Total Kidney Volume Research Articles

Endocannabinoid System in Polycystic Kidney Disease

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited disorder characterized by renal cyst formation. A major pathological feature of ADPKD is the development of interstitial inflammation. The endocannabinoid (EC) system is present in the kidney and has recently emerged as an important player in inflammation and the pathogenesis of progressive kidney disease. Methods: Data on ECs were collected using a validated mass spectrometry assay from a well-characterized cohort of 102 ADPKD patients (at baseline and after 2- and 4 years on standard vs. rigorous blood-pressure control) and compared to 100 healthy subjects. Results: Compared to healthy individuals, we found higher interleukins-6 and -1b as well as reduced plasma levels of anandamide (AEA), 2-arachidonoyl­glycerol (2-AG), and their congeners in ADPKD patients. Baseline AEA concentration negatively associated with the progression of ADPKD as expressed by the yearly percent change in height-corrected total kidney volume and positively with the yearly change in renal function (measured as estimated glomerular filtration rate, ΔeGFR). AEA analog palmitoylethanolamide (PEA) is also associated positively with the yearly change in eGFR. Discussion and Conclusion: The results of the present study suggest that ADPKD patients present with lower levels of ECs and that reestablishing the normality of the renal EC system via augmentation of AEA, PEA, and 2-AG levels, either through the increase of their synthesis or through a reduction of their degradation, could be beneficial and may present a promising therapeutic target in said patients.

Mayo imaging classification is a good predictor of rapid progress among Korean patients with autosomal dominant polycystic kidney disease: results from the KNOW-CKD study.

BackgroundMayo imaging classification (MIC) is a useful biomarker to predict disease progression in autosomal dominant polycystic kidney disease (ADPKD). This study was performed to validate MIC in the prediction of renal outcome in a prospective Korean ADPKD cohort and evaluate clinical parameters associated with rapid disease progression.MethodsA total of 178 ADPKD patients were enrolled and prospectively observed for an average duration of 6.2 ± 1.9 years. Rapid progressor was defined as MIC 1C through 1E while slow progressor was defined as 1A through 1B. Renal composite outcome (doubling of serum creatinine, 50% decline of estimated glomerular filtration rate [eGFR], or initiation of renal replacement therapy) as well as the annual percent change of height-adjusted total kidney volume (mHTKV-α) and eGFR decline (mGFR-α) were compared between groups.ResultsA total of 110 patients (61.8%) were classified as rapid progressors. These patients were younger and showed a higher proportion of male patients. Rapid progressor was an independent predictor for renal outcome (hazard ratio, 4.09; 95% confidence interval, 1.23–13.54; p = 0.02). The mGFR-α was greater in rapid progressors (–3.58 mL/min per year in 1C, –3.7 in 1D, and –4.52 in 1E) compared with that in slow progressors (–1.54 in 1A and –2.06 in 1B). The mHTKV-α was faster in rapid progressors (5.3% per year in 1C, 9.4% in 1D, and 11.7% in 1E) compared with that in slow progressors (1.2% in 1A and 3.8% in 1B).ConclusionMIC is a good predictive tool to define rapid progressors in Korean ADPKD patients.

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

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. 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. 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). 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.

Pooled Data Analysis of the Long-Term Treatment Effects of Tolvaptan in ADPKD

IntroductionIn 1- and 3-year randomized trials, tolvaptan slowed kidney function decline in subjects with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. The 3-year trial also evaluated effects on total kidney volume (TKV); slowing of TKV growth was demonstrated. Subjects were followed in open-label extension trials. To characterize longer-term effects of treatment, an analysis was conducted comparing tolvaptan-treated subjects with subjects from standard of care (SOC) ADPKD studies without tolvaptan.MethodsThis was a pooled, longitudinal analysis of data from 8 tolvaptan clinical trials and 5 studies without tolvaptan (natural history or SOC) in ADPKD. Data from subjects who participated in multiple studies were linked for longer follow-up. Outcomes were rates of change in estimated glomerular filtration rate (eGFR) and TKV over 5.5 years. To control for heterogeneity in disease characteristics between tolvaptan and SOC treatment groups, analysis populations matched for baseline demographic and disease characteristics were constructed.ResultsMatched analysis (n = 1186 in each treatment group) indicated that tolvaptan slowed annualized eGFR decline by 1.01 ml/min per 1.73 m2 (P < 0.001) versus SOC over 5.5 years. An analysis conducted on the full, unmatched data set (tolvaptan: n = 2928; SOC: n = 4189) confirmed significant reduction in annual eGFR decline. Among subjects with TKV data, TKV was significantly reduced at years 1, 3, and 5 for tolvaptan versus SOC in both matched and full data sets.ConclusionComparison of a pooled tolvaptan cohort to a pooled control cohort with ADPKD supports longer-term treatment effects of tolvaptan.

Potential effect of tolvaptan on polycystic liver disease for patients with ADPKD meeting the Japanese criteria of tolvaptan use.

Polycystic liver disease (PLD) is a common extrarenal complication of autosomal dominant polycystic kidney disease (ADPKD), which causes compression-related syndrome and ultimately leads to liver dysfunction. Tolvaptan, a V2 receptor antagonist, is widely used to protect kidney function in ADPKD but its effect on PLD remains unknown. An observational cohort study was conducted to evaluate tolvaptan's effect on patients with PLD due to ADPKD. After screening 902 patients, we found the 107 ADPKD patients with PLD who met the criteria of tolvaptan use in Japan. Among them, tolvaptan was prescribed for 62 patients (tolvaptan group), while the other was defined as the non-tolvaptan group. Compared with the non-tolvaptan group, the tolvaptan group had larger height-adjusted total kidney volume (median 994(range 450-4152) mL/m, 513 (405-1928) mL/m, p = 0.01), lower albumin level (mean 3.9±SD 0.4 g/dL, 4.3±0.4g/dL, p<0.01), and higher serum creatinine level (1.2±0.4 mg/dL, 0.9±0.2 mg/dL, p<0.01). Although the median change in annual growth rate of total liver volume (TLV) was not statistically different between the tolvaptan group (-0.8 (-15.9, 16.7) %/year) and the non-tolvaptan group (1.7 (-15.6-18.7) %/year)(p = 0.52), 20 (43.5%) patients in the tolvaptan group experienced a decrease in the growth rate of TLV (responders). A multivariable logistic regression model adjusting for related variables showed that older age (odds ratio 1.15 [95% CI 1.01-1.32]) and a higher growth rate of TLV in the non-tolvaptan period (odds 1.45 95% CI 1.10-1.90) were significantly associated with responders. In conclusion, the change in annual growth rate of TLV in ADPKD patients taking tolvaptan was not statistically different compared with that in ADPKD patients without taking tolvaptan. However, tolvaptan may have the potential to suppress the growth rate of TLV in some PLD patients due to ADPKD, especially in older patients or those that are rapid progressors of PLD. Several limitations were included in this study, therefore well-designed prospective studies were required to confirm the effect of tolvaptan on PLD.

Deployed Deep Learning Kidney Segmentation for Polycystic Kidney Disease MRI.

This study develops, validates, and deploys deep learning for automated total kidney volume (TKV) measurement (a marker of disease severity) on T2-weighted MRI studies of autosomal dominant polycystic kidney disease (ADPKD). The model was based on the U-Net architecture with an EfficientNet encoder, developed using 213 abdominal MRI studies in 129 patients with ADPKD. Patients were randomly divided into 70% training, 15% validation, and 15% test sets for model development. Model performance was assessed using Dice similarity coefficient (DSC) and Bland-Altman analysis. External validation in 20 patients from outside institutions demonstrated a DSC of 0.98 (IQR, 0.97-0.99) and a Bland-Altman difference of 2.6% (95% CI: 1.0%, 4.1%). Prospective validation in 53 patients demonstrated a DSC of 0.97 (IQR, 0.94-0.98) and a Bland-Altman difference of 3.6% (95% CI: 2.0%, 5.2%). Last, the efficiency of model-assisted annotation was evaluated on the first 50% of prospective cases (n = 28), with a 51% mean reduction in contouring time (P < .001), from 1724 seconds (95% CI: 1373, 2075) to 723 seconds (95% CI: 555, 892). In conclusion, our deployed artificial intelligence pipeline accurately performs automated segmentation for TKV estimation of polycystic kidneys and reduces expert contouring time. Keywords: Convolutional Neural Network (CNN), Segmentation, Kidney ClinicalTrials.gov identification no.: NCT00792155 Supplemental material is available for this article. © RSNA, 2022.

Kidney Perfusion in Contrast-Enhanced Ultrasound (CEUS) Correlates with Renal Function in Living Kidney Donors.

Contrast-enhanced ultrasound (CEUS) is a widely used diagnostic tool for analyzing perfusion and characterizing lesions in several organs. However, to date, it has not been sufficiently investigated whether there is an association between CEUS findings and kidney function. This study aimed at identifying the potential relationship between kidney function and the renal perfusion status determined by CEUS in living kidney donors. A total of 30 living kidney donors examined between April 2018 and March 2020 were included in the study. All patients underwent various diagnostic procedures for evaluation of renal function. CEUS was performed in all 30 donors one day before nephrectomy. Kidney perfusion was quantified using a postprocessing tool (VueBox, Bracco Imaging). Various perfusion parameters were subsequently analyzed and compared with the results of the other methods used to evaluate kidney function. Of all parameters, mean signal intensity (MeanLin) had the strongest correlation, showing significant correlations with eGFR (CG) (r = −0.345; p = 0.007) and total kidney volume (r = −0.409; p = 0.001). While there was no significant correlation between any perfusion parameter and diethylenetriaminepentaacetic acid (DTPA), we detected a significant correlation between MeanLin and DTPA (r = −0.502; p = 0.005) in the subgroup of normal-weight donors. The results indicate that signal intensity in CEUS is associated with kidney function in normal-weight individuals. Body mass index (BMI) may be a potential confounder of signal intensity in CEUS. Thus, more research is needed to confirm these results in larger study populations.

Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD: A Randomized Controlled Trial.

Clinical manifestations of autosomal dominant polycystic kidney disease (ADPKD), including evidence of vascular dysfunction, can begin in childhood. Curcumin is a polyphenol found in turmeric that reduces vascular dysfunction in rodent models and humans without ADPKD. It also slows kidney cystic progression in a murine model of ADPKD. We hypothesized that oral curcumin therapy would reduce vascular endothelial dysfunction and arterial stiffness in children/young adults with ADPKD. In a randomized, placebo-controlled, double-blind trial, 68 children/young adults 6-25 years of age with ADPKD and eGFR>80 ml/min per 1.73 m2 were randomized to either curcumin supplementation (25 mg/kg body weight per day) or placebo administered in powder form for 12 months. The coprimary outcomes were brachial artery flow-mediated dilation and aortic pulse-wave velocity. We also assessed change in circulating/urine biomarkers of oxidative stress/inflammation and kidney growth (height-adjusted total kidney volume) by magnetic resonance imaging. In a subgroup of participants ≥18 years, vascular oxidative stress was measured as the change in brachial artery flow-mediated dilation following an acute infusion of ascorbic acid. Enrolled participants were 18±5 (mean ± SD) years, 54% were girls, baseline brachial artery flow-mediated dilation was 9.3±4.1% change, and baseline aortic pulse-wave velocity was 512±94 cm/s. Fifty-seven participants completed the trial. Neither coprimary end point changed with curcumin (estimated change [95% confidence interval] for brachial artery flow-mediated dilation [percentage change]: curcumin: 1.14; 95% confidence interval, -0.84 to 3.13; placebo: 0.33; 95% confidence interval, -1.34 to 2.00; estimated difference for change: 0.81; 95% confidence interval, -1.21 to 2.84; P=0.48; aortic pulse-wave velocity [centimeters per second]: curcumin: 0.6; 95% confidence interval, -25.7 to 26.9; placebo: 6.5; 95% confidence interval, -20.4 to 33.5; estimated difference for change: -5.9; 95% confidence interval, -35.8 to 24.0; P=0.67; intent to treat). There was no curcumin-specific reduction in vascular oxidative stress or changes in mechanistic biomarkers. Height-adjusted total kidney volume also did not change as compared with placebo. Curcumin supplementation does not improve vascular function or slow kidney growth in children/young adults with ADPKD. Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD, NCT02494141. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_02_07_CJN08950621.mp3.

Increased Body Fat and Organic Acid Anions Production Are Associated with Larger Kidney Size in ADPKD.

Background and Objectives: A high body mass index (BMI) is associated with the progression of autosomal dominant polycystic kidney disease (ADPKD). However, body fat (BF), which is another adiposity marker, has not yet been studied. Excessive weight may promote elevation in the endogenous synthesis of organic acid (OA) anions. Accordingly, we aimed to investigate the possible association of the aforementioned markers with kidney volume and renal function in patients with ADPKD. Materials and Methods: We conducted a retrospective cohort study of adult ADPKD outpatients involving clinical, serum, and urinary laboratorial data and body composition assessments retrieved from their medical records. BF was estimated by skinfold thickness (mm) on the non-dominant arm and was considered as normal or high for each sex. Total kidney volume (TKV) and height-adjusted volume (htTKV) were measured by magnetic resonance imaging. The annual estimated glomerular filtration rate (eGFR) slope was analyzed during a median follow-up time of 6 (5.0–7.0) years to calculate rapid progression (decline in renal function ≥2.5 mL/min/year over 5 years). Results: A total of 104 patients were included (41.9 ± 11.9 years old, 38.5% men), with 62.5% of the patients classified as high BF. The High BF group presented higher levels of OA, glycosylated hemoglobin (HbA1c), C-reactive protein (CRP), 24 h urinary sodium (UNa), and htTKV, and lower eGFR than those with a normal BF. In the multivariate linear regression, the associated variables with TKV were high BF, OA and BMI (std. β 0.47, p < 0.05; std. β 0.36, p = 0.001; std. β 0.25, p = 0.01, respectively). In the binary logistic regression, when adjusted for potential confounders, UNa was the only parameter associated with an increased risk of eGFR decline ≥2.5 mL/min/year (OR 1.02, 95% CI 1.01–1.03, p = 0.02). Conclusions: Increased body fat and endogenous production of organic acid anions are associated with larger kidney size in ADPKD but not with a decline in renal function.

Nephron mass determines the excretion rate of urinary extracellular vesicles.

Urinary extracellular vesicles (uEVs) are emerging as non‐invasive biomarkers for various kidney diseases, but it is unknown how differences in nephron mass impact uEV excretion. To address this, uEV excretion was measured before and after human kidney donor nephrectomy and rat nephrectomy. In male and female donors, uEVs were quantified in cell‐free spot and 24‐h urine samples using nanoparticle tracking analysis (NTA), EVQuant, and CD9‐time‐resolved fluorescence immunoassay. Female donors had significantly lower total kidney volume (TKV) and excreted 49% fewer uEVs than male donors. uEV excretion correlated positively with estimated glomerular filtration rate (eGFR), creatinine clearance, and TKV (R's between 0.6 and 0.7). uEV excretion rate could also be predicted from spot urines after multiplying spot uEV/creatinine by 24‐h urine creatinine. Donor nephrectomy reduced eGFR by 36% ± 10%, but the excretion of uEVs by only 16% (CD9+ uEVs ‐37%, CD9‐ uEVs no decrease). Donor nephrectomy increased the podocyte marker WT‐1 and the proximal tubule markers NHE3, NaPi‐IIa, and cubilin in uEVs two‐ to four‐fold when correcting for the nephrectomy. In rats, the changes in GFR and kidney weight correlated with the changes in uEV excretion rate (R = 0.46 and 0.60, P < 0.01). Furthermore, the estimated degree of hypertrophy matched the change in uEV excretion rate (1.4‐ to 1.5‐fold after uninephrectomy and four‐fold after 5/6th nephrectomy). Taken together, our data show that uEV excretion depends on nephron mass, and that nephrectomy reduces uEV excretion less than expected based on nephron loss due to compensatory hypertrophy. The major implication of our findings is that a measure for nephron mass or uEV excretion rate should be included when comparing uEV biomarkers between individuals.

Safety and feasibility of synchronous unilateral nephrectomy and contralateral heminephrectomy for extremely severe autosomal dominant polycystic kidney disease: Techniques and outcome.

PurposeTo demonstrate the safety and feasibility of synchronous unilateral nephrectomy and contralateral heminephrectomy in extremely severe autosomal dominant polycystic kidney disease (ADPKD), which corresponds to the Mayo imaging classification classes 1D and 1E.Materials and MethodsWe retrospectively reviewed patients who underwent unilateral nephrectomy and contralateral heminephrectomy at the Seoul National University Hospital (Seoul, Korea) between May 1, 2016 and August 1, 2021. The preoperative kidney volume was calculated using the ellipsoid equation (length×width×thickness×π/6). The Mayo imaging classification was determined by height-adjusted total kidney volume and age. Using a midline vertical incision, heminephrectomy was performed first by horizontal transection, followed by contralateral nephrectomy. Hilar vessel clamping or resection-bed suturing was not required.ResultsIn all, nine patients with ADPKD of the highest severity (Mayo class 1D/1E) underwent unilateral heminephrectomy and contralateral nephrectomy for the most common cause of severe abdominal discomfort and malnutrition. All nine patients had end-stage renal disease with hypertension and anemia. The median preoperative total kidney volume was 10,905.8 mL (interquartile range [IQR], 8,170.4–16,227.6 mL). The median operation time was 140 minutes (IQR, 125–185 min) and the median estimated blood loss was 250 mL (IQR, 200–425 mL). Eight of the nine patients were discharged without ICU care or any complications. Delayed pseudoaneurysm occurred in one case and was successfully managed by embolization. All patients were symptom-free for a median follow-up period of 2 years.ConclusionsSynchronous unilateral nephrectomy and contralateral heminephrectomy are safe and feasible treatment options for severe bilateral ADPKD.

Octreotide Lar in Patients with Autosomal Dominant Polycystic Kidney Disease: From Bench to A Novel Perspective of Therapy

Polycystins 1 or 2 congenital defects result in impaired Ca2+ inflow through the tubular cell membrane with reduced intracellular Ca2+ concentration and secondary adenylcyclase over-activation with increased intracellular cAMP. This activates chloride-driven fluid secretion and tubular cell proliferation and de-differentiation with cyst formation and growth. Thus, medications, such as the somatostatin analogue Octreotide LAR or the vasopressin antagonist Tolvaptan, that reduce intracellular cAMP, have been tested to inhibit cAMP-mediated chloride secretion and cell proliferation in experimental and human polycystic kidney disease. Seminal studies conducted in the early ‘80s by Franklin Epstein showed that in the shark rectal gland chloride secretion is markedly inhibited by somatostatin in a way suggesting inhibition of adenylcyclase. Evidence that specific receptors for somatostatin, in particular the sst2 subtype, are present in tubular cell membranes suggested that Octreotide LAR binding to its specific renal receptors could exert similar effects in ADPKD cells. In a pilot, cross-over safety study we found that 6-month Octreotide LAR therapy was safe and well tolerated in 12 patients with ADPKD and significantly decreased total kidney volume growth as compared to placebo. Then, the ALADIN and ALADIN II academic, prospective, randomized, placebo-controlled clinical trials found that 3-year Octreotide LAR treatment significantly slowed total kidney and cyst volume growth. In ALADIN treatment slowed chronic decline of directly measured GFR in 79 patients with estimated GFR ≥ 40 ml/min/1.73 m2. In ALADIN II treatment slowed progression to doubling of serum creatinine or ESKD in 100 patients with stage 3b-4 CKD. Treatment was equally safe and well tolerated in both studies. Sub-studies also showed that 3-year Octreotide LAR therapy reduced total liver volume in 27 ADPKD patients with associated polycystic livers and improved left ventricular twisting and untwisting function in 34 ADPKD patients assessed by speckled-tracked echocardiography. Future trials should confirm the long-term benefits of Octreotide LAR in larger populations of ADPKD patients. Moreover, recent studies found that somatostatin analogues and Tolvaptan have additional beneficial effects in experimental polycystic kidney disease. Thus, clinical trials should also explore whether Octreotide LAR and Tolvaptan in combined therapy may have an additional beneficial effect even in human disease.

The Natural Course of Total Kidney Volume in Patients with Autosomal Dominant Polycystic Kidney Disease undergoing Hemodialysis

Objectives The natural course of native kidneys after hemodialysis initiation in patients with autosomal dominant polycystic kidney disease (ADPKD) remains poorly understood. Methods We measured the total volumes of native kidneys in 12 patients who had at least one enhanced computed tomography (CT) image both before and after initiation of hemodialysis (group 1) and in 18 patients who had no image before dialysis but more than two images after dialysis (group 2). In patients with images, the last image was used for analysis only after dialysis. Results The mean total kidney volume (TKV) (± SD) before hemodialysis initiation was 3132 ± 1413 mL and the mean TKV of the last image was 3047 ± 1323 mL in group 1. The mean TKV change rate (%) was −5.2 ± 27.4% ( P &amp;gt; 0.05) during follow-up of 3.9 ± 1.9 years in group 1. The mean TKV change rate was 2.8 ± 34.4% ( P &amp;gt; 0.05) in group 2. The follow-up period after dialysis initiation ranged from 4.2 ± 4.7 to 8.0 ± 5.2 years. Conclusions The results suggest that the TKV of native polycystic kidneys decreases substantially after hemodialysis initiation. This reduction occurs mainly during the early post-hemodialysis period and followed by a slow enlargement of TKV.

Comparative analysis of tools to predict rapid progression in autosomal dominant polycystic kidney disease.

ABSTRACTBackgroundAutosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease and shows a wide phenotype. Only patients with rapid progression (RP) are included in clinical trials or are approved to receive disease-modifying drugs. This study aims at comparing different available predictive tools in ADPKD with the Mayo classification (MC) identification of rapid progressors based on high total kidney volume (TKV) according to age.MethodsA total of 164 ADPKD patients were recruited retrospectively from a single centre. The performance of diverse tools to identify RP defined as being in MC categories 1C–1E was assessed.ResultsA total of 118 patients were MC 1C–1E. The algorithm developed by the European Renal Association–European Dialysis and Transplant Association Working Group on Inherited Kidney Disorders/European Renal Best Practice had a low sensitivity in identifying MC 1C–1E. The sensitivity and specificity of TKV to predict RP depend on the cut-off used. A kidney length of >16.5 cm before age 45 years has high specificity but low sensitivity. Assessing the MC by ultrasonography had high levels of agreement with magnetic resonance imaging (MRI) data, especially for 1A, 1D and 1E. The estimated glomerular filtration rate (eGFR) decline was very sensitive but had low specificity. In contrast, the Predicting Renal Outcome in Polycystic Kidney Disease (PROPKD) score was very specific but had poor sensitivity. Having hypertension before 35 years of age is a good clinical predictor of MC 1C–1E. Family history can be of help in suggesting RP, but by itself it lacks sufficient sensitivity and specificity.ConclusionsThe MC by ultrasonography could be an option in hospitals with limited access to MRI as it performs well generally, and especially at the extremes of the MC, i.e. classes 1A, 1D and 1E. The eGFR decline is sensitive but not very specific when compared with the MC, whereas the PROPKD score is very specific but has low sensitivity. Integrating the different tools currently available to determine RP should facilitate the identification of rapid progressors among patients with ADPKD.

Two compound techniques for total body irradiation.

Total body irradiation (TBI) is an important treatment modality that is used in combination with chemotherapy in many stem cell transplantation protocols. Therefore, the quality of the irradiation is important. Two techniques for planning and delivering TBI are presented and compared. The technique named ExIMRT is a combination of manually shaped conventional fields from an extended SSD and isocentric IMRT fields. The technique named ExVMAT is a combination of conventional and IMRT fields from an extended SSD and isocentric VMAT fields. Dosimetric data from 32 patients who were planned and treated according to one of the two techniques were compared. When comparing the two techniques, it is determined that the ExVMAT technique is able to significantly reduce the mean total volume overdosed by 120% from 408 to 12cm3. The dose covering 98% of the total lung volume is significantly increased by this technique from a mean of 9.7Gy to 10.3Gy. Additionally, the dose covering 2% of the total kidney volume is significantly decreased from a mean of 12.8 to 12.5Gy. Furthermore, the population-based variance of the median dose to the total lung volume, the heart and the volume of the body prescribed to 12.5Gy is significantly reduced. The results are obtained without compromising overall treatment quality as treatment time or dose rate to the lungs. Using the ExVMAT technique, a superior dose distribution can be delivered both from a patient and a population perspective compared to the ExIMRT technique.

Germline Mutations for Kidney Volume in ADPKD

IntroductionValid prediction models or predictors of disease progression in children and young patients with autosomal dominant polycystic kidney disease (ADPKD) are lacking. Although total kidney volume (TKV) and Mayo imaging classification are generally used to predict disease progression in patients with ADPKD, it remains unclear whether germline mutation types are associated with these factors. We therefore investigated the association between mutation type and TKV and Mayo imaging classification among patients with ADPKD.MethodsA total of 129 patients with ADPKD who underwent genetic analyses were enrolled in the study. The associations between the severity of PKD (TKV ≥ 1000 ml and Mayo classes 1C–1E) and the PKD1 mutation types (nonsense mutation, frameshift or splicing mutation, and substitution) were evaluated.ResultsAmong the mutation types, only PKD1 splicing/frameshift mutation had significant associations with TKV ≥ 1000 ml in sex-adjusted and multivariable logistic analyses. Similarly, only the PKD1 splicing/frameshift mutation was significantly associated with Mayo 1C–1E in sex-adjusted and multivariable logistic analyses. PKD1 nonsense mutation, PKD1 substitution, or PKD1 mutation position had no significant association with TKV ≥ 1000 ml or Mayo 1C–1E.ConclusionKidney cyst severity differs according to the mutation types in PKD1. Patients with PKD1 splicing mutations or PKD1 frameshift mutations are associated with TKV ≥ 1000 ml or Mayo 1C–1E. Detailed assessment of mutation types may be useful for predicting renal prognosis in patients with ADPKD and may especially contribute to the care of a high-risk group of children with ADPKD.

Long-Term Outcomes of Longitudinal Efficacy Study With Tolvaptan in ADPKD

IntroductionThe effects of long-term and uninterrupted tolvaptan treatment on autosomal dominant polycystic kidney disease (ADPKD) are unclear. Therefore, a more than 3-year continuous treatment study was performed.MethodsFrom the Kyorin University cohort, 299 patients were surveyed and 179 patients were indicated for tolvaptan having a total kidney volume (TKV) ≥750 ml, TKV slope ≥5%/yr, and estimated glomerular filtration rate (eGFR) ≥15 ml/min per 1.73 m2. Among 179 patients, 118 patients consented to the study.ResultsRetrospective pretreatment and prospective on-treatment periods had a median of 1.8 and 4.0 years, respectively. During the 5 treatment-years, the log10(TKV) slope/yr decreased from the pretreatment period (P < 0.0001) and the estimated height-adjusted TKV growth rate α (eHTKV-α, %/yr) decreased from baseline (P < 0.0001). The decline in eGFR improved in female patients (P < 0.0001), but not in males (P = 0.6321). Furthermore, during the 5 treatment-years, eGFR remained significantly better in the group with a percent decrease in eHTKV-α from baseline to the first treatment-year ≥ the median (2.94%) than in the group with a decrease <2.94%. The free-water clearance was higher in males than in females irrespective of treatment.ConclusionThe TKV growth rate decreased in 4 years with tolvaptan in both sexes. The insignificant effects of tolvaptan on the eGFR slope in males were likely due to androgen stimulation of cystogenesis and analytical difficulty of longitudinal changes in nonlinear trajectories of eGFR. The larger decrease in eHTKV-α in the first year was related to a better renal prognosis. The vasopressin-mediated water reabsorption was activated more in females than males irrespective of tolvaptan administration.

Early childhood height-adjusted total kidney volume as a risk marker of kidney survival in ARPKD

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by bilateral fibrocystic changes resulting in pronounced kidney enlargement. Impairment of kidney function is highly variable and widely available prognostic markers are urgently needed as a base for clinical decision-making and future clinical trials. In this observational study we analyzed the longitudinal development of sonographic kidney measurements in a cohort of 456 ARPKD patients from the international registry study ARegPKD. We furthermore evaluated correlations of sonomorphometric findings and functional kidney disease with the aim to describe the natural disease course and to identify potential prognostic markers. Kidney pole-to-pole (PTP) length and estimated total kidney volume (eTKV) increase with growth throughout childhood and adolescence despite individual variability. Height-adjusted PTP length decreases over time, but such a trend cannot be seen for height-adjusted eTKV (haeTKV) where we even observed a slight mean linear increase of 4.5 ml/m per year during childhood and adolescence for the overall cohort. Patients with two null PKHD1 variants had larger first documented haeTKV values than children with missense variants (median (IQR) haeTKV 793 (450–1098) ml/m in Null/null, 403 (260–538) ml/m in Null/mis, 230 (169–357) ml/m in Mis/mis). In the overall cohort, estimated glomerular filtration rate decreases with increasing haeTKV (median (IQR) haeTKV 210 (150–267) ml/m in CKD stage 1, 472 (266–880) ml/m in stage 5 without kidney replacement therapy). Strikingly, there is a clear correlation between haeTKV in the first eighteen months of life and kidney survival in childhood and adolescence with ten-year kidney survival rates ranging from 20% in patients of the highest to 94% in the lowest quartile. Early childhood haeTKV may become an easily obtainable prognostic marker of kidney disease in ARPKD, e.g. for the identification of patients for clinical studies.

Prescribed Water Intake in Autosomal Dominant Polycystic Kidney Disease

BackgroundArginine vasopressin promotes kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD). Increased water intake reduces arginine vasopressin and urine osmolality and may slow kidney cyst growth.MethodsIn this randomized controlled 3-year clinical trial, we randomly assigned adults with ADPKD who had a height-corrected total kidney volume in Mayo imaging subclass categories 1B to 1E and an estimated glomerular filtration rate of 30 ml/min/1.73 m2 or greater to (1) water intake prescribed to reduce 24-hour urine osmolality to 270 mOsmol/kg or less or (2) ad libitum water intake irrespective of 24-hour urine osmolality. The primary end point was the percentage annualized rate of change in height-corrected total kidney volume.ResultsA total of 184 patients participated in either the ad libitum water intake group (n=92) or the prescribed water intake group (n=92). Over 3 years, there was no difference in the annualized rate of change in height-corrected total kidney volume between the ad libitum (7.8% per year; 95% confidence interval [CI], 6.6 to 9.0) and prescribed (6.8% per year; 95% CI, 5.8 to 7.7) water intake groups (mean difference, −0.97% per year; 95% CI, −2.37 to 0.44; P=0.18). The difference in mean 24-hour urine osmolality between the ad libitum and prescribed water intake groups was −91 mOsmol/kg (95% CI, −127 to −54 mOsmol/kg), with 52.3% of patients achieving adherence to the target 24-hour urine osmolality and no reduction in serum copeptin over 3 years. The frequency of adverse events was similar between groups.ConclusionsFor patients with ADPKD, prescribed water intake was not associated with excess adverse events and achieved the target 24-hour urine osmolality for half of the patients but did not reduce copeptin or slow the growth of total kidney volume over 3 years compared with ad libitum water intake. (Funded by the National Health and Medical Research Council of Australia [grant GNT1138533], Danone Research, PKD Australia, the University of Sydney, and the Westmead Medical Research Foundation; Australian New Zealand Clinical Trials Registry number, ACTRN12614001216606).

AI Integration in the Clinical Workflow.

Machine learning and artificial intelligence (AI) algorithms hold significant promise for addressing important clinical needs when applied to medical imaging; however, integration of algorithms into a radiology department is challenging. Vended algorithms are integrated into the workflow, successfully, but are typically closed systems and unavailable for site researchers to deploy algorithms. Rather than AI researchers creating one-off solutions, a general, multi-purpose integration system is desired. Here, we present a set of use cases and requirements for a system designed to enable rapid deployment of AI algorithms into the radiologist's workflow. The system uses standards-compliant digital imaging and communications in medicine structured reporting (DICOM SR) to present AI measurements, results, and findings to the radiologist in a clinical context and enables acceptance or rejection of results. The system also implements a feedback mechanism for post-processing technologists to correct results as directed by the radiologist. We demonstrate integration of a body composition algorithm and an algorithm for determining total kidney volume for patients with polycystic kidney disease.