the medulla of mammalian kidneys generates a gradient of oxygen tension between the renal cortex and the papillary tip that results in a state of relative hypoxia within the renal medulla. Exploration of the pathophysiological implications of medullary hypoxia has been hampered by the absence of a noninvasive technique to estimate intrarenal oxygenation in different zones of the kidney. In the present study, we demonstrate the feasibility of such a method on the basis of blood oxygenation level–dependent (BOLD) MRI, which allows sequential measurements in humans in response to a variety of physiological/pharmacological stimuli in health and disease. Methods and Results BOLD MRI measurements were obtained in healthy young human subjects (n=7), and the effects of three different pharmacological/physiological maneuvers that induce diuresis were studied. Spin-spin relaxation rate, R 2 *, was measured, which is directly related to the amount of deoxyhemoglobin in blood and in turn to tissue P o 2 . Furosemide but not acetazolamide (n=6 each) increased medullary oxygenation (ΔR 2 *=7.62 Hz; P 2 *=6.43 Hz; P Conclusions BOLD MRI can be used to monitor changes in intrarenal oxygenation in humans in a noninvasive fashion.

RATIONALE AND OBJECTIVES. MR angiography is proving to be a useful clinical study for the diagnosis of vascular disorders of renal arteries. However, its utility in terms of stenosis characterization is still limited. Renal perfusion could provide supplemental information that could allow for a comprehensive evaluation of renal artery stenosis by MR imaging. METHODS. MS-325 is a small-molecule blood pool agent that reversibly binds with serum albumin and hence leads to higher relaxivity and longer residence times in the blood. In this study, the authors evaluated the use of MS-325 to perform first-pass perfusion imaging and contrast-enhanced MR angiography in the characterization of renal artery stenosis in an animal model. RESULTS. Quantitative perfusion estimates were obtained in the renal cortex (258 ± 19.8 mL/min/100 g) and are comparable to microsphere measurements (198 ± 12.2 mL/min/100 g), given the practical constraints. Based on these measurements, perfusion showed minimal changes even when the diameter reductions reached 75%. CONCLUSIONS. MS-325 could provide quantitative perfusion estimates that when combined with MR angiography may lead to comprehensive evaluation of renal artery stenosis.