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      Renal resistive index in chronic kidney disease patients: Possible determinants and risk profile

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          Abstract

          Background

          High ultrasound renal resistive index (RI) predicts poor cardiorenal outcomes in chronic kidney disease (CKD) and has recently emerged as a marker of nephroprotective drugs response. Thus, having a risk profile of CKD patients with abnormal RI may be relevant for the clinicians.

          Methods

          Consecutive patients referred to our non-dialysis CKD clinic from 01/01/2016 to 01/12/2016, were evaluated by clinical and ultrasound analysis. Inclusion criteria were age >18 years and presence of CKD defined as estimated glomerular filtration rate (eGFR)<60 mL/min/1.73m 2 and/or proteinuria>0.150g/24h. Renal artery stenosis, solitary kidney, acute kidney injury were the main exclusion criteria. RI value was the mean of three measures in segmental arteries in each kidney. Univariate analysis was performed to evaluate associations between continuous RI and clinical variables. Multivariate linear regression analysis, based on stepwise method with an elimination criterion of p<0.10, was used to assess the independent correlates of RI as continuous variable.

          Results

          We studied 73 patients (69.9% men). Mean RI was 0.67±0.09. Frequencies of diabetes and cardiovascular disease (CVD) were 19.2% and 20.6% and median eGFR 54.1 [30.0–84.6] mL/min/1.73m 2. From low (<0.65) to intermediate (0.65–0.70) to high (>0.70) RI categories, eGFR and haemoglobin levels were decreased while diabetes, cardiovascular disease (CVD), phosphate and smokers were higher. At univariate analysis, RI was significantly associated with age, presence of diabetes, CVD, serum phosphorus, eGFR, Urea and haemoglobin. Multi-adjusted stepwise regression analysis showed that lower eGFR levels (p<0.001), diabetes (p = 0.042), CVD (p = 0.009), smoking habit (p = 0.021) and higher serum phosphorus levels (p = 0.001) were associated with higher continuous RI. Serum phosphorus showed Area Under the Curves (AUC) values of 0.714 and 0.664 for discriminating RI cut-offs of 0.70 and 0.65.

          Conclusions

          This analysis suggests that RI is higher in CKD patients with CVD, diabetes, smoking habit and higher serum phosphorus, regardless of eGFR. Further studies are needed to verify whether higher RI indicates more complex pathway of intrarenal damage, besides and beyond kidney function.

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          Most cited references46

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          Youden Index and optimal cut-point estimated from observations affected by a lower limit of detection.

          The receiver operating characteristic (ROC) curve is used to evaluate a biomarker's ability for classifying disease status. The Youden Index (J), the maximum potential effectiveness of a biomarker, is a common summary measure of the ROC curve. In biomarker development, levels may be unquantifiable below a limit of detection (LOD) and missing from the overall dataset. Disregarding these observations may negatively bias the ROC curve and thus J. Several correction methods have been suggested for mean estimation and testing; however, little has been written about the ROC curve or its summary measures. We adapt non-parametric (empirical) and semi-parametric (ROC-GLM [generalized linear model]) methods and propose parametric methods (maximum likelihood (ML)) to estimate J and the optimal cut-point (c *) for a biomarker affected by a LOD. We develop unbiased estimators of J and c * via ML for normally and gamma distributed biomarkers. Alpha level confidence intervals are proposed using delta and bootstrap methods for the ML, semi-parametric, and non-parametric approaches respectively. Simulation studies are conducted over a range of distributional scenarios and sample sizes evaluating estimators' bias, root-mean square error, and coverage probability; the average bias was less than one percent for ML and GLM methods across scenarios and decreases with increased sample size. An example using polychlorinated biphenyl levels to classify women with and without endometriosis illustrates the potential benefits of these methods. We address the limitations and usefulness of each method in order to give researchers guidance in constructing appropriate estimates of biomarkers' true discriminating capabilities. Copyright 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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            Albuminuria reflects widespread vascular damage. The Steno hypothesis.

            Albuminuria in Type 1 (insulin-dependent) diabetes is not only an indication of renal disease, but a new, independent risk-marker of proliferative retinopathy and macroangiopathy. The coincidence of generalised vascular dysfunction and albuminuria, advanced mesangial expansion, proliferative retinopathy, and severe macroangiopathy suggests a common cause of albuminuria and the severe renal and extrarenal complications associated with it. Enzymes involved in the metabolism of anionic components of the extracellular matrix (e.g. heparan sulphate proteoglycan) vulnerable to hyperglycaemia, seem to constitute the primary cause of albuminuria and the associated complications. Genetic polymorphism of such enzymes is possibly the main reason for variation in susceptibility.
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              Klotho, phosphate and FGF-23 in ageing and disturbed mineral metabolism.

              High concentrations of extracellular phosphate are toxic to cells. Impaired urinary phosphate excretion increases serum phosphate level and induces a premature-ageing phenotype. Urinary phosphate levels are increased by dietary phosphate overload and might induce tubular injury and interstitial fibrosis. Extracellular phosphate exerts its cytotoxic effects by forming insoluble nanoparticles with calcium and fetuin-A; these nanoparticles are referred to in this Review as calciprotein particles. Calciprotein particles are highly bioactive ligands that can induce various cellular responses, including the osteogenic transformation of vascular smooth muscle cells and cell death of vascular endothelial cells and renal tubular epithelial cells. Calciprotein particles are detected in the serum of animal models of kidney disease and in patients with chronic kidney disease (CKD) and might be associated with a (mal)adaptation of the endocrine axes mediated by fibroblast growth factors and Klothos that regulate phosphate homeostasis and ageing. These observations raise the possibility that calciprotein particles contribute to the pathogenesis of CKD. This theory, if verified, is expected to provide novel diagnostic markers and therapeutic targets in CKD.
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                Author and article information

                Contributors
                Role: Writing – original draftRole: Writing – review & editing
                Role: Writing – original draft
                Role: Formal analysisRole: InvestigationRole: Methodology
                Role: Writing – review & editing
                Role: Data curation
                Role: Investigation
                Role: Writing – review & editing
                Role: VisualizationRole: Writing – review & editing
                Role: ValidationRole: Visualization
                Role: ConceptualizationRole: Data curationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draft
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                1 April 2020
                2020
                : 15
                : 4
                : e0230020
                Affiliations
                [1 ] Nephrology Unit of Magna Graecia University in Catanzaro, Catanzaro, Italy
                [2 ] Division of Nephrology, Department of Scienze Mediche e Chirurgiche Avanzate, University of Campania “Luigi Vanvitelli”, Naples, Italy
                [3 ] Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
                [4 ] Interuniversity Center of Phlebolymphology (CIFL), International Research and Educational Program in Clinical and Experimental Biotechnology, Headquarters: Magna Graecia University of Catanzaro, Catanzaro, Italy
                International University of Health and Welfare, School of Medicine, JAPAN
                Author notes

                Competing Interests: NO authors have competing interests

                Author information
                http://orcid.org/0000-0002-2168-702X
                Article
                PONE-D-19-33219
                10.1371/journal.pone.0230020
                7112174
                32236125
                5bd2f6db-b654-4708-9778-5bcde695ba5b
                © 2020 Provenzano et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 30 November 2019
                : 18 February 2020
                Page count
                Figures: 2, Tables: 3, Pages: 14
                Funding
                All the Authors received no specific funding for this work.
                Categories
                Research Article
                Medicine and Health Sciences
                Nephrology
                Chronic Kidney Disease
                Medicine and Health Sciences
                Cardiovascular Medicine
                Cardiovascular Diseases
                Medicine and Health Sciences
                Endocrinology
                Endocrine Disorders
                Diabetes Mellitus
                Medicine and Health Sciences
                Metabolic Disorders
                Diabetes Mellitus
                Biology and Life Sciences
                Psychology
                Behavior
                Habits
                Smoking Habits
                Social Sciences
                Psychology
                Behavior
                Habits
                Smoking Habits
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
                Physical Sciences
                Chemistry
                Chemical Compounds
                Phosphates
                Medicine and Health Sciences
                Nephrology
                Medicine and Health Sciences
                Vascular Medicine
                Blood Pressure
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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