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.

Volume Progression and Imaging Classification of Polycystic Liver in Early Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND AND OBJECTIVES: The progression of polycystic liver disease is not well understood. The purpose of the study is to evaluate the associations of polycystic liver progression with other disease progression variables and classify liver progression on the basis of patient's age, height-adjusted liver cystic volume, and height-adjusted liver volume. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Prospective longitudinal magnetic resonance images from 670 patients with early autosomal dominant polycystic kidney disease for up to 14 years of follow-up were evaluated to measure height-adjusted liver cystic volume and height-adjusted liver volume. Among them, 245 patients with liver cyst volume >50 ml at baseline were included in the longitudinal analysis. Linear mixed models on log-transformed height-adjusted liver cystic volume and height-adjusted liver volume were fitted to approximate mean annual rate of change for each outcome. The association of sex, body mass index, genotype, baseline height-adjusted total kidney volume, and Mayo imaging class was assessed. We calculated height-adjusted liver cystic volume ranges for each specific age and divided them into five classes on the basis of annual percentage increase in height-adjusted liver cystic volume. RESULTS: The mean annual growth rate of height-adjusted liver cystic volume was 12% (95% confidence interval, 11.1% to 13.1%; P<0.001), whereas that for height-adjusted liver volume was 2% (95% confidence interval, 1.9% to 2.6%; P<0.001). Women had higher baseline height-adjusted liver cystic volume than men, but men had higher height-adjusted liver cystic volume growth rate than women by 2% (95% confidence interval, 0.4% to 4.5%; P=0.02). Whereas the height-adjusted liver cystic volume growth rate decreased in women after menopause, no decrease was observed in men at any age. Body mass index, genotype, and baseline height-adjusted total kidney volume were not associated with the growth rate of height-adjusted liver cystic volume or height-adjusted liver volume. According to the height-adjusted liver cystic volume growth rate, patients were classified into five classes (number of women, men in each class): A (24, six); B (44, 13); C (43, 48); D (28, 17); and E (13, nine). CONCLUSIONS: Compared with height-adjusted liver volume, the use of height-adjusted liver cystic volume showed greater separations in volumetric progression of polycystic liver disease. Similar to the Mayo imaging classification for the kidney, the progression of polycystic liver disease may be categorized on the basis of patient's age and height-adjusted liver cystic volume.

Novel 3D capsule device to restrict kidney volume expansion on polycystic kidney progression: feasibility study in a rat model.

BACKGROUND: Cystogenesis in polycystic kidney disease (PKD) is likely accelerated by various renal insults, including crystal deposition, that activate renal tubule obstruction and dilation. We developed a capsule-based device that can be applied to cystic kidneys to restrict tubular lumen dilatation and cyst expansion. METHODS: Kidney capsule devices were designed from computed tomography images of wild-type and Cy/+ rats. Capsule devices were surgically implanted on kidneys in six surgical sessions over a period of 14 months in 7 wild-type rats of 6.5-8 weeks (3 sham operations, 2 right, 2 left) and 6 Cy/+ rats of 6.5 weeks (2 sham, 3 left, 1 bilateral). After surgery, the rats were followed for 5.4-12.4 weeks' growth and sacrificed to retrieve the kidneys. During the follow-up, serum creatinine was measured and retrieved kidneys were weighed. Histological analysis including cystic area measurement and immunohistochemistry was performed. RESULTS: Morphometric capsule devices were configured and developed by an image processing technique and produced using a 3D printer. Encapsulated Cy/+ kidneys (n = 5; mean weight 3.64 g) were consistently smaller in size (by 21-36%; p < 0.001) than unencapsulated Cy/+ kidneys (n = 7; mean weight 5.52 g). Encapsulated Cy/+ kidneys (mean %cyst area: 29.4%) showed smaller histological cystic area (by 28-58%; p < 0.001) than unencapsulated Cy/+ kidneys (mean %cyst area 48.6%). Cell proliferation and macrophages were also markedly reduced in encapsulated Cy/+ kidneys, compared to unencapsulated Cy/+ kidneys. CONCLUSIONS: We report a pilot feasibility study for the application of a novel morphometric 3D capsule device to the Cy/+ rat model showing restricted kidney volume expansion on polycystic kidney disease progression.

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.

Baseline Characteristics and Patient-Reported Outcomes of ADPKD Patients in the Multicenter TAME-PKD Clinical Trial.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) has been associated with metabolic disturbances characterized by downregulation of AMP-activated protein kinase (AMPK), a critical sensor of the cellular energy status. Therapeutic activation of AMPK by metformin could inhibit cyst enlargement by inhibition of both the mammalian target of rapamycin pathway and fluid secretion via the CFTR chloride channel. METHODS: We designed a phase-2, randomized, placebo-controlled, clinical trial to assess the safety, tolerability, and efficacy of metformin on total kidney volume in adults without diabetes (age 18-60 years) with ADPKD and eGFR of ≥50 ml/min per 1.73 m2. There were no eligibility criteria relating to kidney volume. In addition to demographics and clinical/family history, baseline parameters included eGFR, total kidney and liver volumes measured by MRI, and patient-reported outcomes were ascertained by the Medical Outcomes Study Short Form-36, the Gastrointestinal Safety Rating Scale, and the HALT-PKD pain questionnaire. RESULTS: We successfully randomized 97 participants recruited from two university-based clinical sites in Baltimore and Boston. The mean age of participants was 41.9 years, 72% were female, and 94% of participants were White. The majority of study participants had early stage disease, with a mean eGFR of 86.8±19.0 ml/min per 1.73 m2. Approximately half of the study participants (48%) were classified as high risk for progression (Mayo imaging classes 1C, 1D, or 1E). There was no correlation between kidney and/or liver size and health-related quality of life (HRQoL) or gastrointestinal symptom severity. CONCLUSIONS: We report successful recruitment in this ongoing, novel, clinical trial of metformin in ADPKD, with a study sample comprising patients with early stage disease and nearly a half of participants considered at high estimated risk for progression. Participants reported a low gastrointestinal symptom burden at baseline, and HRQoL similar to that of the general population, with no differences in symptoms or HRQoL related to organomegaly. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Metformin as a Novel Therapy for Autosomal Dominant Polycystic Kidney Disease (TAME), NCT02656017.

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.

Growth Pattern of Kidney Cyst Number and Volume in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND AND OBJECTIVES: To evaluate the growth pattern of kidney cyst number and cyst volume in association with kidney size, demographics, and genotypes in autosomal dominant polycystic kidney disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Kidney cyst number and cyst volume were measured from serial magnetic resonance images, giving a maximum follow-up of 14.23 years, from 241 patients with autosomal dominant polycystic kidney disease (15-46 years old at baseline). The growth pattern was analyzed, in association with sex, age, height-adjusted total kidney volume, and genotype, using linear mixed models of repeated measurements and tests of interactions with age (as a time-dependent covariate) to assess rates of change over time. Models were also fit using Irazabal class. Genotypic groups were characterized as either (1) PKD1 truncating, PKD1 nontruncating, and PKD2 plus patients with no mutation detected; or (2) in combination with PKD1 mutation strength groups. RESULTS: Imaging and genetic data were collected (at least one visit) for 236 participants. The mean height-adjusted total cyst number increased exponentially over time from a baseline value of 762 to 1715 at the last clinic visit, while the mean height-adjusted total cyst volume increased exponentially from 305 to 770 ml. Height-adjusted total kidney volume, height-adjusted total cyst number, and height-adjusted total cyst volume were all highly correlated over time. Female participants and participants with larger height-adjusted total kidney volume at baseline showed smaller rates of change in the log of height-adjusted total cyst number and cyst volume. PKD1 was associated with significant increases in both cyst number and volume at a given age, but genotype did not significantly affect the rate of growth. CONCLUSIONS: Both height-adjusted total cyst number and height-adjusted total cyst volume increased exponentially and more than doubled over 14.23 years of follow-up. Compared with PKD2 plus no mutation detected, PKD1 was associated with a greater cyst number and volume at a given age, but no significant difference in the rate of growth.

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.

A radiogenomic analysis of hepatocellular carcinoma: association between fractional allelic imbalance rate index and the liver imaging reporting and data system (LI-RADS) categories and features.

OBJECTIVE: To evaluate the association between the liver imaging reporting and data system (LI-RADS) categories and features and the fractional allelic imbalance (FAI) rate index of hepatocellular carcinoma (HCC). METHODS: The institutional review board approved this retrospective study. Medical records collected between January 2008 and December 2013 were reviewed to find patients with histologically confirmed HCC, FAI analysis, and CT or MR imaging of the liver. The final population included 71 patients (54 males, 17 females). Three radiologists reviewed the images using the LI-RADS v. 2014. The association between FAI and LI-RADS categories and features was tested using the Spearman's rank correlation coefficient (rho) and the Wilcoxon rank-sum test [low FAI (<40%) vs high FAI (≥40%)]. A p value < 0.007 was used as the threshold for statistical significance after application of the Bonferroni correction for multiple comparisons. RESULTS: HCCs were classified as LR-3 (n = 4), LR-4 (n = 22), and LR-5 (n = 45). There was a positive correlation (rho = 0.264) between FAI rate index and LI-RADS category, although not statistically significant after Bonferroni correction (p = 0.024). 14 of the 20 (70%) HCCs with high FAI (≥40%) were categorized as LR-5, 6/20 (30%) as LR-4 and none as LR-3 (p = 0.377). Among the evaluated LI-RADS imaging features, only lesion size showed a statistically significant different distribution in tumors with high FAI compared to those with low FAI. HCCs with FAI ≥40% were larger (56 ± 42 mm) compared to those with FAI <40% (36 ± 30 mm; p = 0.005). CONCLUSION: There was a positive correlation, although not statistically significant, between the LI-RADS diagnostic categories and the FAI rate of HCC. Tumors with high FAI were larger compared to those with low FAI. Advances in knowledge: HCCs with high (≥40%) FAI are larger compared to those with low (<40%) FAI.

Is Magnetic Resonance Imaging Detection of Kidney Iron Deposition Increased in Haptoglobin 2-2 Genotype Carriers with Type 1 Diabetes?

Haptoglobin's (Hp) main role is to bind free hemoglobin (Hb), reducing its oxidative potential. The Hp-Hb complex formed is cleared from the circulation by macrophage receptor CD163. In diabetes, impaired Hp 2-2-Hb CD163 clearance and abnormal glomerular permeability allow the large Hp 2-2-Hb complex to cross the barrier, where its redox active iron leads to cellular toxicity. Although Hp 2-2 predicts renal function decline, whether renal iron deposition differs by Hp is unknown. We used renal quantitative T2* magnetic resonance imaging to estimate iron level in the cortex and medullar of type 1 diabetes (T1D) adults [15 Hp 1-1 and 15 Hp 2-2 carriers of similar age (53 years), duration (45 years), and gender]. Total kidney iron level was estimated as the sum of the cortex and medullar iron. Albuminuria was defined as urinary albumin to creatinine ratio >30 mg/g in two of three samples. Total kidney iron did not differ by gender or Hp but was higher in those with albuminuria (p = 0.05), an association confined to Hp 2-2 carriers (p = 0.04 vs. p = 0.51 in Hp 1-1). These data lead to the hypothesis that kidney iron deposition is increased among Hp 2-2 carriers with albuminuria in T1D. Antioxid. Redox Signal. 29, 735-741.

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.

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.

Gadoxetic acid-enhanced high temporal-resolution hepatic arterial-phase imaging with view-sharing technique: Impact on the LI-RADS category.

PURPOSE: To evaluate the value of view-sharing multi-hepatic arterial-phase (mHAP) imaging for diagnosis of hypervascular hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Forty-seven consecutive patients with HCC underwent gadoxetic acid-enhanced magnetic resonance (MR) imaging before angiographic and lipiodol CT. Hepatic arterial-phase images were obtained at 5 consecutive phases with shared central k-space of 25%, followed by portal venous, late (2 and 3min), and hepatobiliary phase imaging. One-hundred-eight HCC nodules (size: 5-88mm, mean size: 18.2mm) confirmed on angiographic CT and lipiodol CT were evaluated for LI-RADS category and compared with single arterial-phase and mHAP findings regarding wash out, capsule, corona enhancement, and image quality. RESULTS: Twenty-four HCCs (22.2%) (size: 6-19mm, mean size: 12.3mm) were categorized as LR-3 based on the single arterial-phase. Capsule appearance (25.9%) and washout (57.4%) were most frequently observed in late phase (2min). Corona enhancement was observed in 73.1% of all HCCs on mHAP. For the 24 HCCs of LR-3, corona enhancement was observed in 75% on mHAP and contributed to upgrade category. No significant difference was found in the frequency of corona enhancement between mHAP and angiographic CT (P=0.11). Image quality was valued as good or excellent in all cases. CONCLUSION: View-sharing mHAP was feasible without compromising image quality and contributed to the improvement in diagnostic confidence for hypervascular HCC in gadoxetic acid-enhance MR imaging.

Effect of Statin Therapy on the Progression of Autosomal Dominant Polycystic Kidney Disease. A Secondary Analysis of the HALT PKD Trials.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) commonly results in end-stage renal disease (ESRD), yet a long-term treatment that is well tolerated is still lacking. In a small randomized trial in children and adolescents pravastatin administration for 3 years was associated with reduced renal cyst growth, but no large trial has tested the effect of statins in adults. METHODS: We performed a post-hoc analysis of the HALT PKD trials to compare outcomes of participants who never used statins with those who used statin for at least 3 years. Because statins were not randomly allocated, we used propensity score models with inverse probability of treatment weighting to account for imbalances between the groups. For subjects in Study A (preserved renal function, n=438) relevant outcomes were percent change in total kidney and liver volume and the rate of decline in estimated glomerular filtration rate (eGFR); for those in Study B (reduced renal function, n=352) we compared time to the composite endpoint of death, ESRD or 50% decline in eGFR. Follow-up was 5-8 years. RESULTS: There was no difference in any outcome between the 2 groups. However, limitations of this analysis are the small number of statin users in Study A, different statin drugs and doses used, non-randomized allocation and advanced disease stage in Study B. CONCLUSION: Although this post-hoc analysis of the HALT PKD trials does not demonstrate a benefit of statin therapy, conclusions remain preliminary. A larger randomized trial in young people with ADPKD is necessary to answer the question whether statins can slow renal cyst growth and preserve kidney function.

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.

Biliary tract enhancement in gadoxetic acid-enhanced MRI correlates with liver function biomarkers.

PURPOSE: To evaluate the association between gadoxetic-acid-enhanced magnetic resonance (MR) imaging measurements and laboratory and clinical biomarkers of liver function and fibrosis. MATERIALS AND METHODS: One hundred thirty nine consecutive patients with suspected liver disease or liver tumor underwent gadoxetic-acid-enhanced MR imaging. MR imaging measurements during the hepatobiliary phase included biliary tract structure-to-muscle signal intensity ratio (SIR). These measurements were compared with Child-Pugh classification, end-stage liver disease (MELD) score, and aspartate aminotransferase-to-platelet ratio index (APRI). RESULTS: The SIRs of cystic duct and common bile duct were significantly correlated with Child-Pugh classification (P=0.012 for cystic duct and P<0.0001 for common bile duct), MELD score (P=0.0016 and P=0.0033), and APRI (P=0.0022 and P=0.0015). The sensitivity, specificity, and area under the receiver-operating-characteristic curve were: (74%, 88%, 0.86) with the SIR of common bile duct for the detection of patients with Child-Pugh class B or C; (100%, 87%, 0.94) with the SIR of cystic duct for MELD score (>10); (65%, 76%, 0.70) with the SIR of common bile duct for APRI (>1.5). CONCLUSION: Gadoxetic-acid contrast enhancement of cystic duct and common bile duct could be used as biomarkers to assess liver function.

Automated segmentation of liver and liver cysts from bounded abdominal MR images in patients with autosomal dominant polycystic kidney disease.

Liver and liver cyst volume measurements are important quantitative imaging biomarkers for assessment of disease progression in autosomal dominant polycystic kidney disease (ADPKD) and polycystic liver disease (PLD). To date, no study has presented automated segmentation and volumetric computation of liver and liver cysts in these populations. In this paper, we proposed an automated segmentation framework for liver and liver cysts from bounded abdominal MR images in patients with ADPKD. To model the shape and variations in ADPKD livers, the spatial prior probability map (SPPM) of liver location and the tissue prior probability maps (TPPMs) of liver parenchymal tissue intensity and cyst morphology were generated. Formulated within a three-dimensional level set framework, the TPPMs successfully captured liver parenchymal tissues and cysts, while the SPPM globally constrained the initial surfaces of the liver into the desired boundary. Liver cysts were extracted by combined operations of the TPPMs, thresholding, and false positive reduction based on spatial prior knowledge of kidney cysts and distance map. With cross-validation for the liver segmentation, the agreement between the radiology expert and the proposed method was 84% for shape congruence and 91% for volume measurement assessed by the intra-class correlation coefficient (ICC). For the liver cyst segmentation, the agreement between the reference method and the proposed method was ICC = 0.91 for cyst volumes and ICC = 0.94 for % cyst-to-liver volume.