Total Kidney Volume Research Articles

#5559 BONE SPECIFIC ALKALINE PHOSPHATASE AS A POTENTIAL BIOMARKER OF AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE PROGRESSION

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disease, resulting in a dysfunction of the primary cilium, a sensory organelle ubiquitously present in human cells. Ciliopathies are characterized by disorders of seemingly unrelated organs and functions, which depend on integrity of the primary cilium, among them the skeleton and the kidneys. A distinct bone phenotype has been reported in ADPKD patients in several cohort studies. Findings, however, were heterogenous. Present study aimed to measure bone turnover biomarkers in patients with ADPKD across disease severity measured by eGFR and height-adjusted total kidney volume (HtTKV). Method In this cross-sectional study, we included 80 ADPKD patients with different chronic kidney disease (CKD) stages (G1 and G2 (n = 39), and G3 and G4 (n = 41)) with median age 44.0 (33.5-50.5) years, 62.5% men, and BMI 25.1 (23.3-28.7) kg/m2. HtTKV was measured with magnetic resonance imaging. We measured biochemical parameters of mineral metabolism, including bone specific alkaline phosphatase (BALP) and total ALP, calcium (Ca), parathyroid hormone (PTH), and 25(OH) vitamin D (25(OH)D) and bone strength index (BSi) with microindentation, using an OsteoProbe® (Active Life Scientific, USA). Microindentation is minimally invasive technique assessing bone quality. The cortical bone at the mid-shaft of the tibia is penetrated with the indenter to measure bone resistance. Results Bone biomarkers expressed as median and interquartile range were as follow: Ca 9.6 (9.3-9.9) mg/dL, BALP 9.0 (7.0-12.5) ug/L, ALP 59.0 (46.0-72.0) U/L, PTH 43.5 (26.6-72.0) pg/mL and 25(OH)D 25.4 (16.6-33.5) ng/mL. Median BSi was 79.1(73.5-82.1) in men and 68.5 (62.1-78.6) in women (lower than the average score in healthy caucasians). Among analyzed bone markers only BALP significantly associated with severity of ADPKD. BALP - but not eGFR - associated with HtTKV and was different across HtTKV tertiles. BALP was also higher in the highest BSi group, but BSi did not associate with HtTKV (Figure 1). Conclusion In patients with ADPKD and different stages of CKD, BALP associates with bone strength and kidney volume, suggesting that it may be a sensitive marker of systemic ADPKD manifestations. Further studies should elucidate whether BALP may be a more sensitive marker for ADPKD progression than GFR.

Copeptin in autosomal dominant polycystic kidney disease: real-world experiences from a large prospective cohort study.

The identification of new biomarkers in autosomal-dominant polycystic kidney disease (ADPKD) is crucial to improve and simplify prognostic assessment as a basis for patient selection for targeted therapies. Post hoc analyses of the TEMPO 3:4 study indicated that copeptin could be one of those biomarkers. Copeptin was tested in serum samples from patients of the AD(H)PKD study. Serum copeptin levels were measured using a time-resolved amplified cryptate emission (TRACE)-based assay. In total, we collected 711 values from 389 patients without tolvaptan treatment and a total of 243 values (of which 64 were pre-tolvaptan) from 94 patients on tolvaptan. These were associated with rapid progression and disease-causing gene variants and their predictive capacity tested and compared with the Mayo Classification. As expected, copeptin levels showed a significant negative correlation with estimated glomerular filtration rate (eGFR). Measurements on tolvaptan showed significantly higher copeptin levels (9.871pmol/L vs 23.90pmol/L at 90/30mg; P<.0001) in all chronic kidney disease stages. Linear regression models (n=133) show that copeptin is an independent predictor of eGFR slope. A clinical model (including eGFR, age, gender, copeptin) was nearly as good (R2=0.1196) as our optimal model (including height-adjusted total kidney volume, eGFR, copeptin, R2=0.1256). Adding copeptin to the Mayo model improved future eGFR estimation. Copeptin levels are associated with kidney function and independently explained future eGFR slopes. As expected, treatment with tolvaptan strongly increases copeptin levels.

VOLUMETRIC ANALYSIS OF RENAL MASSES AS PREDICTORS OF PARTIAL NEPHRECTOMY OUTCOMES.

Objective To examine the role of endophytic tumor volume assessment (endophycity) on perioperative partial nephrectomy outcomes. Patients and Methods Retrospective review of 212 consecutive laparoscopic and open partial nephrectomies from single institution using pre-operative imaging and one-year follow-up. Demographics, comorbidities, RENAL Nephrometry scores, and all peri- and post-operative outcomes were recorded. Volumetric analysis performed using imaging software, independently assessed by two, blinded radiologists. Univariate and multivariate statistical analysis were completed to assess predictive value of endophycity for all clinically meaningful outcomes. Results Among those undergoing minimally invasive surgery (MIS), lower tumor endophycity was associated with higher likelihood of trifecta outcome (negative surgical margin, <10% decline in eGFR, the absence of complications) irrespective of max tumor size. For MIS, estimated blood loss (EBL) increased with greater tumor endophycity regardless of tumor size. Among those who underwent open partial nephrectomy, lower tumor endophycity was associated with trifecta outcomes for tumors >4cm only. On multivariate analysis with log-scaled odds ratios (OR), tumor endophycity and total kidney volume had the strongest correlation with tumor-related complications (OR=3.23, 2.66). The analysis identified that tumor endophycity and tumor volume on imaging were inversely correlated with of trifecta outcomes (OR=0.53 for both covariates). Conclusions Volumetric assessment of tumor endophycity performed well in identifying partial nephrectomy outcomes. As automated imaging software improves, volumetric analysis may prove to be a useful adjunct in pre-operative planning and patient counseling.

Urinary Biomarkers in Monitoring the Progression and Treatment of Autosomal Dominant Polycystic Kidney Disease-The Promised Land?

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease, and it leads to end-stage renal disease (ESRD). The clinical manifestations of ADPKD are variable, with extreme differences observable in its progression, even among members of the same family with the same genetic mutation. In an age of new therapeutic options, it is important to identify patients with rapidly progressive evolution and the risk factors involved in the disease's poor prognosis. As the pathophysiological mechanisms of the formation and growth of renal cysts have been clarified, new treatment options have been proposed to slow the progression to end-stage renal disease. Furthermore, in addition to the conventional factors (PKD1 mutation, hypertension, proteinuria, total kidney volume), increasing numbers of studies have recently identified new serum and urinary biomarkers of the disease's progression, which are cheaper and more easily to dosing from the early stages of the disease. The present review discusses the utility of new biomarkers in the monitoring of the progress of ADPKD and their roles in new therapeutic approaches.

The safety and efficacy of tolvaptan in the treatment of patients with autosomal dominant polycystic kidney disease: A systematic review and meta-analysis

BackgroundThe irreversible progression of autosomal dominant polycystic kidney disease (ADPKD) to end-stage renal disease (ESRD) is delayed by tolvaptan. Therefore, we aim to systematically estimate and evaluate the efficacy and safety of tolvaptan in the treatment of ADPKD. MethodsTwo reviewers independently searched all published randomized controlled trials studies in PubMed, EMBASE, Web of Science and Cochrane databases, extracted data, assessed bias risk and rated the quality of evidence. Data were analyzed by the RevMan software. ResultsWe identified 8 trials including 2135 patients. Both of the decline of estimated glomerular filtration rate (eGFR) [MD=1.89, 95% CI (0.74, 3.04), P=0.001] and total kidney volume (TKV) [MD=−3.32, 95% CI (−4.57, −2.07), P<0.001] were delayed in tolvaptan group compared with placebo group in ADPKD patients. The use of tolvaptan delayed TKV progression in the different-month subgroups [MD=−69.99, 95% CI (−91.05, −48.94), P<0.001]. Tolvaptan reduced renal pain [RR=0.66, 95% CI (0.54, 0.81), P<0.001] and hematuria events [RR=0.55, 95% CI (0.41, 0.74), P<0.001] in ADPKD patients. However, the prevalence of thirst [RR=2.75, 95% CI (2.34, 3.24), P<0.001] and nocturia events [RR=3.01, 95% CI (1.27, 7.11), P=0.01] were increased in tolvaptan group. There is no significant difference of hypertension events [RR=0.92, 95% CI (0.82, 1.03), P=0.13] in tolvaptan group compared placebo group. ConclusionsThis meta-analysis suggests that tolvaptan may improve clinical progression in patients with ADPKD without significantly increasing the risk of adverse reactions.

Effect of Kidney transplantation on cyst growth in autosomal dominant polycystic kidney disease.

In patients with autosomal dominant polycystic kidney disease (ADPKD), there is limited evidence of the rate of cyst progression after kidney transplantation. To compare the height-adjusted total kidney volume (Ht-TKV) before and after transplantation in kidney transplant recipients (KTR) with -ADPKD. Retrospective cohort study. The estimate of Ht-TKV was calculated by the ellipsoid volume equation using measurements from CT or yearly MRI scans before and after transplantation. We included 30 patients with -ADPKD who underwent kidney transplantation (age 49±10.1 years, 11 (37%) females, dialysis vintage 3 (1-6) years, and 4 (13%) underwent unilateral nephrectomy during the peritransplant period). The median follow-up time was 5 years (range 2-16 years). Transplantation was associated with a significant decrease in Ht-TKV after transplantation in 27 (90%) KTR. Median Ht-TKV decreased from 1,708 (IQR 1,100-2,350) mL/m to 710 (IQR 420 - 1,380) mL/m after 6 years of follow-up (p<0.001), with a mean Ht-TKV change rate per year after transplantation of -1.4, -11.8, -9.7, -12.7, -7.0, and -9.4% after 1, 2, 3, 4, 5, and 6 years, respectively. Even in 2 (7%) KTR without regression, the annual growth was < 1.5% per year after transplantation. Kidney transplantation reduced Ht-TKV after the first 2years of transplantation, and this decline was continuous for more than 6 years of follow-up.

Studying the effect of donor kidney volume ratios to recipients' body surface area, body mass index, and total body weight on post-transplant graft function.

The goal of this study was to retrospectively investigate the relationship between renal transplanted volume indexes (Total kidney volume (TKV)/Body surface area (BSA), Renal parenchymal volume (RPV)/BSA, Renal cortical volume (RCV)/BSA, RPV/Body mass index (BMI), RCV/BMI, RPV/Weight, RCV/Weight), and short- and long-term function of the graft. One-hundred and twelve live donor-recipient pairs from 2017 to 2018, whose donors underwent preoperative renal computed tomography angiography and recipients survived during 12months of follow-up, were included in this study. The crude and adjusted linear regressions for the effect of volume measurements by voxel and ellipsoid methods on the estimated glomerular filtration rate (eGFR) at different post-transplantation times demonstrated that the RPV/weight ratio had the most substantial crude effect on the eGFR 12months and 4 years after renal transplant. Receiver operating characteristic (ROC) curves for six different renal volume ratios demonstrated no significant difference between these ratios in terms of discriminative ability (p value < 0.05). A strong direct correlation between TKV calculated by the ellipsoid formula with RPV and RCV measured using OsiriX software was noted. Analysis of ROC curves for renal volume indices has demonstrated fair to good discriminative ability of our cut-off points to estimate 4-year post-transplantation eGFR > 60mL/min. Renal transplant recipients' volume indices, such as RPV/weight, had strong correlations with eGFR at different points in time, and renal transplant recipients with the volume ratios higher than our cut-off points had a good chance of having a 4-year post-transplantation eGFR higher than 60mL/min.

Recent updates in therapeutic approach using tolvaptan for autosomal dominant polycystic kidney disease.

As a genetic disease, there has been a long-standing effort to identify therapeutic options for autosomal dominant polycystic kidney disease (ADPKD). Following the development of tolvaptan, a vasopressin 2 receptor antagonist, the treatment strategy for ADPKD patients with rapid disease progression has been changed with a disease-targeted approach. Tolvaptan showed significant efficacy in preserving kidney function and reducing the total kidney volume (TKV) growth rate. These effects were especially pronounced in patients with more severe clinical phenotypes, such as higher TKV and rapidly declining kidney function. Despite the therapeutic effects of tolvaptan, aquaretic symptoms are unavoidable side effects related to the mechanism of the drug and are also directly related to the quality of life. A shared decision-making process could be a valuable strategy for reducing the incidence of side effects and improving medication adherence. Herein, we aimed to review overall clinical trials for applying tolvaptan and suggest important factors during the shared decision-making process.

Parasympathetic activity and total fibrotic kidney in autosomal-dominant polycystic kidney disease patients: a pilot study

PurposeRenin–angiotensin system hyperactivation in autosomal-dominant polycystic kidney disease (ADPKD) patients leads to early hypertension. Cystic enlargement probably causes parenchymal hypoxia, renin secretion, and endothelial dysfunction. Sympathetic and parasympathetic balance is altered in this condition, especially during the night, also affecting blood pressure circadian rhythm. Aim of this study was to evaluate sympathetic/parasympathetic balance using heart rate variability (HRV) parameters and find a correlation between HRV and renal damage progression, as total kidney volume enlargement, in ADPKD patients.MethodsSixteen adult ADPKD patients were enrolled in the study. Eleven patients (68.8%) were male, and the median age was 42 years (IQR 36–47.5). HRV parameters were calculated using 24 h-ECG Holter. A kidney magnetic resonance imaging (MRI) scan 3 Tesla was performed to evaluate total kidney volume (TKV) and total fibrotic volume (TFV).ResultsA statistically significant positive linear correlation was observed between length of kidneys and frequency domain parameters as low frequency (LF) (r = 0.595, p < 0.05) and LFday (r = 0.587, p < 0.05). Moreover, a statistically significant positive linear correlation exists between high frequency (HF) and TFV (r = 0.804, p < 0.01) or height-adjusted (ha) TFV (r = 0.801, p < 0.01). Finally, we found a statistically significant positive linear correlation between HFnight and TKV (r = 0.608, p < 0.05), ha-TKV (r = 0.685, p < 0.01), TFV (r = 0.594, p < 0.05), and ha-TFV (r = 0.615, p < 0.05).ConclusionWe suppose that the increase in TKV and TFV could lead to a parasympathetic tone hyperactivation, probably in response to hypoxic stress and vasoconstriction due to cystic enlargement.

Diffusion magnetic resonance imaging for kidney cyst volume quantification and non-cystic tissue characterisation in ADPKD.

Beyond total kidney and cyst volume (TCV), non-cystic tissue plays an important role in autosomal dominant polycystic kidney disease (ADPKD) progression. This study aims at presenting and preliminarily validating a diffusion MRI (DWI)-based TCV quantification method and providing evidence of DWI potential in characterising non-cystic tissue microstructure. T2-weighted MRI and DWI scans (b = 0, 15, 50, 100, 200, 350, 500, 700, 1000; 3 directions) were acquired from 35 ADPKD patients with CKD stage 1 to 3a and 15 healthy volunteers on a 1.5T scanner. ADPKD classification was performed using the Mayo model. DWI scans were processed by mono- and segmented bi-exponential models. TCV was quantified on T2-weighted MRI by the reference semi-automatic method and automatically computed by thresholding the pure diffusivity (D) histogram. The agreement between reference and DWI-based TCV values and the differences in DWI-based parameters between healthy and ADPKD tissue components were assessed. There was strong correlation between DWI-based and reference TCV (rho = 0.994, p < 0.001). Non-cystic ADPKD tissue had significantly higher D, and lower pseudo-diffusion and flowing fraction than healthy tissue (p < 0.001). Moreover, apparent diffusion coefficient and D values significantly differed by Mayo imaging class, both in the whole kidney (Wilcoxon p = 0.007 and p = 0.004) and non-cystic tissue (p = 0.024 and p = 0.007). DWI shows potential in ADPKD to quantify TCV and characterise non-cystic kidney tissue microstructure, indicating the presence of microcysts and peritubular interstitial fibrosis. DWI could complement existing biomarkers for non-invasively staging, monitoring, and predicting ADPKD progression and evaluating the impact of novel therapies, possibly targeting damaged non-cystic tissue besides cyst expansion. This study shows diffusion-weighted MRI (DWI) potential to quantify total cyst volume and characterise non-cystic kidney tissue microstructure in ADPKD. DWI could complement existing biomarkers for non-invasively staging, monitoring, and predicting ADPKD progression and evaluating the impact of novel therapies, possibly targeting damaged non-cystic tissue besides cyst expansion. • Diffusion magnetic resonance imaging shows potential to quantify total cyst volume in ADPKD. • Diffusion magnetic resonance imaging might allow to non-invasively characterise non-cystic kidney tissue microstructure. • Diffusion magnetic resonance imaging-based biomarkers significantly differ by Mayo imaging class, suggesting their possible prognostic value.

Clinical Implementation of an Artificial Intelligence Algorithm for Magnetic Resonance–Derived Measurement of Total Kidney Volume

ObjectiveTo evaluate the performance of an internally developed and previously validated artificial intelligence (AI) algorithm for magnetic resonance (MR)–derived total kidney volume (TKV) in autosomal dominant polycystic kidney disease (ADPKD) when implemented in clinical practice. Patients and MethodsThe study included adult patients with ADPKD seen by a nephrologist at our institution between November 2019 and January 2021 and undergoing an MR imaging examination as part of standard clinical care. Thirty-three nephrologists ordered MR imaging, requesting AI-based TKV calculation for 170 cases in these 161 unique patients. We tracked implementation and performance of the algorithm over 1 year. A radiologist and a radiology technologist reviewed all cases (N=170) for quality and accuracy. Manual editing of algorithm output occurred at radiology or radiology technologist discretion. Performance was assessed by comparing AI-based and manually edited segmentations via measures of similarity and dissimilarity to ensure expected performance. We analyzed ADPKD severity class assignment of algorithm-derived vs manually edited TKV to assess impact. ResultsClinical implementation was successful. Artificial intelligence algorithm–based segmentation showed high levels of agreement and was noninferior to interobserver variability and other methods for determining TKV. Of manually edited cases (n=84), the AI-algorithm TKV output showed a small mean volume difference of –3.3%. Agreement for disease class between AI-based and manually edited segmentation was high (five cases differed). ConclusionPerformance of an AI algorithm in real-life clinical practice can be preserved if there is careful development and validation and if the implementation environment closely matches the development conditions.

The association of urinary epidermal growth factors with ADPKD disease severity and progression.

The epidermal growth factor receptor (EGFR) pathway is involved in kidney tissue repair and growth. Preclinical interventional data and scarce human data have suggested a role for this pathway in the pathophysiology of Autosomal Dominant Polycystic Kidney Disease (ADPKD), while other data have suggested that its activation is causally linked to repair of damaged kidney tissue. We hypothesize that urinary EGFR ligands, as a reflection of EGFR activity, are associated with kidney function decline in ADPKD in the context of tissue repair following injury, and as the disease progresses as a sign of insufficient repair. In the present study, we measured the EGFR ligands, EGF and heparin binding-EGF (HB-EGF), in 24-h urine samples of 301 ADPKD patients and 72 age- and sex matched living kidney donors to dissect the role of the EGFR pathway in ADPKD. During a median follow-up of 2.5 years, the association of urinary EGFR ligand excretion with annual change in estimated glomerular filtration rate (eGFR) and height adjusted total kidney volume (htTKV) in ADPKD patients was analyzed using mixed-models methods and the expression of three closely related EGFR family receptors in ADPKD kidney tissue was investigated by immunohistochemistry. Additionally, the effect of reducing renal mass (after kidney donation), was assessed to investigate whether urinary EGF matches this reduction and thus reflects the amount of remaining healthy kidney tissue. At baseline, urinary HB-EGF did not differ between ADPKD patients and healthy controls (p=0.6), whereas a lower urinary EGF excretion was observed in ADPKD patients (18.6 [11.8-27.8] compared to healthy controls (51.0 [34.9-65.4] µg/24h, p<0.001). Urinary EGF was positively associated with baseline eGFR (R=0.54, p<0.001) and a lower EGF was strongly associated with a more rapid GFR decline, even when adjusted for ADPKD severity markers (β = 1.96, p<0.001), whereas HB-EGF was not. Expression of the EGFR, but not other EGFR-related receptors, was observed in renal cysts but was absent in non-ADPKD kidney tissue. Finally, unilateral nephrectomy resulted in a decrease of 46.4 [-63.3 to -17.6]% in urinary EGF excretion, alongside a decrease of 35.2±7.2% in eGFR and 36.8±6.9% in mGFR, whereas maximal mGFR (measured after dopamine induced hyperperfusion) decreased by 46.1±7.8% (all p<0.001). Our data suggest that lower urinary EGF excretion may be a valuable novel predictor for kidney function decline in patients with ADPKD.

Elevated checkpoint inhibitor expression and Treg cell number in autosomal dominant polycystic kidney disease and their correlation with disease parameters and hypertension.

Autosomal dominant polycystic kidney disease (ADPKD) has cancer-like pathophysiology. In this study, we aimed to investigate the phenotype of peripheral blood (PB) T cell subsets and immune checkpoint inhibitor expression of ADPKD patients across different chronic kidney disease (CKD) stages. Seventy-two patients with ADPKD and twenty-three healthy controls were included in the study. The patients were grouped into five different CKD stages, according to glomerular filtration rate (GFR). PB mononuclear cells were isolated and T cell subsets and cytokine production were examined by flow cytometry. CRP levels, height-adjusted total kidney volume (htTKV), rate of hypertension (HT) differed significantly across different GFR stages in ADPKD. T cell phenotyping revealed significantly elevated CD3+ T cells, CD4+, CD8+, double-negative, and double-positive subsets and significantly elevated IFN-γ and TNF-α producing subsets of CD4+, CD8+ cells. The expression of checkpoint inhibitors CTLA-4, PD-1, and TIGIT by T cell subsets was also increased to various extent. Additionally, Treg cell numbers and suppressive markers CTLA-4, PD-1, and TIGIT were significantly elevated in ADPKD patients' PB. Treg CTLA4 expression and CD4CD8DP T cell frequency in patients with HT were significantly higher. Lastly, HT and increased htTKV and higher frequency of PD1+ CD8SP were found to be risk factors for rapid disease progression. Our data provide the first detailed analyses of checkpoint inhibitor expression by PB T cell subsets during stages of ADPKD, and that a higher frequency of PD1+ CD8SP cells is associated with rapid disease progression.

Atypical Polycystic Kidney Disease as defined by Imaging

Using age- and height-adjusted total kidney volume, the Mayo Clinic Imaging Classification provides a validated approach to assess the risk of chronic kidney disease (CKD) progression in autosomal dominant polycystic kidney disease (ADPKD), but requires excluding patients with atypical imaging patterns, whose clinical characteristics have been poorly defined. We report an analysis of the prevalence, clinical and genetic characteristics of patients with atypical polycystic kidney disease by imaging. Patients from the extended Toronto Genetic Epidemiology Study of Polycystic Kidney Disease recruited between 2016 and 2018 completed a standardized clinical questionnaire, kidney function assessment, genetic testing, and kidney imaging by magnetic resonance or computed tomography. We compared the prevalence, clinical features, genetics, and renal prognosis of atypical versus typical polycystic kidney disease by imaging. Forty-six of the 523 (8.8%) patients displayed atypical polycystic kidney disease by imaging; they were older (55 vs. 43 years; P < 0.001), and less likely to have a family history of ADPKD (26.1% vs. 74.6%; P < 0.001), a detectable PKD1 or PKD2 mutation (9.2% vs. 80.4%; P < 0.001), or progression to CKD stage 3 or stage 5 (P < 0.001). Patients with atypical polycystic kidney disease by imaging represent a distinct prognostic group with a low likelihood of progression to CKD.

Risk Severity Model for Pediatric Autosomal Dominant Polycystic Kidney Disease Using 3D Ultrasound Volumetry.

Height-adjusted total kidney volume (htTKV) measured by imaging defined as Mayo Imaging Class (MIC) is a validated prognostic measure for autosomal dominant polycystic kidney disease (ADPKD) in adults to predict and stratify disease progression. However, no stratification tool is currently available in pediatric ADPKD. Because magnetic resonance imaging and computed tomography in children are difficult, we propose a novel 3D ultrasound-based pediatric Leuven Imaging Classification to complement the MIC. A prospective study cohort of 74 patients with genotyped ADPKD (37 female) was followed longitudinally with ultrasound, including 3D ultrasound, and they underwent in total 247 3D ultrasound assessments, with patients' median age (interquartile range [IQR]) at diagnosis of 3 (IQR, 0-9) years and at first 3D ultrasound evaluation of 10 (IQR, 5-14) years. First, data matching was done to the published MIC classification, followed by subsequent optimization of parameters and model type. PKD1 was confirmed in 70 patients (95%), PKD2 in three (4%), and glucosidase IIα unit only once (1%). Over these 247 evaluations, the median height was 143 (IQR, 122-166) cm and total kidney volume was 236 (IQR, 144-344) ml, leading to an htTKV of 161 (IQR, 117-208) ml/m. Applying the adult Mayo classification in children younger than 15 years strongly underestimated ADPKD severity, even with correction for height. We therefore optimized the model with our pediatric data and eventually validated it with data of young patients from Mayo Clinic and the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease used to establish the MIC. We proposed a five-level Leuven Imaging Classification ADPKD pediatric model as a novel classification tool on the basis of patients' age and 3D ultrasound-htTKV for reliable discrimination of childhood ADPKD severity.

Accuracy and processing time of kidney volume measurement methods in rodents polycystic kidney disease models: superiority of semiautomated kidney segmentation.

Measurement of total kidney volume (TKV) using magnetic resonance imaging (MRI) is a valuable approach for monitoring disease progression in autosomal dominant polycystic kidney disease (PKD) and is becoming more common in preclinical studies using animal models. Manual contouring of kidney MRI areas [i.e., manual method (MM)] is a conventional, but time-consuming, way to determine TKV. We developed a template-based semiautomatic image segmentation method (SAM) and validated it in three commonly used PKD models: Cys1cpk/cpk mice, Pkd1RC/RC mice, and Pkhd1pck/pck rats (n = 10 per model). We compared SAM-based TKV with that obtained by clinical alternatives including the ellipsoid formula-based method (EM) using three kidney dimensions, the longest kidney length method (LM), and MM, which is considered the gold standard. Both SAM and EM presented high accuracy in TKV assessment in Cys1cpk/cpk mice [interclass correlation coefficient (ICC) ≥ 0.94]. SAM was superior to EM and LM in Pkd1RC/RC mice (ICC = 0.87, 0.74, and <0.10 for SAM, EM, and LM, respectively) and Pkhd1pck/pck rats (ICC = 0.59, <0.10, and <0.10, respectively). Also, SAM outperformed EM in processing time in Cys1cpk/cpk mice (3.6 ± 0.6 vs. 4.4 ± 0.7 min/kidney) and Pkd1RC/RC mice (3.1 ± 0.4 vs. 7.1 ± 2.6 min/kidney, both P < 0.001) but not in Pkhd1PCK/PCK rats (3.7 ± 0.8 vs. 3.2 ± 0.5 min/kidney). LM was the fastest (∼1 min) but correlated most poorly with MM-based TKV in all studied models. Processing times by MM were longer for Cys1cpk/cpk mice, Pkd1RC/RC mice, and Pkhd1pck.pck rats (66.1 ± 7.3, 38.3 ± 7.5, and 29.2 ± 3.5 min). In summary, SAM is a fast and accurate method to determine TKV in mouse and rat PKD models.NEW & NOTEWORTHY Total kidney volume (TKV) is a valuable readout in preclinical studies for autosomal dominant and autosomal recessive polycystic kidney diseases (ADPKD and ARPKD). Since conventional TKV assessment by manual contouring of kidney areas in all images is time-consuming, we developed a template-based semiautomatic image segmentation method (SAM) and validated it in three commonly used ADPKD and ARPKD models. SAM-based TKV measurements were fast, highly reproducible, and accurate across mouse and rat ARPKD and ADPKD models.

OVERTURE: A Worldwide, Prospective, Observational Study of Disease Characteristics in Patients With ADPKD

The course of autosomal dominant polycystic kidney disease (ADPKD) varies greatly among affected individuals, necessitating natural history studies to characterize the determinants and effects of disease progression. Therefore, we conducted an observational, longitudinal study (OVERTURE; NCT01430494) of patients with ADPKD. This prospective study enrolled a large international population (N= 3409) encompassing a broad spectrum of ages (12-78 years), chronic kidney disease (CKD) stages (G1-G5), and Mayo imaging classifications (1A-1E). Outcomes included kidney function, complications, quality of life, health care resource utilization, and work productivity. Most subjects (84.4%) completed≥12 months of follow-up. Consistent with earlier findings, each additional l/m of height-adjusted total kidney volume (htTKV) on magnetic resonance imaging (MRI) was associated with worse outcomes, including lower estimated glomerular filtration rate (eGFR) (regression coefficient 17.02, 95% confidence interval [CI] 15.94-18.11) and greater likelihood of hypertension (odds ratio [OR] 1.25, 95% CI 1.17-1.34), kidney pain (OR 1.22, 95% CI 1.11-1.33), and hematuria (OR 1.35, 95% CI 1.21-1.51). Greater baseline htTKV was also associated with worse patient-reported health-related quality of life (e.g., ADPKD Impact Scale physical score, regression coefficient 1.02, 95% CI 0.65-1.39), decreased work productivity (e.g., work days missed, regression coefficient 0.55, 95% CI 0.18-0.92), and increased health care resource utilization (e.g., hospitalizations, OR 1.48, 95% CI 1.33-1.64) during follow-up. Although limited by a maximum 3-year duration of follow-up, this observational study characterized the burden of ADPKD in a broad population and indicated the predictive value of kidney volume for outcomes other than kidney function.

Acute renal intracystic hemorrhage in patients with autosomal dominant polycystic kidney disease.

Renal cyst bleeding is a frequent problem in patients with autosomal dominant polycystic kidney disease (ADPKD). However, information is still limitedon its frequency, causative factors, and effects on enlargement of polycystic kidneys in ADPKD. We investigated the total volume of acute renal intracystic hemorrhage and its association with total kidney volume (TKV) in a large seriesofpatients with ADPKD on dialysis, referred forrenal transcatheter arterial embolization. All patients had undergone CT scan and MRI scan before the procedure.We evaluated factors potentially associated with acute renal intracystic hemorrhage.The association between thevolume of acute renal intracystic hemorrhage and the potential predisposing and associated factors was analysed by univariable and multivariable regressions. RESULTS: We enrolled 199 patients who underwent renal transcatheter arterial embolization from 2014 to 2018 (107 men, 92 women; mean age 59.1 ± 8.6years). The median volume of acute renal intracystic hemorrhage was 97.3ml (interquartile range 36.6-261.7ml). Multivariable analysis revealed that body weight, kidney stones, systolic blood pressure, and total volume of acute renal intracystic hemorrhage were significantly associated with TKV; age, body mass index, smoking, renal cyst infection, serum alkaline phosphatase, and TKV were significantly associated withthe volume ofacute renal intracystic hemorrhage ; and sex, age, dialysis vintage, TKV, and total volume of acute renal intracystic hemorrhage were significantly associated with the number of microcoils required to achieve renal transcatheter arterial embolization. Total volume of acute renal intracystic hemorrhage was significantly associated with TKV(r = 0.15, p = 0.0325)and wasgreater inyounger patients (r= - 0.32, p < 0.0001). Total volume of acute renal intracystic hemorrhagewas also correlated with the number ofmicrocoils required for renal transcatheter arterial embolization(r = 0.23, p = 0.0012). Acute renal intracystic hemorrhage is frequent among ADPKD patients on dialysis, and total volume of acute renal intracystic hemorrhage significantly associated with TKV.Total volume of acute renal intracystic hemorrhage was greater in younger patients with higher renal artery luminal size. These results suggest that renal cyst bleeding and renal artery blood flow may synergistically accelerate the enlargement of polycystic kidneysin ADPKDpatients on dialysis.

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

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

Case of the Month from the Peter MacCallum Cancer Centre, Melbourne, Australia: combination of stereotactic ablative body radiotherapy and radical nephrectomy for synchronous bilateral primary renal cell carcinoma.

Case of the Month from the Peter MacCallum Cancer Centre, Melbourne, Australia: combination of stereotactic ablative body radiotherapy and radical nephrectomy for synchronous bilateral primary renal cell carcinoma.