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      Modeling the renoprotective mechanisms of SGLT2 inhibition in hypertensive chronic kidney disease

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          Abstract

          Sodium‐glucose cotransporter (SGLT)‐2 inhibitors have recently been approved for chronic kidney disease (CKD) based on their ability to lower proteinuria and slow CKD progression independent of diabetes status. In diabetic renal disease, modulation of tubuloglomerular feedback (TGF) leading to lower intraglomerular pressure has been postulated as one of the mechanisms of renal protection with SGLT2 inhibition; however, this mechanism has not been sufficiently explored in non‐diabetic CKD. We hypothesized that SGLT2 inhibition exerts renoprotection in CKD through increasing TGF despite normoglycemia. To test this hypothesis, we used an integrative mathematical model of human physiology, HumMod. Stage 3 CKD conditions were simulated by reducing nephron mass which was associated with hypertension, low glomerular filtration rate (GFR) (55 mL/min), hyperfiltration of remnant nephrons, elevated albuminuria (500 mg/day), and minimal levels of urinary glucose (0.02 mmol/L). SGLT2 inhibition was associated with acute reductions in GFR associated with afferent arteriolar vasoconstriction due to TGF. After 12 months, glomerular pressure, nephron damage, and chronic GFR decline were reduced with SGLT2 inhibition with additional SGLT1 inhibitory effects further enhancing these effects. This model supports the use of SGLT2 inhibitors to reduce hyperfiltration in CKD and mitigate renal disease progression, even in the absence of diabetes.

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          Dapagliflozin in Patients with Chronic Kidney Disease

          Patients with chronic kidney disease have a high risk of adverse kidney and cardiovascular outcomes. The effect of dapagliflozin in patients with chronic kidney disease, with or without type 2 diabetes, is not known.
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            Chronic kidney disease: global dimension and perspectives.

            Chronic kidney disease is defined as a reduced glomerular filtration rate, increased urinary albumin excretion, or both, and is an increasing public health issue. Prevalence is estimated to be 8-16% worldwide. Complications include increased all-cause and cardiovascular mortality, kidney-disease progression, acute kidney injury, cognitive decline, anaemia, mineral and bone disorders, and fractures. Worldwide, diabetes mellitus is the most common cause of chronic kidney disease, but in some regions other causes, such as herbal and environmental toxins, are more common. The poorest populations are at the highest risk. Screening and intervention can prevent chronic kidney disease, and where management strategies have been implemented the incidence of end-stage kidney disease has been reduced. Awareness of the disorder, however, remains low in many communities and among many physicians. Strategies to reduce burden and costs related to chronic kidney disease need to be included in national programmes for non-communicable diseases. Copyright © 2013 Elsevier Ltd. All rights reserved.
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              Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease

              The efficacy and safety of sodium-glucose cotransporter 2 inhibitors such as sotagliflozin in preventing cardiovascular events in patients with diabetes with chronic kidney disease with or without albuminuria have not been well studied.
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                Author and article information

                Contributors
                jclemmer@umc.edu
                Journal
                Physiol Rep
                Physiol Rep
                10.1002/(ISSN)2051-817X
                PHY2
                physreports
                Physiological Reports
                John Wiley and Sons Inc. (Hoboken )
                2051-817X
                13 November 2023
                November 2023
                : 11
                : 21 ( doiID: 10.1002/phy2.v11.21 )
                : e15836
                Affiliations
                [ 1 ] Department of Physiology and Biophysics University of Mississippi Medical Center Jackson Mississippi USA
                [ 2 ] Department of Medicine, Division of Nephrology University of Mississippi Medical Center Jackson Mississippi USA
                Author notes
                [*] [* ] Correspondence

                John S. Clemmer, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216‐4505, USA.

                Email: jclemmer@ 123456umc.edu

                Author information
                https://orcid.org/0000-0003-2250-2960
                Article
                PHY215836 PHYSREP-2023-07-267-T
                10.14814/phy2.15836
                10643202
                37957121
                889d9bda-6b1e-4988-b179-2bcbeebe95d9
                © 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 20 September 2023
                : 01 August 2023
                : 21 September 2023
                Page count
                Figures: 8, Tables: 1, Pages: 12, Words: 6416
                Funding
                Funded by: HHS | NIH | National Institute of General Medical Sciences (NIGMS) , doi 10.13039/100000057;
                Award ID: U54 GM115428
                Award ID: P20 GM104357
                Award ID: P30 GM149404
                Funded by: HHS | NIH | National Institute on Minority Health and Health Disparities (NIMHD) , doi 10.13039/100006545;
                Award ID: R00 MD014738
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                November 2023
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.3.4 mode:remove_FC converted:13.11.2023

                chronic kidney disease,physiological modeling,sglt2 inhibitor

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