In vivo demonstration of microscopic anisotropy in the human kidney using multidimensional diffusion MRI.

PURPOSE: To demonstrate the feasibility of multidimensional diffusion MRI to probe and quantify microscopic fractional anisotropy (µFA) in human kidneys in vivo. METHODS: Linear tensor encoded (LTE) and spherical tensor encoded (STE) renal diffusion MRI scans were performed in 10 healthy volunteers. Respiratory triggering and image registration were used to minimize motion artefacts during the acquisition. Kidney cortex-medulla were semi-automatically segmented based on fractional anisotropy (FA) values. A model-free analysis of LTE and STE signal dependence on b-value in the renal cortex and medulla was performed. Subsequently, µFA was estimated using a single-shell approach. Finally, a comparison of conventional FA and µFA is shown. RESULTS: The hallmark effect of µFA (divergence of LTE and STE signal with increasing b-value) was observed in all subjects. A statistically significant difference between LTE and STE signal was found in the cortex and medulla, starting from b = 750 s/mm2 and b = 500 s/mm2 , respectively. This difference was maximal at the highest b-value sampled (b = 1000 s/mm2 ) which suggests that relatively high b-values are required for µFA mapping in the kidney compared to conventional FA. Cortical and medullary µFA were, respectively, 0.53 ± 0.09 and 0.65 ± 0.05, both respectively higher than conventional FA (0.19 ± 0.02 and 0.40 ± 0.02). CONCLUSION: The feasibility of combining LTE and STE diffusion MRI to probe and quantify µFA in human kidneys is demonstrated for the first time. By doing so, we show that novel microstructure information-not accessible by conventional diffusion encoding-can be probed by multidimensional diffusion MRI. We also identify relevant technical limitations that warrant further development of the technique for body MRI.

Robust kidney perfusion mapping in pediatric chronic kidney disease using single-shot 3D-GRASE ASL with optimized retrospective motion correction.

PURPOSE: To develop a robust renal arterial spin labeling (ASL) acquisition and processing strategy for mapping renal blood flow (RBF) in a pediatric cohort with severe kidney disease. METHODS: A single-shot background-suppressed 3D gradient and spin-echo (GRASE) flow-sensitive alternating inversion recovery (FAIR) ASL acquisition method was used to perform 2 studies. First, an evaluation of the feasibility of single-shot 3D-GRASE and retrospective noise reduction methods was performed in healthy volunteers. Second, a pediatric cohort with severe chronic kidney disease underwent single-shot 3D-GRASE FAIR ASL and RBF was quantified following several retrospective motion correction pipelines, including image registration and threshold-free weighted averaging. The effect of motion correction on the fit errors of saturation recovery (SR) images (required for RBF quantification) and on the perfusion-weighted image (PWI) temporal signal-to-noise ratio (tSNR) was evaluated, as well as the intra- and inter-session repeatability of renal longitudinal relaxation time (T1 ) and RBF. RESULTS: The mean cortical and/or functional renal parenchyma RBF in healthy volunteers and CKD patients was 295 ± 97 and 95 ± 47 mL/100 g/min, respectively. Motion-correction reduced image artefacts in both T1 and RBF maps, significantly reduced SR fit errors, significantly increased the PWI tSNR and improved the improved the repeatability of T1 and RBF in the pediatric patient cohort. CONCLUSION: Single-shot 3D-GRASE ASL combined with retrospective motion correction enabled repeatable non-invasive RBF mapping in the first pediatric cohort with severe kidney disease undergoing ASL scans.

Magnetic resonance imaging biomarkers for chronic kidney disease: a position paper from the European Cooperation in Science and Technology Action PARENCHIMA.

Functional renal magnetic resonance imaging (MRI) has seen a number of recent advances, and techniques are now available that can generate quantitative imaging biomarkers with the potential to improve the management of kidney disease. Such biomarkers are sensitive to changes in renal blood flow, tissue perfusion, oxygenation and microstructure (including inflammation and fibrosis), processes that are important in a range of renal diseases including chronic kidney disease. However, several challenges remain to move these techniques towards clinical adoption, from technical validation through biological and clinical validation, to demonstration of cost-effectiveness and regulatory qualification. To address these challenges, the European Cooperation in Science and Technology Action PARENCHIMA was initiated in early 2017. PARENCHIMA is a multidisciplinary pan-European network with an overarching aim of eliminating the main barriers to the broader evaluation, commercial exploitation and clinical use of renal MRI biomarkers. This position paper lays out PARENCHIMA's vision on key clinical questions that MRI must address to become more widely used in patients with kidney disease, first within research settings and ultimately in clinical practice. We then present a series of practical recommendations to accelerate the study and translation of these techniques.

Non-Invasive Renal Perfusion Imaging Using Arterial Spin Labeling MRI: Challenges and Opportunities.

Tissue perfusion allows for delivery of oxygen and nutrients to tissues, and in the kidneys is also a key determinant of glomerular filtration. Quantification of regional renal perfusion provides a potential window into renal (patho) physiology. However, non-invasive, practical, and robust methods to measure renal perfusion remain elusive, particularly in the clinic. Arterial spin labeling (ASL), a magnetic resonance imaging (MRI) technique, is arguably the only available method with potential to meet all these needs. Recent developments suggest its viability for clinical application. This review addresses several of these developments and discusses remaining challenges with the emphasis on renal imaging in human subjects.

Renal blood flow using arterial spin labelling MRI and calculated filtration fraction in healthy adult kidney donors Pre-nephrectomy and post-nephrectomy.

OBJECTIVES: Renal plasma flow (RPF) (derived from renal blood flow, RBF) and glomerular filtration rate (GFR) allow the determination of the filtration fraction (FF), which may have a role as a non-invasive renal biomarker. This is a hypothesis-generating pilot study assessing the effect of nephrectomy on renal function in healthy kidney donors. METHODS: Eight living kidney donors underwent arterial spin labelling (ASL) magnetic resonance imaging (MRI) and GFR measurement prior to and 1 year after nephrectomy. Chromium-51 labelled ethylenediamine tetraacetic acid ((51)Cr-EDTA) with multi-blood sampling was undertaken and GFR calculated. The RBF and GFR obtained were used to calculate FF. RESULTS: All donors showed an increase in single kidney GFR of 24 - 75 %, and all but two showed an increase in FF (-7 to +52 %) after nephrectomy. The increase in RBF, and hence RPF, post-nephrectomy was not as great as the increase in GFR in seven out of eight donors. As with any pilot study, the small number of donors and their relatively narrow age range are potential limiting factors. CONCLUSIONS: The ability to measure RBF, and hence RPF, non-invasively, coupled with GFR measurement, allows calculation of FF, a biomarker that might provide a sensitive indicator of loss of renal reserve in potential donors. KEY POINTS: • Non-invasive MRI measured renal blood flow and calculated renal plasma flow. • Effect of nephrectomy on blood flow and filtration in donors is presented. • Calculated filtration fraction may be a useful new kidney biomarker.

Comparison of ASL and DCE MRI for the non-invasive measurement of renal blood flow: quantification and reproducibility.

OBJECTIVES: To investigate the reproducibility of arterial spin labelling (ASL) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and quantitatively compare these techniques for the measurement of renal blood flow (RBF). METHODS: Sixteen healthy volunteers were examined on two different occasions. ASL was performed using a multi-TI FAIR labelling scheme with a segmented 3D-GRASE imaging module. DCE MRI was performed using a 3D-FLASH pulse sequence. A Bland-Altman analysis was used to assess repeatability of each technique, and determine the degree of correspondence between the two methods. RESULTS: The overall mean cortical renal blood flow (RBF) of the ASL group was 263 ± 41 ml min(-1) [100 ml tissue](-1), and using DCE MRI was 287 ± 70 ml min(-1) [100 ml tissue](-1). The group coefficient of variation (CVg) was 18 % for ASL and 28 % for DCE-MRI. Repeatability studies showed that ASL was more reproducible than DCE with CVgs of 16 % and 25 % for ASL and DCE respectively. Bland-Altman analysis comparing the two techniques showed a good agreement. CONCLUSIONS: The repeated measures analysis shows that the ASL technique has better reproducibility than DCE-MRI. Difference analysis shows no significant difference between the RBF values of the two techniques. KEY POINTS: Reliable non-invasive monitoring of renal blood flow is currently clinically unavailable. Renal arterial spin labelling MRI is robust and repeatable. Renal dynamic contrast-enhanced MRI is robust and repeatable. ASL blood flow values are similar to those obtained using DCE-MRI.

Precise measurement of renal filtration and vascular parameters using a two-compartment model for dynamic contrast-enhanced MRI of the kidney gives realistic normal values.

OBJECTIVE: To model the uptake phase of T(1)-weighted DCE-MRI data in normal kidneys and to demonstrate that the fitted physiological parameters correlate with published normal values. METHODS: The model incorporates delay and broadening of the arterial vascular peak as it appears in the capillary bed, two distinct compartments for renal intravascular and extravascular Gd tracer, and uses a small-vessel haematocrit value of 24%. Four physiological parameters can be estimated: regional filtration K ( trans ) (ml min(-1) [ml tissue](-1)), perfusion F (ml min(-1) [100 ml tissue](-1)), blood volume v ( b ) (%) and mean residence time MRT (s). From these are found the filtration fraction (FF; %) and total GFR (ml min(-1)). Fifteen healthy volunteers were imaged twice using oblique coronal slices every 2.5 s to determine the reproducibility. RESULTS: Using parenchymal ROIs, group mean values for renal biomarkers all agreed with published values: K ( trans ): 0.25; F: 219; v ( b ): 34; MRT: 5.5; FF: 15; GFR: 115. Nominally cortical ROIs consistently underestimated total filtration (by ~50%). Reproducibility was 7-18%. Sensitivity analysis showed that these fitted parameters are most vulnerable to errors in the fixed parameters kidney T(1), flip angle, haematocrit and relaxivity. CONCLUSIONS: These renal biomarkers can potentially measure renal physiology in diagnosis and treatment. KEY POINTS: • Dynamic contrast-enhanced magnetic resonance imaging can measure renal function. • Filtration and perfusion values in healthy volunteers agree with published normal values. • Precision measured in healthy volunteers is between 7 and 15%.

Repeatability of renal arterial spin labelling MRI in healthy subjects.

OBJECT: Arterial spin labelling (ASL) can be used to measure renal perfusion non-invasively. The aim of this study was to determine the repeatability of this technique in healthy kidneys to vindicate its use in clinic. MATERIALS AND METHODS: Two groups of healthy volunteers were imaged two different days to assess intra- and inter-session repeatability. Oblique-coronal data volumes were acquired on a 1.5 T scanner with a dedicated abdominal 32-channel body phased array coil. ASL was performed using a multi-TI FAIR labelling scheme and 3D GRASE imaging module. Background suppression and respiratory triggering were used. T(1) maps of the kidney were acquired using the same sequence with background suppression disabled. RESULTS: For the group with multiple intra-session ASL measurements, the average cortical perfusion was 197 mL min(-1)100 g(-1) and average cortical T(1) was 1265 ms. For both perfusion and T(1) the variation shown by the within-subject standard deviation (SDws) (14.6 mL min(-1)100 g(-1) and 33.4 ms) and coefficient of variation (CVws) (7.52 and 2.69%, respectively) was small for all the analyses carried out. Bland-Altman plots were also used to visualise the variation between the same parameters collected from the different scanning sessions in both groups, and demonstrated good reproducibility. CONCLUSION: We have shown that in healthy volunteers, ASL parameters are repeatable over a short and long period. This supports the overall aim of using ASL in the clinic to assess longitudinal renal perfusion changes in patients.

Guidelines for standard and diuretic renogram in children.

Special consideration needs to be given to children who undergo dynamic renography. The Paediatric Committee of the European Association of Nuclear Medicine has updated the previous guidelines. Details are provided on how to manage the child, the equipment, and the acquisition and processing protocols. The pitfalls, difficulties and controversies that are encountered are also discussed, as well as the interpretation of the results.

Test-retest reliability and repeatability of renal diffusion tensor MRI in healthy subjects.

PURPOSE: This study assessed test-retest reliability and repeatability of diffusion tensor imaging (DTI) in the kidneys. MATERIALS AND METHODS: Seven healthy volunteers (age range, 19-31 years), were imaged three consecutive times on the same day (short-term reliability) and the same imaging protocol was repeated after a month (long-term reliability). Diffusion-weighted magnetic resonance imaging scans in the coronal-oblique projection of the kidney were acquired on a 1.5 T scanner using a multi-section echo-planar sequence; six contiguous slices each 5 mm thick, diffusion sensitisation along 20 non-collinear directions, TR=730 ms, TE=73 ms and 2 b-values (0 and 400 s mm(-2)). Volunteers were asked to hold their breath throughout each data acquisition (approx. 20 s). The apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values were obtained from maps generated using dedicated software MIStar (Apollo Medical Imaging, Melbourne, Australia). RESULTS: Statistical analyses of both short- and long-term repeats were carried out from which the within-subject coefficient of variation (wsCV) was calculated. The wsCV obtained for both the ADC and FA values were less than 10% in all the analyses carried out. In addition, paired (repeated measures) t-test was used to measure the variation between the diffusion parameters collected from the two scanning sessions a month apart. It showed no significant difference and the wsCV obtained after comparing the first and second scans were found to be smaller than 15% for both ADC and FA. CONCLUSION: Renal DTI produces reliable and repeatable results which make longitudinal investigation of patients viable.

Pilot study of F(18)-Fluorodeoxyglucose Positron Emission Tomography/computerised tomography in Wilms' tumour: correlation with conventional imaging, pathology and immunohistochemistry.

Wilms' tumour is the second most common paediatric solid tumour. Prognosis is good although higher stage disease carries significant mortality and treatment related morbidity. In the UK, risk stratification is based on histological response to pre-operative chemotherapy. F(18)-Fluorodeoxyglucose Positron Emission Tomography (F(18)FDG-PET) is an emerging functional imaging technique in paediatric oncology. Little is known about the relationship between F(18)FDG-PET images and the disease process of Wilms' tumour. We performed F(18)FDG-PET/CT scans in seven children with Wilms' tumour after induction chemotherapy, immediately before surgery. The standard uptake values (SUV) of F(18)FDG-PET/CT images were related to conventional imaging and histopathological findings. In total seven children were studied. F(18)FDG-PET/CT was consistently safely performed. All tumours showed F(18)FDG activity. Four tumours had activity with SUV/bw max >5 g/ml. Histological examination of these active areas revealed viable anaplastic Wilms' tumour. Furthermore, in these four tumours GLUT-1 and Ki67 immunostaining was strongly positive. Three further tumours demonstrated lower uptake (SUV/bw max <5 g/ml), which represented areas of microscopic foci of residual viable tumour mixed with post chemotherapy change. Metastatic disease was F(18)FDG avid in two of four children with stage four diseases. In conclusion, following chemotherapy, active Wilms' tumour is F(18)FDG avid and higher SUV was seen in histologically high risk disease.

Lung ventilation-perfusion scintigraphy in children on long-term parenteral nutrition.

PURPOSE: Pulmonary emboli (PE) are one of the major complications associated with total parenteral nutrition (TPN). Ventilation-perfusion scintigraphy (V/Q) remains the most used test for the diagnosis of PE and follow-up of patients on TPN. The aim of our study was to demonstrate the high prevalence of undiagnosed PE in children on TPN. METHODS: The medical and imaging files of 64 patients on TPN who underwent V/Q examinations covering the period of 1986-2004 were reviewed. Children were aged between 3.18 months and 21.6 years. TPN was started at birth (range 0-15 years). All children had a normal chest radiograph and no symptoms at the time of the V/Q scan. A comparative analysis between the prevalence of PE and risk factors (number of days per week with lipophilic content of the TPN, bowel inflammation and thrombophilic factors (protein C and S) was performed. RESULTS: Of the 64 patients, 25 (39%) had an abnormal V/Q scan. A total of 29 PE episodes were diagnosed in all patients. Two children had three episodes of PE. The median age at PE diagnosis was 4.6 years. In 17 patients (68%) diagnosis was achieved on the first V/Q scan performed. PE was bilateral in 56% and unilateral in 44%. PE was the main cause of 2 out 15 recorded deaths. All risk factors were associated with an increase in PE prevalence by statistical analysis. CONCLUSION: PE is underdiagnosed in children on long-term TPN. Lung V/Q scintigraphy is useful in the diagnosis of PE in children with a low pretest probability.

Improvement of MRI-functional measurement with automatic movement correction in native and transplanted kidneys.

PURPOSE: To improve 2D software for motion correction of renal dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and to evaluate its effect using the Patlak-Rutland model. MATERIALS AND METHODS: A subpixel-accurate method to correct for kidney motion during DCE-MRI was evaluated on native and transplanted kidneys using data from two different institutions with different magnets and protocols. The Patlak-Rutland model was used to calculate glomerular filtration rate (GFR) on a voxel-by-voxel basis providing mean (Kp) and uncertainty (sigma(K(p))) values for GFR. RESULTS: In transplanted kidneys, average absolute variation of Kp was 6.4% +/- 4.8% (max = 16.6%). In native kidneys average absolute variation of Kp was 12.11% +/- 6.88% (max = 25.6%) for the right and 11.6% +/- 6% (max = 20.8%) for the left. Movement correction showed an average reduction of sigma(K(p)) of 6.9% +/- 6.6% (max = 21.4%) in transplanted kidneys, 30.9% +/- 17.6% (max = 60.8%) for the right native kidney, and 31.8% +/- 14% (max = 55.3%) for the left kidney. CONCLUSION: The movement correction algorithm showed improved uncertainty on GFR computation for both native and transplanted kidneys despite different spatial resolution from the different MRI systems and different levels of signal-to-noise ratios on DCE-MRI.

Clinical governance improves the quality of nuclear medicine reporting.

OBJECTIVE: To assess the quality of nuclear medicine reporting, within a private UK hospital, of five physicians from four different National Health Service trusts and compare it with a similar previous clinical governance exercise. METHODS: Reports (n=140) were shown anonymously to all five physicians, including the one who produced the report. Each physician ranked them on a scale of 1-5, with 1 and 5 corresponding to complete disagreement and complete agreement, respectively. All reports with at least one score of <4 were subjected to consensus review by all five physicians and subsequently given a consensus score. RESULTS: Six hundred and ninety-one audit opinions were present out of a possible 700 (98.7%). Forty-three reports were reviewed, of which 11 received a consensus score of <4 (7.9%). This is not significantly different from the proportion of nontrivial errors in our earlier study (10.2%). Only three reports were present, however, with a score of <3 (2.1%), significantly fewer (P<0.02) than the proportion of nontrivial errors in our earlier study. No scores of 1 were recorded. No reporter attracted significantly more scores of <4 compared with the overall proportion of such scores. A score given by an auditing physician which was 2 or more points different from the consensus score was defined as a suboptimal audit. Forty-four of 691 suboptimal audits (6.4%) were present, significantly fewer than the proportion of suboptimal audits in our earlier study (9.7%; P<0.03). CONCLUSION: Studies such as these provide a useful framework for monitoring performance. This improved significantly in this study as compared with our previous audit.

The fault is not in her parents but in her insula--a neurobiological hypothesis of anorexia nervosa.

The reported abnormalities of brain function in anorexia nervosa (AN) include impairment of neural circuits involving cortical (orbito-frontal, somatosensory and parietal) and sub-cortical (amygdala, hippocampus, thalamus, hypothalamus and striatum) structures. The insular cortex serves an integrative function for all the structures relevant to the features of AN and as such may be central to this impairment. We hypothesise that a rate limiting dysfunction of neural circuitry integrated by the insula can account for the clinical phenomena of AN. Such dysfunction could account for the known psychopathology, neuroimaging abnormalities and neuropsychological deficits. Proposals to test this hypothesis are made.

Normal differential renal function does not indicate a normal kidney after partial ureteropelvic obstruction and subsequent relief in 2-week-old piglets.

PURPOSE: We investigated the functional consequences of relieving ureteric obstruction in young pigs with experimental hydronephrosis (HN) induced by partial unilateral ureteropelvic obstruction. MATERIALS AND METHODS: Three groups of animals were followed from the age of 2 weeks to the age of 14 weeks: Eight animals had severe or grades 3-4 HN throughout the study. Six animals had relief of the obstruction after 4 weeks. Six animals received sham operations at both ages. Morphological and functional examinations were performed at age 6 weeks and again at age 14 weeks and consisted of magnetic resonance imaging (MRI), technetium-diethylenetriaminepentaaceticacid ((99m)Tc-DTPA) renography, renal technetium-dimercaptosuccinicacid ((99m)Tc-DMSA) scintigraphy, and glomerular filtration rate (GFR) measurement. RESULTS: After relief of the partial obstruction, there was reduction of the pelvic diameter and improvement of urinary drainage. Global and relative kidney function was not significantly affected by either obstruction or its relief. Renal (99m)Tc-DMSA scintigraphy showed a change in both the appearance of the kidney and a change in the distribution within kidneys even after relief of obstruction. CONCLUSION: This study shows that partial ureteric obstruction in young pigs may be associated with little effect on global and differential kidney function. However, even after relief of HN, the distribution of (99m)Tc-DMSA in the kidney remains abnormal suggesting that a normal differential renal function may not represent a normal kidney.

How accurate is dynamic contrast-enhanced MRI in the assessment of renal glomerular filtration rate? A critical appraisal.

PURPOSE: To evaluate the current literature to see if the published results of MRI-glomerular filtration rate (GFR) stand up to the claim that MRI-GFR may be used in clinical practice. Claims in the current literature that Gadolinium (Gd) DTPA dynamic contrast enhanced (DCE) MRI clearance provides a reliable estimate of glomerular filtration are an overoptimistic interpretation of the results obtained. Before calculating absolute GFR from Gd-enhanced MRI, numerous variables must be considered. MATERIALS AND METHODS: We examine the methodology in the published studies on absolute quantification of MRI-GFR. The techniques evaluated included the dose and volume of Gd-DTPA used, the speed of injection, acquisition sequences, orientation of the subject, re-processing, conversion of signal to concentration and the model used for analysis of the data as well as the MRI platform. RESULTS: Claims in the current literature that using DCE MRI "Gd DTPA clearance provides a good estimate of glomerular filtration" are not supported by the data presented and a more accurate conclusion should be that "no MRI approach used provides a wholly satisfactory measure of renal GFR function." CONCLUSION: This study suggests that DCE MRI-GFR results are not yet able to be used as a routine clinical or research tool. The published literature does not show what change in DCE MRI-GFR is clinically significant, nor do the results in the literature allow a single DCE MRI-GFR measurement to be correlated directly with a multiple blood sampling technique.

Measurement of glomerular filtration rate with magnetic resonance imaging: principles, limitations, and expectations.

Glomerular filtration rate (GFR) is the most useful quantitative index of renal function and is used clinically as the gold standard of renal dysfunction. Follow-up of patients with impaired renal function requires reliable measurements of GFR. Thus, serial GFR values estimated from magnetic resonance imaging (MRI) would be worthwhile if easy to obtain, accurate, and reproducible. Nuclear medicine-based techniques remain at present the reference method for quantification of GFR, but MRI should be able to compete in the near future. Several methods are available for measurement of GFR using MRI and freely filtered Gd-chelates: (1) measurement of the clearance of the agent using blood samplings; (2) measurement of the plasma clearance of the agent using signal intensity changes within abdominal organs; (3) measurement of the extraction fraction of the agent; and (4) monitoring of tracer intrarenal kinetics. A high heterogeneity of protocols (e.g., in acquisition mode, dose of contrast, postprocessing techniques) is noted in the literature, reflecting the number of technical challenges that will have to be solved before to reach a consensus, and the reported accuracy and reproducibility are insufficient for justifying their use in clinical practice now.

Imaging in childhood urinary tract infections: time to reduce investigations.

The correct protocol for investigating urinary tract infections (UTI) is unknown but remains a hotly debated topic. The main objective in investigating children with UTI is to prevent the long-term complications of developing hypertension, chronic kidney disease (CKD) and/or pregnancy complications. However, the prognosis for childhood UTI remains good, with low long-term risks, from epidemiological studies, of developing these sequelae. Although childhood UTI is common, the occurrence of CKD and the likelihood that acute pyelonephritis will cause renal damage progressing to CKD are rare. We studied the current literature on investigations of childhood UTI and propose a protocol for carrying out selected investigations in high-risk children. By identifying this group of children with increased risk of having an abnormal urinary tract that warrant investigation, we recommend that targeting investigations to specific children (as opposed to protocol-based investigations of all children with UTI), will be clinically safe and effective and will avoid the unnecessary distress and cost of invasive investigations.