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      Early Urinary Biomarkers in Pediatric Autosomal Dominant Polycystic Kidney Disease (ADPKD): No Evidence in the Interest of Urinary Neutrophil Gelatinase-Associated Lipocalin (uNGAL)

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          Abstract

          Background: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is increasingly diagnosed during childhood by the presence of renal cysts in patients with a positive familial history. No curative treatment is available and early detection and diagnosis confronts pediatricians with the lack of early markers to decide whether to introduce renal-protective agents and prevent the progression of renal failure. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a tubular protein that has been recently proposed as an early biomarker of renal impairment in the ADPKD adult population.

          Methods: Urinary NGAL (uNGAL) levels were measured in 15 ADPKD children and compared with 15 age and gender matched controls using parametric, non-parametric, and Bayesian statistics. We also tested the association of uNGAL levels with markers of disease progression, such as proteinuria, albuminuria, blood pressure, and Total Kidney Volume (TKV) using correlation analysis. TKV was calculated by ultrasound, using the ellipsoid method.

          Results: No difference in mean uNGAL levels was observed between groups (ADPKD: 26.36 ng/ml; Controls: 27.24 ng/ml; P = 0.96). Moreover, no correlation was found between uNGAL and proteinuria ( P = 0.51), albuminuria ( P = 0.69), TKV ( P = 0.68), or mean arterial pressure ( P = 0.90). By contrast, TKV was positively correlated with proteinuria ( P = 0.04), albuminuria ( P = 0.001), and mean arterial pressure ( P = 0.03).

          Conclusion: uNGAL did not confirm its superiority as a marker of disease progression in a pediatric ADPKD population. In the contrary, TKV appears to be an easy measurable variable and may be promising as a surrogate marker to follow ADPKD progression in children.

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          Most cited references33

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          Volume progression in polycystic kidney disease.

          Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of cyst-filled kidneys. In a three-year study, we measured the rates of change in total kidney volume, total cyst volume, and iothalamate clearance in patients with ADPKD. Of a total of 241 patients, in 232 patients without azotemia who were 15 to 46 years old at baseline we used magnetic-resonance imaging to correlate the total kidney volume and total cyst volume with iothalamate clearance. Statistical methods included analysis of variance, Pearson correlation, and multivariate regression analysis. Total kidney volume and total cyst volume increased exponentially, a result consistent with an expansion process dependent on growth. The mean (+/-SD) total kidney volume was 1060+/-642 ml at baseline and increased by a mean of 204+/-246 ml (5.27+/-3.92 percent per year, P<0.001) over a three-year period among 214 patients. Total cyst volume increased by 218+/-263 ml (P<0.001) during the same period among 210 patients. The baseline total kidney volume predicted the subsequent rate of increase in volume, independently of age. A baseline total kidney volume above 1500 ml in 51 patients was associated with a declining glomerular filtration rate (by 4.33+/-8.07 ml per minute per year, P<0.001). Total kidney volume increased more in 135 patients with PKD1 mutations (by 245+/-268 ml) than in 28 patients with PKD2 mutations (by 136+/-100 ml, P=0.03). Kidney enlargement resulting from the expansion of cysts in patients with ADPKD is continuous and quantifiable and is associated with the decline of renal function. Higher rates of kidney enlargement are associated with a more rapid decrease in renal function. Copyright 2006 Massachusetts Medical Society.
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            Bayes factor approaches for testing interval null hypotheses.

            Psychological theories are statements of constraint. The role of hypothesis testing in psychology is to test whether specific theoretical constraints hold in data. Bayesian statistics is well suited to the task of finding supporting evidence for constraint, because it allows for comparing evidence for 2 hypotheses against each another. One issue in hypothesis testing is that constraints may hold only approximately rather than exactly, and the reason for small deviations may be trivial or uninteresting. In the large-sample limit, these uninteresting, small deviations lead to the rejection of a useful constraint. In this article, we develop several Bayes factor 1-sample tests for the assessment of approximate equality and ordinal constraints. In these tests, the null hypothesis covers a small interval of non-0 but negligible effect sizes around 0. These Bayes factors are alternatives to previously developed Bayes factors, which do not allow for interval null hypotheses, and may especially prove useful to researchers who use statistical equivalence testing. To facilitate adoption of these Bayes factor tests, we provide easy-to-use software.
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              Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease.

              Autosomal dominant polycystic kidney disease (ADPKD) is characterized by increased total kidney volume (TKV) and renal failure. This study aimed to determine if height-adjusted TKV (htTKV) predicts the onset of renal insufficiency. This prospective, observational, longitudinal, multicenter study included 241 adults with ADPKD and preserved renal function. Magnetic resonance imaging and iothalamate clearance were used to measure htTKV and GFR, respectively. The association between baseline htTKV and the attainment of stage 3 CKD (GFR <60 ml/min per 1.73 m(2)) during follow-up was determined. After a mean follow-up of 7.9 years, stage 3 CKD was attained in 30.7% of the enrollees. Using baseline htTKV, negative correlations with GFR increased from -0.22 at baseline to -0.65 at year 8. In multivariable analysis, a baseline htTKV increase of 100 cc/m significantly predicted the development of CKD within 8 years with an odds ratio of 1.48 (95% confidence interval: 1.29, 1.70). In receiver operator characteristic curve analysis, baseline htTKV of 600 cc/m most accurately defined the risk of developing stage 3 CKD within 8 years with an area under the curve of 0.84 (95% confidence interval: 0.79, 0.90). htTKV was a better predictor than baseline age, serum creatinine, BUN, urinary albumin, or monocyte chemotactic protein-1 excretion (P<0.05). Baseline htTKV ≥600 cc/m predicted the risk of developing renal insufficiency in ADPKD patients at high risk for renal disease progression within 8 years of follow-up, qualifying htTKV as a prognostic biomarker in ADPKD.
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                Author and article information

                Contributors
                Journal
                Front Pediatr
                Front Pediatr
                Front. Pediatr.
                Frontiers in Pediatrics
                Frontiers Media S.A.
                2296-2360
                22 March 2019
                2019
                : 7
                : 88
                Affiliations
                [1] 1Pediatric Nephrology Unit, Department of Pediatrics, Children's Hospital, Geneva University Hospital , Geneva, Switzerland
                [2] 2Pediatric Radiology Unit, Department of Radiology, Children's Hospital, Geneva University Hospital , Geneva, Switzerland
                [3] 3Laboratory of Cognitive Neuroscience, Brain Mind Institute and Center for Neuroprosthetics, School of Life Sciences, École Polytechnique Fédérale de Lausanne , Geneva, Switzerland
                Author notes

                Edited by: Max Christoph Liebau, Universitätsklinikum Köln, Germany

                Reviewed by: Andrew Mallett, Royal Brisbane and Women's Hospital, Australia; Erum Aftab Hartung, Children's Hospital of Philadelphia, United States

                *Correspondence: Marianthi Tsingos marianthi.tsingos@ 123456hcuge.ch

                This article was submitted to Pediatric Nephrology, a section of the journal Frontiers in Pediatrics

                Article
                10.3389/fped.2019.00088
                6439434
                b880dc04-8353-480f-8764-a6956e0953b6
                Copyright © 2019 Tsingos, Merlini, Solcà, Goischke, Wilhelm-Bals and Parvex.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 09 December 2018
                : 28 February 2019
                Page count
                Figures: 3, Tables: 3, Equations: 0, References: 39, Pages: 8, Words: 5847
                Categories
                Pediatrics
                Original Research

                adpkd,ungal,children,renal impairment,tkv
                adpkd, ungal, children, renal impairment, tkv

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