Utility of new image-derived biomarkers for autosomal dominant polycystic kidney disease prognosis using automated instance cyst segmentation.

New image-derived biomarkers for patients affected by autosomal dominant polycystic kidney disease are needed to improve current clinical management. The measurement of total kidney volume (TKV) provides critical information for clinicians to drive care decisions. However, patients with similar TKV may present with very different phenotypes, often requiring subjective decisions based on other factors (e.g., appearance of healthy kidney parenchyma, a few cysts contributing significantly to overall TKV, etc.). In this study, we describe a new technique to individually segment cysts and quantify biometric parameters including cyst volume, cyst number, parenchyma volume, and cyst parenchyma surface area. Using data from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study the utility of these new parameters was explored, both quantitatively as well as visually. Total cyst number and cyst parenchyma surface area showed superior prediction of the slope of estimated glomerular filtration rate decline, kidney failure and chronic kidney disease stages 3A, 3B, and 4, compared to TKV. In addition, presentations such as a few large cysts contributing significantly to overall kidney volume were shown to be much better stratified in terms of outcome predictions. Thus, these new image biomarkers, which can be obtained automatically, will have great utility in future studies and clinical care for patients affected by autosomal dominant polycystic kidney disease.

A Deep Learning Approach for Automated Segmentation of Kidneys and Exophytic Cysts in Individuals with Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Total kidney volume (TKV) is an important imaging biomarker in autosomal dominant polycystic kidney disease (ADPKD). Manual computation of TKV, particularly with the exclusion of exophytic cysts, is laborious and time consuming. METHODS: We developed a fully automated segmentation method for TKV using a deep learning network to selectively segment kidney regions while excluding exophytic cysts. We used abdominal T2 -weighted magnetic resonance images from 210 individuals with ADPKD who were divided into two groups: one group of 157 to train the network and a second group of 53 to test it. With a 3D U-Net architecture using dataset fingerprints, the network was trained by K-fold cross-validation, in that 80% of 157 cases were for training and the remaining 20% were for validation. We used Dice similarity coefficient, intraclass correlation coefficient, and Bland-Altman analysis to assess the performance of the automated segmentation method compared with the manual method. RESULTS: The automated and manual reference methods exhibited excellent geometric concordance (Dice similarity coefficient: mean±SD, 0.962±0.018) on the test datasets, with kidney volumes ranging from 178.9 to 2776.0 ml (mean±SD, 1058.5±706.8 ml) and exophytic cysts ranging from 113.4 to 2497.6 ml (mean±SD, 549.0±559.1 ml). The intraclass correlation coefficient was 0.9994 (95% confidence interval, 0.9991 to 0.9996; P<0.001) with a minimum bias of -2.424 ml (95% limits of agreement, -49.80 to 44.95). CONCLUSIONS: We developed a fully automated segmentation method to measure TKV that excludes exophytic cysts and has an accuracy similar to that of a human expert. This technique may be useful in clinical studies that require automated computation of TKV to evaluate progression of ADPKD and response to treatment.

Expanded Imaging Classification of Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: The Mayo Clinic imaging classification of autosomal dominant polycystic kidney disease (ADPKD) uses height-adjusted total kidney volume (htTKV) and age to identify patients at highest risk for disease progression. However, this classification applies only to patients with typical diffuse cystic disease (class 1). Because htTKV poorly predicts eGFR decline for the 5%-10% of patients with atypical morphology (class 2), imaging-based risk modeling remains unresolved. METHODS: Of 558 adults with ADPKD in the HALT-A study, we identified 25 patients of class 2A with prominent exophytic cysts (class 2Ae) and 43 patients of class 1 with prominent exophytic cysts; we recalculated their htTKVs to exclude exophytic cysts. Using original and recalculated htTKVs in association with imaging classification in logistic and mixed linear models, we compared predictions for developing CKD stage 3 and for eGFR trajectory. RESULTS: Using recalculated htTKVs increased specificity for developing CKD stage 3 in all participants from 82.6% to 84.2% after adjustment for baseline age, eGFR, BMI, sex, and race. The predicted proportion of class 2Ae patients developing CKD stage 3 using a cutoff of 0.5 for predicting case status was better calibrated to the observed value of 13.0% with recalculated htTKVs (45.5%) versus original htTKVs (63.6%). Using recalculated htTKVs reduced the mean paired difference between predicted and observed eGFR from 17.6 (using original htTKVs) to 4.0 ml/min per 1.73 m2 for class 2Ae, and from -1.7 (using original htTKVs) to 0.1 ml/min per 1.73 m2 for class 1. CONCLUSIONS: Use of a recalculated htTKV measure that excludes prominent exophytic cysts facilitates inclusion of class 2 patients and reclassification of class 1 patients in the Mayo classification model.

Detection and characterization of mosaicism in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited, progressive nephropathy accounting for 4-10% of end stage renal disease worldwide. PKD1 and PKD2 are the most common disease loci, but even accounting for other genetic causes, about 7% of families remain unresolved. Typically, these unsolved cases have relatively mild kidney disease and often have a negative family history. Mosaicism, due to de novo mutation in the early embryo, has rarely been identified by conventional genetic analysis of ADPKD families. Here we screened for mosaicism by employing two next generation sequencing screens, specific analysis of PKD1 and PKD2 employing long-range polymerase chain reaction, or targeted capture of cystogenes. We characterized mosaicism in 20 ADPKD families; the pathogenic variant was transmitted to the next generation in five families and sporadic in 15. The mosaic pathogenic variant was newly discovered by next generation sequencing in 13 families, and these methods precisely quantified the level of mosaicism in all. All of the mosaic cases had PKD1 mutations, 14 were deletions or insertions, and 16 occurred in females. Analysis of kidney size and function showed the mosaic cases had milder disease than a control PKD1 population, but only a few had clearly asymmetric disease. Thus, in a typical ADPKD population, readily detectable mosaicism by next generation sequencing accounts for about 1% of cases, and about 10% of genetically unresolved cases with an uncertain family history. Hence, identification of mosaicism is important to fully characterize ADPKD populations and provides informed prognostic information.

Overweight and Obesity Are Predictors of Progression in Early Autosomal Dominant Polycystic Kidney Disease.

The association of overweight/obesity with disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) remains untested. We hypothesized that overweight/obesity associates with faster progression in early-stage ADPKD. Overall, 441 nondiabetic participants with ADPKD and an eGFR>60 ml/min per 1.73 m2 who participated in the Halt Progression of Polycystic Kidney Disease Study A were categorized on the basis of body mass index (BMI; calculated using nonkidney and nonliver weight) as normal weight (18.5-24.9 kg/m2; reference; n=192), overweight (25.0-29.9 kg/m2; n=168), or obese (≥30 kg/m2; n=81). We evaluated the longitudinal (5-year) association of overweight/obesity with change in total kidney volume (TKV) by magnetic resonance imaging using linear regression and multinomial logistic regression models. Among participants, mean±SD age was 37±8 years, annual percent change in TKV was 7.4%±5.1%, and BMI was 26.3±4.9 kg/m2 The annual percent change in TKV increased with increasing BMI category (normal weight: 6.1%±4.7%, overweight: 7.9%±4.8%, obese: 9.4%±6.2%; P<0.001). In the fully adjusted model, higher BMI associated with greater annual percent change in TKV (ß=0.79; 95% confidence interval [95% CI], 0.18 to 1.39, per 5-unit increase in BMI). Overweight and obesity associated with increased odds of annual percent change in TKV ≥7% compared with <5% (overweight: odds ratio, 2.02; 95% CI, 1.15 to 3.56; obese: odds ratio, 3.76; 95% CI, 1.81 to 7.80). Obesity also independently associated with greater eGFR decline (slope) versus normal weight (fully adjusted ß =-0.08; 95% CI, -0.15 to -0.02). In conclusion, overweight and, particularly, obesity are strongly and independently associated with rate of progression in early-stage ADPKD.

Baseline total kidney volume and the rate of kidney growth are associated with chronic kidney disease progression in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of kidney cysts leading to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Identification of an early biomarker that can predict progression of CKD is urgently needed. In an earlier Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study (a prospective, multicenter, observational analysis of 241 patients with ADPKD initiated in 2000), baseline height-adjusted total kidney volume (htTKV) was shown to be associated with development of CKD stage 3 after eight years of follow-up. Here we conducted an extended study and found that in a multivariable logistic regression model, baseline htTKV was shown to be a strong, independent predictor for the development of CKD after a median follow-up of 13 years. The odds ratio of reaching each CKD stage per 100 mL/m increment in htTKV was 1.38 (95% confidence interval 1.19-1.60) for stage 3, 1.42 (1.23-1.64) for stage 4, and 1.35 (1.18-1.55) for stage 5 or ESRD. Baseline htTKV was also associated with relative decreases in the glomerular filtration rate of 30%, and 57% or more. Moreover, the rate of change in htTKV was negatively correlated with the slope of the glomerular filtration rate. While ADPKD genotype was also associated with CKD outcomes, it was not an independent prognostic factor after adjusting for htTKV. Thus, baseline total kidney volume and the rate of kidney growth are strongly associated with the development of advanced stages of CKD. These findings support the use of total kidney volume as a prognostic and potentially monitoring biomarker in ADPKD.

Patterns of Kidney Function Decline in Autosomal Dominant Polycystic Kidney Disease: A Post Hoc Analysis From the HALT-PKD Trials.

BACKGROUND: Previous clinical studies of autosomal dominant polycystic kidney disease (ADPKD) reported that loss of kidney function usually follows a steep and relentless course. A detailed examination of individual patterns of decline in estimated glomerular filtration rate (eGFR) has not been performed. STUDY DESIGN: Longitudinal post hoc analysis of data collected during the Halt Progression of Polycystic Kidney Disease (HALT-PKD) trials. SETTING & PARTICIPANTS: 494 HALT-PKD Study A participants (younger; preserved eGFR) and 435 Study B participants (older; reduced eGFR) who had more than 3 years of follow-up and 7 or more eGFR assessments. MEASUREMENTS: Longitudinal eGFR assessments using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation. PREDICTORS: Demographic, clinical, laboratory, and imaging features of participants. OUTCOMES: Probability of linear and nonlinear decline patterns or of stable eGFR calculated for each participant from a Bayesian model of individual eGFR trajectories. RESULTS: Most (62.5% in Study A and 81% in Study B) participants had a linear decline in eGFR during up to 8 years of follow-up. A proportion (22% in Study A and 13% in Study B) of progressors had a nonlinear pattern. 15.5% of participants in Study A and 6% in Study B had a prolonged (≥4.5 years) period of stable eGFRs. These individuals (Study A) had significantly smaller total kidney volumes, higher renal blood flows, lower urinary albumin excretion, and lower body mass index at baseline and study end. In Study B, participants with reduced but stable eGFRs were older than the progressors. Two-thirds of nonprogressors in both studies had PKD1 mutations, with enrichment for weak nontruncating mutations. LIMITATIONS: Relatively short follow-up of a clinical trial population. CONCLUSIONS: Although many individuals with ADPKD have a linear decline in eGFR, prolonged intervals of stable GFRs occur in a substantial fraction. Lower body mass index was associated with more stable kidney function in early ADPKD.

Computer-aided diagnosis program for classifying the risk of hepatocellular carcinoma on MR images following liver imaging reporting and data system (LI-RADS).

PURPOSE: To develop and evaluate a computer-aided diagnosis (CAD) program for liver lesions on magnetic resonance (MR) images for classification of the risk of hepatocellular carcinoma (HCC) following the liver imaging reporting and data system (LI-RADS). MATERIALS AND METHODS: Liver MR images from 41 patients with hyperenhancing liver lesions categorized as LR 3, 4, and 5 were evaluated by two radiologists. The major LI-RADS features of each index liver lesion were recorded, including size (maximum transverse diameter), presence of hyperenhancement, washout appearance, and capsule appearance. A CAD program was implemented to register MR images at different contrast-enhancement phases, segment liver lesions, extract lesion features, and classify lesions according to LI-RADS. The LI-RADS features quantified by CAD were compared with those assessed by radiologists using the intraclass correlation coefficient (ICC) and receiver operator curve (ROC) analyses. The LI-RADS categorization between CAD and radiologists was evaluated using the weighted Cohen's kappa coefficient. RESULTS: The mean and standard deviation of the lesion diameters were 21 ± 11 mm (range, 7-70 mm) by radiologists and 22 ± 11 mm (range, 8-72 mm) by CAD (ICC, 0.96-0.97). The area under the curve (AUC) for the washout assessment by CAD was 0.79-0.93 with sensitivity 0.69-0.82 and specificity 0.79-1. The AUC for the capsule assessment by CAD was 0.79-0.9 with sensitivity 0.75-0.9 and specificity 0.82-0.96. The classifications by the radiologists and CAD coincided in 76-83% lesions (k = 0.57-0.71), while the agreements between radiologists were in 78% lesions (k = 0.59). CONCLUSION: We developed a CAD program for liver lesions on MR images and showed a substantial agreement in the LI-RADS-based classification of the risk of HCCs between the CAD and radiologists. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:710-722.

Simultaneous acquisition of MR angiography and diagnostic images of abdomen at view-sharing multiarterial phases and comparing the effect of two different contrast agents.

BACKGROUND: Simultaneous acquisition of magnetic resonance angiography (MRA) and diagnostic images is challenging in contrast-enhanced upper abdominal MRI. PURPOSE: To evaluate the image quality of MRA of the abdomen acquired simultaneously with diagnostic MR images, and to compare the contrast effect, conspicuity of aortic branches, and pancreatic lesions in MRA between gadobutrol and gadoterate meglumine. STUDY TYPE: Prospective. POPULATION: Eighty-eight patients with known and suspected upper abdominal disease. FIELD STRENGTH/SEQUENCES: 3T/4D-eTHRIVE (T1 -weighted fat-suppressed 3D fast gradient echo) for multiarterial phase imaging. ASSESSMENT: The artery-to-muscle signal intensity ratio (SIR), conspicuity of aortic branches on the axial, maximum intensity projection (MIP), and volume-rendered (VR) images, and conspicuity of focal pancreatic lesions were compared between gadobutrol and gadoterate meglumine. The diameters of aortic branches were measured on axial MRA and computed tomography angiography (CTA) images and then compared. STATISTICAL TESTS: Quantitative and qualitative data were assessed with the Mann-Whitney U-test. The diameters of aortic branches between MRA and CTA were compared with a Spearman rank correlation test. RESULTS: View-sharing multiarterial phase imaging was successfully performed in all patients. The SIRs of common hepatic artery (P = 0.0051) and left renal artery (RA) (P = 0.045), vascular conspicuities of right and left hepatic arteries (P = 0.010 and 0.030) and right and left RAs on axial (P = 0.0065 and 0.036), and that of gastroduodenal artery on MIP (P = 0.039) with gadobutrol were significantly higher than those with gadoterate meglumine. The conspicuity of focal pancreatic lesions were comparable between the gadobutrol and gadoterate meglumine (P = 0.73). The vascular diameters on MRA and CTA were strongly correlated in all aortic branches (r = 0.842-0.942, P < 0.0001). DATA CONCLUSION: High-quality MRA of the abdomen was obtained simultaneously with the diagnostic MR images using view-sharing multiarterial phase imaging that also demonstrated comparable image quality between gadobutrol and gadoterate meglumine. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage 1 J. Magn. Reson. Imaging 2017.

Modified National Comprehensive Cancer Network Criteria for Assessing Resectability of Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: The objective of our study was to assess the preoperative resectability of pancreatic ductal adenocarcinoma (PDAC) using the National Comprehensive Cancer Network (NCCN) guideline, the general rules of the Japan Pancreas Society (JPS), and both of them combined. MATERIALS AND METHODS: Eighty-six consecutive patients with PDAC (50 men and 36 women; mean age ± SD, 70.8 ± 9.0 years; age range, 49-86 years) underwent dynamic contrast-enhanced CT. Following the NCCN guideline, the degree of vascular invasion was evaluated to determine the NCCN score: 0 points for absence of vascular invasion, 1 point for tumor contact ≤ 180°, and 2 points for tumor contact > 180°. Direct invasion to adjacent structures was rated according to the general rules of JPS to determine the JPS score: 0 points for absence and 1 point for presence. The NCCN score, JPS score, and sum of the two scores, which we refer to as the "combined score," were compared with histopathologic or intraoperative findings as well as for the differentiation of R0 resection (negative resection margins) from R1 (microscopic tumor infiltration) and R2 (macroscopic residual tumor) using ROC curve analysis. RESULTS: The sensitivities, specificities, and areas under the ROC curves (AUCs) for the differentiation of R0 from R1 and R2 were 100.0%, 40.0%, and 0.725, respectively, with the NCCN score; 63.9%, 84.0%, and 0.824 with the JPS score; and 86.9%, 68.0%, and 0.874 with the combined score. The AUC of the combined score was significantly greater than that of the NCCN score (p = 0.0059). CONCLUSION: The assessment of resectability of PDAC based on the combined criteria of the NCCN guideline and general rules of JPS was superior to that based on either criterion alone.

Image texture features predict renal function decline in patients with autosomal dominant polycystic kidney disease.

Magnetic resonance imaging (MRI) examinations provide high-resolution information about the anatomic structure of the kidneys and are used to measure total kidney volume (TKV) in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). Height-adjusted TKV (HtTKV) has become the gold-standard imaging biomarker for ADPKD progression at early stages of the disease when estimated glomerular filtration rate (eGFR) is still normal. However, HtTKV does not take advantage of the wealth of information provided by MRI. Here we tested whether image texture features provide additional insights into the ADPKD kidney that may be used as complementary information to existing biomarkers. A retrospective cohort of 122 patients from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study was identified who had T2-weighted MRIs and eGFR values over 70 mL/min/1.73m2 at the time of their baseline scan. We computed nine distinct image texture features for each patient. The ability of each feature to predict subsequent progression to CKD stage 3A, 3B, and 30% reduction in eGFR at eight-year follow-up was assessed. A multiple linear regression model was developed incorporating age, baseline eGFR, HtTKV, and three image texture features identified by stability feature selection (Entropy, Correlation, and Energy). Including texture in a multiple linear regression model (predicting percent change in eGFR) improved Pearson correlation coefficient from -0.51 (using age, eGFR, and HtTKV) to -0.70 (adding texture). Thus, texture analysis offers an approach to refine ADPKD prognosis and should be further explored for its utility in individualized clinical decision making and outcome prediction.

Dietary salt restriction is beneficial to the management of autosomal dominant polycystic kidney disease.

The CRISP study of polycystic kidney disease (PKD) found that urinary sodium excretion associated with the rate of total kidney volume increase. Whether sodium restriction slows the progression of Autosomal Dominant PKD (ADPKD) is not known. To evaluate this we conducted a post hoc analysis of the HALT-PKD clinical trials of renin-angiotensin blockade in patients with ADPKD. Linear mixed models examined whether dietary sodium affected rates of total kidney volume or change in estimated glomerular filtration rate (eGFR) in patients with an eGFR over 60 ml/min/1.73 m2 (Study A) or the risk for a composite endpoint of 50% reduction in eGFR, end-stage renal disease or death, or the rate of eGFR decline in patients with an eGFR 25-60 ml/min/1.73 m2 (Study B) all in patients initiated on an under100 mEq sodium diet. During the trial urinary sodium excretion significantly declined by an average of 0.25 and 0.41 mEq/24 hour per month in studies A and B, respectively. In Study A, averaged and time varying urinary sodium excretions were significantly associated with kidney growth (0.43%/year and 0.09%/year, respectively, for each 18 mEq urinary sodium excretion). Averaged urinary sodium excretion was not significantly associated with faster eGFR decline (-0.07 ml/min/1.73m2/year for each 18 mEq urinary sodium excretion). In Study B, the averaged but not time-varying urinary sodium excretion significantly associated with increased risk for the composite endpoint (hazard ratio 1.08 for each 18 mEq urinary sodium excretion) and a significantly faster eGFR decline (-0.09 ml/min/1.73m2/year for each mEq 18 mEq urinary sodium excretion). Thus, sodium restriction is beneficial in the management of ADPKD.

Blood pressure in early autosomal dominant polycystic kidney disease.

BACKGROUND: Hypertension is common in autosomal dominant polycystic kidney disease (ADPKD) and is associated with increased total kidney volume, activation of the renin-angiotensin-aldosterone system, and progression of kidney disease. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 558 hypertensive participants with ADPKD (15 to 49 years of age, with an estimated glomerular filtration rate [GFR] >60 ml per minute per 1.73 m(2) of body-surface area) to either a standard blood-pressure target (120/70 to 130/80 mm Hg) or a low blood-pressure target (95/60 to 110/75 mm Hg) and to either an angiotensin-converting-enzyme inhibitor (lisinopril) plus an angiotensin-receptor blocker (telmisartan) or lisinopril plus placebo. The primary outcome was the annual percentage change in the total kidney volume. RESULTS: The annual percentage increase in total kidney volume was significantly lower in the low-blood-pressure group than in the standard-blood-pressure group (5.6% vs. 6.6%, P=0.006), without significant differences between the lisinopril-telmisartan group and the lisinopril-placebo group. The rate of change in estimated GFR was similar in the two medication groups, with a negative slope difference in the short term in the low-blood-pressure group as compared with the standard-blood-pressure group (P<0.001) and a marginally positive slope difference in the long term (P=0.05). The left-ventricular-mass index decreased more in the low-blood-pressure group than in the standard-blood-pressure group (-1.17 vs. -0.57 g per square meter per year, P<0.001); urinary albumin excretion was reduced by 3.77% with the low-pressure target and increased by 2.43% with the standard target (P<0.001). Dizziness and light-headedness were more common in the low-blood-pressure group than in the standard-blood-pressure group (80.7% vs. 69.4%, P=0.002). CONCLUSIONS: In early ADPKD, the combination of lisinopril and telmisartan did not significantly alter the rate of increase in total kidney volume. As compared with standard blood-pressure control, rigorous blood-pressure control was associated with a slower increase in total kidney volume, no overall change in the estimated GFR, a greater decline in the left-ventricular-mass index, and greater reduction in urinary albumin excretion. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study A] ClinicalTrials.gov number, NCT00283686.).

Urine peptidome analysis predicts risk of end-stage renal disease and reveals proteolytic pathways involved in autosomal dominant polycystic kidney disease progression.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by slowly progressive bilateral renal cyst growth ultimately resulting in loss of kidney function and end-stage renal disease (ESRD). Disease progression rate and age at ESRD are highly variable. Therapeutic interventions therefore require early risk stratification of patients and monitoring of disease progression in response to treatment. Methods: We used a urine peptidomic approach based on capillary electrophoresis-mass-spectrometry (CE-MS) to identify potential biomarkers reflecting the risk for early progression to ESRD in the Consortium of Radiologic Imaging in Polycystic Kidney Disease (CRISP) cohort. Results: A biomarker-based classifier consisting of 20 urinary peptides allowed the prediction of ESRD within 10-13 years of follow-up in patients 24-46 years of age at baseline. The performance of the biomarker score approached that of height-adjusted total kidney volume (htTKV) and the combination of the biomarker panel with htTKV improved prediction over either one alone. In young patients (<24 years at baseline), the same biomarker model predicted a 30 mL/min/1.73 m 2 glomerular filtration rate decline over 8 years. Sequence analysis of the altered urinary peptides and the prediction of the involved proteases by in silico analysis revealed alterations in distinct proteolytic pathways, in particular matrix metalloproteinases and cathepsins. Conclusion: We developed a urinary test that accurately predicts relevant clinical outcomes in ADPKD patients and suggests altered proteolytic pathways involved in disease progression.

Predicted Mutation Strength of Nontruncating PKD1 Mutations Aids Genotype-Phenotype Correlations in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) often results in ESRD but with a highly variable course. Mutations to PKD1 or PKD2 cause ADPKD; both loci have high levels of allelic heterogeneity. We evaluated genotype-phenotype correlations in 1119 patients (945 families) from the HALT Progression of PKD Study and the Consortium of Radiologic Imaging Study of PKD Study. The population was defined as: 77.7% PKD1, 14.7% PKD2, and 7.6% with no mutation detected (NMD). Phenotypic end points were sex, eGFR, height-adjusted total kidney volume (htTKV), and liver cyst volume. Analysis of the eGFR and htTKV measures showed that the PKD1 group had more severe disease than the PKD2 group, whereas the NMD group had a PKD2-like phenotype. In both the PKD1 and PKD2 populations, men had more severe renal disease, but women had larger liver cyst volumes. Compared with nontruncating PKD1 mutations, truncating PKD1 mutations associated with lower eGFR, but the mutation groups were not differentiated by htTKV. PKD1 nontruncating mutations were evaluated for conservation and chemical change and subdivided into strong (mutation strength group 2 [MSG2]) and weak (MSG3) mutation groups. Analysis of eGFR and htTKV measures showed that patients with MSG3 but not MSG2 mutations had significantly milder disease than patients with truncating cases (MSG1), an association especially evident in extreme decile populations. Overall, we have quantified the contribution of genic and PKD1 allelic effects and sex to the ADPKD phenotype. Intrafamilial correlation analysis showed that other factors shared by families influence htTKV, with these additional genetic/environmental factors significantly affecting the ADPKD phenotype.

Enhancement of functional MRI signal at high-susceptibility regions of brain using simultaneous multiecho multithin-slice summation imaging technique.

PURPOSE: To increase temporal-signal-to-noise ratio (tSNR) and blood oxygen level-dependent (BOLD) sensitivity at high-susceptibility regions of the brain by means of a simultaneous multiecho multithin-slice summation imaging technique. MATERIALS AND METHODS: The simultaneous multislice (SMS) technique was implemented with multiecho (SMSME) and multiecho with thin-slice summation (SMSME-thin) at 3T. Multiecho data were summated based on the local apparent T2* weighting factor. Ten healthy subjects were studied for the whole brain activation by breath-holding. The tSNR values and the number of activated pixels acquired with SMSME and SMSME-thin were compared with those acquired with the conventional gradient-echo EPI in multiple brain regions RESULTS: SMS methods accelerated imaging time by 5-fold as compared with the conventional method, resulting in the acquisition of three echoes and four thin-slices during the same TR of 2.5 seconds. At high-susceptibility regions, including the amygdala, inferior and middle temporal, and anterior frontal lobes, SMSME increased tSNR values by up to ∼80% and BOLD activation by up to ∼20% (paired t-test, P < 0.05). SMSME-thin further increased values as compared with SMSME (∼45% for tSNR and ∼20% for activation, P < 0.05). CONCLUSION: The SMSME-thin imaging technique enhanced the temporal-signal-to-noise ratio and functional activation at high susceptibility regions of the brain. J. Magn. Reson. Imaging 2016;44:478-485.

Diffusion kurtosis imaging of the pancreas for the assessment of HbA1c levels.

PURPOSE: To evaluate the feasibility of diffusion kurtosis (DK) imaging of the pancreas for the assessment of hemoglobin (Hb) A1c values. MATERIALS AND METHODS: Our Institutional Review Board approved this prospective study and written informed consent was obtained. In all, 102 consecutive patients with suspected pancreatic disease underwent magnetic resonance imaging (MRI), including DK imaging. Patients were classified into three groups according to American Diabetes Association criteria: HbA1c < 5.7% (group 1), 5.7% ≤ HbA1c < 6.5% (group 2), and HbA1c ≥ 6.5% (group 3). Mean kurtosis (MK) and apparent diffusion coefficient (ADC) of pancreatic parenchyma were computed. MRI measurements and HbA1c values were then compared. RESULTS: HbA1c values positively correlated with MK (r = 0.66, P < 0.0001). Group 3 was significantly (P < 0.05) higher (P < 0.05) in MK than groups 1 and 2. The sensitivity, specificity, and area under the ROC curve of the MK for the detection of group 3 were 90%, 88%, and 0.92, respectively. CONCLUSION: The MK measurement on DK imaging of the pancreas could be a potential biomarker for assessing HbA1c level.

Findings in pancreatic MRI associated with pancreatic fibrosis and HbA1c values.

PURPOSE: To evaluate the diagnostic performance of noncontrast-enhanced magnetic resonance imaging (MRI) to grade pancreatic fibrosis and to assess hemoglobin (Hb) A1c values. MATERIALS AND METHODS: Twenty-nine consecutive patients with pancreatic or biliary malignancy who underwent pancreatectomy were evaluated. Patients were classified into three groups: HbA1c < 5.7 (group 1), 5.7 ≤ HbA1c < 6.5 (group 2), and HbA1c ≥ 6.5 (group 3). MRI of the pancreas was performed using a 1.5T MR system. The pancreas-to-muscle signal intensity ratio (SIR) on in- and opposed-phase T1 -, T2 -, and diffusion-weighted images, as well as the apparent diffusion coefficient were calculated. MRI measurements, degrees of pancreatic fibrosis, and HbA1c values were compared using multiple regression analysis and Kruskal-Wallis test. RESULTS: The pancreatic fibrosis grade was negatively correlated with the SIR on in-phase T1 -weighted images (r = -0.67, P = 0.0002). The pancreatic fibrosis grade and HbA1c value were negatively correlated with the SIR on opposed-phase T1 -weighted images (r = -0.47, P = 0.019 and r = -0.51, P = 0.0089, respectively). SIRs on in- and opposed-phase T1 -weighted images were significantly lower in group 3 than in groups 1 and 2 (P < 0.05). CONCLUSION: The pancreas-to-muscle SIRs on in- and opposed-phase T1 -weighted images could be a potential biomarker for pancreatic fibrosis and elevated HbA1c values.

Minimally Required Iodine Dose for the Detection of Hypervascular Hepatocellular Carcinoma on 80-kVp CT.

OBJECTIVE: The objective of our study was to determine the iodine dose per unit of body weight (BW) or body surface area (BSA) that is minimally required to detect hypervascular hepatocellular carcinoma (HCC) on 80-kVp CT. SUBJECTS AND METHODS: One hundred eleven patients (78 men and 33 women; mean age, 68 years; age range, 43-85 years) with chronic hepatitis were randomized into three groups with different iodine loads (0.5, 0.4, and 0.3 g I/kg BW) and underwent contrast-enhanced CT at 80 kVp. Enhancement of the liver and of hypervascular HCCs was quantitatively and qualitatively assessed on hepatic arterial, portal venous, and equilibrium phase images and compared between the groups. Values for iodine dose per unit of BSA (g I/m(2)) were also computed and analyzed. RESULTS: No significant differences in the contrast-to-noise ratio (CNR) of hypervascular HCCs in any phase were found between the groups (p = 0.34-0.99). In the portal venous phase, the mean increase in hepatic contrast enhancement (ΔHU) of the 0.5 g I/kg group (80.3 HU) was higher than those of the 0.4 g I/kg (63.4 HU) and 0.3 g I/kg (53.3 HU) groups (p < 0.001). Linear correlation equations for the increase in hepatic contrast enhancement were as follows: ΔHU = 5.9 + 150.0 × IL(BW) (r = 0.69, p < 0.001), where IL(BW) is the iodine load per unit of BW (g I/kg), and ΔHU = 13.0 + 3.68 × IL(BSA) (r = 0.66, p < 0.001), where IL(BSA) is the iodine load pre unit of BSA (g I/m(2)). CONCLUSION: The minimal iodine dose required to achieve a tumor-to-liver CNR that is acceptable for the detection of hypervascular HCCs on 80-kVp CT was 0.3 g I/kg BW or 11.0 g I/m(2) BSA.

Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials.

The rate of renal disease progression varies widely among patients with autosomal dominant polycystic kidney disease (ADPKD), necessitating optimal patient selection for enrollment into clinical trials. Patients from the Mayo Clinic Translational PKD Center with ADPKD (n=590) with computed tomography/magnetic resonance images and three or more eGFR measurements over ≥6 months were classified radiologically as typical (n=538) or atypical (n=52). Total kidney volume (TKV) was measured using stereology (TKVs) and ellipsoid equation (TKVe). Typical patients were randomly partitioned into development and internal validation sets and subclassified according to height-adjusted TKV (HtTKV) ranges for age (1A-1E, in increasing order). Consortium for Radiologic Imaging Study of PKD (CRISP) participants (n=173) were used for external validation. TKVe correlated strongly with TKVs, without systematic underestimation or overestimation. A longitudinal mixed regression model to predict eGFR decline showed that log2HtTKV and age significantly interacted with time in typical patients, but not in atypical patients. When 1A-1E classifications were used instead of log2HtTKV, eGFR slopes were significantly different among subclasses and, except for 1A, different from those in healthy kidney donors. The equation derived from the development set predicted eGFR in both validation sets. The frequency of ESRD at 10 years increased from subclass 1A (2.4%) to 1E (66.9%) in the Mayo cohort and from 1C (2.2%) to 1E (22.3%) in the younger CRISP cohort. Class and subclass designations were stable. An easily applied classification of ADPKD based on HtTKV and age should optimize patient selection for enrollment into clinical trials and for treatment when one becomes available.