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      The Association of Pioglitazone and Urinary Tract Disease in Type 2 Diabetic Taiwanese: Bladder Cancer and Chronic Kidney Disease

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          Abstract

          Objective

          Although studies have shown an association between pioglitazone and bladder cancer, the associated factors have not been identified. The aim of this study was to investigate the factors that may link pioglitazone to bladder cancer.

          Materials and Methods

          In total, 34,970 study subjects were identified from the National Health Insurance Research Database in 2003 with follow-up from 2005 to 2009. The demographic characteristics of patients who had used and had never used pioglitazone, including age, sex, diabetes duration, urinary tract disease, nephropathy, bladder cancer, and cumulative dose and duration of pioglitazone therapy, were analyzed using the χ2 test. Cox proportional hazard regression models were used to determine the independent effects of pioglitazone on bladder cancer and newly developed chronic kidney disease.

          Results

          Among 3,497 ever users and 31,473 never users of pioglitazone, the respective incident cases of bladder cancer were 12 (0.4%) and 72 (0.2%), and for newly developed chronic kidney disease 245 (8.1%) and 663 (2.3%), respectively. Ever use of pioglitazone [1.59(1.32–1.91)], cumulative dose of pioglitazone <10,500 mg [1.69 (1.37–2.01)] and >10,500 mg [1.34 (1.04–1.73)], and duration of therapy <12 months [1.68 (1.36–2.08)] and >12 months [1.39 (1.09–1.76)] were associated with the development of chronic kidney disease.

          Conclusions

          There was no association of pioglitazone use with bladder cancer development, however, there was an association with an increased risk of newly developed chronic kidney disease.

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          Most cited references32

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          The mechanisms of action of PPARs.

          The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPAR gamma, PPAR alpha, and PPAR delta, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors such that the rate of transcription initiation is increased. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Fatty acids and eicosanoids have been identified as natural ligands for the PPARs. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes. Use of such ligands has allowed researchers to unveil many potential roles for the PPARs in pathological states including atherosclerosis, inflammation, cancer, infertility, and demyelination. Here, we present the current state of knowledge regarding the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases.
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            Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial.

            The cardiovascular risk associated with early renal insufficiency is unknown. Clinicians are often reluctant to use angiotensin-converting enzyme inhibitors in patients with renal insufficiency. To determine whether mild renal insufficiency increases cardiovascular risk and whether ramipril decreases that risk. Post hoc analysis. The Heart Outcomes and Prevention Evaluation (HOPE) study, a randomized, double-blind, multinational trial involving 267 study centers. 980 patients with mild renal insufficiency (serum creatinine concentration >/= 124 micromol/L [>/=1.4 mg/dL]) and 8307 patients with normal renal function (serum creatinine concentration 0.2 for the difference). In patients who had preexisting vascular disease or diabetes combined with an additional cardiovascular risk factor, mild renal insufficiency significantly increased the risk for subsequent cardiovascular events. Ramipril reduced cardiovascular risk without increasing adverse effects.
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              Age changes in glomerular filtration rate, effective renal plasma flow, and tubular excretory capacity in adult males.

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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                10 January 2014
                : 9
                : 1
                : e85479
                Affiliations
                [1 ]Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan
                [2 ]Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
                [3 ]Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
                [4 ]Graduate Institute of Medical Genetics, Kaohsiung Medical University, Kaohsiung, Taiwan
                [5 ]Statistical Analysis Laboratory, Department of Clinical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
                National Taiwan University, Taiwan
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SJS MYL. Performed the experiments: MYL KDL. Analyzed the data: MYL SJS PJH YHY. Contributed reagents/materials/analysis tools: MYL KDL YHY. Wrote the paper: MYL.

                Article
                PONE-D-13-29404
                10.1371/journal.pone.0085479
                3888419
                24427312
                c4592f87-a8d5-427d-b38e-6950e0ed85fc
                Copyright @ 2014

                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
                : 17 July 2013
                : 28 November 2013
                Page count
                Pages: 8
                Funding
                This study was funded by the Department of Internal Medicine, Kaohsiung Medical University Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Mathematics
                Statistics
                Biostatistics
                Statistical Methods
                Medicine
                Drugs and Devices
                Endocrinology
                Diabetic Endocrinology
                Diabetes Mellitus Type 2
                Metabolic Disorders
                Nephrology
                Bladder and Ureteric Disorders
                Chronic Kidney Disease
                Non-Clinical Medicine
                Health Care Policy
                Health Risk Analysis
                Oncology
                Cancers and Neoplasms
                Genitourinary Tract Tumors
                Bladder Cancer
                Urology
                Bladder and Ureteric Disorders
                Bladder Cancer and Urothelial Neoplasias of the Urinary Tract
                Genitourinary Infections

                Uncategorized
                Uncategorized

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