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      The effect of sodium/glucose cotransporter 2 (SGLT2) inhibition on the urinary proteome

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          Abstract

          Treatment with empagliflozin, an inhibitor of the sodium/glucose cotransporter 2 (SGLT2), is associated with slower progression of diabetic kidney disease. In this analysis, we explored the hypothesis that empagliflozin may have an impact on urinary peptides associated with chronic kidney disease (CKD). In this post-hoc, exploratory analysis, we investigated urine samples obtained from 40 patients with uncomplicated type 1 diabetes (T1D) before and after treatment with empagliflozin for 8 weeks to for significant post-therapy changes in urinary peptides. We further assessed the association of these changes with CKD in an independent cohort, and with a previously established urinary proteomic panel, termed CKD273. 107 individual peptides significantly changed after treatment. The majority of the empagliflozin-induced changes were in the direction of “CKD absent” when compare to patients with CKD and controls. A classifier consisting of these 107 peptides scored significantly different in controls, in comparison to CKD patients. However, empagliflozin did not impact the CKD273 classifier. Our data indicate that empagliflozin induces multiple significant changes in the urinary proteomic markers such as mucin and clusterin. The relationship between empagliflozin-induced proteomic changes and clinical outcomes merits further investigation.

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications.

            Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and natriuretic effects contributing to plasma volume contraction, and decreases in systolic and diastolic blood pressures by 4 to 6 and 1 to 2 mm Hg, respectively, which may underlie cardiovascular and kidney benefits. SGLT2 inhibition also is associated with an acute, dose-dependent reduction in estimated glomerular filtration rate by ≈5 mL·min(-1)·1.73 m(-2) and ≈30% to 40% reduction in albuminuria. These effects mirror preclinical observations suggesting that proximal tubular natriuresis activates renal tubuloglomerular feedback through increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction. On the basis of reduced glomerular filtration, glycosuric and weight loss effects are attenuated in patients with chronic kidney disease (estimated glomerular filtration rate 30% reductions in cardiovascular mortality, overall mortality, and heart failure hospitalizations associated with empagliflozin, even though, by design, the hemoglobin A1c difference between the randomized groups was marginal. Aside from an increased risk of mycotic genital infections, empagliflozin-treated patients had fewer serious adverse events, including a lower risk of acute kidney injury. In light of the EMPA-REG OUTCOME results, some diabetes clinical practice guidelines now recommend that SGLT2 inhibitors with proven cardiovascular benefit be prioritized in patients with type 2 diabetes mellitus who have not achieved glycemic targets and who have prevalent atherosclerotic cardiovascular disease. With additional cardiorenal protection trials underway, sodium-related physiological effects of SGLT2 inhibitors and clinical correlates of natriuresis, such as the impact on blood pressure, heart failure, kidney protection, and mortality, will be a major management focus.
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              Bile proteomic profiles differentiate cholangiocarcinoma from primary sclerosing cholangitis and choledocholithiasis.

              Early detection of malignant biliary tract diseases, especially cholangiocarcinoma (CC) in patients with primary sclerosing cholangitis (PSC), is very difficult and often comes too late to give the patient a therapeutic benefit. We hypothesize that bile proteomic analysis distinguishes CC from nonmalignant lesions. We used capillary electrophoresis mass spectrometry (CE-MS) to identify disease-specific peptide patterns in patients with choledocholithiasis (n = 16), PSC (n = 18), and CC (n = 16) in a training set. A model for differentiation of choledocholithiasis from PSC and CC (PSC/CC model) and another model distinguishing CC from PSC (CC model) were subsequently validated in independent cohorts (choledocholithiasis [n = 14], PSC [n = 18] and CC [n = 25]). Peptides were characterized by sequencing. Application of the PSC/CC model in the independent test cohort resulted in correct exclusion of 12/14 bile samples from patients with choledocholithiasis and identification of 40/43 patients with PSC or CC (86% specificity, 93% sensitivity). The corresponding receiver operating characteristic (ROC) analysis revealed an area under the curve (AUC) of 0.93 (95% confidence interval [CI]: 0.82-0.98, P = 0.0001). The CC model succeeded in an accurate detection of 14/18 bile samples from patients with PSC and 21/25 samples with CC (78% specificity, 84% sensitivity) in the independent cohort, resulting in an AUC value of 0.87 (95% CI: 0.73-0.95, P = 0.0001) in ROC analysis. Eight out of 10 samples of patients with CC complicating PSC were identified. Bile proteomic analysis discriminates benign conditions from CC accurately. This method may become a diagnostic tool in future as it offers a new possibility to diagnose malignant bile duct disease and thus enables efficient therapy particularly in patients with PSC. Copyright © 2011 American Association for the Study of Liver Diseases.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                30 October 2017
                2017
                : 12
                : 10
                : e0186910
                Affiliations
                [1 ] Division of Nephrology, University Health Network, University of Toronto, Toronto, Canada
                [2 ] Division of Endocrinology, University Health Network, University of Toronto, Toronto, Canada
                [3 ] Department of Clinical Pharmacology University Medical Center Groningen, Groningen, the Netherlands
                [4 ] Instituto de Investigación Sanitaria Fundación Jiménez Díaz. Fundación Renal Iñigo Álvarez de Toledo. Universidad Autónoma de Madrid. REDinREN, Madrid, Spain
                [5 ] Mosaiques diagnostics GmbH, Hanover, Germany
                [6 ] BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
                Icahn School of Medicine at Mount Sinai, UNITED STATES
                Author notes

                Competing Interests: DC has received consulting fees or speaking honorarium or both from Janssen, Boehringer Ingelheim-Eli Lilly, AstraZeneca, Merck, Sanofi, and his institution has received operating funding from Janssen, Boehringer Ingelheim-Eli Lilly, AstraZeneca, Merck. HM is the co-founder and co-owner of Mosaiques Diagnostics, and employed by Mosaiques Diagnostics. BAP has received fees for continuing medical education events from Janssen and Boehringer Ingelheim, has served as an advisor for Boehringer Ingelheim, and his research institute has received research grants on his behalf from Boehringer Ingelheim. All other authors have no conflict of interest to report. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0003-0323-0306
                Article
                PONE-D-17-20536
                10.1371/journal.pone.0186910
                5662219
                29084249
                f7893aff-61cb-44d6-a6bf-36450abceffc
                © 2017 Cherney 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
                : 31 May 2017
                : 14 September 2017
                Page count
                Figures: 3, Tables: 1, Pages: 12
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100011272, FP7 Health;
                Award ID: 603288
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100011272, FP7 Health;
                Award ID: 305507
                Award Recipient :
                DC has received consulting fees or speaking honorarium or both from Janssen, Boehringer Ingelheim-Eli Lilly, AstraZeneca, Merck, Sanofi, and his institution has received operating funding from Janssen, Boehringer Ingelheim-Eli Lilly, AstraZeneca, Merck. HM is the co-founder and co-owner of Mosaiques Diagnostics. BAP has received fees for continuing medical education events from Janssen and Boehringer Ingelheim, has served as an advisor for Boehringer Ingelheim, and his research institute has received research grants on his behalf from Boehringer Ingelheim. The funder provided support in the form of salaries for author HM, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.
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