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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.

Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed. Plasma and urine biomarker levels were measured using independent prospective cohorts of CKD: the Boston Kidney Biopsy Cohort, a cohort of individuals with biopsy-confirmed semiquantitative assessment of kidney fibrosis, and the Seattle Kidney Study, a cohort of patients with common forms of CKD. Ordinal logistic regression and Cox proportional hazards regression models were used to test associations of biomarkers with interstitial fibrosis and tubular atrophy and progression to end-stage kidney disease and death, respectively. Sc/snRNA-seq data confirmed cell-specific expression of biomarker genes in fibroblasts. After multivariable adjustment, higher levels of plasma CDH11, SMOC2, and PEDF and urinary CDH11 and PEDF were significantly associated with increasing severity of interstitial fibrosis and tubular atrophy in the Boston Kidney Biopsy Cohort. In both cohorts, higher levels of plasma and urinary SMOC2 and urinary CDH11 were independently associated with progression to end-stage kidney disease. Higher levels of urinary PEDF associated with end-stage kidney disease in the Seattle Kidney Study, with a similar signal in the Boston Kidney Biopsy Cohort, although the latter narrowly missed statistical significance. Thus, we identified CDH11, SMOC2, and PEDF as promising non-invasive biomarkers of kidney fibrosis.

Purpose A standard MRI system phantom has been designed and fabricated to assess scanner performance, stability, comparability and assess the accuracy of quantitative relaxation time imaging. The phantom is unique in having traceability to the International System of Units, a high level of precision, and monitoring by a national metrology institute. Here, we describe the phantom design, construction, imaging protocols, and measurement of geometric distortion, resolution, slice profile, signal-to-noise ratio (SNR), proton-spin relaxation times, image uniformity and proton density. Methods The system phantom, designed by the International Society of Magnetic Resonance in Medicine ad hoc committee on Standards for Quantitative MR, is a 200 mm spherical structure that contains a 57-element fiducial array; two relaxation time arrays; a proton density/SNR array; resolution and slice-profile insets. Standard imaging protocols are presented, which provide rapid assessment of geometric distortion, image uniformity, T1 and T2 mapping, image resolution, slice profile, and SNR. Results Fiducial array analysis gives assessment of intrinsic geometric distortions, which can vary considerably between scanners and correction techniques. This analysis also measures scanner/coil image uniformity, spatial calibration accuracy, and local volume distortion. An advanced resolution analysis gives both scanner and protocol contributions. SNR analysis gives both temporal and spatial contributions. Conclusions A standard system phantom is useful for characterization of scanner performance, monitoring a scanner over time, and to compare different scanners. This type of calibration structure is useful for quality assurance, benchmarking quantitative MRI protocols, and to transition MRI from a qualitative imaging technique to a precise metrology with documented accuracy and uncertainty.

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.

Purpose The potential of renal MRI biomarkers has been increasingly recognised, but clinical translation requires more standardisation. The PARENCHIMA consensus project aims to develop and apply a process for generating technical recommendations on renal MRI. Methods A task force was formed in July 2018 focused on five methods. A draft process for attaining consensus was distributed publicly for consultation and finalised at an open meeting (Prague, October 2018). Four expert panels completed surveys between October 2018 and March 2019, discussed results and refined the surveys at a face-to-face meeting (Aarhus, March 2019) and completed a second round (May 2019). Results A seven-stage process was defined: (1) formation of expert panels; (2) definition of the context of use; (3) literature review; (4) collection and comparison of MRI protocols; (5) consensus generation by an approximate Delphi method; (6) reporting of results in vendor-neutral and vendor-specific terms; (7) ongoing review and updating. Application of the process resulted in 166 consensus statements. Conclusion The process generated meaningful technical recommendations across very different MRI methods, while allowing for improvement and refinement as open issues are resolved. The results are likely to be widely supported by the renal MRI community and thereby promote more harmonisation.

Summary Objective Examine associations of hip abductor strength with (1) cartilage damage worsening in the tibiofemoral and patellofemoral compartments 2 years later, and (2) poor function and disability outcomes 5 years later. Methods Participants had knee osteoarthritis (K/L ≥ 2) in at least one knee. Hip abductor strength was measured using Biodex Dynamometry. Participants underwent 3.0T MRI of both knees at baseline and 2 years later. Baseline-to-2-year cartilage damage progression, defined as any worsening of WORMS cartilage damage score, was assessed at each tibiofemoral and patellofemoral surface. LLFDI (Late-Life Function and Disability Instrument) and Chair-Stand-Rate were recorded at baseline and 5-year follow-up; outcomes analyzed using quintiles. Poor outcomes were defined as remaining in the same low-function quintiles or being in a worse quintile at 5-year follow-up. We analyzed associations of baseline hip abductor strength with cartilage damage worsening and function and disability outcomes using multivariable log-binomial models. Results 275 knees from 164 persons [age = 63.7 (SD = 9.8) years, 79.3% women] comprised the structural outcome sample, and 187 persons [age = 64.2 (9.7), 78.6% women] the function and disability outcomes sample. Greater baseline hip abductor strength was associated with reduced risks of baseline-to-2-year medial patellofemoral and lateral tibiofemoral cartilage damage worsening [adjusted relative risks (RRs) range: 0.80–0.83) and with reduced risks of baseline-to-5-year poor outcomes for Chair-Stand-Rate and LLFDI Basic Lower-Extremity Function and Disability Limitation (adjusted RRs range: 0.91–0.94). Conclusion Findings support a beneficial role of hip abductor strength for disease modification and for function and disability outcomes, and as a potential therapeutic target in managing knee osteoarthritis.

Renal hypoxia is generally accepted as a key pathophysiologic event in acute kidney injury of various origins, and has also been suggested to play a role in the development of chronic kidney disease. Here we describe a step-by-step experimental protocol for indirect monitoring of renal blood oxygenation in rodents via the deoxyhemoglobin sensitive MR parameters T2* and T2—a contrast mechanism known as the blood oxygenation level dependent (BOLD) effect. Since an absolute quantification of renal oxygenation from T2*/T2 remains challenging, the effects of controlled and standardized variations in the fraction of inspired oxygen are used for bench marking. This MRI method may be useful for investigating renal blood oxygenation of small rodents in vivo under various experimental (patho)physiological conditions.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. This experimental protocol chapter is complemented by two separate chapters describing the basic concept and data analysis.

Glomerular filtration rate (GFR) is a major determinant of renal energy expenditure. Animal models support a mismatch between renal oxygenation (RO2) and energy expenditure in diabetic kidney disease (DKD). The objective of this study was to compare the ratio of RO2 to GFR (RO2:GFR) in adolescents with and without type 1 diabetes (T1D) and correlate the ratio with albuminuria, effective renal plasma flow (ERPF), blood pressure, trunk mass and renal oxygen consumption. RO2 was measured by blood oxygenation level dependent (BOLD) MRI before and after 20 mg of I.V. furosemide, trunk mass by DXA, GFR by iohexol clearance, ERPF by p-aminohippurate clearance and albuminuria by urine albumin-to-creatinine ratio (UACR) in 50 adolescents with T1D (mean age 16.1±3.0 yrs, trunk mass 44.8±2.2%, HbA1c 8.6±1.2%, GFR 189±40 ml/min) and 20 non-obese controls (mean age 16.1±2.9 yrs, trunk mass 44.9±2.2%, HbA1c 5.2±0.2%, GFR 136±22 ml/min). The RO2:GFR (s/ml/min*1000) was calculated as renal oxygenation (T2*, s) divided by GFR (ml/min), and furosemide-suppressible oxygenation (FSOC) as change in RO2 in responses to furosemide. Relationships were evaluated by correlation and multivariable generalized linear regression models. RO2:GFR was 25% lower in adolescents with T1D vs. controls (mean±SD: 0.24±0.04 vs. 0.32±0.04, p Disclosure C.L. Vinovskis: None. K.J. Nadeau: None. K.L. Tommerdahl: None. P.V. Prasad: None. L. Li: None. L. Pyle: None. M. Rewers: None. M. Pragnell: None. F.H. Mahmud: Advisory Panel; Self; Eli Lilly and Company, Insulet Corporation. D.H. van Raalte: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Sanofi. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Sanofi. D. Cherney: Research Support; Self; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. Other Relationship; Self; from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS and Novo-Nordisk. R. Nelson: None. P. Bjornstad: Advisory Panel; Self; XORTX Therapeutics Inc. Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Novo Nordisk Foundation. Research Support; Self; Horizon Pharma. Funding JDRF (2-SRA-2018-627-M-B); National Institute of Diabetes and Digestive and Kidney Diseases (K23DK116720)

Background: Chronic hypoxia is a well-recognized factor in the pathogenesis of chronic kidney disease (CKD). Loss of microcirculation is thought to lead to enhanced renal hypoxia, which in turn results in the development of fibrosis, a hallmark of progressive CKD. To evaluate the role of functional magnetic resonance imaging (MRI), we performed perfusion, oxygenation, and diffusion MRI measurements in individuals with diabetes and stage 3 CKD. Methods: Fifty-four subjects (41 individuals with diabetes and stage 3 CKD and 13 healthy controls) participated in this study. Data with blood oxygenation level dependent (BOLD), arterial spin labeling perfusion and diffusion MRI were acquired using a 3T scanner. Results: Renal cortical perfusion was reduced in CKD compared to the controls (109.54 ± 25.38 vs. 203.17 ± 27.47 mL/min/100 g; p < 0.001). Cortical apparent diffusion coefficient showed no significant reduction in CKD compared to controls (1,596.10 ± 196.64 vs. 1,668.72 ± 77.29 × 10–6 mm2/s; p = 0.45) but was significantly associated with perfusion. Cortical R2* values were modestly increased in CKD (20.76 ± 4.08 vs. 18.74 ± 2.37 s–1; p = 0.12). Within the CKD group, R2*_Medulla and R2*_Kidney were moderately and negatively associated with estimated glomerular filtration rate. There was a significant association between cortical perfusion and medullary response to furosemide with annual loss of renal function, used as an estimate of CKD progression. Conclusions: Subjects with a moderate degree of CKD had significantly lower renal perfusion. Diffusion and BOLD MRI showed more modest differences between the groups. Individuals with progressive CKD had lower perfusion and response to furosemide.

Mitochondrial dysfunction is thought to be a critical pathway in the development and progression of kidney diseases, but optimal methods to assess kidney mitochondrial dysfunction are not well known. Saeki and colleagues use positron emission tomography imaging with a novel probe, 2-tert-butyl-4-chloro-5-[6-(4-(18)F-fluorobutoxy)-pyridin-3-ylmethoxy]-2H-pyridazin-3-one ((18)F-BCPP-BF), to visualize and assess kidney mitochondrial status. The authors demonstrate that reduced uptake of (18)F-BCPP-BF, as assessed by positron emission tomography imaging, corresponds to reduced functioning mitochondria in 3 separate animal models of kidney diseases.

Tissue hypoxia plays a key role in the development and progression of many kidney diseases. Blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) is the most promising imaging technique to monitor renal tissue oxygenation in humans. BOLD-MRI measures renal tissue deoxyhaemoglobin levels voxel by voxel. Increases in its outcome measure R2* (transverse relaxation rate expressed as per second) correspond to higher deoxyhaemoglobin concentrations and suggest lower oxygenation, whereas decreases in R2* indicate higher oxygenation. BOLD-MRI has been validated against micropuncture techniques in animals. Its reproducibility has been demonstrated in humans, provided that physiological and technical conditions are standardized. BOLD-MRI has shown that patients suffering from chronic kidney disease (CKD) or kidneys with severe renal artery stenosis have lower tissue oxygenation than controls. Additionally, CKD patients with the lowest cortical oxygenation have the worst renal outcome. Finally, BOLD-MRI has been used to assess the influence of drugs on renal tissue oxygenation, and may offer the possibility to identify drugs with nephroprotective or nephrotoxic effects at an early stage. Unfortunately, different methods are used to prepare patients, acquire MRI data and analyse the BOLD images. International efforts such as the European Cooperation in Science and Technology (COST) action ‘Magnetic Resonance Imaging Biomarkers for Chronic Kidney Disease’ (PARENCHIMA) are aiming to harmonize this process, to facilitate the introduction of this technique in clinical practice in the near future. This article represents an extensive overview of the studies performed in this field, summarizes the strengths and weaknesses of the technique, provides recommendations about patient preparation, image acquisition and analysis, and suggests clinical applications and future developments.

Background Identification of patients with progressive chronic kidney disease (CKD) and those likely to respond to candidate therapeutics is urgently needed. Functional MRI measurements have shown promise. However, knowledge about the consistency of the measurements is essential to conduct longitudinal studies. Purpose/hypothesis To investigate the consistency of repeated functional MRI measurements in healthy subjects. Study type Prospective, longitudinal study. Subjects Seventeen healthy subjects were examined on two different occasions, 18 months apart. Field strength/sequence Multiple gradient-recalled-echo, 2D navigator-gated flow-sensitive alternating inversion recovery True-FISP and spin-echo planar diffusion-weighted sequences were used on a 3T scanner. Images were acquired on two different scanner configurations. Assessment Blood oxygenation level-dependent (BOLD) R2*, arterial spin labeling (ASL) perfusion-derived blood flow (BF) and apparent diffusion coefficient (ADC) maps were analyzed using a custom image processing toolbox. Regions of interest (ROIs) were placed on renal cortex, medulla, and whole kidney. Multiple researchers were involved in defining the ROIs. Statistical tests Intra- and intersubject coefficients of variation (CV) and Bland-Altman plots were used to measure consistency and evaluate bias in the measurements. A nonparametric Wilcoxon test was used to compare differences between two timepoints. Results The intrasubject CV for R2* and ADC were 6.8% and 5.3% with small (-3.8 and 5.3%) bias, respectively, comparing baseline and 18-month data. Intrasubject CV for renal cortex BF was higher (18.7%) compared to R2* and ADC, but comparable to prior literature values over shorter durations. It also exhibited a larger bias (-15.4%) between two timepoints and significantly lower values (P = 0.022) at 18-month data. Data conclusion All three MRI parameters over 18 months, even with a scanner upgrade and involving multiple observers, showed good consistency. These results are useful for the interpretation of longitudinal data and support the use of these methods to monitor progression in patients with CKD. Level of evidence 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2018;48:514-521.

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.

The article Consensus-based technical recommendations for clinical translation of renal diffusion-weighted MRI

Diabetic kidney disease is the most common cause of end-stage kidney disease and poses a major global health problem. Finding new, safe, and effective strategies to halt this disease has proven to be challenging. In part that is because the underlying mechanisms are complex and not fully understood. However, in recent years, evidence has accumulated suggesting that chronic hypoxia may be the primary pathophysiological pathway driving diabetic kidney disease and chronic kidney disease of other etiologies and was called the chronic hypoxia hypothesis. Hypoxia is the result of a mismatch between oxygen delivery and oxygen demand. The primary determinant of oxygen delivery is renal perfusion (blood flow per tissue mass), whereas the main driver of oxygen demand is active sodium reabsorption. Diabetes mellitus is thought to compromise the oxygen balance by impairing oxygen delivery owing to hyperglycemia-associated microvascular damage and exacerbate oxygen demand owing to increased sodium reabsorption as a result of sodium–glucose cotransporter upregulation and glomerular hyperfiltration. The resultant hypoxic injury creates a vicious cycle of capillary damage, inflammation, deposition of the extracellular matrix, and, ultimately, fibrosis and nephron loss. This review will frame the role of chronic hypoxia in the pathogenesis of diabetic kidney disease and its prospect as a promising therapeutic target. We will outline the cellular mechanisms of hypoxia and evidence for renal hypoxia in animal and human studies. In addition, we will highlight the promise of newer imaging modalities including blood oxygenation level–dependent magnetic resonance imaging and discuss salutary interventions such as sodium–glucose cotransporter 2 inhibition that (may) protect the kidney through amelioration of renal hypoxia.

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. 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. 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. 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.

Purpose Blood oxygen level-dependent (BOLD) MRI has been effectively used to monitor changes in renal oxygenation. However, R2* (or T2*) is not specific to blood oxygenation and is dependent on other factors. This study investigates the use of a statistical model that takes these factors into account and maps BOLD MRI measurements to blood pO2. Methods Spin echo and gradient echo images were obtained in six Sprague-Dawley rats and R2 and R2* maps were computed. Measurements were made at baseline, post-nitric oxide synthase inhibitor (L-NAME), and post-furosemide administration. A simulation of each region was performed to map R2′ (computed as R2*–R2) to blood pO2. Results At baseline, blood pO2 in the outer medulla was 30.5 ± 1.2 mmHg and 51.9 ± 5.2 mmHg in the cortex, in agreement with previous invasive studies. Blood pO2 was found to decrease within the outer medulla following L-NAME (P

Functional magnetic resonance (MR) imaging of the kidneys has gained interest recently, especially in the detection of early changes in acute kidney injury or to predict progression of chronic kidney disease (CKD). The application of these methods to cardiorenal syndrome (CRS) is novel. CRS is widely accepted as a complex clinical problem routinely faced by clinicians. In this issue, Chang et al ( 1 ) present their preliminary experience applying blood oxygen level-dependent (BOLD) MR imaging to the kidneys in mice with experimental myocardial infarction. They showed that R2* in the kidney increases after induced myocardial infarction and that the response was higher in animals with larger infarcts and over time. The authors also for the first time correlated the BOLD MR imaging findings against hypoxia-inducible factor-1α (HIF-1α) expression, an independent marker of renal hypoxia. In addition, they showed evidence for renal injury by using a kidney injury marker, kidney injury molecule-1 (KIM-1). The results of their study support the use of renal BOLD MR imaging in subjects with heart failure, in whom the risk of subsequent renal ischemia and/or hypoxia is known to exist. These results, along with those of other recent reports ( 2 ), suggest that functional imaging methods could play a key role in evaluating changes in both the primary and secondary organs involved in complex disease processes such as CRS. Availability of such methods could facilitate translation to the clinic and improve the mechanistic understanding of the complicated and interrelated pathophysiology.

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.

Summary Objective Test the hypothesis that greater baseline peak external knee adduction moment (KAM), KAM impulse, and peak external knee flexion moment (KFM) during the stance phase of gait are associated with baseline-to-2-year medial tibiofemoral cartilage damage and bone marrow lesion progression, and cartilage thickness loss. Methods Participants all had knee OA in at least one knee. Baseline peak KAM, KAM impulse, and peak KFM (normalized to body weight and height) were captured and computed using a motion analysis system and six force plates. Participants underwent MRI of both knees at baseline and 2 years later. To assess the association between baseline moments and baseline-to-2-year semiquantitative cartilage damage and bone marrow lesion progression and quantitative cartilage thickness loss, we used logistic and linear regressions with generalized estimating equations (GEE), adjusting for gait speed, age, gender, disease severity, knee pain severity, and medication use. Results The sample consisted of 391 knees (204 persons): mean age 64.2 years (SD 10.0); BMI 28.4 kg/m 2 (5.7); 156 (76.5%) women. Greater baseline peak KAM and KAM impulse were each associated with worsening of medial bone marrow lesions, but not cartilage damage. Higher baseline KAM impulse was associated with 2-year medial cartilage thickness loss assessed both as % loss and as a threshold of loss, whereas peak KAM was related only to % loss. There was no relationship between baseline peak KFM and any medial disease progression outcome measures. Conclusion Findings support targeting KAM parameters in an effort to delay medial OA disease progression.

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.

Background To validate DCE MRI method of placental perfusion estimation and to demonstrate application of the method in a rabbit model of fetal antenatal hypoxia-ischemia. Methods Placental perfusion was estimated by dynamic contrast imaging with bolus injection of Gd-DTPA in 3 Tesla GE magnet in a rabbit model of placental ischemia–reperfusion in rabbit dams at embryonic day 25 gestation age. Placental perfusion was measured using steepest slope method on DCE MRI before and after intermittent 40 min uterine ischemia. Antioxidants (n = 2 dams, 9 placentas imaged) or vehicle (n = 5 dams, 23 placenta imaged) were given systemically in a separate group of dams during reperfusion–reoxygenation. Placental perfusion was also measured in two dams from the antioxidant group (10 placentas) and two dams from the control group (12 placentas) by fluorescent microspheres method. Results While placental perfusion estimates between fluorescent microspheres and DCE MRI were significantly correlated (R2 = 0.85; P

Identifying subjects with progressive chronic kidney disease will be important both in clinical practice and in conducting clinical trials. Pruijm et al. (in this issue) demonstrate for the first time that cortical oxygenation as evaluated by blood oxygenation level–dependent magnetic resonance imaging can predict future loss of renal function. These observations provide the necessary stimulus to continue the development of renal blood oxygenation level–dependent magnetic resonance imaging to further improve the sensitivity and specificity to renal oxygenation and hence the predictive power.

Objectives Standardization is an important milestone in the validation of DWI-based parameters as imaging biomarkers for renal disease. Here, we propose technical recommendations on three variants of renal DWI, monoexponential DWI, IVIM and DTI, as well as associated MRI biomarkers (ADC, D, D*, f, FA and MD) to aid ongoing international efforts on methodological harmonization. Materials and methods Reported DWI biomarkers from 194 prior renal DWI studies were extracted and Pearson correlations between diffusion biomarkers and protocol parameters were computed. Based on the literature review, surveys were designed for the consensus building. Survey data were collected via Delphi consensus process on renal DWI preparation, acquisition, analysis, and reporting. Consensus was defined as ≥ 75% agreement. Results Correlations were observed between reported diffusion biomarkers and protocol parameters. Out of 87 survey questions, 57 achieved consensus resolution, while many of the remaining questions were resolved by preference (65–74% agreement). Summary of the literature and survey data as well as recommendations for the preparation, acquisition, processing and reporting of renal DWI were provided. Discussion The consensus-based technical recommendations for renal DWI aim to facilitate inter-site harmonization and increase clinical impact of the technique on a larger scale by setting a framework for acquisition protocols for future renal DWI studies. We anticipate an iterative process with continuous updating of the recommendations according to progress in the field.

Purpose To investigate whether arterial spin labeling (ASL) MRI is sensitive to changes by pharmacologically induced vasodilation and vasoconstriction in rat kidneys. Materials and Methods Changes in renal cortical blood flow in seven rats were induced by adenosine infusion (vasodilation) and L-NAME injection (vasoconstriction). All imaging studies were performed on a 3 Tesla scanner using a FAIR-TrueFISP sequence for the ASL implementation. The acquisition time for each ASL scan was 6 min. Cortical perfusion rates were calculated using regions of interest analysis, and the differences in perfusion rates during baseline, vasodilation, and vasoconstriction were compared and assessed for statistical significance. Results Compared with the baseline, an average of 94 mL/100 g/min increase and 157 mL/100 g/min decrease in cortical perfusion was observed following adenosine infusion and L-NAME administration, respectively. The changes in cortical perfusion were significant between baseline and vasodilation (P

Purpose To evaluate longitudinal changes in renal oxygenation and diffusion measurements in a model of reversible unilateral ureteral obstruction (rUUO) which has been shown to induce chronic renal functional deficits in a strain dependent way. C57BL/6 mice show higher degree of functional deficit compared with BALB/c mice. Because hypoxia and development of fibrosis are associated with chronic kidney diseases and are responsible for progression, we hypothesized that MRI measurements would be able to monitor the longitudinal changes in this model and will show strain dependent differences in response. Here blood oxygenation level dependent (BOLD) and diffusion MRI measurements were performed at three time points over a 30 day period in mice with rUUO. Materials and Methods The studies were performed on a 4.7T scanner with the mice anesthetized with isoflurane before UUO, 2 and 28 days postrelease of 6 days of obstruction. Results We found at the early time point (∼2 days after releasing the obstruction), the relative oxygenation in C57Bl/6 mice were lower compared with BALB/c. Diffusion measurements were lower at this time point and reached statistical significance in BALB/c Conclusion These methods may prove valuable in better understanding the natural progression of kidney diseases and in evaluating novel interventions to limit progression. J. Magn. Reson. Imaging 2014;39:835–841. © 2013 Wiley Periodicals, Inc.

Established as a method to study anatomic changes, such as renal tumors or atherosclerotic vascular disease, magnetic resonance imaging (MRI) to interrogate renal function has only recently begun to come of age. In this review, we briefly introduce some of the most important MRI techniques for renal functional imaging, and then review current findings on their use for diagnosis and monitoring of major kidney diseases. Specific applications include renovascular disease, diabetic nephropathy, renal transplants, renal masses, acute kidney injury, and pediatric anomalies. With this review, we hope to encourage more collaboration between nephrologists and radiologists to accelerate the development and application of modern MRI tools in nephrology clinics.

Purpose To develop a navigator technique enabling free-breathing acquisition to afford sufficient signal averaging for quantitative renal perfusion measurement using arterial spin labeling MRI. Methods A novel two-dimensional (2D) navigator technique was implemented in concert with flow-sensitive alternating inversion recovery (FAIR) preparation and true fast imaging with steady precession (True-FISP) readout. The navigator images were obtained with a low-resolution fast low angle shot readout at end of each arterial spin labeling acquisition. A retrospective algorithm was developed to automatically detect respiratory motion for selective signal averaging. The 2D navigator-gated FAIR True-FISP sequence was performed in ten healthy volunteers and five patients with chronic kidney disease. Results Excellent image quality and comparable cortical perfusion rates (healthy: 276 ± 28 mL/100 g/min, patients: 155 ± 25 mL/100 g/min) to literature values were obtained. An average of 3-fold signal-to-noise ratio improvement was obtained in the 2D navigator-gated approach compared with the breath-hold acquisition in healthy volunteers. Good image quality was achieved in patients while the results from breath-hold acquisition were unusable. The quantitative perfusion rates were significantly lower in chronic kidney disease patients compared with the healthy volunteers. Conclusion 2D navigator-gated free breathing arterial spin labeling is feasible and is a noninvasive method to evaluate renal perfusion both in healthy subjects and those with chronic kidney disease. Magn Reson Med 71:570–579, 2014. © 2013 Wiley Periodicals, Inc.

Introduction Chronic kidney disease (CKD) is known to be associated with reduced renal blood flow. However, data in humans are limited to date. Methods In this study, noninvasive arterial spin labeling magnetic resonance imaging data were acquired in 33 patients with diabetes and stage 3 CKD as well as in 30 healthy controls. Results A significantly lower renal blood flow in both the cortex (108.4 ± 36.4 vs. 207.3 ± 41.8; P < 0.001, d = 2.52) and medulla (23.2 ± 8.9 vs. 42.6 ± 15.8; P < 0.001, d = 1.5) was observed. Both cortical (ρ = 0.67, P < 0.001) and medullary (ρ = 0.62, P < 0.001) blood flow were correlated with estimated glomerular filtration rate, and cortical blood flow was found to be confounded by age and body mass index. However, in a subset of subjects who were matched for age and body mass index (n = 6), the differences between CKD patients and control subjects remained significant in both the cortex (107.4 ± 42.8 vs. 187.51 ± 20.44; P = 0.002) and medulla (15.43 ± 8.43 vs. 39.18 ± 11.13; P = 0.002). A threshold value to separate healthy controls and CKD patients was estimated to be a cortical blood flow of 142.9 and a medullary blood flow of 24.1. Discussion These results support the use of arterial spin labeling in the evaluation of renal blood flow in patients with a moderate level of CKD. Whether these measurements can identify patients at risk for progressive CKD requires further longitudinal follow-up.

Objective Knee sagittal dynamic joint stiffness (DJS) describes the biomechanical interaction between change in external knee flexion moment and flexion angular excursion during gait. In theory, greater DJS may particularly stress the patellofemoral (PF) compartment and thereby contribute to PF osteoarthritis (OA) worsening. We hypothesized that greater baseline knee sagittal DJS is associated with PF cartilage damage worsening 2 years later. Methods Participants all had OA in at least one knee. Knee kinematics and kinetics during gait were recorded using motion capture systems and force plates. Knee sagittal DJS was computed as the slope of the linear regression line for knee flexion moments vs angles during the loading response phase. Knee magnetic resonance imaging (MRI) scans were obtained at baseline and 2 years later. We assessed the association between baseline DJS and baseline-to-2-year PF cartilage damage worsening using logistic regression with generalized estimating equations (GEE). Results Our sample had 391 knees (204 persons): mean age 64.2 years (SD 10.0); body mass index (BMI) 28.4 kg/m2 (5.7); 76.5% women. Baseline knee sagittal DJS was associated with baseline-to-2-year cartilage damage worsening in the lateral (OR = 5.35, 95% CI: 2.37-12.05) and any PF (OR = 2.99, 95% CI: 1.27-7.04) compartment. Individual components of baseline DJS (i.e., change in knee moment or angle) were not associated with subsequent PF disease worsening. Conclusion Capturing the concomitant effect of knee kinetics and kinematics during gait, knee sagittal DJS is a potentially modifiable risk factor for PF disease worsening.

Purpose: To compare the effects of osmolality versus viscosity of radio-contrast media on intra-renal oxygenation as determined by blood oxygenation level-dependent (BOLD) MRI in a model of contrast induced nephropathy (CIN). Materials and Methods: Twenty-four Sprague-Dawley rats were divided into five groups. Nitric oxide synthase inhibitor L-NAME (10 mg/kg), cyclooxygenase inhibitor indomethacin (10 mg/kg), or saline, and radio-contrast iodixanol (high viscosity, 784 or 1600 mg I/kg) or iothalamate (high osmolality, 1600 mg I/kg) were administered. BOLD MRI images were acquired on Siemens 3 Tesla (T) scanner using a multiple gradient recalled echo sequence at baseline, following L-NAME (or saline), indomethacin (or saline), and radio-contrast agents. R2* (=1/T2*) was used as the BOLD MRI parameter in renal medulla and cortex. Mixed-effects models with first order auto-regressive variance-covariance models were used to analyze the data. Results: The magnitude of change in medullary R2* (MR2*) with same dose of iodine was larger with iodixanol compared with iothalalmate both in pretreated groups (303% versus 225.6%, < 0.01) and the control group (191.6% versus −1.8%, P < 0.01). The MR2* change in high dose iodixanol was approximately twice compared with the low dose (303% versus 133%, P < 0.01). Conclusion: The viscosity of radio-contrast seems to play a more significant role than osmolality in terms of renal oxygenation changes as evaluated by BOLD MRI. Additionally, iodixanol induced a dose-dependent increase in renal medullary hypoxia. J. Magn. Reson. Imaging 2012;36:1162–1167. © 2012 Wiley Periodicals, Inc.

The early antecedents of cerebral palsy (CP) are unknown but are suspected to be due to hypoxia-ischemia (H-I). In our rabbit model of CP, the MRI biomarker, apparent diffusion coefficient (ADC) on diffusion-weighted imaging, predicted which fetuses will develop postnatal hypertonia. Surviving H-I fetuses experience reperfusion-reoxygenation but a subpopulation manifested a continued decline of ADC during early reperfusion-reoxygenation, which possibly represented greater brain injury (RepReOx). We hypothesized that oxidative stress in reperfusion-reoxygenation is a critical trigger for postnatal hypertonia. We investigated whether RepReOx predicted postnatal neurobehavior, indicated oxidative stress, and whether targeting antioxidants at RepReOx ameliorated motor deficits, which included testing of a new superoxide dismutase mimic (MnTnHex-2-PyP). Rabbit dams, 79% gestation (E25), were subjected to 40 min uterine ischemia. Fetal brain ADC was followed during H-I, immediate reperfusion-reoxygenation, and 4–72 h after H-I. Endpoints were postnatal neurological outcome at E32, ADC at end of H-I, ADC nadir during H-I and reperfusion-reoxygenation, and area under ADC curve during the first 20 min of reperfusion-reoxygenation. Antioxidants targeting RepReOx were administered before and/or after uterine ischemia. The new MRI-ADC biomarker for RepReOx improved prediction of postnatal hypertonia. Greater superoxide production, mitochondrial injury, and oligodendroglial loss occurred in fetal brains exhibiting RepReOx than in those without. The antioxidants, MnTnHex-2-PyP and Ascorbate and Trolox combination, significantly decreased postnatal motor deficits and extent of RepReOx. The etiological link between early injury and later motor deficits can thus be investigated by MRI, and allows us to distinguish between critical oxidative stress that causes motor deficits and noncritical oxidative stress that does not.

Objectives Meniscal tears have been linked to knee osteoarthritis progression, presumably by impaired load attenuation. How meniscal tears affect osteoarthritis is unclear; subregional examination may help to elucidate whether the impact is local. This study examined the association between a tear within a specific meniscal segment and subsequent 2-year cartilage loss in subregions that the torn segment overlies. Methods Participants with knee osteoarthritis underwent bilateral knee MRI at baseline and 2 years. Mean cartilage thickness within each subregion was quantified. Logistic regression with generalised estimating equations were used to analyse the relationship between baseline meniscal tear in each segment and baseline to 2-year cartilage loss in each subregion, adjusting for age, gender, body mass index, tear in the other two segments and extrusion. Results 261 knees were studied in 159 individuals. Medial meniscal body tear was associated with cartilage loss in external subregions and in central and anterior tibial subregions, and posterior horn tear specifically with posterior tibial subregion loss; these relationships were independent of tears in the other segments and persisted in tibial subregions after adjustment for extrusion. Lateral meniscal body and posterior horn tear were also associated with cartilage loss in underlying subregions but not after adjustment for extrusion. Cartilage loss in the internal subregions, not covered by the menisci, was not associated with meniscal tear in any segment. Conclusion These results suggest that the detrimental effect of meniscal tears is not spatially uniform across the tibial and femoral cartilage surfaces and that some of the effect is experienced locally.

The lack of noninvasive methods to study dysmenorrhea has resulted in poor understanding of the mechanisms underlying pain, insufficient diagnostic tests, and limited treatment options. To address this knowledge gap, we have developed a magnetic resonance imaging-based strategy for continuously monitoring the uterus in relationship to participants' spontaneous pain perception.The study objective was to evaluate whether magnetic resonance imaging can detect real-time changes in myometrial activity during cramping episodes in women with dysmenorrhea, with a handheld squeeze bulb for pain reporting.Sixteen women with dysmenorrhea and 10 healthy control women both on and off their menses were evaluated with magnetic resonance imaging while not taking analgesic medication. Continuous magnetic resonance imaging was acquired using half-Fourier acquisition single-shot turbo spin echo sequence along with simultaneous reporting of pain severity with a squeeze bulb. Pearson's coefficient was used to compare results between reviewers. Proportional differences between women with dysmenorrhea and controls on/off menses were evaluated with a Fisher exact test. The temporal relationships between signal changes were evaluated with Monte Carlo simulations.Spontaneous progressive decreases in myometrial signal intensity were more frequently observed in women on their menses than in the absence of pain in the same women off their menses or participants without dysmenorrhea (P.01). Women without reductions in myometrial signal intensity on their menses either had a history of endometriosis or were not in pain. Observations of myometrial events were consistently reported between 2 raters blinded to menstrual pain or day status (r = 0.97, P.001). Episodes of cramping occurred either immediately before or 32-70 seconds after myometrial signal change onset (P.05).Transient decreases in myometrial uterine T2-weighted signal intensity can be reliably measured in women with menstrual pain. The directionality of signal change and temporal relationship to pain onset suggest that cramping pain may be caused by a combination of uterine pressure and hemodynamic dysfunction.

Summary Objective To identify subregional differences in femorotibial cartilage morphology between healthy controls and women with different grades of radiographic knee osteoarthritis (OA). Design 158 women aged ≥40 years were studied. Weight-bearing extended anterior-posterior (AP) and Lyon schuss radiographs were obtained and the Kellgren Lawrence grade (KLG) determined. 97 women had a body mass index (BMI)≤28, no symptoms, and were AP KLG0. 61 women had a BMI≥30, symptoms in the target knee, and mild (KLG2=31) to moderate (KLG3=30) medial femorotibial radiographic OA in the AP views. Coronal spoiled gradient echo water excitation sequences were acquired at 3.0 Tesla. Total plate and regional measures of cartilage morphology of the weight-bearing femorotibial joint were quantified. Results KLG2 participants displayed, on average, thicker cartilage than healthy controls in the medial femorotibial compartment (particularly anterior subregion of the medial tibia (MT) and peripheral [external, internal] subregions of the medial femur), and in the lateral femur. KLG3 participants displayed significantly thinner cartilage than KLG0 participants in the medial weight-bearing femur (central subregion), in the external subregion of the MT, and in the internal subregion of the lateral tibia. These differences were generally unaffected when possible effects of demographic covariates were considered. Conclusions The results indicate that in femorotibial OA regional cartilage thickening and thinning may occur, dependent on the (radiographic) disease status of the joint. These changes appear to display a heterogeneous spatial pattern, where certain subregions are more strongly affected than others.

Objective. Malalignment is known to alter medial-to-lateral femorotibial load distribution and to affect osteoarthritis (OA) progression in the mechanically stressed compartment. We investigated the pattern of cartilage loss in neutral, varus, and valgus knees. Methods. Alignment was measured from full-limb radiographs in 174 participants with symptomatic knee OA. Coronal magnetic resonance images were acquired at baseline and a mean SD of 26.6 5.4 months later. The weight-bearing femorotibial cartilages were segmented from paired images. Cartilage volume, surface area, and thickness were determined in total cartilage plates and defined subregions using proprietary software. Results. The medial-to-lateral ratio of femorotibial cartilage loss was 1.4:1 in neutral knees (n 74), 3.7:1 in varus knees (n 57), and 1:6.0 in valgus knees (n 43). The relative contribution of cartilage thickness change tended to be greater in knees with mild cartilage loss, whereas the increase of denuded area was greater in knees with accelerated cartilage loss. In both varus and neutral knees, the greatest changes were observed in the same subregions of the medial femorotibial compartment (central and external medial tibia, and central medial femur). In valgus and neutral knees, the subregions with the greatest changes in the lateral femorotibial compartment were also similar (internal and central lateral tibia, external lateral femur). Conclusion. The medial-to-lateral rate of femorotibial cartilage loss strongly depended on alignment. Subregions of greater-than-average cartilage loss within the stressed compartment were, however, similar in neutral, varus, and valgus knees. This indicates that the medial-to-lateral loading pattern is different, but that the (sub)regional loading pattern may not differ substantially between neutral and malaligned knees.

Oxygenation status plays a major role in renal physiology and pathophysiology, and thus has attracted considerable attention in recent years. While much of the early work and a significant amount of present work is based on invasive methods or ex vivo analysis, and is therefore restricted to animal models, blood oxygen level-dependent (BOLD) MR imaging has been shown to extend these findings to human beings. BOLD MR imaging is most useful in monitoring effects of physiologic or pharmacologic maneuvers. Several teams around the world have demonstrated reproducible data and have illustrated several useful applications. Studies supporting the use of renal BOLD MR imaging in characterizing disease with prognostic value have also been reported. This article provides an overview of current state-of-the art of renal BOLD MR imaging.

Objective Progressive knee osteoarthritis (OA) is believed to result from local factors acting in a systemic environment. Previous studies have not examined these factors concomitantly or compared quantitative and qualitative cartilage loss outcomes. The aim of this study was to test whether meniscal damage, meniscal extrusion, malalignment, and laxity each predicted tibiofemoral cartilage loss after controlling for the other factors. Methods Laxity and alignment were measured at baseline in individuals with knee OA. Magnetic resonance imaging included spin-echo coronal and sagittal imaging for meniscal scoring and axial and coronal spoiled gradient echo sequences with water excitation for cartilage quantification. Tibial and weight-bearing femoral condylar subchondral bone area and cartilage surface were segmented. Cartilage volume, denuded bone area, and cartilage thickness were quantified in each plate, with progression defined as cartilage loss >2 times the coefficient of variation for each plate. Qualitative outcome was assessed as worsening of the cartilage score. Logistic regression analysis with generalized estimating equations yielded odds ratios for each factor, adjusting for age, sex, body mass index, and the other factors. Results We studied 251 knees in 153 persons. After full adjustment, medial meniscal damage predicted medial tibial cartilage volume loss and tibial and femoral denuded bone increase, while varus malalignment predicted medial tibial cartilage volume and thickness loss and tibial and femoral denuded bone increase. Lateral meniscal damage predicted every lateral outcome. Laxity and meniscal extrusion had inconsistent effects. After full adjustment, no factor except medial laxity predicted qualitative outcome. Conclusion Using quantitative cartilage loss assessment, local factors that independently predicted tibial and femoral loss included medial meniscal damage and varus malalignment (medially) and lateral meniscal damage (laterally). A measurement of quantitative outcome was more sensitive at revealing these relationships than a qualitative approach.

Purpose To validate the accuracy of T1 measurement by three-dimensional Look-Locker method (3D LL) for delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) of human subjects with and without osteoarthritis (OA), as compared with two-dimensional inversion recovery fast spin-echo (2D IR-FSE) technique. Materials and Methods MR sagittal images of the knees were acquired for T1 mapping in 29 subjects with standard 2D IR-FSE and 3D LL sequences 90–135 min following administration of 0.2 mmol/kg Gd-DTPA2−. T1 maps of femoral and tibial cartilage were generated using custom software. Comparisons in T1 values between the two techniques were performed using regression analysis. Results Good agreement in T1 values between 2D IR-FSE and 3D LL was observed (R values of 0.90, and 0.85, and 0.86 for all, OA, and control subjects, respectively) when acquired within 15 min. Conclusion The 3D LL sequence provides accurate T1 estimates of articular cartilage with advantages of entire joint coverage, shorter acquisition time, and a wide range of inversion times sampled within a single acquisition. J. Magn. Reson. Imaging 2008. © 2008 Wiley-Liss, Inc.

To prospectively test--in a swine model of renal artery stenosis (RAS)--the hypothesis that magnetic resonance (MR) imaging can reveal changes in renal function at the time of percutaneous transluminal angioplasty (PTA).In this animal care and use committee-approved study, high-grade unilateral RAS was surgically induced in six pigs. MR imaging at 3.0 T was used for intraprocedural assessment of the anatomic and physiologic changes induced by x-ray-guided PTA. With use of MR imaging, changes in single-kidney glomerular filtration rate, extraction fraction, and renal blood flow were assessed during PTA. The arterial diameter of stenosis before and after PTA was assessed by using conventional digital subtraction angiography. Mean changes in functional and anatomic parameters were compared by using the Wilcoxon signed rank test (alpha = .05).At digital subtraction angiography, the mean percentage of stenosis was 69% +/- 10 (standard deviation) before PTA and 26% +/- 10 after PTA (P.03). Mean pre- and post-PTA extraction fraction values were 0.11 +/- 0.03 and 0.19 +/- 0.06, respectively (P.03). The mean single-kidney glomerular filtration rate before PTA, 19 mL/min +/- 13, increased to 41 mL/min +/- 33 after PTA (P.03). There was no significant change in mean renal blood flow after PTA (P=.44).In swine, MR imaging can reveal changes in renal function after x-ray-guided PTA for unilateral RAS.

Purpose To extend observations on intra-renal oxygenation with blood oxygen level-dependent (BOLD) MRI in human and rats to mouse kidneys imaged with a human whole-body scanner. Materials and Methods Renal BOLD MRI studies were performed on a 3.0T scanner using a multiple gradient-echo (mGRE) sequence with a custom-designed 2.0-cm surface coil to acquire six T2*-weighted images in mice (N = 8) at an in-plane resolution of 156 × 156 μm2. BOLD MRI data were obtained before and after administration of furosemide (10 mg/kg intravenously [i.v.]). Results The mean weight of eight mice was 24.6 ± 1.0 g. The baseline renal R2* (mean ± standard error [SE]) was 28.6 ± 2.1 seconds–1 in the renal cortex (CO), 35.4 ± 2.2 in the outer medulla (OM), and 21.2 ± 2.1 seconds–1 in the inner medulla (IM). The BOLD response to furosemide (ΔR2*) was 4.1 ± 1.4 in the CO, 10.1 ± 2.1 seconds–1 in the OM, and 3.4 ± 0.8 seconds–1 in the IM in mice. Conclusion Intrarenal BOLD MR images with sufficiently high resolution can be obtained on a human whole-body scanner when combined with a small receiver coil to allow studies in mice. Both baseline R2* and ΔR2* values following administration of furosemide were consistent with previous experience in humans and rats. J. Magn. Reson. Imaging 2007. © 2007 Wiley-Liss, Inc.

Background The current clinical classification of chronic kidney disease (CKD) is not perfect and may be overestimating both the prevalence and the risk for progressive disease. Novel markers are being sought to identify those at risk of progression. This preliminary study evaluates the feasibility of magnetic resonance imaging based markers to identify early changes in CKD. Methods Fifty-nine subjects (22 healthy, 7 anemics with no renal disease, 30 subjects with CKD) participated. Data using 3D volume imaging, blood oxygenation level dependent (BOLD) and Diffusion MRI was acquired. BOLD MRI acquisition was repeated after 20 mg of iv furosemide. Results Compared to healthy subjects, those with CKD have lower renal parenchymal volumes (329.6±66.4 vs. 257.1±87.0 ml, p

Hypoxia of the renal medulla is a possible precursor to the onset of acute renal failure in humans and therefore an understanding of the factors influencing the oxygenation status within the renal medulla is very important. Blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) has been shown to non-invasively evaluate intra-renal oxygenation levels of the renal medulla in humans. A newly implemented three-dimensional (3-D) multiple gradient-recalled echo sequence, which permits examination of temporal responses to physiological or pharmacological stimuli, was used to monitor changes in intra-renal oxygenation status during water diuresis. Five healthy, young subjects (22±1.2 years) took part in the study. BOLD MRI data were acquired before and after water loading. Studies were repeated on a separate day after the subjects were pretreated with naproxen. Water diuresis significantly improved renal medullary oxygenation levels in all subjects (pre-waterload =30.3 1/s vs post-waterload 22.8 1/s); however, the temporal response was found to be subject dependent. In the presence of cyclooxygenase (COX) inhibition by naproxen, the improvement in oxygenation during water diuresis was completely abolished (pre-waterload =27.5 1/s vs post-waterload 28.5 1/s). Monitoring of temporal responses for the first time during water loading allowed for an appreciation of subject dependence. Comparison of the temporal response in terms of slopes demonstrated a significant difference between the waterload studies with and without naproxen (with naproxen =0.056 1/(s min) vs without naproxen =0.25 1/(s min)). The observed effects of naproxen were consistent with previous findings with COX inhibition.

Magnetic resonance imaging (MRI) provides exquisite anatomic detail of various organs and is capable of providing additional functional information. This combination allows for comprehensive diagnostic evaluation of pathologies such as ischemic renal disease. Noninvasive MRI techniques could facilitate translation of many studies performed in controlled animal models using technologies that are invasive to humans. Such a translation is being recognized as essential because many proposed interventions and drugs that prove efficacious in animal models fail to do so in humans. In this article, we review the state-of-the-art functional MRI technique as applied to the kidneys.

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.

Blood oxygenation level-dependent (BOLD) magnetic resonance (MR) imaging is a noninvasive method to assess changes in oxygen delivery to tissues. It was hypothesized that BOLD MR imaging can detect changes in rabbit VX2 liver tumor oxygenation after hepatic artery embolization with polyvinyl alcohol particles. In four discrete VX2 liver tumors, a statistically significant mean reduction in apparent transverse relaxation time was shown, from 55 milliseconds before embolization to 41 milliseconds after embolization (P.01). This reduction corresponded to a decrease in hepatic tumor oxygenation. The use of BOLD MR imaging to monitor changes in hepatic tumor oxygenation after embolization is feasible. These functional MR imaging measurements of hypoxia may be targeted as an endpoint for therapy in future studies.