Autosomal Dominant Polycystic Kidney Disease Subjects Research Articles

Prevalence of Spinal Meningeal Diverticula in Autosomal Dominant Polycystic Kidney Disease.

Patients with autosomal dominant polycystic kidney disease (ADPKD) develop cysts in the kidneys, liver, spleen, pancreas, prostate, and arachnoid spaces. In addition, spinal meningeal diverticula have been reported. To determine whether spinal meningeal diverticula are associated with ADPKD, we compared their prevalence in subjects with ADPKD with a control cohort without ADPKD. Subjects with ADPKD and age- and sex-matched controls without ADPKD undergoing abdominal MRI from the midthorax to the pelvis from 2003 to 2023 were retrospectively evaluated for spinal meningeal diverticula by 4 blinded observers. The prevalence of spinal meningeal diverticula in ADPKD was compared with that in control subjects, using t tests and correlated with clinical and laboratory data and MR imaging features, including cyst volumes and cyst counts. Identification of spinal meningeal diverticula in ADPKD (n = 285, median age, 47; interquartile range [IQR], 37-56 years; 54% female) and control (n = 285, median age, 47; IQR, 37-57 years; 54% female) subjects had high interobserver agreement (pairwise Cohen κ = 0.74). Spinal meningeal diverticula were observed in 145 of 285 (51%) subjects with ADPKD compared with 66 of 285 (23%) control subjects without ADPKD (P < .001). Spinal meningeal diverticula in ADPKD were more prevalent in women (98 of 153 [64%]) than men (47 of 132 [36%], P < .001). The mean number of spinal meningeal diverticula per affected subject with ADPKD was 3.6 ± 2.9 compared with 2.4 ± 1.9 in controls with cysts (P < .001). The median volume (IQR, 25%-75%) of spinal meningeal diverticula was 400 (IQR, 210-740) mm3 in those with ADPKD compared with 250 (IQR, 180-440) mm3 in controls (P < .001). The mean spinal meningeal diverticulum diameter was greater in the sacrum (7.3 [SD, 4.1] mm) compared with thoracic (5.4 [SD, 1.8] mm) and lumbar spine (5.8 [SD, 2.0] mm), (P < .001), suggesting that hydrostatic pressure contributed to enlargement. ADPKD has a high prevalence of spinal meningeal diverticula, particularly in women.

Improved predictions of total kidney volume growth rate in ADPKD using two-parameter least squares fitting

Mayo Imaging Classification (MIC) for predicting future kidney growth in autosomal dominant polycystic kidney disease (ADPKD) patients is calculated from a single MRI/CT scan assuming exponential kidney volume growth and height-adjusted total kidney volume at birth to be 150 mL/m. However, when multiple scans are available, how this information should be combined to improve prediction accuracy is unclear. Herein, we studied ADPKD subjects (n=36\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$n = 36$$\\end{document}) with 8+ years imaging follow-up (mean = 11 years) to establish ground truth kidney growth trajectory. MIC annual kidney growth rate predictions were compared to ground truth as well as 1- and 2-parameter least squares fitting. The annualized mean absolute error in MIC for predicting total kidney volume growth rate was 2.1%±2%\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$2.1\\% \\pm 2\\%$$\\end{document} compared to 1.1%±1%\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$1.1\\% \\pm 1\\%$$\\end{document} (p=0.002\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$p = 0.002$$\\end{document}) for a 2-parameter fit to the same exponential growth curve used for MIC when 4 measurements were available or 1.4%±1%\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$1.4\\% \\pm 1\\%$$\\end{document} (p=0.01\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$p = 0.01$$\\end{document}) with 3 measurements averaging together with MIC. On univariate analysis, male sex (p=0.05\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$p = 0.05$$\\end{document}) and PKD2 mutation (p=0.04\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$p = 0.04$$\\end{document}) were associated with poorer MIC performance. In ADPKD patients with 3 or more CT/MRI scans, 2-parameter least squares fitting predicted kidney volume growth rate better than MIC, especially in males and with PKD2 mutations where MIC was less accurate.

Deep learning-based liver cyst segmentation in MRI for autosomal dominant polycystic kidney disease

Abstract Background Autosomal dominant polycystic kidney disease (ADPKD) can lead to polycystic liver disease (PLD), characterized by liver cysts. Although majority of the patients are asymptomatic, massively enlarged liver secondary to PLD can cause discomfort, and compression on adjacent structures requiring cyst aspiration/fenestration, partial liver resection, or liver transplantation. Monitoring PLD by measuring liver volume fails to track the early stages when liver cyst volume is too small to affect liver volume. Purpose To improve PLD assessment in the early stages by automating detection and segmentation of liver cysts using deep learning (DL) models. Materials and Methods A self-configured UNet-based platform (nnU-Net) was trained with 40 ADPKD subjects with liver cysts annotated by a radiologist. Internal (n = 7), External (n = 10), and test-retest reproducibility (n = 17) validations included macro- and micro-level performance metrics: patient-level Dice scores (PDice), along with voxel-level true positive rates (VTPR), as well as analysis of time saved in a model-assisted scenario. Additionally, we assessed human-level reliability in liver cyst segmentation and evaluated the model’s test-retest reproducibility. We further compared liver volume vs cyst volume for tracking disease in a subject with 16+ years follow-up. Results The model achieved an 82% ± 11% PDice and a 75% ± 15% VTPR on the internal test sets (n = 7 patients), and 80% ± 12% Dice score and a 91% ± 7% VTPR on the external test sets (n = 10 patients). It excelled particularly in detecting small liver cysts, a challenging task for manual annotation. This efficiency translated to a median of 91% (IQR: 14%) reduction in annotation time compared to manual labeling. Test-retest assessment demonstrated excellent reproducibility, with coefficients of variation of 94% for liver cyst fraction and 92% for cyst count. Conclusion DL automation of liver cyst segmentations demonstrates potential to improve tracking of liver cyst volume in polycystic liver disease.

Test Retest Reproducibility of Organ Volume Measurements in ADPKD Using 3D Multimodality Deep Learning

Following autosomal dominant polycystic kidney disease (ADPKD) progression by measuring organ volumes requires low measurement variability. The objective of this study is to reduce organ volume measurement variability on MRI of ADPKD patients by utilizing all pulse sequences to obtain multiple measurements which allows outlier analysis to find errors and averaging to reduce variability. In order to make measurements on multiple pulse sequences practical, a 3D multi-modality multi-class segmentation model based on nnU-net was trained/validated using T1, T2, SSFP, DWIand CT from 413 subjects. Reproducibility was assessed with test-re-test methodology on ADPKD subjects (n=19) scanned twice within a 3-week interval correcting outliers and averaging the measurements across all sequences. Absolute percent differences in organ volumes were compared topaired students t-test. Dice similarlity coefficient >97%, Jaccard Index >0.94, mean surface distance <1mmand mean Hausdorff Distance <2cm for all three organs and all five sequences werefound on internal (n=25), external (n=37) and test-re-test reproducibility assessment (38 scans in 19 subjects). When averaging volumes measured from fiveMRI sequences, the model automatically segmented kidneys with test-re-test reproducibility (percent absolute difference between exam 1 and exam 2) of 1.3% which was better than all fiveexpert observers. It reliably stratified ADPKD into Mayo Imaging Classification (area under the curve=100%) compared to radiologist. 3D deep learning measures organ volumes on fiveMRI sequences leveraging the power of outlier analysis and averaging to achieve 1.3% total kidney test-re-test reproducibility.

The Role of Angiotensin II Type 1 Receptor A1166C Polymorphism in Autosomal Dominant Polycystic Kidney Disease.

Introduction Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic disorder that affects the kidney, which affects all ethnical groups worldwide, with varied clinical presentations and severity. The studies done in various parts of the world on the association between angiotensin II type 1 receptor (AT1R) A1166C gene polymorphism and ADPKD patientshave revealed inconsistent results. This study was done to assess the role of AT1R A1166C gene polymorphism in ADPKDin the South Indian population, which is the first of its kind. Methodology This is a case-control study, conducted at a tertiary care centerin South India. This study was concerned with the frequency of exposure (genotype) in ADPKD patients. Peripheral blood samples from 85 unrelated ADPKD patients and 94 controls without diabetes, hypertension, or any kidney-related disease were collected. The AT1R A1166C polymorphism was compared between (i) the cases and controls, (ii) early and late stages of chronic kidney disease(CKD) (ADPKD) subjects, and (iii) ADPKD subjects with and without hypertension. Results Among the ADPKD patients, 45 (52.9%) subjects showed early stage (CKD stages 1-3), and 40 (47%) subjects showed late stage CKD (CKD stages 4 and 5). The genotype distribution of the studied 85 ADPKD patients was almost similar. No significant association was found between the genotype distribution of AT1R A1166C polymorphism in AA vs. AC (OR = 1.11; 95% CI = 0.37-3.32; p < 0.844) and A vs. C (OR = 1.11; 95% CI = 0.38-3.32; p < 0.847) between cases and controls. The genotype distributions in genetic model AA vs. AC (OR = 3.07; 95% CI = 0.56-16.8; p < 0.177) and allelic model A vs. C (OR = 2.13; 95% CI = 0.40-11.3; p < 0.364) between the early and late CKD stages of ADPKD were also not significant. No significant association of gene polymorphism was found between the non-hypertensive and hypertensive groups of ADPKD. Conclusion The results of our study suggest there is no significant association between AT1R A1166C polymorphisms and ADPKD in the South Indian population. Further, the gene polymorphism is not related to the progression of ADPKD or the presence of hypertension in ADPKD cases in South India.

Effect of Averaging Measurements From Multiple MRI Pulse Sequences on Kidney Volume Reproducibility in Autosomal Dominant Polycystic Kidney Disease.

Total kidney volume (TKV) is an important biomarker for assessing kidney function, especially for autosomal dominant polycystic kidney disease (ADPKD). However, TKV measurements from a single MRI pulse sequence have limited reproducibility, ± ~5%, similar to ADPKD annual kidney growth rates. To improve TKV measurement reproducibility on MRI by extending artificial intelligence algorithms to automatically segment kidneys on T1-weighted, T2-weighted, and steady state free precession (SSFP) sequences in axial and coronal planes and averaging measurements. Retrospective training, prospective testing. Three hundred ninety-seven patients (356 with ADPKD, 41 without), 75% for training and 25% for validation, 40 ADPKD patients for testing and 17 ADPKD patients for assessing reproducibility. T2-weighted single-shot fast spin echo (T2), SSFP, and T1-weighted 3D spoiled gradient echo (T1) at 1.5 and 3T. 2D U-net segmentation algorithm was trained on images from all sequences. Five observers independently measured each kidney volume manually on axial T2 and using model-assisted segmentations on all sequences and image plane orientations for two MRI exams in two sessions separated by 1-3 weeks to assess reproducibility. Manual and model-assisted segmentation times were recorded. Bland-Altman, Schapiro-Wilk (normality assessment), Pearson's chi-squared (categorical variables); Dice similarity coefficient, interclass correlation coefficient, and concordance correlation coefficient for analyzing TKV reproducibility. P-value < 0.05 was considered statistically significant. In 17 ADPKD subjects, model-assisted segmentations of axial T2 images were significantly faster than manual segmentations (2:49 minute vs. 11:34 minute), with no significant absolute percent difference in TKV (5.9% vs. 5.3%, P=0.88) between scans 1 and 2. Absolute percent differences between the two scans for model-assisted segmentations on other sequences were 5.5% (axial T1), 4.5% (axial SSFP), 4.1% (coronal SSFP), and 3.2% (coronal T2). Averaging measurements from all five model-assisted segmentations significantly reduced absolute percent difference to 2.5%, further improving to 2.1% after excluding an outlier. Measuring TKV on multiple MRI pulse sequences in coronal and axial planes is practical with deep learning model-assisted segmentations and can improve TKV measurement reproducibility more than 2-fold in ADPKD. 2 TECHNICAL EFFICACY: Stage 1.

Pleural Effusions on MRI in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) has cystic fluid accumulations in the kidneys, liver, pancreas, arachnoid spaces as well as non-cystic fluid accumulations including pericardial effusions, dural ectasia and free fluid in the male pelvis. Here, we investigate the possible association of ADPKD with pleural effusion. ADPKD subjects (n = 268) and age-gender matched controls without ADPKD (n = 268) undergoing body magnetic resonance imaging from mid-thorax down into the pelvis were independently evaluated for pleural effusion by 3 blinded expert observers. Subjects with conditions associated with pleural effusion were excluded from both populations. Clinical and laboratory data as well as kidney, liver and spleen volume, pleural fluid volume, free pelvic fluid and polycystic kidney disease genotype were evaluated. Pleural effusions were observed in 56 of 268 (21%) ADPKD subjects compared with 21 of 268 (8%) in controls (p < 0.0001). In a subpopulation controlling for renal function by matching estimated glomerular filtration rate (eGFR), 28 of 110 (25%) ADPKD subjects had pleural effusions compared to 5 of 110 (5%) controls (p < 0.001). Pleural effusions in ADPKD subjects were more prevalent in females (37/141; 26%) than males (19/127,15%; p = 0.02) and in males were weakly correlated with the presence of free pelvic fluid (r = 0.24, p = 0.02). ADPKD subjects with pleural effusions were younger (48 ± 14 years old vs. 43 ± 14 years old) and weighed less (77 vs. 70 kg; p ≤ 0.02) than those without pleural effusions. For ADPKD subjects with pleural effusions, the mean volume of fluid layering dependently in the posterior−inferior thorax was 19 mL and was not considered to be clinically significant. Pleural effusion is associated with ADPKD, but its role in the pathogenesis of ADPKD requires further evaluation.

Pericardial Effusion on MRI in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) has been associated with cardiac abnormalities including mitral valve prolapse and aneurysmal dilatation of the aortic root. Herein, we investigated the potential association of pericardial effusion with ADPKD. Subjects with ADPKD (n = 117) and control subjects without ADPKD matched for age, gender and renal function (n = 117) undergoing MRI including ECG-gated cine MRI of the aorta and heart were evaluated for pericardial effusion independently by three observers measuring the maximum pericardial effusion thickness in diastole using electronic calipers. Pericardial effusion thickness was larger in ADPKD subjects compared to matched controls (Mann–Whitney p = 0.001) with pericardial effusion thickness >5 mm observed in 24 of 117 (21%) ADPKD subjects compared to 4 of 117 (3%) controls (p = 0.00006). Pericardial effusion thickness in ADPKD was associated with female gender patients (1.2 mm greater than in males, p = 0.03) and pleural effusion thickness (p < 0.001) in multivariate analyses. No subjects exhibited symptoms related to pericardial effusion or required pericardiocentesis. In conclusion, pericardial effusion appears to be more prevalent in ADPKD compared to controls. Although in this retrospective cross-sectional study we did not identify clinical significance, future investigations of pericardial effusion in ADPKD subjects may help to more fully understand its role in this disease.

Semi-Mechanistic Pharmacokinetic Model to Guide the Dose Selection of Nimotuzumab in Patients with Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by an overexpression of epidermal growth factor receptor (EGFR). Nimotuzumab is a recombinant humanized monoclonal antibody against human EGFR. The aim of this study was to develop a population pharmacokinetic model for nimotuzumab and to identify demographic and clinical predictive factors of the pharmacokinetic variability. The population pharmacokinetics (PopPK) of nimotuzumab was characterized using a nonlinear mixed-effect modeling approach with NONMEM®. A total of 422 log-transformed concentration-versus-time datapoints from 20 patients enrolled in a single-center phase I clinical trial were used. Quasi steady state approximation of the full TMDD (target-mediated drug disposition) model with constant target concentration best described the concentration-time profiles. A turnover mediator was included which stimulates the non-specific clearance of mAb in the central compartment in order to explain the reduced levels at higher doses. Covariates had no influence on the PK (pharmacokinetics) parameters. The model was able to detect that the maximum effective dose in ADPKD subjects is 100 mg. The developed PopPK model may be used to guide the dose selection for nimotuzumab during routine clinical practice in patients with polycystic kidney disease. The model will further support the ongoing investigations of the PK/PD relationships of nimotuzumab to improve its therapeutic use in other disease areas.

Prevalence of Inferior Vena Cava Compression in ADPKD

IntroductionKidney and liver cysts in autosomal dominant polycystic kidney disease (ADPKD) can compress the inferior vena cava (IVC), but IVC compression prevalence and its risk factors are unknown.MethodsPatients who have ADPKD (n = 216) with abdominal magnetic resonance imaging (MRI) studies and age-/sex-matched controls (n = 216) were evaluated for IVC compression as well as azygous vein diameter (a marker of collateral blood flow) and IVC aspect ratio (left-to-right dimension divided by anterior-to-posterior dimension with a value of 1 corresponding to a circular (high pressure) IVC caudal to compression.ResultsSevere IVC compression (≥70%) was observed in 33 (15%) ADPKD subjects and mild compression (≥50% to <70%) was observed in 33 (15%) subjects; whereas controls had no IVC compression (P < 0.001). Severe IVC compression was associated with larger azygous vein (4.0 ± 1.3 mm versus 2.3 ± 0.8 mm without IVC compression; P < 0.001) and a more circular IVC cross-section upstream (mean IVC aspect ratio: 1.16 ± 0.27 vs. 1.69 ± 0.67, P < 0.001), suggesting higher pressure upstream from the compression. IVC compression was associated with older age, lower estimated glomerular filtration rate (eGFR), greater height-adjusted total kidney volumes, greater height-adjusted liver volume (ht-LV), and greater liver and renal cyst fractions (P < 0.001). No subject younger than 30 years had IVC compression, but ADPKD subjects ≥40 years old had 12-fold higher risk of IVC compression (95% confidence interval [CI]: 4.2–42.4), with highest predicted probability for Mayo Clinic classes 1D (59%; 95% CI: 39%–76%) and 1E (74%; 95% CI: 49%–90%) after adjustment (P < 0.001). Women with ht-LV ≥ 2000 ml/m had 83% (95% CI: 59%–95%) prevalence of IVC compression. Complications of IVC compression included deep vein thrombosis (DVT) and symptomatic hypotension.ConclusionsIVC compression is common in ADPKD patients >40 years old, with Mayo Clinic class 1D/E, and in females with ht-LV > 2000 ml/m.

Hemorrhagic Cysts and Other MR Biomarkers for Predicting Renal Dysfunction Progression in Autosomal Dominant Polycystic Kidney Disease.

Screening for rapidly progressing autosomal dominant polycystic kidney disease (ADPKD) is necessary for assigning and monitoring therapies. Height-adjusted total kidney volume (ht-TKV) is an accepted biomarker for clinical prognostication, but represents only a small fraction of information on abdominal MRI. To investigate the utility of other MR features of ADPKD to predict progression. Single-center retrospective. Longitudinal data from 186 ADPKD subjects with baseline serum creatinine, PKD gene testing, abdominal MRI measurements, and ≥2 follow-up serum creatinine were reviewed. 1.5T, T2 -weighted single-shot fast spin echo, T1 -weighted 3D spoiled gradient echo (liver accelerated volume acquisition) and 2D cine velocity encoded gradient echo (phase contrast MRA). Ht-TKV, renal blood flow (RBF), number and fraction of renal and hepatic cysts, bright T1 hemorrhagic renal cysts, and liver and spleen volumes were independently assessed by three observers blinded to estimated glomerular filtration rate (eGFR) data. Linear mixed-effect models were applied to predict eGFR over time using MRI features at baseline adjusted for confounders. Validation was performed in 158 patients who had follow-up MRI using receiver operator characteristic, sensitivity, and specificity. Hemorrhagic cysts, fraction of renal and hepatic cysts, height-adjusted liver and spleen volumes were significant independent predictors of future eGFR (final prediction model R2 = 0.88 P < 0.05). The number of hemorrhagic cysts significantly improved the prediction compared to ht-TKV in predicting future eGFR (area under the curve [AUC] = 0.94, 95% confidence interval [CI]: 0.9-0.94 vs. R2 = 0.9, 95% CI: 0.85-0.9, P = 0.045). For baseline eGFR ≥60 ml/min/1.73m2 , sensitivity for predicting eGFR<45 ml/min/1.73m2 by ht-TKV alone was 29%. Sensitivity increased to 72% with all MRI variables in the model (P < 0.05 = 0.019), whereas specificity was unchanged, 100% vs. 99%. Combining multiple MR features including hemorrhagic renal cysts, renal cyst fraction, liver and spleen volume, hepatic cyst fraction, and renal blood flow enhanced sensitivity for predicting eGFR decline in ADPKD compared to the standard model including only ht-TKV. Level of Evidence 2 Technical Efficacy Stage 2 J. MAGN. RESON. IMAGING 2021;53:564-576.

Genetic Characteristics of Korean Patients with Autosomal Dominant Polycystic Kidney Disease by Targeted Exome Sequencing

Autosomal dominant polycystic kidney disease (ADPKD) is one of the main causes of end-stage renal disease (ESRD). Genetic information is of the utmost importance in understanding pathogenesis of ADPKD. Therefore, this study aimed to demonstrate the genetic characteristics of ADPKD and their effects on renal function in 749 Korean ADPKD subjects from 524 unrelated families. Genetic studies of PKD1/2 were performed using targeted exome sequencing combined with Sanger sequencing in exon 1 of the PKD1 gene and a multiple ligation probe assay. The mutation detection rate was 80.7% (423/524 families, 331 mutations) and 70.7% was novel. PKD1 protein-truncating (PKD1-PT) genotype was associated with younger age at diagnosis, larger kidney volume, lower renal function compared to PKD1 non-truncating and PKD2 genotypes. The PKD1 genotype showed earlier onset of ESRD compared to PKD2 genotype (64.9 vs. 72.9 years old, P < 0.001). In frailty model controlled for age, gender, and familial clustering effect, PKD2 genotype had 0.2 times lower risk for reaching ESRD than PKD1-PT genotype (p = 0.037). In conclusion, our results suggest that genotyping can contribute to selecting rapid progressors for new emerging therapeutic interventions among Koreans.

SUN-198 GENETIC CHARACTERISTICS OF KOREAN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE BY TARGETED EXOME SEQUENCING

Autosomal dominant polycystic kidney disease (ADPKD) is one of the main causes of end-stage renal disease (ESRD). Since it is caused by mutations either in PKD1 or PKD2, genetic information is utmost important in understanding pathogenesis of ADPKD. Therefore, this study aimed to demonstrate genetic characteristics of ADPKD and its effect on renal function in 749 Korean ADPKD subjects from 524 unrelated families. Genetic analysis of PKD 1 and PKD2 were performed using targeted exome sequencing. The SureSelectXT Custom probe set and the Agilent SureSelect™ target enrichment protocol (version B.3, June 2015) was used and sequencing was performed using the HiSeq™ 2500 platform (Illumina, San Diego, CA, USA). For cases with inadequate results, Sanger sequencing for exon 1 of PKD1 and multiple ligation probe assay were done. For determining pathogenicity, familial segregation analysis was performed. A total of 476 variants were detected among 524 families. Among them, nonsense variants consist of 26.3%, frameshift 30.9%, typical splicing 5%, large deletion 2.7%, missense 32.6%, and small in-frame indel 2.5%. The overall mutation detection rate was 80.7% (423/524 families). Among them, novel mutation was 70.7%. The prevalence of PKD1 and PKD2 was 84% and 16%, respectively. Mutations were divided into PKD1 protein truncating (PKD1-PT), PKD1 non-truncating (PKD1-NT), and PKD2 genotypes according to their effect on protein function. PKD1-PT genotype was associated with younger age at 1st visit (40.2±12.9 vs. 43.3±12.6 and 45.9±13.0 years, p<0.001), larger height-adjusted total kidney volume (HtTKV) (median 898 vs. 609 and 629 mL/m, p<0.001), lower estimated glomerular filtration rate (eGFR) (63.5±42.2 vs. 66.6±37.8 and 73.1±33.8 mL/min/1.73m2, p=0.052) and higher proportion of Mayo imaging classification 1C-1E (76.3 vs. 58.9 and 47.9%, p<0.001) compared to PKD1-NT and PKD2 genotypes. The PKD1 genotype showed earlier onset of ESRD compared to PKD2 genotype (52.6 ± 9.3 vs. 60.5 ± 10.7 years, P=0.003). In frailty model adjusted for age, gender, and familial clustering effect, PKD2 genotype had 0.2 times lower risk for reaching ESRD than PKD1-PT genotype (p=0.037). Our results demonstrated higher prevalence of novel mutations (70.7%) in Korean ADPKD cohort. Subjects with PKD1-PT genotype had early onset of hypertension, larger htTKV, lower eGFR and higher events of ESRD compared to other genotypes. Genotyping can contribute to selecting rapid progressors for new emerging therapeutic interventions.

Endothelin-1 as a therapeutic target in autosomal dominant polycystic kidney disease .

Endothelin-1 (ET-1) is associated with the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD) via cyst progression. Elevated concentrations of ET-1 in ADPKD correlate with many phenotypic changes in the kidney such as renal cyst development, interstitial fibrosis, and glomerulosclerosis. In addition, an imbalance between renal ETA and ETB receptors possibly leads to more severe disease progression. The objective of this review is to determine whether evaluating the efficacy of these drugs in treatment of cystic kidney disease may be a worthwhile aim, as determined by results from animal and human models. PubMed/Medline, Embase, and Google Scholar databases were searched using the key words "endothelin, endothelin-1 antagonists, and autosomal dominant polycystic kidney disease". All animal and human studies describing the effects of endothelin and endothelin-1 antagonists in ADPKD subjects were included in the review. Urinary ET-1 concentrations could serve as a noninvasive surrogate biomarker for kidney ET-1 levels, as it is inversely associated with eGFR, independent of age, sex, and blood pressure. Elevated urinary excretion of ET-1 may be a biomarker for early renal injury. Antagonization of ET-1 may hopefully be a novel therapy for slowing progression of kidney damage in ADPKD. Based on the literature reviewed in this manuscript, it is proposed that further research evaluating the efficacy of endothelin antagonists in treatment of cystic kidney disease is warranted. More human studies need to be performed with larger sample sizes. Therefore, the recommendation for treatment is inconclusive at this time. .

Population Pharmacokinetic Analyses and Model Validation of Tolvaptan in Subjects With Autosomal Dominant Polycystic Kidney Disease.

Tolvaptan is the first approved drug treatment to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). The objective is to develop (1091 subjects, 7335 observations) and validate (678 subjects, 3012 observations) a population pharmacokinetic model to describe tolvaptan pharmacokinetics in ADPKD subjects. The final model was evaluated with a bootstrapping method. The final model was internally and externally evaluated using visual predictive checks (VPC). Pharmacokinetics was best described by a 1‐compartmental model with 0‐order absorption, nonlinear relative bioavailability (F1), and first‐order elimination. Accounting for changes in F1 significantly improved the model: as the dose increased from 15 mg to 120 mg, F1 decreased by 36%. Population estimates for clearance/F (CL/F), volume of distribution/F (Vd/F), duration of absorption (D1), the highest dose at which F1 is lowest, and the amount of dose at which F1 is 50% were 12.6 L·h‐1, 110 L, 0.58 hour, 182 mg, and 166 mg, respectively. The interindividual variability was 64% in CL/F, 70% in Vd/F, and 238% in D1. Residual variability was described by a combined‐error model. The VPC (500 data sets simulated) showed that 76% to 92% of the observed data fell within the 90% prediction intervals. The model stability assessed by a 1000‐run bootstrap analysis showed that the mean parameter estimates of data were within 10% of those obtained with the final model. The developed model is robust and stable. Internal and external validation confirmed the model ability to describe the data optimally.

Relationship of Seminal Megavesicles, Prostate Median Cysts, and Genotype in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) can involve prostate and seminal vesicles but the potential interrelationship of these findings and associations with PKD gene mutation locus and type is unknown. To determine the interrelationship of seminal megavesicles (seminal vesicles with lumen diameter > 10mm) and prostatic cysts in ADPKD and to determine whether there are associations with PKD gene mutations. Retrospective, case control. Male ADPKD subjects (n = 92) with mutations in PKD1 (n = 71; 77%) or PKD2 (n = 21; 23%), and age/gender-matched controls without ADPKD (n = 92). 1.5T, axial/coronal T2 -weighted MR images. Reviewers blinded to genotype independently measured seminal vesicle lumen diameter and prevalence of cysts in prostate, kidney, and liver. Nonparametric tests for group comparisons and univariate and multivariable logistic regression analyses to identify associations of megavesicles and prostate median cysts with mutations and renal/hepatic cyst burden. Seminal megavesicles were found in 23 of 92 ADPKD (25%) subjects with PKD1 (22/71, 31%) or PKD2 (n = 1/21, 5%) mutations, but in only two control subjects (P < 0.0001). Prostate median cysts were found in 17/92 (18%) ADPKD subjects, compared with only 6/92 (7%) controls (P = 0.01), and were correlated with seminal vesicle diameters (ρ = 0.24, P = 0.02). Nonmedian prostate cyst prevalence was identical between ADPKD and controls (7/92, 8%). After adjusting for age, estimated glomerular filtration rate, and height-adjusted total kidney volume, ADPKD subjects with megavesicles were 10 times more likely to have a PKD1 than a PKD2 mutation. Among PKD1 subjects, seminal megavesicles occurred more frequently with nontruncating mutations with less severe kidney involvement. ADPKD is associated with prostate median cysts near ejaculatory ducts. These cysts correlate with seminal megavesicles (dilated to >10 mm) which predict a 10-fold greater likelihood of PKD1 vs. PKD2 mutation. Cysts elsewhere in the prostate are not related to ADPKD. 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:894-903.

The prevalence of autosomal dominant polycystic kidney disease (ADPKD): A meta-analysis of European literature and prevalence evaluation in the Italian province of Modena suggest that ADPKD is a rare and underdiagnosed condition.

Background and objectivesADPKD is erroneously perceived as a not rare condition, which is mainly due to the repeated citation of a mistaken interpretation of old epidemiological data, as reported in the Dalgaard's work (1957). Even if ADPKD is not a common condition, the correct prevalence of ADPKD in the general population is uncertain, with a wide range of estimations reported by different authors. In this work, we have performed a meta-analysis of available epidemiological data in the European literature. Furthermore we collected the diagnosis and clinical data of ADPKD in a province in the north of Italy (Modena). We describe the point and predicted prevalence of ADPKD, as well as the main clinical characteristics of ADPKD in this region.MethodsWe looked at the epidemiological data according to specific parameters and criteria in the Pubmed, CINAHL, Scopus and Web of Science databases. Data were summarized using linear regression analysis. We collected patients’ diagnoses in the Province of Modena according to accepted clinical criteria and/or molecular analysis. Predicted prevalence has been calculated through a logistic regression prediction applied to the at-risk population.ResultsThe average prevalence of ADPKD, as obtained from 8 epidemiological studies of sufficient quality, is 2.7: 10,000 (CI95 = 0.73–4.67). The point prevalence of ADPKD in the province of Modena is 3.63: 10,000 (CI95 = 3.010–3.758). On the basis of the collected pedigrees and identification of the at-risk subjects, the predicted prevalence in the Province of Modena is 4.76: 10,000 (CI 95% = 4.109–4.918).ConclusionAs identified in our study, point prevalence is comparable with the majority of the studies of literature, while predicted prevalence (4.76: 10,000) generally appears higher than in the previous estimates of the literature, with a few exceptions. Thus, this could suggest that undiagnosed ADPKD subjects, as predicted by our approach, could be relevant and will most likely require more clinical attention. Nevertheless, our estimation, in addition to the averaged ones derived from literature, not exceeding the limit of 5:10,000 inhabitants, are compatible with the definition of rare disease adopted by the European Medicines Agency and Food and Drug Administration.

Complex liver cysts in Autosomal Dominant Polycystic Kidney Disease

PurposeTo determine prevalence of complex liver cysts in Autosomal Dominant Polycystic Kidney Disease (ADPKD). MethodsAbdominal MRI in 186 ADPKD subjects were evaluated by two independent observers to determine prevalence of complex liver cysts. Results23 (12%) of subjects, had at least 1 complex cyst. Only 8 (4%) were reported to have a complex cyst prospectively, representing an under-reporting rate of 65%. Median total cyst volume was 66-times greater for subjects with complex cysts compared to subjects without (p<0.0001). ConclusionComplex hepatic cysts were observed in 12% of ADPKD cases, occurring more frequently in livers with extensive cystic involvement.

Can we further enrich autosomal dominant polycystic kidney disease clinical trials for rapidly progressive patients? Application of the PROPKD score in the TEMPO trial.

BackgroundThe PROPKD score has been proposed to stratify the risk of progression to end-stage renal disease in autosomal dominant polycystic kidney disease (ADPKD) subjects. We aimed to assess its prognostic value in a genotyped subgroup of subjects from the Tolvaptan Phase 3 Efficacy and Safety Study in Autosomal Dominant Polycystic Kidney Disease (TEMPO3/4) trial.MethodsIn the post hoc analysis, PKD1 and PKD2 were screened in 770 subjects and the PROPKD score was calculated in mutation-positive subjects (male: 1 point; hypertension <35 years: 2 points; first urologic event <35 years: 2 points; nontruncating PKD1 mutation: 2 points; truncating PKD1 mutation: 4 points). Subjects were classified into low-risk (LR; 0–3 points), intermediate-risk (IR; 4–6 points) and high-risk (HR; 7–9 points) groups.ResultsThe PROPKD score was calculated in 749 subjects (LR = 132, IR = 344 and HR = 273); age was inversely related to risk (LR = 43.6 years, IR = 39.5 years, HR = 36.2 years; P < 0.001). Subjects from the HR group had significantly higher height-adjusted total kidney volume (TKV) and rates of TKV growth. While baseline renal function was similar across all risk groups, the rate of estimated glomerular filtration rate (eGFR) decline significantly increased from LR to HR in the placebo group. Tolvaptan treatment effectiveness to reduce TKV growth was similar in all three risk categories. While tolvaptan significantly slowed eGFR decline in the IR (tolvaptan = −2.34 versus placebo = −3.33 mL/min/1.73 m2/year; P = 0.008) and HR groups (tolvaptan = −2.74 versus placebo = −3.94 mL/min/1.73 m2/year; P = 0.002), there was no difference in the LR group (tolvaptan = −2.35 versus placebo = −2.50 mL/min/1.73 m2/year; P = 0.72). Excluding the LR subjects from the analysis improved the apparent treatment effect of tolvaptan on eGFR decline.ConclusionThis study confirms the prognostic value of the PROPKD score and suggests that it could reduce costs and enhance endpoint sensitivity by enriching future study populations for rapidly progressing ADPKD subjects.

Association of arginine vasopressin surrogate marker urinary copeptin with severity of autosomal dominant polycystic kidney disease (ADPKD).

Experimental studies suggest a detrimental role for cyclic adenosine monophosphate (cAMP) and vasopressin in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). It is unknown, however, whether urinary cAMP and copeptin concentration are associated with disease severity in patients with ADPKD. Urinary cAMP (u-cAMP) and copeptin concentration (u-copeptin) were measured by immunoassay in ADPKD patients with CKD stage ≤4. We compared our measurements with clinical parameters including estimated glomerular filtration rate (eGFR), total kidney volume (TKV), and height-adjusted TKV (htTKV). Logarithmic transformation of all variables was performed to fulfill the requirement of equal distribution of the residuals. We included 50 patients in this study (24 females and 26 males; mean age: 49.3 years). The median eGFR and TKV were 53.2 ml/min/1.73 m(2) (interquartile range: IQR; 29.4-68.45) and 1138.1 ml (IQR; 814.7-2065.0), respectively. The median u-copeptin level was 12.19 (IQR; 6.91-22.32) ng/ml. Although u-cAMP/u-Cr was not significantly correlated with TKV (R = -0.006, p = 0.967) and eGFR (R = 0.077, p = 0.602), urinary copeptin/u-Cr was statistically associated with the various markers of disease severity in ADPKD [positively with TKV (R = 0.351, p = 0.014), htTKV (R = 0.383, p = 0.008) and negatively with eGFR (R = -0.304, p = 0.036)]. In ADPKD subjects, a higher u-copeptin is associated with disease progression, suggesting that u-copeptin may be a new surrogate marker to predict renal prognosis in ADPKD.