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      Autosomal dominant polycystic kidney disease: updated perspectives

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          Abstract

          Autosomal dominant polycystic kidney disease (ADPKD) is an inherited multisystem disorder, characterized by renal and extra-renal fluid-filled cyst formation and increased kidney volume that eventually leads to end-stage renal disease. ADPKD is considered the fourth leading cause of end-stage renal disease in the United States and globally. Care of patients with ADPKD was, for a long time, limited to supportive lifestyle measures, due to the lack of therapeutic strategies targeting the main pathways involved in the pathophysiology of ADPKD. As the first FDA approved treatment of ADPKD, Vasopressin (V 2) receptor blocking agent, tolvaptan, is an urgently awaited advance for ADPKD patients. In our review, we also shed some lights on what is beyond Tolvaptan as there are other medications in the pipeline and many medications have been or are currently being studied in clinical trials such as Tesevatinib, Metformin and Pravastatin, with the goal of slowing the rate of progression of ADPKD by reducing the increase in total kidney volume or maintaining eGFR. Here, we review updates in the perspectives and management of ADPKD.

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          Most cited references 84

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          Autosomal dominant polycystic kidney disease.

          Autosomal dominant polycystic kidney disease is the most prevalent, potentially lethal, monogenic disorder. It is associated with large interfamilial and intrafamilial variability, which can be explained to a large extent by its genetic heterogeneity and modifier genes. An increased understanding of the disorder's underlying genetic, molecular, and cellular mechanisms and a better appreciation of its progression and systemic manifestations have laid out the foundation for the development of clinical trials and potentially effective treatments.
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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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              Unified criteria for ultrasonographic diagnosis of ADPKD.

              Individuals who are at risk for autosomal dominant polycystic kidney disease are often screened by ultrasound using diagnostic criteria derived from individuals with mutations in PKD1. Families with mutations in PKD2 typically have less severe disease, suggesting a potential need for different diagnostic criteria. In this study, 577 and 371 at-risk individuals from 58 PKD1 and 39 PKD2 families, respectively, were assessed by renal ultrasound and molecular genotyping. Using sensitivity data derived from genetically affected individuals and specificity data derived from genetically unaffected individuals, various diagnostic criteria were compared. In addition, data sets were created to simulate the PKD1 and PKD2 case mix expected in practice to evaluate the performance of diagnostic criteria for families of unknown genotype. The diagnostic criteria currently in use performed suboptimally for individuals with mutations in PKD2 as a result of reduced test sensitivity. In families of unknown genotype, the presence of three or more (unilateral or bilateral) renal cysts is sufficient for establishing the diagnosis in individuals aged 15 to 39 y, two or more cysts in each kidney is sufficient for individuals aged 40 to 59 y, and four or more cysts in each kidney is required for individuals > or = 60 yr. Conversely, fewer than two renal cysts in at-risk individuals aged > or = 40 yr is sufficient to exclude the disease. These unified diagnostic criteria will be useful for testing individuals who are at risk for autosomal dominant polycystic kidney disease in the usual clinical setting in which molecular genotyping is seldom performed.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                TCRM
                tcriskman
                Therapeutics and Clinical Risk Management
                Dove
                1176-6336
                1178-203X
                26 August 2019
                2019
                : 15
                : 1041-1052
                Affiliations
                [1 ]Department of Medicine, Division of Nephrology, David Geffen School of Medicine , Los Angeles, CA, USA
                [2 ]Department of Medicine, Divison of Nephrology, University of Illinois at Chicago/Advocate Christ Medical Center, Section of Nephrology , Oak Lawn, IL, USA
                Author notes
                Correspondence: Edgar V LermaUniversity of Illinois at Chicago/Advocate Christ Medical Center , 4400 W 95th, Oak Lawn, IL60453, USATel +1 708 227 7305Email nephron0@gmail.com
                Article
                196244
                10.2147/TCRM.S196244
                6716585
                © 2019 Rastogi et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 2, Tables: 4, References: 91, Pages: 12
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