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Kugathasan L, Sridhar VS, Tommerdahl KL, Xu C, Bjornstad P, Advani A, Cherney DZI. Minireview: Understanding and targeting inflammatory, hemodynamic and injury markers for cardiorenal protection in type 1 diabetes. Metabolism 2024; 153:155785. [PMID: 38215965 DOI: 10.1016/j.metabol.2024.155785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 12/16/2023] [Accepted: 01/03/2024] [Indexed: 01/14/2024]
Abstract
The coexistence of cardiovascular disease (CVD) and diabetic kidney disease (DKD) is common in people with type 1 diabetes (T1D) and is strongly associated with an increased risk of morbidity and mortality. Hence, it is imperative to explore robust tools that can accurately reflect the development and progression of cardiorenal complications. Several cardiovascular and kidney biomarkers have been identified to detect at-risk individuals with T1D. The primary aim of this review is to highlight biomarkers of injury, inflammation, or renal hemodynamic changes that may influence T1D susceptibility to CVD and DKD. We will also examine the impact of approved pharmacotherapies for type 2 diabetes, including renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) on candidate biomarkers for cardiorenal complications in people with T1D and discuss how these changes may potentially mediate kidney and cardiovascular protection. Identifying predictive and prognostic biomarkers for DKD and CVD may highlight potential drug targets to attenuate cardiorenal disease progression, implement novel risk stratification measures in clinical trials, and improve the assessment, diagnosis, and treatment of at-risk individuals with T1D.
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Affiliation(s)
- Luxcia Kugathasan
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Cardiovascular Sciences Collaborative Specialization, University of Toronto, Toronto, Canada
| | - Vikas S Sridhar
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Kalie L Tommerdahl
- Section of Endocrinology, Department of Pediatrics, University of Colorado, Aurora, CO, USA; Barbara Davis Center for Diabetes, Aurora, CO, USA
| | - Cheng Xu
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada
| | - Petter Bjornstad
- Section of Endocrinology, Department of Pediatrics, University of Colorado, Aurora, CO, USA; Division of Nephrology, Department of Medicine, University of Colorado, Aurora, CO, USA
| | - Andrew Advani
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Cardiovascular Sciences Collaborative Specialization, University of Toronto, Toronto, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
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Wang N, Zhang C. Recent Advances in the Management of Diabetic Kidney Disease: Slowing Progression. Int J Mol Sci 2024; 25:3086. [PMID: 38542060 PMCID: PMC10970506 DOI: 10.3390/ijms25063086] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 02/28/2024] [Accepted: 03/05/2024] [Indexed: 01/03/2025] Open
Abstract
Diabetic kidney disease (DKD) is a major cause of chronic kidney disease (CKD), and it heightens the risk of cardiovascular incidents. The pathogenesis of DKD is thought to involve hemodynamic, inflammatory, and metabolic factors that converge on the fibrotic pathway. Genetic predisposition and unhealthy lifestyle practices both play a significant role in the development and progression of DKD. In spite of the recent emergence of angiotensin receptors blockers (ARBs)/angiotensin converting enzyme inhibitor (ACEI), sodium-glucose cotransporter 2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid receptors antagonists (NS-MRAs), current therapies still fail to effectively arrest the progression of DKD. Glucagon-like peptide 1 receptor agonists (GLP-1RAs), a promising class of agents, possess the potential to act as renal protectors, effectively slowing the progression of DKD. Other agents, including pentoxifylline (PTF), selonsertib, and baricitinib hold great promise as potential therapies for DKD due to their anti-inflammatory and antifibrotic properties. Multidisciplinary treatment, encompassing lifestyle modifications and drug therapy, can effectively decelerate the progression of DKD. Based on the treatment of heart failure, it is recommended to use multiple drugs in combination rather than a single-use drug for the treatment of DKD. Unearthing the mechanisms underlying DKD is urgent to optimize the management of DKD. Inflammatory and fibrotic factors (including IL-1, MCP-1, MMP-9, CTGF, TNF-a and TGF-β1), along with lncRNAs, not only serve as diagnostic biomarkers, but also hold promise as therapeutic targets. In this review, we delve into the potential mechanisms and the current therapies of DKD. We also explore the additional value of combing these therapies to develop novel treatment strategies. Drawing from the current understanding of DKD pathogenesis, we propose HIF inhibitors, AGE inhibitors, and epigenetic modifications as promising therapeutic targets for the future.
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Affiliation(s)
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;
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3
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Adebayo OC, Nkoy AB, van den Heuvel LP, Labarque V, Levtchenko E, Delanaye P, Pottel H. Glomerular hyperfiltration: part 2-clinical significance in children. Pediatr Nephrol 2023; 38:2529-2547. [PMID: 36472656 DOI: 10.1007/s00467-022-05826-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 10/27/2022] [Accepted: 11/10/2022] [Indexed: 12/12/2022]
Abstract
Glomerular hyperfiltration (GHF) is a phenomenon that can occur in various clinical conditions affecting the kidneys such as sickle cell disease, diabetes mellitus, autosomal dominant polycystic kidney disease, and solitary functioning kidney. Yet, the pathophysiological mechanisms vary from one disease to another and are not well understood. More so, it has been demonstrated that GHF may occur at the single-nephron in some clinical conditions while in others at the whole-kidney level. In this review, we explore the pathophysiological mechanisms of GHF in relation to various clinical conditions in the pediatric population. In addition, we discuss the role and mechanism of action of important factors such as gender, low birth weight, and race in the pathogenesis of GHF. Finally, in this current review, we further highlight the consequences of GHF in the progression of kidney disease.
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Affiliation(s)
- Oyindamola C Adebayo
- Center of Vascular and Molecular Biology, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Campus Gasthiusberg, 3000 Leuven, Belgium
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, Katholieke Universiteit Leuven, Campus Gasthiusberg, 3000 Leuven, Belgium
| | - Agathe B Nkoy
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, Katholieke Universiteit Leuven, Campus Gasthiusberg, 3000 Leuven, Belgium
- Division of Nephrology, Department of Pediatrics, Faculty of Medicine, University Hospital of Kinshasa, University of Kinshasa, Kinshasa, Democratic Republic of Congo
| | - Lambertus P van den Heuvel
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, Katholieke Universiteit Leuven, Campus Gasthiusberg, 3000 Leuven, Belgium
- Department of Pediatric Nephrology, Radboud University Medical Centre, 6500 Nijmegen, The Netherlands
| | - Veerle Labarque
- Center of Vascular and Molecular Biology, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Campus Gasthiusberg, 3000 Leuven, Belgium
- Department of Pediatric Hematology, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Elena Levtchenko
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, Katholieke Universiteit Leuven, Campus Gasthiusberg, 3000 Leuven, Belgium
- Department of Pediatric Nephrology, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Pierre Delanaye
- Department of Nephrology-Dialysis-Transplantation, University of Liège, CHU Sart Tilman, Liège, Belgium
- Department of Nephrology-Dialysis-Apheresis, Hôpital Universitaire Carémeau, Nîmes, France
| | - Hans Pottel
- Department of Public Health and Primary Care, Katholieke Universiteit Leuven, Campus Kulak, 8500 Kortrijk, Belgium.
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4
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Abdollahi E, Johnston TP, Ghaneifar Z, Vahedi P, Goleij P, Azhdari S, Moghaddam AS. Immunomodulatory Therapeutic Effects of Curcumin on M1/M2 Macrophage Polarization in Inflammatory Diseases. Curr Mol Pharmacol 2023; 16:2-14. [PMID: 35331128 DOI: 10.2174/1874467215666220324114624] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 07/02/2021] [Accepted: 08/16/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Due to their plasticity, macrophages exert critical effects on both promoting and suppressing inflammatory processes. Pathologic inflammatory conditions are frequently correlated with dynamic alterations in macrophage activation, with classically activated M1 cells associated with the promotion and maintenance of inflammation and M2 cells being linked to the resolution or smouldering of chronic inflammation. Inflammation deputes a common feature of various chronic diseases and the direct involvement in the insurgence and development of these conditions. Macrophages participate in an autoregulatory loop characterizing the inflammatory process, as they produce a wide range of biologically active mediators that exert either deleterious or beneficial effects during the inflammation. Therefore, balancing the favorable ratios of M1/M2 macrophages can help ameliorate the inflammatory landscape of pathologic conditions. Curcumin is a component of turmeric with many pharmacological properties. OBJECTIVE Recent results from both in-vivo and in-vitro studies have indicated that curcumin can affect polarization and/or functions of macrophage subsets in the context of inflammation-related diseases. There is no comprehensive review of the impact of curcumin on cytokines involved in macrophage polarization in the context of inflammatory diseases. The present review will cover some efforts to explore the underlying molecular mechanisms by which curcumin modulates the macrophage polarization in distant pathological inflammatory conditions, such as cancer, autoimmunity, renal inflammation, stroke, atherosclerosis, and macrophage-driven pathogenesis. RESULTS The accumulation of the findings from in vitro and in vivo experimental studies suggests that curcumin beneficially influences M1 and M2 macrophages in a variety of inflammatory diseases with unfavorable macrophage activation. CONCLUSION Curcumin not only enhances anti-tumor immunity (via shifting M polarization towards M1 phenotype and/or up-regulation of M1 markers expression) but ameliorates inflammatory diseases, including autoimmune diseases (experimental autoimmune myocarditis and Behcet's disease), nephropathy, chronic serum sickness, stroke, and atherosclerosis.
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Affiliation(s)
- Elham Abdollahi
- Department of Gynecology, Woman Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Immunology and Allergy, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Thomas P Johnston
- Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Missouri, USA
| | - Zahra Ghaneifar
- Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parviz Vahedi
- Department of Anatomical Sciences, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Pouya Goleij
- Department of Genetics, Faculty of Biology, Sana Institute of Higher Education, Sari, Iran
| | - Sara Azhdari
- Department of Anatomy and Embryology, School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | - Abbas Shapouri Moghaddam
- Department of Immunology, Bu-Ali Research Institute, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Afangbedji N, Jerebtsova M. Glomerular filtration rate abnormalities in sickle cell disease. Front Med (Lausanne) 2022; 9:1029224. [PMID: 36341242 PMCID: PMC9633850 DOI: 10.3389/fmed.2022.1029224] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 10/04/2022] [Indexed: 12/03/2022] Open
Abstract
Sickle cell disease (SCD) is a group of inherited blood disorders affecting the β-globin gene, resulting in the polymerization of hemoglobin and subsequent sickling of the red blood cell. Renal disease, the most common complication in SCD, begins in childhood with glomerular hyperfiltration and then progresses into albuminuria, a fast decline of glomerular filtration, and renal failure in adults. This mini-review focuses on glomerular filtration abnormalities and the mechanisms of hyperfiltration, explores genetic modifiers and methods of estimating glomerular filtration rates, and examines novel biomarkers of glomerular filtration in SCD.
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Affiliation(s)
- Nowah Afangbedji
- Department of Physiology and Biophysics, Howard University, Washington, DC, United States
| | - Marina Jerebtsova
- Department of Microbiology, Howard University, Washington, DC, United States
- *Correspondence: Marina Jerebtsova,
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Lytvyn Y, Kimura K, Peter N, Lai V, Tse J, Cham L, Perkins BA, Soleymanlou N, Cherney DZ. Renal and Vascular Effects of Combined SGLT2 and Angiotensin-Converting Enzyme Inhibition. Circulation 2022; 146:450-462. [PMID: 35862082 PMCID: PMC9354594 DOI: 10.1161/circulationaha.122.059150] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The cardiorenal effects of sodium-glucose cotransporter 2 inhibition (empagliflozin 25 mg QD) combined with angiotensin-converting enzyme inhibition (ramipril 10 mg QD) were assessed in this mechanistic study in patients with type 1 diabetes with potential renal hyperfiltration. METHODS Thirty patients (out of 31 randomized) completed this double-blind, placebo-controlled, crossover trial. Recruitment was stopped early because of an unexpectedly low proportion of patients with hyperfiltration. Measurements were obtained after each of the 6 treatment phases over 19 weeks: (1) baseline without treatment, (2) 4-week run-in with ramipril treatment alone, (3) 4-week combined empagliflozin-ramipril treatment, (4) a 4-week washout, (5) 4-week combined placebo-ramipril treatment, and (6) 1-week follow-up. The primary end point was glomerular filtration rate (GFR) after combination treatment with empagliflozin-ramipril compared with placebo-ramipril. GFR was corrected for ramipril treatment alone before randomization. At the end of study phase, the following outcomes were measured under clamped euglycemia (4 to 6 mmol/L): inulin (GFR) and para-aminohippurate (effective renal plasma flow) clearances, tubular sodium handling, ambulatory blood pressure, arterial stiffness, heart rate variability, noninvasive cardiac output monitoring, plasma and urine biochemistry, markers of the renin-angiotensin-aldosterone system, and oxidative stress. RESULTS Combination treatment with empagliflozin-ramipril resulted in an 8 mL/min/1.73 m2 lower GFR compared with placebo-ramipril treatment (P=0.0061) without significant changes to effective renal plasma flow. GFR decrease was accompanied by a 21.3 mL/min lower absolute proximal fluid reabsorption rate (P=0.0092), a 3.1 mmol/min lower absolute proximal sodium reabsorption rate (P=0.0056), and a 194 ng/mmol creatinine lower urinary 8-isoprostane level (P=0.0084) relative to placebo-ramipril combination treatment. Sodium-glucose cotransporter 2 inhibitor/angiotensin-converting enzyme inhibitor combination treatment resulted in additive blood pressure-lowering effects (clinic systolic blood pressure lower by 4 mm Hg [P=0.0112]; diastolic blood pressure lower by 3 mm Hg [P=0.0032]) in conjunction with a 94.5 dynes × sex/cm5 lower total peripheral resistance (P=0.0368). There were no significant changes observed to ambulatory blood pressure, arterial stiffness, heart rate variability, or cardiac output with the addition of empagliflozin. CONCLUSIONS Adding sodium-glucose cotransporter 2 inhibitor treatment to angiotensin-converting enzyme inhibitor resulted in an expected GFR dip, suppression of oxidative stress markers, additive declines in blood pressure and total peripheral resistance. These changes are consistent with a protective physiologic profile characterized by the lowering of intraglomerular pressure and related cardiorenal risk when adding a sodium-glucose cotransporter 2 inhibitor to conservative therapy. REGISTRATION URL: https://www. CLINICALTRIALS gov; Unique identifier: NCT02632747.
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Affiliation(s)
- Yuliya Lytvyn
- Department of Medicine, Division of Nephrology, Toronto General Hospital (Y.L., V.L., J.T., L.C., D.Z.I.C.),Temerty Faculty of Medicine (Y.L.)
| | - Karen Kimura
- Boehringer Ingelheim Canada Ltd/Ltée, Burlington (K.K.)
| | | | - Vesta Lai
- Department of Medicine, Division of Nephrology, Toronto General Hospital (Y.L., V.L., J.T., L.C., D.Z.I.C.)
| | - Josephine Tse
- Department of Medicine, Division of Nephrology, Toronto General Hospital (Y.L., V.L., J.T., L.C., D.Z.I.C.)
| | - Leslie Cham
- Department of Medicine, Division of Nephrology, Toronto General Hospital (Y.L., V.L., J.T., L.C., D.Z.I.C.)
| | - Bruce A. Perkins
- Department of Medicine, Division of Endocrinology and Metabolism, Mount Sinai Hospital, University of Toronto, Canada (B.A.P.)
| | | | - David Z.I. Cherney
- Department of Medicine, Division of Nephrology, Toronto General Hospital (Y.L., V.L., J.T., L.C., D.Z.I.C.)
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7
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Abstract
Circulating blood is filtered across the glomerular barrier to form an ultrafiltrate of plasma in the Bowman's space. The volume of glomerular filtration adjusted by time is defined as the glomerular filtration rate (GFR), and the total GFR is the sum of all single-nephron GFRs. Thus, when the single-nephron GFR is increased in the context of a normal number of functioning nephrons, single glomerular hyperfiltration results in 'absolute' hyperfiltration in the kidney. 'Absolute' hyperfiltration can occur in healthy people after high protein intake, during pregnancy and in patients with diabetes, obesity or autosomal-dominant polycystic kidney disease. When the number of functioning nephrons is reduced, single-nephron glomerular hyperfiltration can result in a GFR that is within or below the normal range. This 'relative' hyperfiltration can occur in patients with a congenitally reduced nephron number or with an acquired reduction in nephron mass consequent to surgery or kidney disease. Improved understanding of the mechanisms that underlie 'absolute' and 'relative' glomerular hyperfiltration in different clinical settings, and of whether and how the single-nephron haemodynamic and related biomechanical forces that underlie glomerular hyperfiltration promote glomerular injury, will pave the way toward the development of novel therapeutic interventions that attenuate glomerular hyperfiltration and potentially prevent or limit consequent progressive kidney injury and loss of function.
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8
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Barnett AM, Babcock MC, Watso JC, Migdal KU, Gutiérrez OM, Farquhar WB, Robinson AT. High dietary salt intake increases urinary NGAL excretion and creatinine clearance in healthy young adults. Am J Physiol Renal Physiol 2022; 322:F392-F402. [PMID: 35157527 PMCID: PMC8934673 DOI: 10.1152/ajprenal.00240.2021] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 02/02/2022] [Accepted: 02/11/2022] [Indexed: 11/22/2022] Open
Abstract
In rodents and older patients with elevated blood pressure (BP), high dietary sodium increases excretion of biomarkers of kidney injury, but it is unclear whether this effect occurs in healthy young adults. The purpose of this study was to determine whether short-term high dietary salt increases urinary excretion of the kidney injury biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) in healthy young adults. Twenty participants participated in a double-blind, placebo-controlled, randomized crossover study. For 10 days each, participants were asked to consume salt (3,900 mg sodium) or placebo capsules. We measured BP during each visit, obtained 24-h urine samples for measurements of electrolytes, NGAL, and KIM-1, and assessed creatinine clearance. Compared with placebo, salt loading increased daily urinary sodium excretion (placebo: 130.3 ± 62.4 mmol/24 h vs. salt: 287.2 ± 72.0 mmol/24 h, P < 0.01). There was no difference in mean arterial BP (placebo: 77 ± 7 mmHg vs. salt: 77 ± 6 mmHg, P = 0.83) between conditions. However, salt loading increased the urinary NGAL excretion rate (placebo: 59.8 ± 44.4 ng/min vs. salt: 80.8 ± 49.5 ng/min, P < 0.01) and increased creatinine clearance (placebo: 110.5 ± 32.9 mL/min vs. salt: 145.0 ± 24.9 mL/min, P < 0.01). Urinary KIM-1 excretion was not different between conditions. In conclusion, in healthy young adults 10 days of dietary salt loading increased creatinine clearance and increased urinary excretion of the kidney injury biomarker marker NGAL but not KIM-1.NEW & NOTEWORTHY In healthy young adults, 10 days of dietary salt loading increased creatinine clearance and increased urinary excretion of the kidney injury biomarker marker neutrophil gelatinase-associated lipocalin despite no change in resting blood pressure.
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Affiliation(s)
- Alex M Barnett
- Neurovascular Physiology Laboratory, School of Kinesiology, Auburn University, Auburn, Alabama
| | - Matthew C Babcock
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, Delaware
- Division of Geriatric Medicine, University of Colorado-Anschutz Medical Campus, Aurora, Colorado
| | - Joseph C Watso
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, Delaware
- Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Kamila U Migdal
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, Delaware
- War Related Illness and Injury Study Center, Washington DC Department of Veteran Affairs Medical Center, Washington, District of Columbia
| | - Orlando M Gutiérrez
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - William B Farquhar
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, Delaware
| | - Austin T Robinson
- Neurovascular Physiology Laboratory, School of Kinesiology, Auburn University, Auburn, Alabama
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9
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Park S, Lee S, Kim Y, Cho S, Huh H, Kim K, Kim YC, Han SS, Lee H, Lee JP, Joo KW, Lim CS, Kim YS, Kim DK. Nonlinear causal effects of estimated glomerular filtration rate on myocardial infarction risks: Mendelian randomization study. BMC Med 2022; 20:44. [PMID: 35109828 PMCID: PMC8811984 DOI: 10.1186/s12916-022-02251-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 01/11/2022] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Previous observational studies suggested that a reduction in estimated glomerular filtration rate (eGFR) or a supranormal eGFR value was associated with adverse cardiovascular risks. However, a previous Mendelian randomization (MR) study under the linearity assumption reported null causal effects from eGFR on myocardial infarction (MI) risks. Further investigation of the nonlinear causal effect of kidney function assessed by eGFR on the risk of MI by nonlinear MR analysis is warranted. METHODS In this MR study, genetic instruments for log-eGFR based on serum creatinine were developed from European samples included in the CKDGen genome-wide association study (GWAS) meta-analysis (N=567,460). Alternate instruments for log-eGFR based on cystatin C were developed from a GWAS of European individuals that included the CKDGen and UK Biobank data (N=460,826). Nonlinear MR analysis for the risk of MI was performed using the fractional polynomial method and the piecewise linear method on data from individuals of white British ancestry in the UK Biobank (N=321,024, with 12,205 MI cases). RESULTS Nonlinear MR analysis demonstrated a U-shaped (quadratic P value < 0.001) association between MI risk and genetically predicted eGFR (creatinine) values, as MI risk increased as eGFR declined in the low eGFR range and the risk increased as eGFR increased in the high eGFR range. The results were similar even after adjustment for clinical covariates, such as blood pressure, diabetes mellitus, dyslipidemia, or urine microalbumin levels, or when genetically predicted eGFR (cystatin C) was included as the exposure. CONCLUSION Genetically predicted eGFR is significantly associated with the risk of MI with a parabolic shape, suggesting that kidney function impairment, either by reduced or supranormal eGFR, may be causally linked to a higher MI risk.
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Affiliation(s)
- Sehoon Park
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.,Department of Internal Medicine, Armed Forces Capital Hospital, Gyeonggi-do, South Korea
| | - Soojin Lee
- Department of Internal Medicine, Uijeongbu Eulji University Medical Center, Seoul, South Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Yaerim Kim
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea
| | - Semin Cho
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Hyeok Huh
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Kwangsoo Kim
- Transdisciplinary Department of Medicine & Advanced Technology, Seoul National University Hospital, Seoul, South Korea
| | - Yong Chul Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Seung Seok Han
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.,Kidney Research Institute, Seoul National University, Seoul, South Korea
| | - Hajeong Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Jung Pyo Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Kidney Research Institute, Seoul National University, Seoul, South Korea.,Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, South Korea
| | - Kwon Wook Joo
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.,Kidney Research Institute, Seoul National University, Seoul, South Korea
| | - Chun Soo Lim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Kidney Research Institute, Seoul National University, Seoul, South Korea.,Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, South Korea
| | - Yon Su Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.,Kidney Research Institute, Seoul National University, Seoul, South Korea
| | - Dong Ki Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea. .,Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. .,Kidney Research Institute, Seoul National University, Seoul, South Korea.
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10
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Banerjee D, Winocour P, Chowdhury TA, De P, Wahba M, Montero R, Fogarty D, Frankel AH, Karalliedde J, Mark PB, Patel DC, Pokrajac A, Sharif A, Zac-Varghese S, Bain S, Dasgupta I. Management of hypertension and renin-angiotensin-aldosterone system blockade in adults with diabetic kidney disease: Association of British Clinical Diabetologists and the Renal Association UK guideline update 2021. BMC Nephrol 2022; 23:9. [PMID: 34979961 PMCID: PMC8722287 DOI: 10.1186/s12882-021-02587-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 10/28/2021] [Indexed: 12/31/2022] Open
Abstract
People with type 1 and type 2 diabetes are at risk of developing progressive chronic kidney disease (CKD) and end-stage kidney failure. Hypertension is a major, reversible risk factor in people with diabetes for development of albuminuria, impaired kidney function, end-stage kidney disease and cardiovascular disease. Blood pressure control has been shown to be beneficial in people with diabetes in slowing progression of kidney disease and reducing cardiovascular events. However, randomised controlled trial evidence differs in type 1 and type 2 diabetes and different stages of CKD in terms of target blood pressure. Activation of the renin-angiotensin-aldosterone system (RAAS) is an important mechanism for the development and progression of CKD and cardiovascular disease. Randomised trials demonstrate that RAAS blockade is effective in preventing/ slowing progression of CKD and reducing cardiovascular events in people with type 1 and type 2 diabetes, albeit differently according to the stage of CKD. Emerging therapy with sodium glucose cotransporter-2 (SGLT-2) inhibitors, non-steroidal selective mineralocorticoid antagonists and endothelin-A receptor antagonists have been shown in randomised trials to lower blood pressure and further reduce the risk of progression of CKD and cardiovascular disease in people with type 2 diabetes. This guideline reviews the current evidence and makes recommendations about blood pressure control and the use of RAAS-blocking agents in different stages of CKD in people with both type 1 and type 2 diabetes.
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Affiliation(s)
- D Banerjee
- St George's Hospitals NHS Foundation Trust, London, UK
| | - P Winocour
- ENHIDE, East and North Herts NHS Trust, Stevenage, UK
| | | | - P De
- City Hospital, Birmingham, UK
| | - M Wahba
- St Helier Hospital, Carshalton, UK
| | | | - D Fogarty
- Belfast Health and Social Care Trust, Belfast, UK
| | - A H Frankel
- Imperial College Healthcare NHS Trust, London, UK
| | | | - P B Mark
- University of Glasgow, Glasgow, UK
| | - D C Patel
- Royal Free London NHS Foundation Trust, London, UK
| | - A Pokrajac
- West Hertfordshire Hospitals, London, UK
| | - A Sharif
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | | | - S Bain
- Swansea University, Swansea, UK
| | - I Dasgupta
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
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11
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Yang Y, Xu G. Update on Pathogenesis of Glomerular Hyperfiltration in Early Diabetic Kidney Disease. Front Endocrinol (Lausanne) 2022; 13:872918. [PMID: 35663316 PMCID: PMC9161673 DOI: 10.3389/fendo.2022.872918] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
In the existing stages of diabetic kidney disease (DKD), the first stage of DKD is called the preclinical stage, characterized by glomerular hyperfiltration, an abnormally elevated glomerular filtration rate. Glomerular hyperfiltration is an independent risk factor for accelerated deterioration of renal function and progression of nephropathy, which is associated with a high risk for metabolic and cardiovascular disease. It is imperative to understand hyperfiltration and identify potential treatments to delay DKD progress. This paper summarizes the current mechanisms of hyperfiltration in early DKD. We pay close attention to the effect of glucose reabsorption mediated by sodium-glucose cotransporters and renal growth on hyperfiltration in DKD patients, as well as the mechanisms of nitric oxide and adenosine actions on renal afferent arterioles via tubuloglomerular feedback. Furthermore, we also focus on the contribution of the atrial natriuretic peptide, cyclooxygenase, renin-angiotensin-aldosterone system, and endothelin on hyperfiltration. Proposing potential treatments based on these mechanisms may offer new therapeutic opportunities to reduce the renal burden in this population.
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12
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Chang HC, Huang CJ, Yang AC, Cheng HM, Chuang SY, Yu WC, Chiang CE, Chen CH, Sung SH. Role of Heart Rate Variability in Association Between Glomerular Hyperfiltration and All-Cause Mortality. J Am Heart Assoc 2021; 10:e021585. [PMID: 34889105 PMCID: PMC9075221 DOI: 10.1161/jaha.121.021585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background Glomerular hyperfiltration (GHF) is paradoxically associated with increased cardiovascular events in healthy individuals, but the pathogenesis remains unclear. We aim to investigate whether GHF is associated with mortality and whether decreased heart rate variability (HRV) is associated with GHF. Methods and Results We retrospectively analyzed 1615 participants (aged 66.1±17.3 years, 61.9% men) without prior cardiovascular events. The glomerular filtration rate was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. GHF was defined as glomerular filtration rate >the 95th percentile after stratification for age and sex, whereas normal filtration was defined as the 25th to 75th percentiles. HRV indexes, including time domain, frequency domain, and sample entropy, were measured using 24‐hour ambulatory electrocardiography. Clinical outcomes were defined as all‐cause mortality at 2 years. During a mean follow‐up of 16.5±8.2 months, there were 117 deaths (7.2%). GHF was associated with a higher risk of death (hazard ratio and 95% CIs, 1.97 [1.15–3.37]). Reduced HRV indexes, including time domain, frequency domain, and sample entropy (odds ratio and 95% CIs, 0.79 [0.70–0.89]) were all independently associated with the presence of GHF after accounting for age, sex, mean heart rate, morbidities, and medications. In subgroup analysis, reduced HRV was more predictive of GHF in the young than the elderly. Mediation analysis revealed a significant mediation effect between HRV and GHF in addition to their respective detrimental effects on survival. Conclusions Reduced HRV was independently associated with the presence of GHF. Autonomic dysfunction may be involved in the pathogenesis of adverse outcomes of GHF in individuals without prior cardiovascular events.
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Affiliation(s)
- Hao-Chih Chang
- Division of Cardiology Department of Medicine Taipei Veterans General Hospital Taipei Taiwan.,Department of Medicine Taipei Veterans General Hospital Yuanshan and Suao Branch Yilan Taiwan.,Cardiovascular Research Center National Yang Ming Chiao Tung University Taipei Taiwan
| | - Chi-Jung Huang
- Center for Evidence-based Medicine Taipei Veterans General Hospital Taipei Taiwan
| | - Albert C Yang
- Digital Medicine Center and Institute of Brain Science National Yang Ming Chiao Tung University Taipei Taiwan
| | - Hao-Min Cheng
- Cardiovascular Research Center National Yang Ming Chiao Tung University Taipei Taiwan.,Center for Evidence-based Medicine Taipei Veterans General Hospital Taipei Taiwan.,Department of Medical Education Taipei Veterans General Hospital Taipei Taiwan
| | - Shao-Yuan Chuang
- Institute of Population Health Science National Health Research Institutes Miaoli Taiwan
| | - Wen-Chung Yu
- Division of Cardiology Department of Medicine Taipei Veterans General Hospital Taipei Taiwan.,Cardiovascular Research Center National Yang Ming Chiao Tung University Taipei Taiwan
| | - Chern-En Chiang
- Department of Internal Medicine National Yang Ming Chiao Tung University College of Medicine Taipei Taiwan.,General Clinical Research Center Taipei Veterans General Hospital Taipei Taiwan
| | - Chen-Huan Chen
- Cardiovascular Research Center National Yang Ming Chiao Tung University Taipei Taiwan.,Department of Internal Medicine National Yang Ming Chiao Tung University College of Medicine Taipei Taiwan.,Institute of Public Health National Yang Ming Chiao Tung University College of Medicine Taipei Taiwan.,Department of Medical Education Taipei Veterans General Hospital Taipei Taiwan
| | - Shih-Hsien Sung
- Division of Cardiology Department of Medicine Taipei Veterans General Hospital Taipei Taiwan.,Cardiovascular Research Center National Yang Ming Chiao Tung University Taipei Taiwan.,Department of Internal Medicine National Yang Ming Chiao Tung University College of Medicine Taipei Taiwan.,Institute of Public Health National Yang Ming Chiao Tung University College of Medicine Taipei Taiwan
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13
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Cherney DZ, Udell JA, Drucker DJ. Cardiorenal mechanisms of action of glucagon-like-peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors. MED 2021; 2:1203-1230. [DOI: 10.1016/j.medj.2021.10.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/14/2021] [Accepted: 10/05/2021] [Indexed: 12/14/2022]
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14
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DeFronzo RA, Abdul-Ghani M. Sodium-Glucose Cotransporter 2 Inhibitors and the Kidney. Diabetes Spectr 2021; 34:225-234. [PMID: 34511848 PMCID: PMC8387612 DOI: 10.2337/ds20-0071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Diabetic kidney disease (DKD) accounts for about half of individuals entering end-stage renal disease programs. Patients with DKD frequently have associated microvascular complications and are at very high risk for developing macrovascular complications. Comprehensive treatment involves slowing or preventing the decline in glomerular filtration rate (GFR) and preventing macrovascular and further microvascular complications. Maintaining an A1C <6.5% represents primary prevention; in established DKD, tight blood pressure control is essential. ACE inhibitors/angiotensin receptor blockers (ARBs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors can be used in combination to slow the rate of decline in GFR. This article reviews the general approach to DKD treatment and summarizes renal outcomes in four cardiovascular outcomes trials of SGLT2 inhibitors. Together, these trials provide conclusive evidence that SGLT2 inhibitors, added to an ACE inhibitor or ARB, slow the progression of DKD.
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Samadi-Noshahr Z, Ebrahimzadeh-Bideskan A, Hadjzadeh MAR, Shafei MN, Salmani H, Hosseinian S, Khajavi-Rad A. trans-Anethole attenuated renal injury and reduced expressions of angiotensin II receptor (AT1R) and TGF-β in streptozotocin-induced diabetic rats. Biochimie 2021; 185:117-127. [PMID: 33771655 DOI: 10.1016/j.biochi.2021.03.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 03/15/2021] [Accepted: 03/16/2021] [Indexed: 12/25/2022]
Abstract
Fibrosis is a pathological process in diabetic nephropathy that causes renal failure and dysfunction. Given the known anti-diabetic effects of trans-Anethole (TA), we aimed to investigate its renoprotective and anti-fibrotic effect alone and in combination with losartan in diabetic nephropathy. Male Wistar rats received a single intraperitoneal injection of 65 mg/kg streptozotocin (STZ) for diabetes induction. Diabetic rats were treated orally with saline, TA (80 mg/kg), losartan (Los; 10 mg/kg), or the combination of TA and losartan (TA-Los) daily for five weeks. Renal function was monitored during the study, and renal fibrosis, oxidative stress markers, apoptotic cells, and the expression and localization of AT1R, TGF-β1, and Col-IV were detected in the kidney. Results showed that TA alone and in combination with losartan was able to decrease blood glucose, urea, and creatinine levels and improve kidney function parameters. TA, Los, and TA-Los significantly reduced tubule vascular degeneration, glomerular and tubulointerstitial sclerosis, oxidative stress, and apoptotic cells. Immunohistochemistry analyses showed that TA, losartan, and TA-losartan combination downregulated the AT1R, Col IV, and TGF-β1 expression and distribution in diabetic rat kidneys. Results suggest that TA is able to suppress diabetic nephropathy in rats effectively, probably by decreasing blood glucose levels and downregulating AT1R and TGF-β1 expression.
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Affiliation(s)
- Zahra Samadi-Noshahr
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Mosa-Al-Reza Hadjzadeh
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Naser Shafei
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Division of Neurocognitive Sciences, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Salmani
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sara Hosseinian
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abolfazl Khajavi-Rad
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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16
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Piani F, Reinicke T, Lytvyn Y, Melena I, Lovblom LE, Lai V, Tse J, Cham L, Orszag A, Perkins BA, Cherney DZI, Bjornstad P. Vasopressin associated with renal vascular resistance in adults with longstanding type 1 diabetes with and without diabetic kidney disease. J Diabetes Complications 2021; 35:107807. [PMID: 33288413 PMCID: PMC8397596 DOI: 10.1016/j.jdiacomp.2020.107807] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 11/12/2020] [Accepted: 11/13/2020] [Indexed: 02/09/2023]
Abstract
OBJECTIVE Arginine vasopressin (AVP) and its surrogate, copeptin, have been implicated in diabetic kidney disease (DKD) pathogenesis, which develops in a subset of people with longstanding type 1 diabetes, but not in others (DKD Resistors). We hypothesized that patients with DKD would exhibit higher copeptin concentrations vs. DKD Resistors. METHODS Participants with type 1 diabetes (n = 62, duration ≥50 years) were stratified into 42 DKD Resistors and 20 with DKD (eGFR ≤60 mL/min/1.73m2 or ≥30 mg/day urine albumin), and age/sex-matched controls (HC, n = 74) were included. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were calculated by inulin and p-aminohippurate clearance before and after angiotensin II (ang II) infusion. Renal vascular resistance (RVR) was calculated as mean arterial pressure/renal blood flow. Plasma copeptin, renin, aldosterone, neutrophil gelatinase-associated lipocalin (NGAL), and urea concentrations were measured, along with 24-h urine volume. RESULTS DKD resistors had lower copeptin (95% CI: 4.0 [3.4-4.8] pmol/l) compared to DKD (5.8 [4.5-7.6] pmol/l, p = 0.02) and HC (4.8 [4.1-5.5] pmol/l, p = 0.01) adjusting for age, sex and HbA1c. In type 1 diabetes, higher copeptin correlated with lower GFR (r: -0.32, p = 0.01) and higher renin concentration (r: 0.40, p = 0.002) after multivariable adjustments. These relationships were not evident in HC. Copeptin inversely associated with RVR change following exogenous ang II only in participants with type 1 diabetes (β ± SE: -6.9 ± 3.4, p = 0.04). CONCLUSIONS In longstanding type 1 diabetes, copeptin was associated with intrarenal renin-angiotensin-aldosterone system (RAAS) activation and renal hemodynamic function, suggesting interplay between AVP and RAAS in DKD pathogenesis.
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Affiliation(s)
- Federica Piani
- Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, CO, USA; Department of Pediatrics, Section of Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Trenton Reinicke
- Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, CO, USA; Department of Pediatrics, Section of Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Yuliya Lytvyn
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Isabella Melena
- Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, CO, USA; Department of Pediatrics, Section of Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Leif E Lovblom
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Vesta Lai
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Josephine Tse
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Leslie Cham
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Andrej Orszag
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Bruce A Perkins
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - David Z I Cherney
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Canada
| | - Petter Bjornstad
- Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, CO, USA; Department of Pediatrics, Section of Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA.
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17
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Westreich KD, Isom S, Divers J, D'Agostino R, Lawrence JM, Kanakatti Shankar R, Dolan LM, Imperatore G, Dabelea D, Mayer-Davis EJ, Mottl AK. Trajectories in estimated glomerular filtration rate in youth-onset type 1 and type 2 diabetes: The SEARCH for Diabetes in Youth Study. J Diabetes Complications 2021; 35:107768. [PMID: 33168393 PMCID: PMC7855388 DOI: 10.1016/j.jdiacomp.2020.107768] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 10/14/2020] [Accepted: 10/14/2020] [Indexed: 11/29/2022]
Abstract
AIMS We sought to characterize the direction and associated factors of eGFR change following diagnosis of youth-onset type 1 and type 2 diabetes. METHODS We assessed the direction of eGFR change at two visits (mean 6.6 years apart) in SEARCH, a longitudinal cohort study of youth-onset type 1 and type 2 diabetes. We used the CKiDCr-CysC equation to estimate GFR and categorized 'rising' and 'declining' eGFR as an annual change of ≥3 ml/min/1.73 m2 in either direction. Multivariable logistic regression evaluated factors associated with directional change in eGFR. RESULTS Estimated GFR declined in 23.8% and rose in 2.8% of participants with type 1 diabetes (N = 1225; baseline age 11.4 years), and declined in 18.1% and rose in 15.6% of participants with type 2 diabetes (N = 160; baseline age 15.0 years). Factors associated with rising and declining eGFR (versus stable) in both type 1 and type 2 diabetes included sex, age at diagnosis, baseline eGFR and difference in fasting glucose between study visits. Additional factors in type 1 diabetes included time from baseline visit, HbA1c and body mass index. CONCLUSIONS Over the first decade of diabetes, eGFR decline is more common in type 1 diabetes whereas eGFR rise is more common in type 2 diabetes.
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Affiliation(s)
- Katherine D Westreich
- University of North Carolina Kidney Center, UNC School of Medicine, Chapel Hill, NC, United States of America.
| | - Scott Isom
- Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, United States of America.
| | - Jasmin Divers
- Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, United States of America.
| | - Ralph D'Agostino
- Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, United States of America.
| | - Jean M Lawrence
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, United States of America.
| | - Roopa Kanakatti Shankar
- Division of Endocrinology, Children's National Medical Center, Washington, DC, United States of America
| | - Lawrence M Dolan
- Division of Endocrinology, Cincinnati Children's Hospital, Cincinnati, OH, United States of America.
| | - Giuseppina Imperatore
- Division of Diabetes Translation, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA, United States of America.
| | - Dana Dabelea
- Department of Epidemiology, School of Public Health, University of Colorado Denver, Aurora, CO, United States of America.
| | - Elizabeth J Mayer-Davis
- Department of Nutrition, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, United States of America; Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America.
| | - Amy K Mottl
- University of North Carolina Kidney Center, UNC School of Medicine, Chapel Hill, NC, United States of America.
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Ould Setti M, Voutilainen A, Tuomainen TP. Renal hyperfiltration, fatty liver index, and the hazards of all-cause and cardiovascular mortality in Finnish men. Epidemiol Health 2020; 43:e2021001. [PMID: 33445827 PMCID: PMC7952838 DOI: 10.4178/epih.e2021001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 12/18/2020] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES Renal hyperfiltration (RHF) and fatty liver are separately associated with adverse health outcomes. In this study, we investigated the mortality hazard of coexisting RHF and fatty liver. METHODS Middle-aged men from the Kuopio Ischaemic Disease Risk Factor Study (n=1,552) were followed up for a median of 29 years. Associations among RHF, fatty liver index (FLI) score, age, body mass index, smoking status, alcohol consumption, and hypertension status were assessed using logistic regression. Cox proportional hazards models were used to determine the hazard ratios (HRs) for all-cause and cardiovascular disease (CVD) mortality with respect to RHF and fatty liver. RESULTS Of the men, 5% had RHF (n=73), whereas a majority had fatty liver (n=848). RHF was associated specifically with smoking, and fatty liver was associated specifically with overweight. The all-cause mortality hazard was highest (HR, 1.96; 95% confidence interval [CI], 1.27 to 3.01) among men with RHF and fatty liver (n=33). Among men with RHF but normal FLI (n=40), the HR of all-cause mortality was 1.67 (95% CI, 1.15 to 2.42). Among men with fatty liver but a normal estimated glomerular filtration rate (n=527), the HR of all-cause mortality was 1.35 (95% CI, 1.09 to 1.66). CVD mortality hazard was associated with RHF, but not fatty liver. We detected no interaction effect between RHF and fatty liver for all-cause (synergy index, 0.74; 95% CI, 0.21 to 2.67) or CVD (synergy index, 0.94; 95% CI, 0.34 to 2.60) mortality. CONCLUSIONS RHF and fatty liver are independently associated with all-cause and CVD mortality
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Affiliation(s)
- Mounir Ould Setti
- Department of Public Health, University of Eastern Finland, Kuopio, Finland
| | - Ari Voutilainen
- Department of Public Health, University of Eastern Finland, Kuopio, Finland
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Gronda E, Jessup M, Iacoviello M, Palazzuoli A, Napoli C. Glucose Metabolism in the Kidney: Neurohormonal Activation and Heart Failure Development. J Am Heart Assoc 2020; 9:e018889. [PMID: 33190567 PMCID: PMC7763788 DOI: 10.1161/jaha.120.018889] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The liver is not the exclusive site of glucose production in humans in the postabsorptive state. Robust data support that the kidney is capable of gluconeogenesis and studies have demonstrated that renal glucose production can increase systemic glucose production. The kidney has a role in maintaining glucose body balance, not only as an organ for gluconeogenesis but by using glucose as a metabolic substrate. The kidneys reabsorb filtered glucose through the sodium-glucose cotransporters sodium-glucose cotransporter (SGLT) 1 and SGLT2, which are localized on the brush border membrane of the early proximal tubule with immune detection of their expression in the tubularized Bowman capsule. In patients with diabetes mellitus, the renal maximum glucose reabsorptive capacity, and the threshold for glucose passage into the urine, are higher and contribute to the hyperglycemic state. The administration of SGLT2 inhibitors to patients with diabetes mellitus enhances sodium and glucose excretion, leading to a reduction of the glycosuria threshold and tubular maximal transport of glucose. The net effects of SGLT2 inhibition are to drive a reduction in plasma glucose levels, improving insulin secretion and sensitivity. The benefit of SGLT2 inhibitors goes beyond glycemic control, since inhibition of renal glucose reabsorption affects blood pressure and improves the hemodynamic profile and the tubule glomerular feedback. This action acts to rebalance the dense macula response by restoring adenosine production and restraining renin-angiotensin-aldosterone activation. By improving renal and cardiovascular function, we explain the impressive reduction in adverse outcomes associated with heart failure supporting the current clinical perspective.
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Affiliation(s)
- Edoardo Gronda
- Programma CardiorenaleU.O.C. NefrologiaDialisi e Trapianto Renale dell’AdultoDipartimento di Medicina e Specialità MedicheFondazione IRCCS Ca’ GrandaOspedale Maggiore PoliclinicoMilanItaly
| | | | - Massimo Iacoviello
- SC CardiologiaDipartimento delle Scienze Mediche e ChirurgicheAOU Policlinico Riuniti di FoggiaUniversità degli Studi di FoggiaFoggiaItaly
| | - Alberto Palazzuoli
- Divisione di Malattie CardiovascolariDipartimento di Medicina InternaUniversità di SienaItaly
| | - Claudio Napoli
- Clinical Department of Internal Medicine and SpecialisticsDepartment of Advanced Medical and Surgical SciencesUniversità della Campania "Luigi Vanvitelli"NaplesItaly
- IRCCS SDNNaplesItaly
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Lytvyn Y, Bjornstad P, van Raalte DH, Heerspink HL, Cherney DZI. The New Biology of Diabetic Kidney Disease-Mechanisms and Therapeutic Implications. Endocr Rev 2020; 41:5601424. [PMID: 31633153 PMCID: PMC7156849 DOI: 10.1210/endrev/bnz010] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 10/17/2019] [Indexed: 02/07/2023]
Abstract
Diabetic kidney disease remains the most common cause of end-stage kidney disease in the world. Despite reductions in incidence rates of myocardial infarction and stroke in people with diabetes over the past 3 decades, the risk of diabetic kidney disease has remained unchanged, and may even be increasing in younger individuals afflicted with this disease. Accordingly, changes in public health policy have to be implemented to address the root causes of diabetic kidney disease, including the rise of obesity and diabetes, in addition to the use of safe and effective pharmacological agents to prevent cardiorenal complications in people with diabetes. The aim of this article is to review the mechanisms of pathogenesis and therapies that are either in clinical practice or that are emerging in clinical development programs for potential use to treat diabetic kidney disease.
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Affiliation(s)
- Yuliya Lytvyn
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Petter Bjornstad
- Department of Medicine, Division of Nephrology, Department of Pediatrics, Section of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado
| | - Daniel H van Raalte
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Netherlands
| | - Hiddo L Heerspink
- The George Institute for Global Health, Sydney, Australia.,Department of Clinical Pharmacology, University of Groningen, Groningen, Netherlands
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
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Antihypertensive and Renal Mechanisms of SGLT2 (Sodium-Glucose Linked Transporter 2) Inhibitors. Hypertension 2020; 75:894-901. [DOI: 10.1161/hypertensionaha.119.11684] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Empaglifolzin, canagliflozin, and dapagliflozin are SGLT2 (sodium-glucose linked transporter type 2) inhibitors for treatment of type 2 diabetes mellitus that also reduce blood pressure, mortality, and cardiovascular disease and slow the loss of glomerular filtration rate. SGLT2 inhibitors inhibit the coupled reabsorption of sodium and glucose from the proximal tubules, thereby increasing renal glucose and sodium excretion, but they have more widespread renal effects, including inhibition of the sodium:proton exchanger. They increase the delivery of sodium to the loop of Henle and can thereby activate the tubuloglomerular feedback response to correct glomerular hyperfiltration. There are multiple potential mechanisms whereby these drugs lower blood pressure and preserve kidney function that are the focus of this review.
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Kang MW, Park S, Lee S, Lee Y, Cho S, Han K, Cho H, Kim Y, Kim YC, Han SS, Lee H, Lee JP, Joo KW, Lim CS, Kim YS, Kim DK. Glomerular hyperfiltration is associated with dementia: A nationwide population-based study. PLoS One 2020; 15:e0228361. [PMID: 31990949 PMCID: PMC6986766 DOI: 10.1371/journal.pone.0228361] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 01/13/2020] [Indexed: 01/06/2023] Open
Abstract
Background Glomerular hyperfiltration may be a clinical phenotype of endothelial dysfunction. Endothelial dysfunction may cause vascular dementia through the deterioration of cerebral blood flow. We aimed to identify the risk of dementia in people with glomerular hyperfiltration. Methods Using the Korean National Health Information Database, we included subjects aged ≥45 years who underwent national health screening examinations between 2012 and 2015 and who had no previous history of end-stage renal disease or dementia (n = 2,244,582). The primary exposure was glomerular hyperfiltration. We divided the subjects into groups by sex and five-year age intervals and categorized each group into 8 intervals according to estimated glomerular filtration (eGFR). The subjects with an eGFR ≥95th percentile in each group were defined as the hyperfiltration group. The outcomes were development of all types of dementia, Alzheimer's dementia and vascular dementia. Multivariable Cox proportional hazards models were used to analyze the hazard ratios (HRs) for outcomes. Results The Hyperfiltration group showed a higher risk for the development of all types of dementia [adjusted HR 1.09 (95% CI, 1.03–1.15)] and vascular dementia [adjusted HR 1.33 (95% CI, 1.14–1.55)] than the reference group. However, the association between hyperfiltration and Alzheimer's dementia was not statistically significant. Conclusions Glomerular hyperfiltration may be associated with dementia. In this respect, subjects with glomerular hyperfiltration should be monitored more closely for signs and symptoms of dementia.
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Affiliation(s)
- Min Woo Kang
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Sehoon Park
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Soojin Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Yeonhee Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Semin Cho
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Kyungdo Han
- Department of Medical Statistics, College of Medicine, Catholic University of Korea, Seoul, Korea
| | - Hanna Cho
- Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Yaerim Kim
- Department of Internal Medicine, Keimyung School of Medicine, Seoul, Korea
| | - Yong Chul Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Kidney Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Seung Seok Han
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Kidney Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hajeong Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Kidney Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jung Pyo Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Kidney Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Kwon Wook Joo
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Kidney Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Chun Soo Lim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
- Kidney Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Yon Su Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Kidney Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Dong Ki Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Kidney Research Institute, Seoul National University College of Medicine, Seoul, Korea
- * E-mail:
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23
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Kanbay M, Ertuglu LA, Afsar B, Ozdogan E, Kucuksumer ZS, Ortiz A, Covic A, Kuwabara M, Cherney DZI, van Raalte DH, de Zeeuw D. Renal hyperfiltration defined by high estimated glomerular filtration rate: A risk factor for cardiovascular disease and mortality. Diabetes Obes Metab 2019; 21:2368-2383. [PMID: 31297976 DOI: 10.1111/dom.13831] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 06/30/2019] [Accepted: 07/08/2019] [Indexed: 12/22/2022]
Abstract
Renal hyperfiltration, defined as an increased glomerular filtration rate above normal values, is associated with early phases of kidney disease in the setting of various conditions such as obesity and diabetes. Although it is recognized that glomerular hyperfiltration, that is, increased filtration per nephron unit (usually studied at low glomerular filtration levels and often referred to as single nephron hyperfiltration), is a risk factor for the progression of chronic kidney disease, the implications of having renal hyperfiltration for cardiovascular disease and mortality risk are incompletely understood. Recent evidence from diverse populations, including healthy individuals and patients with diabetes or established cardiovascular disease, suggests that renal hyperfiltration is associated with a higher risk of cardiovascular disease and all-cause mortality. In this review, we critically summarize the existing studies, discuss possible mechanisms, and describe the remaining gaps in our knowledge regarding the association of renal hyperfiltration with cardiovascular disease and mortality risk.
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Affiliation(s)
- Mehmet Kanbay
- Department of Medicine, Division of Nephrology, Koç University School of Medicine, Istanbul, Turkey
| | - Lale A Ertuglu
- Department of Medicine, School of Medicine, Koç University, Istanbul, Turkey
| | - Baris Afsar
- Department of Medicine, Division of Nephrology, Suleyman Demirel University School of Medicine, Isparta, Turkey
| | - Elif Ozdogan
- Department of Medicine, School of Medicine, Koç University, Istanbul, Turkey
| | - Zeynep S Kucuksumer
- Department of Medicine, School of Medicine, Koç University, Istanbul, Turkey
| | - Alberto Ortiz
- Dialysis Unit, School of Medicine, IIS-Fundacion Jimenez Diaz, Universidad Autónoma de Madrid, Madrid, Spain
| | - Adrian Covic
- Nephrology Clinic, Dialysis and Renal Transplant Center, 'C.I. PARHON' University Hospital, and 'Grigore T. Popa' University of Medicine, Iasi, Romania
| | | | - David Z I Cherney
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Daniel H van Raalte
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Dick de Zeeuw
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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24
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Xiong Q, Liu J, Xu Y. Effects of Uric Acid on Diabetes Mellitus and Its Chronic Complications. Int J Endocrinol 2019; 2019:9691345. [PMID: 31737070 PMCID: PMC6815590 DOI: 10.1155/2019/9691345] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 05/26/2019] [Accepted: 09/06/2019] [Indexed: 02/07/2023] Open
Abstract
With the deepening of the researches on uric acid, especially in the study of metabolic diseases, uric acid has been found to be closely related to obesity, metabolic syndrome, nonalcoholic fatty liver disease, diabetes, and other metabolic diseases. Uric acid causes a series of pathophysiological changes through inflammation, oxidative stress, vascular endothelial injury, and so on and thus subsequently promotes the occurrence and development of diseases. This review confirmed the positive correlation between uric acid and diabetes mellitus and its chronic complications through the pathogenesis and clinical studies aspects.
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Affiliation(s)
- Qing Xiong
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
- Department of Endocrinology, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, Hainan 570208, China
| | - Jie Liu
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
| | - Yancheng Xu
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
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25
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van Bommel EJM, Muskiet MHA, van Baar MJB, Tonneijck L, Smits MM, Emanuel AL, Bozovic A, Danser AHJ, Geurts F, Hoorn EJ, Touw DJ, Larsen EL, Poulsen HE, Kramer MHH, Nieuwdorp M, Joles JA, van Raalte DH. The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial. Kidney Int 2019; 97:202-212. [PMID: 31791665 DOI: 10.1016/j.kint.2019.09.013] [Citation(s) in RCA: 247] [Impact Index Per Article: 41.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 08/23/2019] [Accepted: 09/12/2019] [Indexed: 02/08/2023]
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve hard renal outcomes in type 2 diabetes. This is possibly explained by the fact that SGLT2i normalize the measured glomerular filtration rate (mGFR) by increasing renal vascular resistance, as was shown in young people with type 1 diabetes and glomerular hyperfiltration. Therefore, we compared the renal hemodynamic effects of dapagliflozin with gliclazide in type 2 diabetes. The mGFR and effective renal plasma flow were assessed using inulin and para-aminohippurate clearances in the fasted state, during clamped euglycemia (5 mmol/L) and during clamped hyperglycemia (15 mmol/L). Filtration fraction and renal vascular resistance were calculated. Additionally, factors known to modulate renal hemodynamics were measured. In 44 people with type 2 diabetes on metformin monotherapy (Hemoglobin A1c 7.4%, mGFR 113 mL/min), dapagliflozin versus gliclazide reduced mGFR by 5, 10, and 12 mL/min in the consecutive phases while both agents similarly improved Hemoglobin A1c (-0.48% vs -0.65%). Dapagliflozin also reduced filtration fraction without increasing renal vascular resistance, and increased urinary adenosine and prostaglandin concentrations. Gliclazide did not consistently alter renal hemodynamic parameters. Thus, beyond glucose control, SGLT2i reduce mGFR and filtration fraction in type 2 diabetes. The fact that renal vascular resistance was not increased by dapagliflozin suggests that this is due to post-glomerular vasodilation rather than pre-glomerular vasoconstriction.
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Affiliation(s)
- Erik J M van Bommel
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, location VUMC, Amsterdam, The Netherlands.
| | - Marcel H A Muskiet
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, location VUMC, Amsterdam, The Netherlands
| | - Michaël J B van Baar
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, location VUMC, Amsterdam, The Netherlands
| | - Lennart Tonneijck
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, location VUMC, Amsterdam, The Netherlands
| | - Mark M Smits
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, location VUMC, Amsterdam, The Netherlands
| | - Anna L Emanuel
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, location VUMC, Amsterdam, The Netherlands
| | - Andrea Bozovic
- Department of Clinical Biochemistry, University Health Network, University of Toronto, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - A H Jan Danser
- Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Frank Geurts
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Ewout J Hoorn
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Daan J Touw
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, The Netherlands
| | - Emil L Larsen
- Department of Clinical Pharmacology, Bispebjerg-Frederiksberg Hospital, Copenhagen, Denmark
| | - Henrik E Poulsen
- Department of Clinical Pharmacology, Bispebjerg-Frederiksberg Hospital, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Mark H H Kramer
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, location VUMC, Amsterdam, The Netherlands
| | - Max Nieuwdorp
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, location VUMC, Amsterdam, The Netherlands
| | - Jaap A Joles
- Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands
| | - Daniël H van Raalte
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, location VUMC, Amsterdam, The Netherlands
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26
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Dart AB, McGavock J, Sharma A, Chateau D, Schwartz GJ, Blydt-Hansen T. Estimating glomerular filtration rate in youth with obesity and type 2 diabetes: the iCARE study equation. Pediatr Nephrol 2019; 34:1565-1574. [PMID: 31049718 DOI: 10.1007/s00467-019-04250-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 02/14/2019] [Accepted: 03/26/2019] [Indexed: 10/26/2022]
Abstract
BACKGROUND The validity of pediatric estimated glomerular filtration rate equations (eGFRs) in early stages of CKD including hyperfiltration is unknown. The purpose of this study was to develop an eGFR equation for adolescents with obesity and type 2 diabetes (T2D). METHODS eGFRs were developed from iohexol-derived GFRs (iGFRs) in 26 overweight/obese (BMI > 85th percentile) youth and 100 with T2D from the iCARE (Improving renal Complications in Adolescents with T2D through REsearch) cohort. Twenty percent of the cohort was withheld as a validation dataset. Linear regression analyses were used to develop the best formula based on body size, sex, creatinine, urea, ± cystatin C. Comparable validity of commonly used eGFR equations was assessed. RESULTS Mean age 15.4 + 2.4 years, BMI Z-score 2.5 + 1.2, 61% female, and mean iGFR 129.0 + 27.7 ml/min/ 1.73 m2. The best adjusted eGFR formula (ml/min/1.73 m2) was 50.7 × BSA0.816 × (height (cm)/creatinine)0.405 × 0.8994 if sex = female | 1 otherwise. It resulted in 53.8% of eGFRs within 10% of measured iGFR and 96.2% within 30%. Bland-Altman 95% limits of agreement in the external dataset were - 37.6 to 45.5 ml/min/1.73m2 (bias = 3.96), and the correlation was 0.62. This equation performed better than all previously published creatinine-based eGFRs. cystatin C did not significantly improve results; however, some other cystatin C formulas also performed well. CONCLUSIONS The iCARE equation provides a more accurate creatinine-based eGFR in obese youth with and without T2D. Further studies are warranted to evaluate within-subject variability and applicability to lower GFRs and other populations.
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Affiliation(s)
- A B Dart
- Department of Pediatrics and Child Health, Section of Nephrology, Children's Hospital Research Institute of Manitoba, Diabetes Research Envisioned and Accomplished in Manitoba Research Team, University of Manitoba, FE009 - 840 Sherbrook Street, Winnipeg, MB, R3A 1S1, Canada.
| | - J McGavock
- Department of Pediatrics and Child Health, University of Manitoba, FE009 - 840 Sherbrook Street, Winnipeg, MB, R3A 1S1, Canada
| | - A Sharma
- Department of Pediatrics and Child Health, University of Manitoba, FE009 - 840 Sherbrook Street, Winnipeg, MB, R3A 1S1, Canada
| | - D Chateau
- Department of Community Health Sciences, University of Manitoba, Winnipeg, Canada
| | - G J Schwartz
- University of Rochester Medical Center, Rochester, NY, USA
| | - T Blydt-Hansen
- Department of Pediatrics, University of British Columbia, Vancouver, Canada
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27
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Lytvyn Y, Bjornstad P, Lovshin JA, Singh SK, Boulet G, Farooqi MA, Lai V, Tse J, Cham L, Lovblom LE, Weisman A, Keenan HA, Brent MH, Paul N, Bril V, Advani A, Sochett E, Perkins BA, Cherney DZI. Association between uric acid, renal haemodynamics and arterial stiffness over the natural history of type 1 diabetes. Diabetes Obes Metab 2019; 21:1388-1398. [PMID: 30761725 PMCID: PMC6504604 DOI: 10.1111/dom.13665] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 02/03/2019] [Accepted: 02/10/2019] [Indexed: 12/11/2022]
Abstract
AIMS To examine the relationship between normal plasma uric acid (PUA) levels, renal haemodynamic function, arterial stiffness and plasma renin and aldosterone over a wide range of type 1 diabetes (T1D) durations in adolescents, young adults and older adults. MATERIALS AND METHODS PUA, glomerular filtration rate (GFR), effective renal plasma flow (ERPF), vascular stiffness parameters (aortic augmentation index [AIx], carotid AIx, carotid femoral pulse wave velocity [cfPWV]), and plasma renin and aldosterone were measured during a euglycaemic clamp in people with T1D: 27 adolescents (mean ± SD age 16.8 ± 1.9 years), 52 young adults (mean ± SD age 25.6 ± 5.5 years) and 66 older adults (mean ± SD age 65.7 ± 7.5 years). RESULTS PUA was highest in patients with the longest T1D duration: 197 ± 44 μmol/L in adolescents versus 264 ± 82 μmol/L in older adults (P < 0.001). Higher PUA correlated with lower GFR only in older adults, even after correcting for age, glycated haemoglobin and sex (β = -2.12 ± 0.56; P = 0.0003), but not in adolescents or young adults. Higher PUA correlated with lower carotid AIx (β = -1.90, P = 0.02) in adolescents. In contrast, PUA correlated with higher cfPWV (P = 0.02) and higher plasma renin (P = 0.01) in older adults with T1D. CONCLUSIONS The relationship between higher PUA with lower GFR, increased arterial stiffness and renin angiotensin aldosterone system (RAAS) activation was observed only in older adults with longstanding T1D. T1D duration may modify the association between PUA, renal haemodynamic function and RAAS activation, leading to renal vasoconstriction and ischaemia. Further work must determine whether pharmacological PUA-lowering prevents or reverses injurious haemodynamic and neurohormonal sequelae of longstanding T1D, thereby improving clinical outcomes.
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Affiliation(s)
- Yuliya Lytvyn
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Petter Bjornstad
- Department of Pediatrics, Division of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Julie A. Lovshin
- Department of Medicine, Division of Endocrinology and Metabolism, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Sunita K. Singh
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Genevieve Boulet
- Department of Medicine, Division of Endocrinology and Metabolism, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Mohammed A. Farooqi
- Department of Medicine, Division of Endocrinology and Metabolism, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Vesta Lai
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Josephine Tse
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Leslie Cham
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Leif E. Lovblom
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Alanna Weisman
- Department of Medicine, Division of Endocrinology and Metabolism, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Hillary A. Keenan
- Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA
| | - Michael H. Brent
- Department of Ophthalmology and Vision Sciences, Department of Medicine, University of Toronto, Ontario, Canada
| | - Narinder Paul
- Joint Department of Medical Imaging, Division of Cardiothoracic Radiology, University Health Network, Toronto, Ontario, Canada
| | - Vera Bril
- Ellen and Martin Prosserman Centre for Neuromuscular Diseases, Division of Neurology, Department of Medicine, University Health Network, University of Toronto, Toronto, Canada and the Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Andrew Advani
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Etienne Sochett
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Toronto, Ontario, Canada
| | - Bruce A. Perkins
- Department of Medicine, Division of Endocrinology and Metabolism, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - David Z. I. Cherney
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
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Analysis from the EMPA-REG OUTCOME ® trial indicates empagliflozin may assist in preventing the progression of chronic kidney disease in patients with type 2 diabetes irrespective of medications that alter intrarenal hemodynamics. Kidney Int 2019; 96:489-504. [PMID: 31142441 DOI: 10.1016/j.kint.2019.02.033] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 02/19/2019] [Accepted: 02/28/2019] [Indexed: 01/15/2023]
Abstract
In patients with type 2 diabetes mellitus (T2DM) and cardiovascular (CV) disease, empagliflozin (EMPA) decreased progression of chronic kidney disease (CKD), likely via a reduction in intraglomerular pressure. Due to prevalent comorbidities, such as hypertension and albuminuria, patients often receive other agents that alter intrarenal hemodynamics, including angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs), calcium channel blockers (CCBs) and diuretics. Nonsteroidal anti-inflammatory drugs (NSAIDs) may also be used by some individuals. In this exploratory, non-prespecified analysis, we investigated whether the kidney benefits of EMPA are altered in individuals already using the medications in these categories. In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME®) trial, 7020 patients were essentially equally randomized to EMPA 10 mg, 25 mg or placebo added to their standard care. Differences in risk of incident or worsening nephropathy for pooled EMPA vs placebo across subgroups by baseline background medications (to which patients were not randomized) were assessed using a Cox proportional hazards model. Risk reductions in incident or worsening nephropathy with EMPA were consistent across medication subgroups, with no heterogeneity of treatment effect. As a representative example, the risk for acute renal failure was overall slightly increased in patients using ACEi/ARBs in all groups (placebo, EMPA 10 mg or EMPA 25 mg) but incidence rates were numerically lower in those assigned to EMPA. Similar patterns were observed for other medications included in this analysis. Thus, EMPA may assist to prevent CKD progression in patients with T2DM with CV disease, irrespective of common background medications that alter intrarenal hemodynamics, and without increasing acute renal adverse events.
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29
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Bjornstad P, Singh SK, Snell-Bergeon JK, Lovshin JA, Lytvyn Y, Lovblom LE, Rewers MJ, Boulet G, Lai V, Tse J, Cham L, Orszag A, Weisman A, Keenan HA, Brent MH, Paul N, Bril V, Perkins BA, Cherney DZ. The relationships between markers of tubular injury and intrarenal haemodynamic function in adults with and without type 1 diabetes: Results from the Canadian Study of Longevity in Type 1 Diabetes. Diabetes Obes Metab 2019; 21:575-583. [PMID: 30311395 PMCID: PMC6368468 DOI: 10.1111/dom.13556] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 09/28/2018] [Accepted: 10/08/2018] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Our aim was to define the relationships between plasma biomarkers of kidney injury and intrarenal haemodynamic function (glomerular filtration rate [GFR], effective renal plasma flow [ERPF], renal vascular resistance [RVR]) in adults with type 1 diabetes (T1D). METHODS The study sample comprised patients with longstanding T1D (duration ≥50 years), among whom 44 were diabetic kidney disease (DKD) resistors (eGFR >60 mL/min/1.73 m2 and <30 mg/d urine albumin excretion) and 22 had DKD, in addition to 73 control participants. GFRINULIN and ERPFPAH were measured, RVR was calculated, and afferent (RA )/efferent (RE ) areteriolar resistances were derived from Gomez equations. Plasma neutrophil gelatinase-associated lipocalin (NGAL), β2 microglobulin (B2M), osteopontin (OPN) and uromodulin (UMOD) were measured using immunoassay kits from Meso Scale Discovery. RESULTS Plasma NGAL, B2M and OPN were higher and UMOD was lower in DKD patients vs DKD resistors and non-diabetic controls. In participants with T1D, plasma NGAL inversely correlated with GFR (r = -0.33; P = 0.006) and ERPF (r = -0.34; P = 0.006), and correlated positively with RA (r = 0.26; P = 0.03) and RVR (r = 0.31; P = 0.01). In participants without T1D, NGAL and B2M inversely correlated with GFR (NGAL r = -0.18; P = 0.13 and B2M r = -0.49; P < 0.0001) and with ERPF (NGAL r = -0.19; P = 0.1 and B2M r = -0.42; P = 0.0003), and correlated positively with RA (NGAL r = 0.19; P = 0.10 and B2M r = 0.3; P = 0.01) and with RVR (NGAL r = 0.20; P = 0.09 and B2M r = 0.34; P = 0.003). Differences were significant after adjusting for age, sex, HbA1c, SBP and LDL. There were statistical interactions between T1D status, B2M and intrarenal haemodynamic function (P < 0.05). CONCLUSIONS Elevated NGAL relates to intrarenal haemodynamic dysfunction in T1D, whereas elevated NGAL and B2M relate to intrarenal haemodynamic dysfunction in adults without T1D. These data may define a diabetes-specific interplay between tubular injury and intrarenal haemodynamic dysfunction.
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Affiliation(s)
- Petter Bjornstad
- Division of Nephrology, Department of Medicine, University of Toronto. Toronto, Ontario, Canada
- Research Division, Barbara Davis Center for Diabetes. Aurora, Colorado, USA
| | - Sunita K. Singh
- Division of Nephrology, Department of Medicine, University of Toronto. Toronto, Ontario, Canada
| | | | - Julie A. Lovshin
- Division of Nephrology, Department of Medicine, University of Toronto. Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto. Toronto, Ontario, Canada
| | - Yuliya Lytvyn
- Division of Nephrology, Department of Medicine, University of Toronto. Toronto, Ontario, Canada
| | - Leif E. Lovblom
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital. Toronto, Ontario, Canada
| | - Marian J. Rewers
- Research Division, Barbara Davis Center for Diabetes. Aurora, Colorado, USA
| | - Genevieve Boulet
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital. Toronto, Ontario, Canada
| | - Vesta Lai
- Division of Nephrology, Department of Medicine, University of Toronto. Toronto, Ontario, Canada
| | - Josephine Tse
- Division of Nephrology, Department of Medicine, University of Toronto. Toronto, Ontario, Canada
| | - Leslie Cham
- Division of Nephrology, Department of Medicine, University of Toronto. Toronto, Ontario, Canada
| | - Andrej Orszag
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital. Toronto, Ontario, Canada
| | - Alanna Weisman
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital. Toronto, Ontario, Canada
| | - Hillary A. Keenan
- Research Division, Joslin Diabetes Center. Boston, Massachusetts, USA
| | - Michael H. Brent
- Department of Ophthalmology and Vision Sciences, Department of Medicine, University of Toronto. Toronto, Ontario, Canada
| | - Narinder Paul
- Joint Department of Medical Imaging, Division of Cardiothoracic Radiology, University Health Network. Toronto, Ontario, Canada
| | - Vera Bril
- The Ellen and Martin Prosserman Centre for Neuromuscular Diseases, Krembil Neuroscience Centre, Division of Neurology, Department of Medicine, University Health Network, University of Toronto. Toronto, Ontario, Canada
| | - Bruce A. Perkins
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital. Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto. Toronto, Ontario, Canada
| | - David Z.I. Cherney
- Division of Nephrology, Department of Medicine, University of Toronto. Toronto, Ontario, Canada
- Department of Physiology, University of Toronto
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Lytvyn Y, Bjornstad P, Lovshin JA, Boulet G, Farooqi MA, Lai V, Tse J, Cham L, Lovblom LE, Weisman A, Keenan HA, Brent MH, Paul N, Bril V, Advani A, Sochett E, Perkins BA, Cherney DZI. Renal Hemodynamic Function and RAAS Activation Over the Natural History of Type 1 Diabetes. Am J Kidney Dis 2019; 73:786-796. [PMID: 30799029 DOI: 10.1053/j.ajkd.2018.12.034] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 12/17/2018] [Indexed: 01/11/2023]
Abstract
RATIONALE & OBJECTIVE The renin-angiotensin-aldosterone system (RAAS) is associated with renal and cardiovascular disease in diabetes. Unfortunately, early RAAS blockade in patients with type 1 diabetes mellitus (T1DM) does not prevent the development of complications. We sought to examine the role of hyperfiltration and RAAS activation across a wide range of T1DM duration to better understand renal hemodynamic status in patients with T1DM. STUDY DESIGN Post hoc analysis of blood samples. SETTING & PARTICIPANTS 148 Canadian patients with T1DM: 28 adolescents (aged 16.2±2.0 years), 54 young adults (25.4±5.6 years), and 66 older adults (65.7±7.5 years) studied in a clinical investigation unit. EXPOSURE Angiotensin II infusion (1ng/kg/min; a measure of RAAS activation) during a euglycemic clamp. OUTCOMES Glomerular filtration rate measured using inulin clearance, effective renal plasma flow measured using para-aminohippurate, afferent (RA) and efferent (RE) arteriolar resistances, and glomerular hydrostatic pressure estimated using the Gomez equations. RESULTS In a stepwise fashion, glomerular filtration rate, effective renal plasma flow, and glomerular hydrostatic pressure were higher, while renal vascular resistance and RA were lower in adolescents versus young adults versus older adults. RE was similar in adolescents versus young adults but was higher in older adults. Angiotensin II resulted in blunted renal hemodynamic responses in older adults (renal vascular resistance increase of 3.3% ± 1.6% vs 4.9% ± 1.9% in adolescents; P<0.001), suggesting a state of enhanced RAAS activation. LIMITATIONS Homogeneous study participants limit the generalizability of findings to other populations. Studying older adult participants with T1DM may be associated with a survivorship bias. CONCLUSIONS A state of relatively low RAAS activity and predominant afferent dilation rather than efferent constriction characterize early adolescents and young adults with T1DM. This state of endogenous RAAS inactivity in early T1DM may explain why pharmacologic blockade of this neurohormonal system is often ineffective in reducing kidney disease progression in this setting. Older adults with long-standing T1DM who have predominant afferent constriction and RAAS activation may experience renoprotection from therapies that target the afferent arteriole. Further work is required to understand the potential role of non-RAAS pharmacologic agents that target RA in patients with early and long-standing T1DM.
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Affiliation(s)
- Yuliya Lytvyn
- Division of Nephrology, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
| | - Petter Bjornstad
- Division of Endocrinology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - Julie A Lovshin
- Division of Endocrinology and Metabolism, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Genevieve Boulet
- Division of Endocrinology and Metabolism, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Mohammed A Farooqi
- Division of Endocrinology and Metabolism, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Vesta Lai
- Division of Nephrology, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Josephine Tse
- Division of Nephrology, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Leslie Cham
- Division of Nephrology, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Leif E Lovblom
- Lunenfeld-Tanenbaum Research Institute, Mount Sounai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Alanna Weisman
- Division of Endocrinology and Metabolism, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Hillary A Keenan
- Mount Sinai Hospital, Toronto, Ontario, Canada; Genzyme, Cambridge, MA
| | - Michael H Brent
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada; Department of Medicine, University of Toronto, Toronto, Canada
| | - Narinder Paul
- Division of Cardiothoracic Radiology, Joint Department of Medical Imaging, University Health Network, Toronto, Canada
| | - Vera Bril
- Division of Neurology, Department of Medicine, University of Toronto, Toronto, Canada; Ellen and Martin Prosserman Centre for Neuromuscular Diseases, Division of Neurology, Department of Medicine, University Health Network, University of Toronto, Toronto, Canada; Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Andrew Advani
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Ontario, Canada
| | - Etienne Sochett
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Toronto, Ontario, Canada
| | - Bruce A Perkins
- Division of Endocrinology and Metabolism, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - David Z I Cherney
- Division of Nephrology, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
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31
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Lovshin JA, Lytvyn Y, Lovblom LE, Katz A, Boulet G, Bjornstad P, Lai V, Cham L, Tse J, Orszag A, Keenan HA, Paul N, Bril V, Wong DT, McReelis KD, Brent MH, Perkins BA, Cherney DZI. Retinopathy and RAAS Activation: Results From the Canadian Study of Longevity in Type 1 Diabetes. Diabetes Care 2019; 42:273-280. [PMID: 30523033 PMCID: PMC6463750 DOI: 10.2337/dc18-1809] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 10/25/2018] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The importance of renin-angiotensin-aldosterone system (RAAS) activation in retinopathy for long-standing diabetes is not well understood. We determined retinopathy stage and evaluated associations with other vascular complications before and after physiological RAAS activation in adults with long-standing (≥50 years duration) type 1 diabetes. RESEARCH DESIGN AND METHODS Participants underwent retinal examination by digital funduscopic photography and optical coherence tomography and were classified as having nonproliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), or no diabetic retinopathy (NDR) with or without diabetic macular edema (DME). Neuropathy was measured by clinical neuropathy examination scores, electrophysiologically, and by corneal confocal microscopy. Renal function was measured by inulin and para-aminohippurate clearance methods. Arterial stiffness was measured by applanation tonometry. Renal function, blood pressure, and arterial stiffness were measured before and after RAAS activation with angiotensin II (ANGII). Associations were determined using linear regression. RESULTS Twelve (16%) of the 75 participants had NDR, 24 (32%) had NPDR, and 39 (52%) had PDR. A low overall prevalence of DME (4%) was observed. Those with PDR had worse nerve function and reduced corneal nerve density, were more likely to have macrovascular disease, and had increased arterial stiffness in response to ANGII compared with those with NPDR or NDR. Prevalence of kidney disease or renal hemodynamic function did not differ by retinopathy status. CONCLUSIONS PDR was associated with neuropathy severity and cardiovascular and peripheral vascular disease. In those with PDR, RAAS activation may be linked to vascular stiffening, an effect that persists in long-standing type 1 diabetes.
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Affiliation(s)
- Julie A Lovshin
- Division of Endocrinology and Metabolism, Sunnybrook Health Sciences Centre, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Yuliya Lytvyn
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Leif E Lovblom
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Alexandra Katz
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Geneviève Boulet
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Petter Bjornstad
- Division of Endocrinology, Department of Pediatrics, and Division of Nephrology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO
| | - Vesta Lai
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Leslie Cham
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Josephine Tse
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Andrej Orszag
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | | | - Narinder Paul
- Department of Medical Imaging, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
| | - Vera Bril
- Division of Neurology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - David T Wong
- Department of Ophthalmology and Vision Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Kylen D McReelis
- Department of Ophthalmology and Vision Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Michael H Brent
- Department of Ophthalmology and Vision Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Bruce A Perkins
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.,Division of Endocrinology and Metabolism, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - David Z I Cherney
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.,Department of Physiology, University of Toronto, Toronto, Ontario, Canada
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32
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León Jiménez D, Cherney DZI, Bjornstad P, Castilla-Guerra L, Miramontes González JP. Antihyperglycemic agents as novel natriuretic therapies in diabetic kidney disease. Am J Physiol Renal Physiol 2018; 315:F1406-F1415. [PMID: 30066584 PMCID: PMC6293300 DOI: 10.1152/ajprenal.00384.2017] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 07/11/2018] [Accepted: 07/26/2018] [Indexed: 02/07/2023] Open
Abstract
While sodium-glucose cotransporter-2 (SGLT2) inhibitors have been used for the routine management of type 2 diabetes for several years, it is perhaps their natriuretic effects that are most important clinically. This natriuresis activates tubuloglomerular feedback, resulting in reduced glomerular hypertension and proteinuria, leading to renal protective effects in the EMPA-REG OUTCOME and CANVAS Program trials. In the cardiovascular system, it is likely that plasma volume contraction due to natriuresis in response to SGLT2 inhibition is at least in part responsible for the reduction in the risk of heart failure observed in these trials. We compare this mechanism of action with other antidiabetics. Importantly, other diuretic classes, including thiazide and loop diuretics, have not resulted in such robust clinical benefits in patients with type 2 diabetes, possibly because these older agents do not influence intraglomerular pressure directly. In contrast, SGLT2 inhibitors do have important physiological similarities with carbonic anhydrase inhibitors, which also act proximally, and have been shown to activate tubuloglomerular feedback.
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Affiliation(s)
- David León Jiménez
- Vascular Risk Unit, Internal Medicine Clinical Management Unit, Hospital Universitario Virgen Macarena , Seville , Spain
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology. Toronto General Hospital, University of Toronto , Toronto , Ontario, Canada
| | - Petter Bjornstad
- Department of Pediatrics, Division of Endocrinology and Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado , Aurora, Colorado
| | - Luis Castilla-Guerra
- Vascular Risk Unit, Internal Medicine Clinical Management Unit, Hospital Universitario Virgen Macarena , Seville , Spain
| | - José Pablo Miramontes González
- Service of Internal Medicine, Institute of Biomedical Research of Salamanca (IBSAL), Hospital Universitario de Salamanca , Salamanca , Spain
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Clotet-Freixas S, Soler MJ, Palau V, Anguiano L, Gimeno J, Konvalinka A, Pascual J, Riera M. Sex dimorphism in ANGII-mediated crosstalk between ACE2 and ACE in diabetic nephropathy. J Transl Med 2018; 98:1237-1249. [PMID: 29884907 DOI: 10.1038/s41374-018-0084-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 04/25/2018] [Accepted: 05/01/2018] [Indexed: 12/19/2022] Open
Abstract
Angiotensin-converting enzyme (ACE) and ACE2 play a critical role in the renin-angiotensin system (RAS) by altering angiotensin II (ANGII) levels, thus governing its deleterious effects. Both enzymes are altered by sex and diabetes, and play an important role in the development of diabetic nephropathy (DN). Importantly, previous evidence in diabetic and ACE2-deficient (ACE2KO) males suggest a sex-dependent crosstalk between renal ACE and ACE2. In the present work, we aimed to study the sex-specific susceptibility to diabetes and direct infusion of ANGII in kidney disease progression, with a special focus on its link to ACE2 and ACE. In our mouse model, ANGII promoted hypertension, albuminuria, reduced glomerular filtration, and glomerular histological alterations. ANGII adverse effects were accentuated by diabetes and ACE2 deficiency, in a sex-dependent fashion: ACE2 deficiency accentuated ANGII-induced hypertension, albuminuria, and glomerular hypertrophy in diabetic females, whereas in diabetic males exacerbated ANGII-mediated glomerular hypertrophy, mesangial expansion, and podocyte loss. At the molecular level, ANGII downregulated renal ACE gene and enzymatic activity levels, as well as renin gene expression in ACE2KO mice. Interestingly, male sex and diabetes accentuated this effect. Here we show sex dimorphism in the severity of diabetes- and ANGII-related renal lesions, and demonstrate that ACE2- and ACE-related compensatory mechanisms are sex-specific. Supporting our previous findings, the modulation and ANGII-mediated crosstalk between ACE2 and ACE in DN progression was more evident in males. This work increases the understanding of the sex-specific role of ACE2 and ACE in DN, reinforcing the necessity of more personalized treatments targeting RAS.
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Affiliation(s)
- Sergi Clotet-Freixas
- Department of Nephrology, Hospital del Mar - IMIM (Hospital del Mar Medical Research Institute), 08003, Barcelona, Spain.,Division of Nephrology, University Health Network, Toronto, ON, M5G 2N2, Canada
| | - Maria Jose Soler
- Department of Nephrology, Hospital del Mar - IMIM (Hospital del Mar Medical Research Institute), 08003, Barcelona, Spain.
| | - Vanesa Palau
- Department of Nephrology, Hospital del Mar - IMIM (Hospital del Mar Medical Research Institute), 08003, Barcelona, Spain
| | - Lidia Anguiano
- Department of Nephrology, Hospital del Mar - IMIM (Hospital del Mar Medical Research Institute), 08003, Barcelona, Spain
| | - Javier Gimeno
- Department of Pathology, Hospital del Mar - IMIM (Hospital del Mar Medical Research Institute), 08003, Barcelona, Spain
| | - Ana Konvalinka
- Division of Nephrology, University Health Network, Toronto, ON, M5G 2N2, Canada
| | - Julio Pascual
- Department of Nephrology, Hospital del Mar - IMIM (Hospital del Mar Medical Research Institute), 08003, Barcelona, Spain
| | - Marta Riera
- Department of Nephrology, Hospital del Mar - IMIM (Hospital del Mar Medical Research Institute), 08003, Barcelona, Spain
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Do effects of sodium-glucose cotransporter-2 inhibitors in patients with diabetes give insight into potential use in non-diabetic kidney disease? Curr Opin Nephrol Hypertens 2018; 26:358-367. [PMID: 28582367 DOI: 10.1097/mnh.0000000000000343] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
PURPOSE OF REVIEW Our aim was to review the rationale for the role of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) as renoprotective therapy in patients with and without diabetes. RECENT FINDINGS SGLT-2i are antihyperglycemic agents, approved for treating type 2 diabetes to reduce glycosylated hemoglobin, type A1c. Primary glucoregulatory effects occur through selective inhibition of SGLT-2 at the renal proximal tubule promoting glucosuria leading to blood glucose lowering. From a hemodynamic perspective, SGLT-2 inhibition is also associated with decreased glomerular hyperfiltration, an effect that is mediated through natriuresis and tubuloglomerular feedback. With renal injury and progressive nephron loss, diabetic kidney disease, and nondiabetic chronic kidney diseases share overlapping phenotypes exhibiting single nephron hyperfiltration, along with increased proteinuria. Importantly, the impact of SGLT-2 inhibition on renal and systemic hemodynamic function, including effects on lowering blood pressure, hyperfiltration, and plasma volume, are independent of blood glucose lowering and instead are because of natriuresis. Accordingly, large clinical trials with SGLT-2i investigating the potential use of SGLT-2i in patients without diabetes are now underway. SUMMARY Based on prominent nonglycemic effects, the clinical use of SGLT-2i as renoprotective therapy may extend to nondiabetic chronic kidney diseases subtypes, which could help to address a large, unmet clinical need.
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35
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Bjornstad P, Lovshin JA, Lytvyn Y, Boulet G, Lovblom LE, Alhuzaim ON, Farooqi MA, Lai V, Tse J, Cham L, Orszag A, Scarr D, Weisman A, Keenan HA, Brent MH, Paul N, Bril V, Perkins BA, Cherney DZI. Adiposity Impacts Intrarenal Hemodynamic Function in Adults With Long-standing Type 1 Diabetes With and Without Diabetic Nephropathy: Results From the Canadian Study of Longevity in Type 1 Diabetes. Diabetes Care 2018; 41:831-839. [PMID: 29437821 PMCID: PMC5860840 DOI: 10.2337/dc17-2475] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 01/09/2018] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Central adiposity is considered to be an important cardiorenal risk factor in the general population and in type 1 diabetes. We sought to determine the relationship between central adiposity and intrarenal hemodynamic function in adults with long-standing type 1 diabetes with and without diabetic nephropathy (DN). RESEARCH DESIGN AND METHODS Patients with type 1 diabetes (n = 66, duration ≥50 years) and age-/sex-matched control subjects (n = 73) were studied. The cohort was stratified into 44 DN Resistors (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m2 and <30 mg/day urine albumin) and 22 patients with DN (eGFR ≤60 mL/min/1.73 m2 or ≥30 mg/day urine albumin). Intrarenal hemodynamic function (glomerular filtration rate for inulin [GFRINULIN], effective renal plasma flow for p-aminohippuric acid [ERPFPAH]) was measured. Afferent arteriolar resistance, efferent arteriolar resistance, renal blood flow, renal vascular resistance [RVR], filtration fraction, and glomerular pressure were derived from the Gomez equations. Fat and lean mass were quantified by DXA. RESULTS Whereas measures of adiposity did not associate with GFRINULIN or ERPFPAH in healthy control subjects, trunk fat mass inversely correlated with GFRINULIN (r = -0.46, P < 0.0001) and ERPFPAH (r = -0.31, P = 0.01) and positively correlated with RVR (r = 0.53, P = 0.0003) in type 1 diabetes. In analyses stratified by DN status, greater central adiposity related to lower GFRINULIN values in DN and DN Resistors, but the relationships between central adiposity and ERPFPAH and RVR were attenuated and/or reversed in patients with DN compared with DN Resistors. CONCLUSIONS The adiposity-intrarenal hemodynamic function relationship may be modified by the presence of type 1 diabetes and DN, requiring further study of the mechanisms by which adiposity influences renal hemodynamic function.
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Affiliation(s)
- Petter Bjornstad
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada .,Division of Endocrinology, Department of Pediatrics, University of Colorado, Aurora, CO
| | - Julie A Lovshin
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.,Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Yuliya Lytvyn
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Genevieve Boulet
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Leif E Lovblom
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Omar N Alhuzaim
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Mohammed A Farooqi
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Vesta Lai
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Josephine Tse
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Leslie Cham
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Andrej Orszag
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Daniel Scarr
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Alanna Weisman
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | | | - Michael H Brent
- Department of Ophthalmology and Vision Sciences and Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Narinder Paul
- Division of Cardiothoracic Radiology, Joint Department of Medical Imaging, University Health Network, Toronto, Ontario, Canada
| | - Vera Bril
- The Ellen and Martin Prosserman Centre for Neuromuscular Diseases, Krembil Neuroscience Centre, Division of Neurology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Bruce A Perkins
- Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.,Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - David Z I Cherney
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.,Department of Physiology, University of Toronto, Toronto, Ontario, Canada
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36
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Lovshin JA, Boulet G, Lytvyn Y, Lovblom LE, Bjornstad P, Farooqi MA, Lai V, Cham L, Tse J, Orszag A, Scarr D, Weisman A, Keenan HA, Brent MH, Paul N, Bril V, Perkins BA, Cherney DZ. Renin-angiotensin-aldosterone system activation in long-standing type 1 diabetes. JCI Insight 2018; 3:96968. [PMID: 29321380 PMCID: PMC5821172 DOI: 10.1172/jci.insight.96968] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 11/28/2017] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND In type 1 diabetes (T1D), adjuvant treatment with inhibitors of the renin-angiotensin-aldosterone system (RAAS), which dilate the efferent arteriole, is associated with prevention of progressive albuminuria and renal dysfunction. Uncertainty still exists as to why some individuals with long-standing T1D develop diabetic kidney disease (DKD) while others do not (DKD resistors). We hypothesized that those with DKD would be distinguished from DKD resistors by the presence of RAAS activation. METHODS Renal and systemic hemodynamic function was measured before and after exogenous RAAS stimulation by intravenous infusion of angiotensin II (ANGII) in 75 patients with prolonged T1D durations and in equal numbers of nondiabetic controls. The primary outcome was change in renal vascular resistance (RVR) in response to RAAS stimulation, a measure of endogenous RAAS activation. RESULTS Those with DKD had less change in RVR following exogenous RAAS stimulation compared with DKD resistors or controls (19%, 29%, 31%, P = 0.008, DKD vs. DKD resistors), reflecting exaggerated endogenous renal RAAS activation. All T1D participants had similar changes in renal efferent arteroilar resistance (9% vs. 13%, P = 0.37) irrespective of DKD status, which reflected less change versus controls (20%, P = 0.03). In contrast, those with DKD exhibited comparatively less change in afferent arteriolar vascular resistance compared with DKD resistors or controls (33%, 48%, 48%, P = 0.031, DKD vs. DKD resistors), indicating higher endogenous RAAS activity. CONCLUSION In long-standing T1D, the intrarenal RAAS is exaggerated in DKD, which unexpectedly predominates at the afferent rather than the efferent arteriole, stimulating vasoconstriction. FUNDING JDRF operating grant 17-2013-312.
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Affiliation(s)
- Julie A. Lovshin
- Division of Endocrinology and Metabolism and
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Geneviève Boulet
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Yuliya Lytvyn
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Leif E. Lovblom
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Petter Bjornstad
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Research Division, Barbara Davis Center for Diabetes, Aurora, Colorado, USA
| | - Mohammed A. Farooqi
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Vesta Lai
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Leslie Cham
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Josephine Tse
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Andrej Orszag
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Daniel Scarr
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Alanna Weisman
- Division of Endocrinology and Metabolism and
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Hillary A. Keenan
- Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA
| | - Michael H. Brent
- Department of Ophthalmology and Vision Sciences, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Narinder Paul
- Joint Department of Medical Imaging, Division of Cardiothoracic Radiology, University Health Network, Toronto, Ontario, Canada
| | - Vera Bril
- Ellen and Martin Prosserman Centre for Neuromuscular Diseases, Krembil Neuroscience Centre, Division of Neurology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Bruce A. Perkins
- Division of Endocrinology and Metabolism and
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - David Z.I. Cherney
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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Wanner C, Lachin JM, Inzucchi SE, Fitchett D, Mattheus M, George J, Woerle HJ, Broedl UC, von Eynatten M, Zinman B. Empagliflozin and Clinical Outcomes in Patients With Type 2 Diabetes Mellitus, Established Cardiovascular Disease, and Chronic Kidney Disease. Circulation 2018; 137:119-129. [DOI: 10.1161/circulationaha.117.028268] [Citation(s) in RCA: 283] [Impact Index Per Article: 40.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Accepted: 08/31/2017] [Indexed: 12/13/2022]
Affiliation(s)
- Christoph Wanner
- Comprehensive Heart Failure Center and Renal Division, University of Wuerzburg and Hospital, Germany (C.W.)
| | - John M. Lachin
- Biostatistics Center, George Washington University, Rockville, MD (J.M.L.)
| | - Silvio E. Inzucchi
- Section of Endocrinology, Yale University School of Medicine, New Haven, CT (S.E.I.)
| | - David Fitchett
- St. Michael’s Hospital, Division of Cardiology, University of Toronto, Canada (D.F.)
| | - Michaela Mattheus
- Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany (M.M., J.G., H.J.W., U.C.B., M.v.E.)
| | - Jyothis George
- Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany (M.M., J.G., H.J.W., U.C.B., M.v.E.)
| | - Hans J. Woerle
- Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany (M.M., J.G., H.J.W., U.C.B., M.v.E.)
| | - Uli C. Broedl
- Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany (M.M., J.G., H.J.W., U.C.B., M.v.E.)
| | - Maximilian von Eynatten
- Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany (M.M., J.G., H.J.W., U.C.B., M.v.E.)
| | - Bernard Zinman
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada (B.Z.) and Division of Endocrinology, University of Toronto, Canada (B.Z.)
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Bjornstad P, Costacou T, Miller RG, Maahs DM, Rewers MJ, Orchard TJ, Snell-Bergeon JK. Predictors of early renal function decline in adults with Type 1 diabetes: the Coronary Artery Calcification in Type 1 Diabetes and the Pittsburgh Epidemiology of Diabetes Complications studies. Diabet Med 2017; 34:1532-1540. [PMID: 28734104 PMCID: PMC5647234 DOI: 10.1111/dme.13430] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/19/2017] [Indexed: 12/14/2022]
Abstract
AIM Diabetic kidney disease is one of the leading complications of Type 1 diabetes, but its prediction remains a challenge. We examined predictors of rapid decline in estimated GFR (eGFR) in two Type 1 diabetes cohorts: the Coronary Artery Calcification in Type 1 Diabetes (CACTI) and the Pittsburgh Epidemiology of Diabetes Complications (EDC). METHODS A select subset of participants (CACTI: n = 210 and EDC: n = 98) diagnosed before 17 years of age with Type 1 diabetes duration ≥ 7 years, and follow-up data on eGFR by CKD-EPI creatinine for up to 8 years were included in the analyses. Early renal function decline was defined as annual decline in eGFR ≥ 3 ml/min/1.73 m2 , and normal age-related decline as eGFR ≤ 1 ml/min/1.73 m2 . Parallel logistic regression models were constructed in the two cohorts. RESULTS Early renal function decline incidence was 36% in CACTI and 41% in EDC. In both cohorts, greater baseline eGFR (CACTI: OR 3.12, 95% CI 1.97-5.05; EDC: OR 1.92, 95% CI 1.17-3.15 per 10 ml/min/1.73 m2 ) and log albumin-to-creatinine (ACR) (CACTI: OR 3.24, 95% CI 1.80-5.83; EDC: OR 1.87, 95% CI 1.18-2.96 per 1 unit) predicted greater odds of early renal function decline in fully adjusted models. Conversely, ACE inhibition predicted lower odds of early renal function decline in women in CACTI, but similar relationships were not observed in women in EDC. CONCLUSIONS A substantial proportion of people with Type 1 diabetes in the EDC and CACTI cohorts experienced early renal function decline over time. ACE inhibition appeared to be protective only in women in CACTI where the prevalence of its use was twofold higher compared with the EDC.
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Affiliation(s)
- P Bjornstad
- Department of Pediatric Endocrinology, University of Colorado School of Medicine
- Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, CO
| | - T Costacou
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA
| | - R G Miller
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA
| | - D M Maahs
- Department of Pediatric Endocrinology, Stanford University School of Medicine, Palo Alto, CA, USA
| | - M J Rewers
- Department of Pediatric Endocrinology, University of Colorado School of Medicine
- Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, CO
| | - T J Orchard
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA
| | - J K Snell-Bergeon
- Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, CO
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39
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Haymann JP, Hammoudi N, Stankovic Stojanovic K, Galacteros F, Habibi A, Avellino V, Bartolucci P, Benzerara Y, Arlet JB, Djebbar M, Letavernier E, Grateau G, Tabibzadeh N, Girshovich A, Chaignon M, Girot R, Levy P, Lionnet F. Renin-angiotensin system blockade promotes a cardio-renal protection in albuminuric homozygous sickle cell patients. Br J Haematol 2017; 179:820-828. [DOI: 10.1111/bjh.14969] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 08/25/2017] [Indexed: 01/26/2023]
Affiliation(s)
- Jean-Philippe Haymann
- Service d'Explorations Fonctionnelles Hôpital Tenon; Assistance Publique-Hopitaux de Paris; Paris France
- Sorbonne Universites UPMC Univ Paris 06; Paris France
- Institut National de la Sante et de la Recherche Medicale; UMR-S 1155; Paris France
| | - Nadjib Hammoudi
- Service de Cardiologie; Hôpital de la Pitie Salpetrière; Assistance Publique-Hopitaux de Paris; Paris France
- Institute of Cardiometabolism and Nutrition (ICAN); Paris France
| | | | - Frederic Galacteros
- Centre for Sickle Cell Disease; Hôpital Mondor; Assistance Publique-Hopitaux de Paris; Paris France
| | - Anoosha Habibi
- Centre for Sickle Cell Disease; Hôpital Mondor; Assistance Publique-Hopitaux de Paris; Paris France
| | - Virginie Avellino
- Centre for Sickle Cell Disease; Hôpital Tenon; Assistance Publique-Hopitaux de Paris; Paris France
| | - Pablo Bartolucci
- Centre for Sickle Cell Disease; Hôpital Mondor; Assistance Publique-Hopitaux de Paris; Paris France
| | - Yahia Benzerara
- Service d'Explorations Fonctionnelles Hôpital Tenon; Assistance Publique-Hopitaux de Paris; Paris France
| | - Jean-Benoit Arlet
- Centre for Sickle Cell Disease; Hôpital Européen Georges Pompidou; Assistance Publique-Hopitaux de Paris; Paris France
| | - Morad Djebbar
- Service d'Explorations Fonctionnelles Hôpital Tenon; Assistance Publique-Hopitaux de Paris; Paris France
| | - Emmanuel Letavernier
- Service d'Explorations Fonctionnelles Hôpital Tenon; Assistance Publique-Hopitaux de Paris; Paris France
- Sorbonne Universites UPMC Univ Paris 06; Paris France
- Institut National de la Sante et de la Recherche Medicale; UMR-S 1155; Paris France
| | - Gilles Grateau
- Centre for Sickle Cell Disease; Hôpital Tenon; Assistance Publique-Hopitaux de Paris; Paris France
| | - Nathalie Tabibzadeh
- Service d'Explorations Fonctionnelles Hôpital Tenon; Assistance Publique-Hopitaux de Paris; Paris France
| | - Alexei Girshovich
- Service d'Explorations Fonctionnelles Hôpital Tenon; Assistance Publique-Hopitaux de Paris; Paris France
| | - Michel Chaignon
- Service d'Explorations Fonctionnelles Hôpital Tenon; Assistance Publique-Hopitaux de Paris; Paris France
| | - Robert Girot
- Centre for Sickle Cell Disease; Hôpital Tenon; Assistance Publique-Hopitaux de Paris; Paris France
| | - Pierre Levy
- Public Health Department; Hôpital Tenon; Assistance Publique-Hopitaux de Paris; Paris France
| | - Francois Lionnet
- Centre for Sickle Cell Disease; Hôpital Tenon; Assistance Publique-Hopitaux de Paris; Paris France
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Reboldi G, Verdecchia P, Fiorucci G, Beilin LJ, Eguchi K, Imai Y, Kario K, Ohkubo T, Pierdomenico SD, Schwartz JE, Wing L, Saladini F, Palatini P. Glomerular hyperfiltration is a predictor of adverse cardiovascular outcomes. Kidney Int 2017; 93:195-203. [PMID: 28935213 DOI: 10.1016/j.kint.2017.07.013] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 06/23/2017] [Accepted: 07/06/2017] [Indexed: 12/24/2022]
Abstract
The association between glomerular hyperfiltration and cardiovascular events is not well known. To investigate whether glomerular hyperfiltration is independently associated with risk of adverse outcome we analyzed 8794 participants, average age 52 years enrolled in 8 prospective studies. Of these, 89% had hypertension. Using the 5th and 95th percentiles of the age- and sex-specific quintiles of CKD-EPI-calculated estimated glomerular filtration rate (eGFR), we identified three participant groups with low, high and normal eGFR. The ambulatory pulse pressure interval was wider and nighttime blood pressure fall was smaller in both the low and high than in the normal eGFR participants. During a mean follow-up of 6.2 years, there were 722 cardiovascular events. Crude event rates were significantly higher for both high (1.8 per 100-person-year) and low eGFR groups (2.1 per 100 person-year) as compared with group with normal eGFR (1.2 per 100 person-year). In multivariable Cox models including age, sex, average 24-hour blood pressure, smoking, diabetes, and cholesterol, both high eGFR (hazard ratio 1.5 (95% confidence interval 1.2-2.1) and low eGFR (2.0 [1.5-2.6]) participants had a significantly higher risk of cardiovascular events as compared to those with normal eGFR. Addition of body mass index to the multivariable survival model did not change the magnitude of hazard estimates. Thus, glomerular hyperfiltration is a strong and independent predictor of cardiovascular events in a large multiethnic population of predominantly hypertensive individuals. Our findings support a U-shaped relationship between eGFR and adverse outcome.
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Affiliation(s)
| | | | | | - Lawrence J Beilin
- University of Western Australia, Perth, Western Australia, Australia
| | | | | | | | - Takayoshi Ohkubo
- Tohoku University, Sendai, Japan; Shiga University of Medical Science, Otsu, Japan
| | | | - Joseph E Schwartz
- Columbia University, New York, New York, USA; Stony Brook University, Stony Brook, New York, USA
| | - Lindon Wing
- Flinders University, Adelaide, South Australia; Australia
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Lytvyn Y, Har R, Locke A, Lai V, Fong D, Advani A, Perkins BA, Cherney DZI. Renal and Vascular Effects of Uric Acid Lowering in Normouricemic Patients With Uncomplicated Type 1 Diabetes. Diabetes 2017; 66:1939-1949. [PMID: 28408434 DOI: 10.2337/db17-0168] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 04/05/2017] [Indexed: 11/13/2022]
Abstract
Higher plasma uric acid (PUA) levels are associated with lower glomerular filtration rate (GFR) and higher blood pressure (BP) in patients with type 1 diabetes (T1D). Our aim was to determine the impact of PUA lowering on renal and vascular function in patients with uncomplicated T1D. T1D patients (n = 49) were studied under euglycemic and hyperglycemic conditions at baseline and after PUA lowering with febuxostat (FBX) for 8 weeks. Healthy control subjects were studied under normoglycemic conditions (n = 24). PUA, GFR (inulin), effective renal plasma flow (para-aminohippurate), BP, and hemodynamic responses to an infusion of angiotensin II (assessment of intrarenal renin-angiotensin-aldosterone system [RAAS]) were measured before and after FBX treatment. Arterial stiffness, flow-mediated dilation (FMD), nitroglycerin-mediated dilation (GMD), urinary nitric oxide (NO), and inflammatory markers were measured before and after FBX treatment. Gomez equations were used to estimate arteriolar afferent resistance, efferent resistance (RE), and glomerular hydrostatic pressure (PGLO). FBX had a modest systolic BP-lowering effect in T1D patients (112 ± 10 to 109 ± 9 mmHg, P = 0.049) without impacting arterial stiffness, FMD, GMD, or NO. FBX enhanced the filtration fraction response to hyperglycemia in T1D patients through larger increases in RE, PGLO, and interleukin-18 but without impacting the RAAS. FBX lowered systolic BP and modulated the renal RE responses to hyperglycemia but without impacting the RAAS or NO levels, suggesting that PUA may augment other hemodynamic or inflammatory mechanisms that control the renal response to hyperglycemia at the efferent arteriole. Ongoing outcome trials will determine cardiorenal outcomes of PUA lowering in patients with T1D.
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Affiliation(s)
- Yuliya Lytvyn
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
| | - Ronnie Har
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Amy Locke
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Vesta Lai
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Derek Fong
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Andrew Advani
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada
| | - Bruce A Perkins
- Department of Medicine, Division of Endocrinology and Metabolism, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
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Xu L, Li Y, Lang J, Xia P, Zhao X, Wang L, Yu Y, Chen L. Effects of sodium-glucose co-transporter 2 (SGLT2) inhibition on renal function and albuminuria in patients with type 2 diabetes: a systematic review and meta-analysis. PeerJ 2017; 5:e3405. [PMID: 28663934 PMCID: PMC5490461 DOI: 10.7717/peerj.3405] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 05/11/2017] [Indexed: 12/25/2022] Open
Abstract
Aim To evaluate the effects of sodium-glucose co-transporter 2 (SGLT2) inhibition on renal function and albuminuria in patients with type 2 diabetes. Methods We conducted systematic searches of PubMed, Embase and Cochrane Central Register of Controlled Trials up to June 2016 and included randomized controlled trials of SGLT2 inhibitors in adult type 2 diabetic patients reporting estimated glomerular filtration rate (eGFR) and/or urine albumin/creatinine ratio (ACR) changes. Data were synthesized using the random-effects model. Results Forty-seven studies with 22,843 participants were included. SGLT2 inhibition was not associated with a significant change in eGFR in general (weighted mean difference (WMD), −0.33 ml/min per 1.73 m2, 95% CI [−0.90 to 0.23]) or in patients with chronic kidney disease (CKD) (WMD −0.78 ml/min per 1.73 m2, 95% CI [−2.52 to 0.97]). SGLT2 inhibition was associated with eGFR reduction in short-term trials (WMD −0.98 ml/min per 1.73 m2, 95% CI [−1.42 to −0.54]), and with eGFR preservation in long-term trials (WMD 2.01 ml/min per 1.73 m2, 95% CI [0.86 to 3.16]). Urine ACR reduction after SGLT2 inhibition was not statistically significant in type 2 diabetic patients in general (WMD −7.24 mg/g, 95% CI [−15.54 to 1.06]), but was significant in patients with CKD (WMD −107.35 mg/g, 95% CI [−192.53 to −22.18]). Conclusions SGLT2 inhibition was not associated with significant changes in eGFR in patients with type 2 diabetes, likely resulting from a mixture of an initial reduction of eGFR and long-term renal function preservation. SGLT2 inhibition was associated with statistically significant albuminuria reduction in type 2 diabetic patients with CKD.
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Affiliation(s)
- Lubin Xu
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yang Li
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jiaxin Lang
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Peng Xia
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinyu Zhao
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, and School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Li Wang
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, and School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yang Yu
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Limeng Chen
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Han E, Lee YH, Lee BW, Kang ES, Cha BS. Pre-sarcopenia is associated with renal hyperfiltration independent of obesity or insulin resistance: Nationwide Surveys (KNHANES 2008-2011). Medicine (Baltimore) 2017; 96:e7165. [PMID: 28658107 PMCID: PMC5500029 DOI: 10.1097/md.0000000000007165] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Renal hyperfiltration is closely linked to cardiometabolic disorders, and it may increase the mortality risk of the general population. Despite the well-established association between cardiometabolic diseases and sarcopenia, the relationship between renal hyperfiltration and sarcopenia has not yet been assessed.This population-based, cross-sectional study used a nationally representative sample of 13,800 adults from the 2008 to 2011 Korea National Health and Nutrition Examination Survey. Renal hyperfiltration was defined as the age- and sex-specific glomerular filtration rate above the 90th percentile in subjects with normal kidney function (>60 mL/min/1.73 m). Appendicular skeletal muscle (ASM), measured by dual-energy x-ray absorptiometry, was used to assess pre-sarcopenia, which the international consensus defines as both ASM per se and ASM that was adjusted for the body mass index and the height.A total of 1402 (10.2%) participants were classified as having renal hyperfiltration. The prevalence of pre-sarcopenia ranged from 11.6% to 33.0%, by definition. Individuals with pre-sarcopenia had higher risks of renal hyperfiltration compared to those without pre-sarcopenia (10.9% vs 17.4%, P < .001; odds ratio [OR] = 1.71, 95% confidential interval [CI] = 1.48-1.99, P < .001). Multiple logistic regression analyses also demonstrated this independent association between pre-sarcopenia and renal hyperfiltration, following adjustment for confounding factors such as insulin resistance and obesity (OR = 1.84, 95% CI = 1.57-2.15, P < .001).In the general population of healthy individuals, pre-sarcopenia might be associated with renal hyperfiltration independent of obesity or insulin resistance.
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Affiliation(s)
- Eugene Han
- Department of Internal Medicine
- Graduate School
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Yong-ho Lee
- Department of Internal Medicine
- Graduate School
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul
| | - Byung-Wan Lee
- Department of Internal Medicine
- Graduate School
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul
| | - Eun Seok Kang
- Department of Internal Medicine
- Graduate School
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul
| | - Bong-Soo Cha
- Department of Internal Medicine
- Graduate School
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul
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Kawanami D, Matoba K, Takeda Y, Nagai Y, Akamine T, Yokota T, Sango K, Utsunomiya K. SGLT2 Inhibitors as a Therapeutic Option for Diabetic Nephropathy. Int J Mol Sci 2017; 18:ijms18051083. [PMID: 28524098 PMCID: PMC5454992 DOI: 10.3390/ijms18051083] [Citation(s) in RCA: 122] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 05/03/2017] [Accepted: 05/15/2017] [Indexed: 12/11/2022] Open
Abstract
Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD) worldwide. Glycemic and blood pressure (BP) control are important but not sufficient to attenuate the incidence and progression of DN. Sodium–glucose cotransporter (SGLT) 2 inhibitors are a new class of glucose-lowering agent suggested to exert renoprotective effects in glucose lowering-dependent and independent fashions. Experimental studies have shown that SGLT2 inhibitors attenuate DN in animal models of both type 1 diabetes (T1D) and type 2 diabetes (T2D), indicating a potential renoprotective effect beyond glucose reduction. Renoprotection by SGLT2 inhibitors has been demonstrated in T2D patients with a high cardiovascular risk in randomized controlled trials (RCTs). These favorable effects of SGLT2 inhibitors are explained by several potential mechanisms, including the attenuation of glomerular hyperfiltration, inflammation and oxidative stress. In this review article, we discuss the renoprotective effects of SGLT2 inhibitors by integrating experimental findings with the available clinical data.
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Affiliation(s)
- Daiji Kawanami
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
| | - Keiichiro Matoba
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
| | - Yusuke Takeda
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
| | - Yosuke Nagai
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
| | - Tomoyo Akamine
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
- Diabetic Neuropathy Project, Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
| | - Tamotsu Yokota
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
| | - Kazunori Sango
- Diabetic Neuropathy Project, Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
| | - Kazunori Utsunomiya
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
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MacIsaac RJ, Jerums G, Ekinci EI. Effects of glycaemic management on diabetic kidney disease. World J Diabetes 2017; 8:172-186. [PMID: 28572879 PMCID: PMC5437616 DOI: 10.4239/wjd.v8.i5.172] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2016] [Revised: 11/07/2016] [Accepted: 03/17/2017] [Indexed: 02/05/2023] Open
Abstract
Hyperglycaemia contributes to the onset and progression of diabetic kidney disease (DKD). Observational studies have not consistently demonstrated a glucose threshold, in terms of HbA1c levels, for the onset of DKD. Tight glucose control has clearly been shown to reduce the incidence of micro- or macroalbuminuria. However, evidence is now also emerging to suggest that intensive glucose control can slow glomerular filtration rate loss and possibly progression to end stage kidney disease. Achieving tight glucose control needs to be balanced against the increasing appreciation that glucose targets for the prevention of diabetes related complications need be individualised for each patient. Recently, empagliflozin which is an oral glucose lowering agent of the sodium glucose cotransporter-2 inhibitor class has been shown to have renal protective effects. However, the magnitude of empagliflozin’s reno-protective properties are over and above that expected from its glucose lowering effects and most likely largely result from mechanisms involving alterations in intra-renal haemodynamics. Liraglutide and semaglutide, both injectable glucose lowering agents which are analogues of human glucagon like peptide-1 have also been shown to reduce progression to macroalbuminuria through mechanisms that remain to be fully elucidated. Here we review the evidence from observational and interventional studies that link good glucose control with improved renal outcomes. We also briefly review the potential reno-protective effects of newer glucose lowering agents.
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Tonneijck L, Muskiet MHA, Smits MM, van Bommel EJ, Heerspink HJL, van Raalte DH, Joles JA. Glomerular Hyperfiltration in Diabetes: Mechanisms, Clinical Significance, and Treatment. J Am Soc Nephrol 2017; 28:1023-1039. [PMID: 28143897 DOI: 10.1681/asn.2016060666] [Citation(s) in RCA: 540] [Impact Index Per Article: 67.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
An absolute, supraphysiologic elevation in GFR is observed early in the natural history in 10%-67% and 6%-73% of patients with type 1 and type 2 diabetes, respectively. Moreover, at the single-nephron level, diabetes-related renal hemodynamic alterations-as an adaptation to reduction in functional nephron mass and/or in response to prevailing metabolic and (neuro)hormonal stimuli-increase glomerular hydraulic pressure and transcapillary convective flux of ultrafiltrate and macromolecules. This phenomenon, known as glomerular hyperfiltration, classically has been hypothesized to predispose to irreversible nephron damage, thereby contributing to initiation and progression of kidney disease in diabetes. However, dedicated studies with appropriate diagnostic measures and clinically relevant end points are warranted to confirm this assumption. In this review, we summarize the hitherto proposed mechanisms involved in diabetic hyperfiltration, focusing on ultrastructural, vascular, and tubular factors. Furthermore, we review available evidence on the clinical significance of hyperfiltration in diabetes and discuss currently available and emerging interventions that may attenuate this renal hemodynamic abnormality. The revived interest in glomerular hyperfiltration as a prognostic and pathophysiologic factor in diabetes may lead to improved and timely detection of (progressive) kidney disease, and could provide new therapeutic opportunities in alleviating the renal burden in this population.
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Affiliation(s)
- Lennart Tonneijck
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands;
| | - Marcel H A Muskiet
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Mark M Smits
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Erik J van Bommel
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Hiddo J L Heerspink
- Department of Clinical Pharmacology, University Medical Center Groningen, Groningen, The Netherlands; and
| | - Daniël H van Raalte
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Jaap A Joles
- Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands
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van der Sande NG, Blankestijn PJ, Leiner T, van der Graaf Y, de Borst GJ, Cramer MJ, Visseren FL. High ratios of kidney function to kidney size are related to mortality and kidney function decline in high-risk patients. Eur J Prev Cardiol 2017; 24:926-933. [PMID: 28121180 DOI: 10.1177/2047487317690950] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background The ratio of estimated glomerular filtration rate (eGFR) to kidney size reflects the kidney's capacity for filtration per kidney volume or kidney length. High ratios of eGFR to kidney size, which might indicate glomerular hyperfiltration, could be related to kidney function decline, cardiovascular disease and mortality. Methods In 6926 patients with clinically manifest vascular disease, we evaluated the relationship between eGFR/kidney size and the risk of cardiovascular events and all-cause mortality using Cox regression. Quartiles were made for eGFR/kidney size, using the second quartile as the reference category. In 1516 patients with second measurements of eGFR, linear regression was used to evaluate the relationship between eGFR/kidney size and annual kidney function decline. Results The relationship between eGFR/kidney size and all-cause mortality followed a reversed J-shaped curve with increased risk for the lowest (hazard ratio (HR) 1.17; 95% confidence interval (CI) 1.01-1.36) and highest quartile (HR 1.04; 95% CI 0.87-1.25) of eGFR/volume, and for the lowest (HR 1.37;95%CI 1.19-1.59) and highest quartile (HR 1.28; 95% CI 1.06-1.54) of eGFR/length. The risk for cardiovascular events was increased for the lowest quartile of eGFR/length (HR 1.55; 95% CI 1.33-1.82). An increase in eGFR/volume and eGFR/length, was related to a greater kidney function decline, β -0.34 (95% CI -0.42 to -0.26) and β -0.55 (95% CI -0.63 to -0.48) ml/min/1.73 m2 per year respectively. Conclusions High eGFR/volume and eGFR/length, which might indicate glomerular hyperfiltration, are related to kidney function decline. High eGFR/length confers an increased risk for all-cause mortality in patients with clinically manifest vascular disease.
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Affiliation(s)
- Nicolette Gc van der Sande
- 1 Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.,2 Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Peter J Blankestijn
- 2 Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Tim Leiner
- 3 Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Yolanda van der Graaf
- 4 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Gert Jan de Borst
- 5 Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Maarten Jm Cramer
- 6 Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Frank Lj Visseren
- 1 Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
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Qiu Q, Gong Y, Liu X, Dou L, Wang Y, Wang B, Liang J. Serum Uric Acid and Impaired Glucose Tolerance: The Cardiometabolic Risk in Chinese (CRC) Study. Cell Biochem Biophys 2017; 73:155-62. [PMID: 25707501 DOI: 10.1007/s12013-015-0597-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Serum uric acid (SUA) elevation has been previously related to impaired fasting glucose and type 2 diabetes. The present study was comprehensive to examine the associations between SUA and impaired glucose tolerance (IGT) in Chinese adults. For this purpose, data were collected from a community-based health examination survey conducted in Central China; 2-h glucose (OGTT) and SUA were measured in 1956 men and women. In multivariate models, SUA levels were significantly associated with an increasing trend of 2-h glucose (OGTT) (P for trend < 0.0001). The odds ratios (OR; 95 % CI) of IGT across increasing quartiles of SUA were 1.0, 1.354 (0.948-2.087), 1.337 (0.959-2.251), and 2.192 (1.407-3.416), after adjusting for age, sex, body mass index, waist circumference, fasting insulin, blood pressure, serum lipids, serum creatinine, and estimated glomerular filtration rate. (P for trend = 0.001). In addition, we found an additive pattern between SUA and triglyceride (TG; P = 0.038) or between SUA and low-density lipoprotein cholesterol (LDL-C; P = 0.041) in relation to IGT. SUA was related to IGT in the Chinese adults, independent of other conventional metabolic risk factors. TG and LDL-C might modify the associations.
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Affiliation(s)
- Qinqin Qiu
- Xuzhou Medical College, Xuzhou, 221009, Jiangsu, China
| | - Ying Gong
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical College, Affiliated Hospital of Southeast University, 199# South Jiefang Road, Xuzhou, 221009, Jiangsu, China.,Xuzhou Institute of Medical Sciences, Xuzhou Institute of Diabetes, Xuzhou, 221009, Jiangsu, China
| | - Xuekui Liu
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical College, Affiliated Hospital of Southeast University, 199# South Jiefang Road, Xuzhou, 221009, Jiangsu, China.,Xuzhou Institute of Medical Sciences, Xuzhou Institute of Diabetes, Xuzhou, 221009, Jiangsu, China
| | - Lianjun Dou
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical College, Affiliated Hospital of Southeast University, 199# South Jiefang Road, Xuzhou, 221009, Jiangsu, China.,Xuzhou Institute of Medical Sciences, Xuzhou Institute of Diabetes, Xuzhou, 221009, Jiangsu, China
| | - Yu Wang
- Xuzhou Medical College, Xuzhou, 221009, Jiangsu, China.,Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical College, Affiliated Hospital of Southeast University, 199# South Jiefang Road, Xuzhou, 221009, Jiangsu, China.,Xuzhou Institute of Medical Sciences, Xuzhou Institute of Diabetes, Xuzhou, 221009, Jiangsu, China
| | - Ben Wang
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical College, Affiliated Hospital of Southeast University, 199# South Jiefang Road, Xuzhou, 221009, Jiangsu, China.,Xuzhou Institute of Medical Sciences, Xuzhou Institute of Diabetes, Xuzhou, 221009, Jiangsu, China
| | - Jun Liang
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical College, Affiliated Hospital of Southeast University, 199# South Jiefang Road, Xuzhou, 221009, Jiangsu, China. .,Xuzhou Institute of Medical Sciences, Xuzhou Institute of Diabetes, Xuzhou, 221009, Jiangsu, China.
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49
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Škrtić M, Lytvyn Y, Bjornstad P, Reich HN, Scholey JW, Yip P, Sochett EB, Perkins B, Cherney DZI. Influence of sex on hyperfiltration in patients with uncomplicated type 1 diabetes. Am J Physiol Renal Physiol 2016; 312:F599-F606. [PMID: 28031170 DOI: 10.1152/ajprenal.00357.2016] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 11/28/2016] [Accepted: 12/21/2016] [Indexed: 01/26/2023] Open
Abstract
The aim of this analysis was to examine sex-based differences in renal segmental resistances in healthy controls (HCs) and patients with type 1 diabetes (T1D). We hypothesized that hyperfiltration-an early hemodynamic abnormality associated with diabetic nephropathy-would disproportionately affect women with T1D, thereby attenuating protection against the development of renal complications. Glomerular hemodynamic parameters were evaluated in HC (n = 30) and in normotensive, normoalbuminuric patients with T1D and either baseline normofiltration [n = 36, T1D-N, glomerular filtration rate (GFR) 90-134 ml·min-1·1.73 m2] or hyperfiltration (n = 32, T1D-H, GFR ≥ 135 ml·min-1·1.73 m2) during euglycemic conditions (4-6 mmol/l). Gomez's equations were used to derive efferent (RE) and afferent (RA) arteriolar resistances, glomerular hydrostatic pressure (PGLO) from inulin (GFR) and paraaminohippurate [effective renal plasma flow (ERPF)] clearances, plasma protein and estimated ultrafiltration coefficients (KFG). Female patients with T1D with hyperfiltration (T1D-H) had higher RE (1,985 ± 487 vs. 1,381 ± 296 dyne·sec-1·cm-5, P < 0.001) and filtration fraction (FF, 0.20 ± 0.047 vs. 0.16 ± 0.03 P < 0.05) and lower ERPF (876 ± 245 vs. 1,111 ± 298 134 ml·min-1·1.73 m2P < 0.05) compared with male T1D-H patients. Overall, T1D-H patients had higher PGLO and lower RA vs. HC subjects, although there were no sex-based differences. In conclusion, female T1D-H patients had higher RE and FF and lower ERPF than their male counterparts with no associated sex differences in RA Prospective intervention studies should consider sex as a modifier of renal hemodynamic responses to renal protective therapies.
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Affiliation(s)
- Marko Škrtić
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Yuliya Lytvyn
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.,Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
| | - Petter Bjornstad
- Department of Pediatric Endocrinology, Barbara Davis Center for Diabetes University of Colorado School of Medicine, Aurora, CO
| | - Heather N Reich
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - James W Scholey
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Paul Yip
- University Health Network, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Etienne B Sochett
- Department of Pediatrics, Division of Endocrinology, Sickkids Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Bruce Perkins
- Department of Medicine, Division of Endocrinology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada; .,Department of Medicine, Division of Endocrinology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.,Department of Physiology, University of Toronto, Toronto, Ontario, Canada; and.,Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
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Andrianesis V, Glykofridi S, Doupis J. The renal effects of SGLT2 inhibitors and a mini-review of the literature. Ther Adv Endocrinol Metab 2016; 7:212-228. [PMID: 28203358 PMCID: PMC5298360 DOI: 10.1177/2042018816676239] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Sodium-glucose linked transporter 2 (SGLT2) inhibitors are a new and promising class of antidiabetic agents which target renal tubular glucose reabsorption. Their action is based on the blockage of SGLT2 sodium-glucose cotransporters that are located at the luminal membrane of tubular cells of the proximal convoluted tubule, inducing glucosuria. It has been proven that they significantly reduce glycated hemoglobin (HbA1c), along with fasting and postprandial plasma glucose in patients with type 2 diabetes mellitus (T2DM). The glucosuria-induced caloric loss as well as the osmotic diuresis significantly decrease body weight and blood pressure, respectively. Given that SGLT2 inhibitors do not interfere with insulin action and secretion, their efficacy is sustained despite the progressive β-cell failure in T2DM. They are well tolerated, with a low risk of hypoglycemia. Their most frequent adverse events are minor: genital and urinal tract infections. Recently, it was demonstrated that empagliflozin presents a significant cardioprotective effect. Although the SGLT2 inhibitors' efficacy is affected by renal function, new data have been presented that some SGLT2 inhibitors, even in mild and moderate renal impairment, induce significant HbA1c reduction. Moreover, recent data indicate that SGLT2 inhibition has a beneficial renoprotective effect. The role of this review paper is to explore the current evidence on the renal effects of SGLT2 inhibitors.
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