Edwards, Marie E.

Introduction Maintaining fluid intake sufficient to reduce arginine vasopressin (AVP) secretion has been hypothesised to slow kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD). However, evidence to support this as a clinical practice recommendation is of poor quality. The aim of the present study is to determine the long-term efficacy and safety of prescribed water intake to prevent the progression of height-adjusted total kidney volume (ht-TKV) in patients with chronic kidney disease (stages 1–3) due to ADPKD. Methods and analysis A multicentre, prospective, parallel-group, open-label, randomised controlled trial will be conducted. Patients with ADPKD (n=180; age ≤65 years, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m 2 ) will be randomised (1:1) to either the control (standard treatment+usual fluid intake) or intervention (standard treatment+prescribed fluid intake) group. Participants in the intervention arm will be prescribed an individualised daily fluid intake to reduce urine osmolality to ≤270 mOsmol/kg, and supported with structured clinic and telephonic dietetic review, self-monitoring of urine-specific gravity, short message service text reminders and internet-based tools. All participants will have 6-monthly follow-up visits, and ht-TKV will be measured by MRI at 0, 18 and 36 months. The primary end point is the annual rate of change in ht-TKV as determined by serial renal MRI in control vs intervention groups, from baseline to 3 years. The secondary end points are differences between the two groups in systemic AVP activity, renal disease (eGFR, blood pressure, renal pain), patient adherence, acceptability and safety. Ethics and dissemination The trial was approved by the Human Research Ethics Committee, Western Sydney Local Health District. The results will inform clinicians, patients and policy-makers regarding the long-term safety, efficacy and feasibility of prescribed fluid intake as an approach to reduce kidney cyst growth in patients with ADPKD. Trial registration number ANZCTR12614001216606.

Background In kidney transplantation, a contrast CT scan is obtained in the donor candidate to detect subclinical pathology in the kidney. Recent work from the Aging Kidney Anatomy study has characterized kidney, cortex, and medulla volumes using a manual image-processing tool. However, this technique is time consuming and impractical for clinical care, and thus, these measurements are not obtained during donor evaluations. This study proposes a fully automated segmentation approach for measuring kidney, cortex, and medulla volumes. Methods A total of 1930 contrast-enhanced CT exams with reference standard manual segmentations from one institution were used to develop the algorithm. A convolutional neural network model was trained ( n =1238) and validated ( n =306), and then evaluated in a hold-out test set of reference standard segmentations ( n =386). After the initial evaluation, the algorithm was further tested on datasets originating from two external sites ( n =1226). Results The automated model was found to perform on par with manual segmentation, with errors similar to interobserver variability with manual segmentation. Compared with the reference standard, the automated approach achieved a Dice similarity metric of 0.94 (right cortex), 0.90 (right medulla), 0.94 (left cortex), and 0.90 (left medulla) in the test set. Similar performance was observed when the algorithm was applied on the two external datasets. Conclusions A fully automated approach for measuring cortex and medullary volumes in CT images of the kidneys has been established. This method may prove useful for a wide range of clinical applications.

Abstract Background Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenetic disorders in humans and is characterized by numerous fluid-filled cysts that grow slowly, resulting in end-stage renal disease in the majority of patients. Preclinical studies have indicated that treatment with low-dose thiazolidinediones, such as pioglitazone, decrease cyst growth in rodent models of PKD. Methods This Phase 1b cross-over study compared the safety of treatment with a low dose (15 mg) of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone or placebo in PKD patients, with each treatment given for 1 year. The study monitored known side effects of PPAR-γ agonist treatment, including fluid retention and edema. Liver enzymes and risk of hypoglycemia were assessed throughout the study. As a secondary objective, the efficacy of low-dose pioglitazone was followed using a primary assessment of total kidney volume (TKV), blood pressure (BP) and kidney function. Results Eighteen patients were randomized and 15 completed both arms. Compared with placebo, allocation to pioglitazone resulted in a significant decrease in total body water as assessed by bioimpedance analysis {mean difference 0.16 Ω [95% confidence interval (CI) 0.24–2.96], P = 0.024} and no differences in episodes of heart failure, clinical edema or change in echocardiography. Allocation to pioglitazone led to no difference in the percent change in TKV of −3.5% (95% CI −8.4–1.4, P = 0.14), diastolic BP and microalbumin:creatinine ratio. Conclusions In this small pilot trial in people with ADPKD but without diabetes, pioglitazone 15 mg was found to be as safe as placebo. Larger and longer-term randomized trials powered to assess effects on TKV are needed.

Background and objectives We assessed safety and efficacy of another somatostatin receptor analog, pasireotide long-acting release, in severe polycystic liver disease and autosomal dominant polycystic kidney disease. Pasireotide long-acting release, with its broader binding profile and higher affinity to known somatostatin receptors, has potential for greater efficacy. Design, setting, participants, & measurements Individuals with severe polycystic liver disease were assigned in a 2:1 ratio in a 1-year, double-blind, randomized trial to receive pasireotide long-acting release or placebo. Primary outcome was change in total liver volume; secondary outcomes were change in total kidney volume, eGFR, and quality of life. Results Of 48 subjects randomized, 41 completed total liver volume measurements ( n =29 pasireotide long-acting release and n =12 placebo). From baseline, there were −99±189 ml/m absolute and −3%±7% change in annualized change in height-adjusted total liver volume (from 2582±1381 to 2479±1317 ml/m) in the pasireotide long-acting release group compared with 136±117 ml/m absolute and 6%±7% increase (from 2387±759 to 2533±770 ml/m) in placebo ( P <0.001 for both). Total kidney volumes decreased by −12±34 ml/m and −1%±4% in pasireotide long-acting release compared with 21±21 ml/m and 4%±5% increase in the placebo group ( P =0.05 for both). Changes in eGFR were similar between groups. Among the n =48 randomized, adverse events included hyperglycemia (26 of 33 [79%] in pasireotide long-acting release versus four of 15 [27%] in the placebo group; P <0.001), and among the 47 without diabetes at baseline, 19 of 32 (59%) in the pasireotide long-acting release group versus one of 15 (7%) in the placebo group developed diabetes ( P =0.001). Conclusions Another somatostatin analog, pasireotide long-acting release, slowed progressive increase in both total liver volume/total kidney volume growth rates without affecting GFR decline. Participants experienced higher frequency of adverse events (hyperglycemia and diabetes). Clinical Trial registry name and registration number Pasireotide LAR in Severe Polycystic Liver Disease, NCT01670110 Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_08_28_CJN13661119.mp3

Polycystic kidney disease (PKD) is an inherited disorder characterized by renal cyst formation and enlargement of the kidney. PKD severity can be staged noninvasively by measuring total kidney volume (TKV), a promising biomarker that has recently received regulatory qualification. In preclinical mouse models, where the disease is studied and potential therapeutics are evaluated, the most popular noninvasive method of measuring TKV is magnetic resonance imaging (MRI). Although MRI provides excellent 3D resolution and contrast, these systems are expensive to operate, have long acquisition times, and, consequently, are not heavily used in preclinical PKD research. In this study, a new imaging instrument, based on robotic ultrasound (US), was evaluated as a complementary approach for assessing PKD in rodent models. The objective was to determine the extent to which TKV measurements on the robotic US scanner correlated with both in vivo and ex vivo reference standards (MRI and Vernier calipers, respectively). A cross-sectional study design was implemented that included both PKD-affected mice and healthy wild types, spanning sex and age for a wide range of kidney volumes. It was found that US-derived TKV measurements and kidney lengths were strongly associated with both in vivo MRI and ex vivo Vernier caliper measurements ( R 2 =0.94 and 0.90, respectively). In addition to measuring TKV, renal vascular density was assessed using acoustic angiography (AA), a novel contrast-enhanced US methodology. AA image intensity, indicative of volumetric vascularity, was seen to have a strong negative correlation with TKV ( R 2 =0.82), suggesting impaired renal vascular function in mice with larger kidneys. These studies demonstrate that robotic US can provide a rapid and accurate approach for noninvasively evaluating PKD in rodent models.

Significance Statement Because renal function often remains stable in the early stages of autosomal dominant polycystic kidney disease (ADPKD), total kidney volume (TKV) is the most important biomarker of disease severity and progression. The authors developed and validated a fully automated method of simultaneously measuring TKV and total liver volume (TLV) as well as their growth rates from magnetic resonance images. Their findings indicate that the method’s performance is equivalent to the gold standard of manual tracing while requiring a fraction of the time and skill. This approach may address the unmet need for rapid and reliable assessment of TKV and TLV, allowing identification of patients with rapidly progressing ADPKD for emerging drug treatments and serving as a reliable alternative for assessment of disease progression in clinical trials. Background The formation and growth of cysts in kidneys, and often liver, in autosomal dominant polycystic kidney disease (ADPKD) cause progressive increases in total kidney volume (TKV) and liver volume (TLV). Laborious and time-consuming manual tracing of kidneys and liver is the current gold standard. We developed a fully automated segmentation method for TKV and TLV measurement that uses a deep learning network optimized to perform semantic segmentation of kidneys and liver. Methods We used 80% of a set of 440 abdominal magnetic resonance images (T2-weighted HASTE coronal sequences) from patients with ADPKD to train the network and the remaining 20% for validation. Both kidneys and liver were also segmented manually. To evaluate the method’s performance, we used an additional test set of images from 100 patients, 45 of whom were also involved in longitudinal analyses. Results TKV and TLV measured by the automated approach correlated highly with manually traced TKV and TLV (intraclass correlation coefficients, 0.998 and 0.996, respectively), with low bias and high precision (<0.1%±2.7% for TKV and −1.6%±3.1% for TLV); this was comparable with inter-reader variability of manual tracing (<0.1%±3.5% for TKV and −1.5%±4.8% for TLV). For longitudinal analysis, bias and precision were <0.1%±3.2% for TKV and 1.4%±2.9% for TLV growth. Conclusions These findings demonstrate a fully automated segmentation method that measures TKV, TLV, and changes in these parameters as accurately as manual tracing. This technique may facilitate future studies in which automated and reproducible TKV and TLV measurements are needed to assess disease severity, disease progression, and treatment response.

Objectives Pancreatic lesions in autosomal dominant polycystic kidney disease (ADPKD) are primarily cysts. They are increasingly recognized, with isolated reports of intraductal papillary mucinous neoplasia (IPMN). Methods Retrospective study to determine prevalence, number, size, and location of pancreatic abnormalities using abdominal magnetic resonance imaging (MRI) of genotyped ADPKD patients (seen February 1998 to October 2013) and compared with age- and sex-matched non-ADPKD controls. We evaluated presentation, investigation, and management of all IPMNs among individuals with ADPKD (January 1997 to December 2016). Results Abdominal MRIs were examined for 271 genotyped ADPKD patients. A pancreatic cyst lesion (PCL) was detected in 52 patients (19%; 95% confidence interval, 15%–23%). Thirty-seven (71%) had a solitary PCL; 15 (28%) had multiple. Pancreatic cyst lesion prevalence did not differ by genotype. Intraductal papillary mucinous neoplasia was detected in 1% of ADPKD cases. Among 12 IPMN patients (7 branch duct; 5 main duct or mixed type) monitored for about 140 months, 2 with main duct IPMNs required Whipple resection, and 1 patient died of complications from small-bowel obstruction after declining surgical intervention. Conclusions With MRI, PCLs were detected in 19% and IPMNs in 1% of 271 ADPKD patients with proven mutations, without difference across genotypes. Pancreatic cyst lesions were asymptomatic and remained stable in size.