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Gaddy A, Elrggal M, Madariaga H, Kelly A, Lerma E, Colbert GB. Diabetic Kidney Disease. Dis Mon 2025; 71:101848. [PMID: 39753456 DOI: 10.1016/j.disamonth.2024.101848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2025]
Abstract
Diabetic kidney disease is a leading cause of kidney failure worldwide and is easily detectable with screening examination. Diabetes causes hyperfiltration and activation of the renin-angiotensin aldosterone system by hemodynamic changes within the nephron, which perpetuates damaging physiology. Diagnosis is often clinical after detection of heavy proteinuria in a patient with diabetes,but can be confirmed by observation of histologic stages on kidney biopsy. Mainstays of treatment include angiotensin conversion or receptor blockade, mineralocorticoid receptor blockade, and tight glucose control. Newer agents favored in diabetic kidney disease are sodium glucose-cotransporters and glucagon-like peptide 1 receptor agonists, both for glycemic control and for various methods of reversing damaging physiology.
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Affiliation(s)
- Anna Gaddy
- Division of Nephrology, Medical College of Wisconsin, 8700 Watertown Plank Road Milwaukee, WI 53226, USA.
| | - Mohamed Elrggal
- Nephrology Department, Kidney and Urology Center, Alexandria, Egypt
| | | | - Adam Kelly
- Division of Nephrology, Medical College of Wisconsin, 8700 Watertown Plank Road Milwaukee, WI 53226, USA
| | - Edgar Lerma
- Section of Nephrology, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Gates B Colbert
- Division of Nephrology, Texas A&M University College of Medicine in Dallas, Dallas, TX 75246, USA
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Lytvyn Y, Scholtes RA, Boorsma EM, Sridhar VS, Kugathasan L, Liu H, Lovblom LE, Handoko L, Mosterd CM, Floras JS, Burns K, Osuntokun T, Voors A, van Raalte DH, Heerspink HJL, Cherney DZI. Mechanistic evaluation of ertugliflozin in patients with type 2 diabetes and heart failure. Physiol Rep 2025; 13:e70275. [PMID: 40207988 PMCID: PMC11983784 DOI: 10.14814/phy2.70275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 03/05/2025] [Accepted: 03/06/2025] [Indexed: 04/11/2025] Open
Abstract
The effect of sodium-glucose cotransporter-2 (SGLT2) inhibitor ertugliflozin on fluid volume and kidney function was assessed in patients with type 2 diabetes and heart failure. Thirty-four participants were randomized in this double-blind, placebo-controlled, parallel-group, multicenter study. Physiologic measurements were obtained under clamped euglycemia at baseline, 1 week, and 12 weeks of treatment. The primary outcome was the proximal tubular natriuretic effect of ertugliflozin versus placebo, measured by fractional excretion of lithium (FELi). Ertugliflozin did not increase FELi or total FENa at 1 week or 12 weeks. Ertugliflozin increased both mean 24-h urinary sodium excretion (47.5 ± 22.1 mmol/day vs. placebo, p = 0.032) and urinary volume (p = 0.009) at 1 week, which was attenuated at Week 12. Reductions in extracellular fluid (-1.9 ± 0.8 L, p = 0.01), estimated plasma volume (-11.9 ± 13.9%, p = 0.02), and supine mean arterial pressure (-6.6 ± 2.7 mmHg, p = 0.02) were significant at Week 12. Compared to placebo, ertugliflozin acutely increased circulating angiotensinogen and angiotensin-converting enzyme (ACE) levels, as well as urine adenosine and ACE2 activity (p < 0.05). Changes in other neurohormones, sympathetic activity, kidney, and systemic hemodynamics did not differ compared to placebo. Our findings suggest that SGLT2 inhibition shifts systemic volume toward a state of euvolemia, potentially lowering the risk of worsening heart failure.
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Affiliation(s)
- Yuliya Lytvyn
- Division of Nephrology, Department of MedicineUniversity Health NetworkTorontoOntarioCanada
- Temerty Faculty of MedicineUniversity of TorontoTorontoOntarioCanada
| | - Rosalie A. Scholtes
- Department of Internal Medicine, Diabetes CenterAmsterdam UMCAmsterdamThe Netherlands
| | - Eva M. Boorsma
- Department of Clinical Pharmacy and PharmacologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
- Department of Cardiology, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
| | - Vikas S. Sridhar
- Division of Nephrology, Department of MedicineUniversity Health NetworkTorontoOntarioCanada
- Temerty Faculty of MedicineUniversity of TorontoTorontoOntarioCanada
| | - Luxcia Kugathasan
- Division of Nephrology, Department of MedicineUniversity Health NetworkTorontoOntarioCanada
- Temerty Faculty of MedicineUniversity of TorontoTorontoOntarioCanada
| | - Hongyan Liu
- Division of Nephrology, Department of MedicineUniversity Health NetworkTorontoOntarioCanada
- Temerty Faculty of MedicineUniversity of TorontoTorontoOntarioCanada
| | - Leif E. Lovblom
- Biostatistics DepartmentUniversity Health NetworkTorontoOntarioCanada
- Institute of Health Policy, Management and EvaluationUniversity of TorontoTorontoOntarioCanada
| | - Louis Handoko
- Department of Internal Medicine, Diabetes CenterAmsterdam UMCAmsterdamThe Netherlands
| | - Charlotte M. Mosterd
- Department of Internal Medicine, Diabetes CenterAmsterdam UMCAmsterdamThe Netherlands
| | - John S. Floras
- Temerty Faculty of MedicineUniversity of TorontoTorontoOntarioCanada
- Division of CardiologyUniversity Health NetworkTorontoOntarioCanada
| | - Kevin Burns
- Kidney Research Centre, The Ottawa HospitalUniversity of OttawaOttawaOntarioCanada
| | - Tosin Osuntokun
- Division of CardiologyUniversity Health NetworkTorontoOntarioCanada
| | - Adriaan Voors
- Department of Clinical Pharmacy and PharmacologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
- Department of Cardiology, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
| | - Daniel H. van Raalte
- Department of Internal Medicine, Diabetes CenterAmsterdam UMCAmsterdamThe Netherlands
| | - Hiddo J. L. Heerspink
- Department of Clinical Pharmacy and PharmacologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - David Z. I. Cherney
- Division of Nephrology, Department of MedicineUniversity Health NetworkTorontoOntarioCanada
- Temerty Faculty of MedicineUniversity of TorontoTorontoOntarioCanada
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Lopez-Silva C, Surapaneni A, Schmidt IM, Upadhyay D, Srivastava A, Palsson R, Stillman IE, Rhee EP, Waikar SS, Grams ME. Circulating Protein and Metabolite Correlates of Histologically Confirmed Diabetic Kidney Disease. Kidney Med 2024; 6:100920. [PMID: 39634330 PMCID: PMC11615146 DOI: 10.1016/j.xkme.2024.100920] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2024] Open
Abstract
Rationale & Objective Diabetic kidney disease (DKD) is one of the leading causes of end-stage kidney disease globally. We aim to identify proteomic and metabolomic correlates of histologically confirmed DKD that may improve our understanding of its pathophysiology. Study Design A cross-sectional study. Setting & Participants A total of 434 Boston Kidney Biopsy Cohort participants. Predictors Histopathological diagnosis of DKD on biopsy. Outcomes Proteins and metabolites associated with DKD. Analytical Approach We performed linear regression to identify circulating proteins and metabolites associated with a histopathological diagnosis of DKD (n = 81) compared with normal or thin basement membrane (n = 27), and other kidney diseases without diabetes (n = 279). Pathway enrichment analysis was used to explore biological pathways enriched in DKD. Identified proteins were assessed for their discriminative ability in cases of DKD versus a distinct set of 48 patients with diabetes but other kidney diseases. Results After adjusting for age, sex, estimated glomerular filtration, and albuminuria levels, there were 8 proteins and 1 metabolite that differed between DKD and normal/thin basement membrane, and 84 proteins and 11 metabolites that differed between DKD and other kidney diseases without diabetes. Five proteins were significant in both comparisons: C-type mannose receptor 2, plexin-A1, plexin-D1, renin, and transmembrane glycoprotein NMB. The addition of these proteins improved discrimination over clinical variables alone of a histopathological diagnosis of DKD on biopsy among patients with diabetes (change in area under the curve 0.126; P = 0.008). Limitations A cross-sectional approach and lack of an external validation cohort. Conclusions Distinct proteins and biological pathways are correlated with a histopathological diagnosis of DKD.
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Affiliation(s)
- Carolina Lopez-Silva
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Aditya Surapaneni
- Division of Precision Medicine, NYU Grossman School of Medicine, New York City, NY
| | - Insa M. Schmidt
- Section of Nephrology, Department of Medicine, Boston Medical Center and Boston University Chobanian & Avedisian School of Medicine, Boston MA
| | - Dhairya Upadhyay
- Division of Precision Medicine, NYU Grossman School of Medicine, New York City, NY
| | - Anand Srivastava
- Division of Nephrology, University of Illinois Chicago, Chicago, IL
| | - Ragnar Palsson
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard University Medical School, Boston, MA
| | - Isaac E. Stillman
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Eugene P. Rhee
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard University Medical School, Boston, MA
| | - Sushrut S. Waikar
- Section of Nephrology, Department of Medicine, Boston Medical Center and Boston University Chobanian & Avedisian School of Medicine, Boston MA
| | - Morgan E. Grams
- Division of Precision Medicine, NYU Grossman School of Medicine, New York City, NY
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Kawada T, Yamamoto H, Fukumitsu M, Nishikawa T, Matsushita H, Yoshida Y, Sato K, Morita H, Alexander J, Saku K. Acute effects of empagliflozin on open-loop baroreflex function and urine output in streptozotocin-induced type 1 diabetic rats. J Physiol Sci 2024; 74:48. [PMID: 39342112 PMCID: PMC11438138 DOI: 10.1186/s12576-024-00938-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 09/04/2024] [Indexed: 10/01/2024]
Abstract
Although sympathetic suppression is considered one of the mechanisms for cardioprotection afforded by sodium-glucose cotransporter 2 (SGLT2) inhibitors, whether SGLT2 inhibition acutely modifies sympathetic arterial pressure (AP) regulation remains unclear. We examined the acute effect of an SGLT2 inhibitor, empagliflozin (10 mg/kg), on open-loop baroreflex static characteristics in streptozotocin (STZ)-induced type 1 diabetic and control (CNT) rats (n = 9 each). Empagliflozin significantly increased urine flow [CNT: 25.5 (21.7-31.2) vs. 55.9 (51.0-64.5), STZ: 83.4 (53.7-91.7) vs. 121.2 (57.0-136.0) μL·min-1·kg-1, median (1st-3rd quartiles), P < 0.001 for empagliflozin and STZ]. Empagliflozin decreased the minimum sympathetic nerve activity (SNA) [CNT: 15.7 (6.8-18.4) vs. 10.5 (2.9-19.0), STZ: 36.9 (25.7-54.9) vs. 32.8 (15.1-37.5) %, P = 0.021 for empagliflozin and P = 0.003 for STZ], but did not significantly affect the peripheral arc characteristics assessed by the SNA-AP relationship. Despite the significant increase in urine flow and changes in several baroreflex parameters, empagliflozin preserved the overall sympathetic AP regulation in STZ-induced diabetic rats. The lack of a significant change in the peripheral arc may minimize reflex sympathetic activation, thereby enhancing a cardioprotective benefit of empagliflozin.
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Affiliation(s)
- Toru Kawada
- Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center, Osaka, 564-8565, Japan.
| | - Hiromi Yamamoto
- Department of Cardiovascular Medicine, Kurashiki Central Hospital, Ohara HealthCare Foundation, Okayama, 710-8602, Japan
| | - Masafumi Fukumitsu
- Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center, Osaka, 564-8565, Japan
| | - Takuya Nishikawa
- Department of Research Promotion and Management, National Cerebral and Cardiovascular Center, Osaka, 564-8565, Japan
| | - Hiroki Matsushita
- Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center, Osaka, 564-8565, Japan
| | - Yuki Yoshida
- Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center, Osaka, 564-8565, Japan
| | - Kei Sato
- Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center, Osaka, 564-8565, Japan
| | - Hidetaka Morita
- Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center, Osaka, 564-8565, Japan
| | - Joe Alexander
- Medical and Health Informatics Laboratories, NTT Research, Inc, Sunnyvale, CA, 94085, USA
| | - Keita Saku
- Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center, Osaka, 564-8565, Japan
- Bio Digital Twin Center, National Cerebral and Cardiovascular Center, Osaka, 564-8565, Japan
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Nolze A, Matern S, Grossmann C. Calcineurin Is a Universal Regulator of Vessel Function-Focus on Vascular Smooth Muscle Cells. Cells 2023; 12:2269. [PMID: 37759492 PMCID: PMC10528183 DOI: 10.3390/cells12182269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/05/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Calcineurin, a serine/threonine phosphatase regulating transcription factors like NFaT and CREB, is well known for its immune modulatory effects and role in cardiac hypertrophy. Results from experiments with calcineurin knockout animals and calcineurin inhibitors indicate that calcineurin also plays a crucial role in vascular function, especially in vascular smooth muscle cells (VSMCs). In the aorta, calcineurin stimulates the proliferation and migration of VSMCs in response to vascular injury or angiotensin II administration, leading to pathological vessel wall thickening. In the heart, calcineurin mediates coronary artery formation and VSMC differentiation, which are crucial for proper heart development. In pulmonary VSMCs, calcineurin/NFaT signaling regulates the release of Ca2+, resulting in increased vascular tone followed by pulmonary arterial hypertension. In renal VSMCs, calcineurin regulates extracellular matrix secretion promoting fibrosis development. In the mesenteric and cerebral arteries, calcineurin mediates a phenotypic switch of VSMCs leading to altered cell function. Gaining deeper insights into the underlying mechanisms of calcineurin signaling will help researchers to understand developmental and pathogenetical aspects of the vasculature. In this review, we provide an overview of the physiological function and pathophysiology of calcineurin in the vascular system with a focus on vascular smooth muscle cells in different organs. Overall, there are indications that under certain pathological settings reduced calcineurin activity seems to be beneficial for cardiovascular health.
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Affiliation(s)
| | | | - Claudia Grossmann
- Julius Bernstein Institute of Physiology, Martin Luther University Halle-Wittenberg, 06112 Halle (Saale), Germany
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Zheng L, Qin R, Rao Z, Xiao W. High-intensity interval training induces renal injury and fibrosis in type 2 diabetic mice. Life Sci 2023; 324:121740. [PMID: 37120014 DOI: 10.1016/j.lfs.2023.121740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/13/2023] [Accepted: 04/24/2023] [Indexed: 05/01/2023]
Abstract
AIMS Previous studies showed that high-intensity interval training (HIIT) improved fasting blood glucose and insulin resistance in type 2 diabetes mellitus (T2DM) mice. However, the effect of HIIT on the kidneys of mice with T2DM has not been examined. This study aimed to investigate the impact of HIIT on the kidneys of T2DM mice. MATERIALS AND METHODS T2DM mice were induced with a high-fat diet (HFD) and one-time 100 mg/kg streptozotocin intraperitoneal injection, and then T2DM mice were treated with 8 weeks of HIIT. Renal function and glycogen deposition were observed by serum creatinine levels and PAS staining, respectively. Sirius red staining, hematoxylin-eosin staining, and Oil red O staining were used to detect fibrosis and lipid deposition. Western blotting was performed to detect the protein levels. KEY FINDINGS HIIT significantly ameliorated the body composition, fasting blood glucose, and serum insulin of the T2DM mice. HIIT also improved glucose tolerance, insulin tolerance, and renal lipid deposition of T2DM mice. However, we found that HIIT increased serum creatinine and glycogen accumulation in the kidneys of T2DM mice. Western blot analysis showed that the PI3K/AKT/mTOR signaling pathway was activated after HIIT. The expression of fibrosis-related proteins (TGF-β1, CTGF, collagen-III, α-SMA) increased, while the expression of klotho (sklotho) and MMP13 decreased in the kidneys of HIIT mice. SIGNIFICANCE This study concluded that HIIT induced renal injury and fibrosis, although it also improved glucose homeostasis in T2DM mice. The current study reminds us that patients with T2DM should be cautious when participating in HIIT.
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Affiliation(s)
- Lifang Zheng
- College of Physical Education, Shanghai University, Shanghai 200444, China; Shanghai Key Lab of Human Performance, Shanghai University of sport, Shanghai 200438, China
| | - Ruiting Qin
- College of Physical Education, Shanghai University, Shanghai 200444, China
| | - Zhijian Rao
- College of Physical Education, Shanghai Normal University, Shanghai 200234, China; Exercise Biological Center, China Institute of Sport Science, Beijing, China.
| | - Weihua Xiao
- Shanghai Key Lab of Human Performance, Shanghai University of sport, Shanghai 200438, China.
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Saulnier PJ, Bjornstad P. Renal hemodynamic changes in patients with type 2 diabetes and their clinical impact. Presse Med 2023; 52:104175. [PMID: 37783424 DOI: 10.1016/j.lpm.2023.104175] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 07/19/2023] [Indexed: 10/04/2023] Open
Abstract
The dysfunction of the internal mechanics within the kidney's filtering units, known as glomeruli, has been linked to the emergence and progression of diabetic kidney disease (DKD). To better understand this crucial aspect of kidney function and the pathology of DKD, a variety of methods are employed in research, from the introduction of external compounds, such as inulin, iohexol, iothalamate and p-aminohippurate, to cutting-edge imaging techniques and computational analysis. Given the significance of intraglomerular hemodynamic dysfunction in the pathogenesis and treatment of DKD, it is essential to thoroughly examine the available data on this topic. Accordingly, the aim of this review is to provide a comprehensive appraisal of the role of intraglomerular hemodynamic dysfunction in the development of DKD and the effects of current therapies used to mitigate DKD. Through this analysis, we can gain a deeper understanding of the complex pathogenesis of DKD and potentially discover new avenues for tailored therapeutic management of patients with DKD.
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Affiliation(s)
- Pierre-Jean Saulnier
- Clinical Investigation Center INSERM CIC1402 CHU Poitiers, Poitiers University, School of Medicine, Poitiers, France, and NIDDK, Phoenix, AZ, USA.
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Trovato GM. Taking care of the clues already under our eyes: Early carotid plaque ultrasound detection may enlighten the age-old paradigm shift of glomerular hyperfiltration. Atherosclerosis 2023; 369:27-29. [PMID: 36872187 DOI: 10.1016/j.atherosclerosis.2023.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 02/16/2023] [Indexed: 02/23/2023]
Affiliation(s)
- Guglielmo M Trovato
- The University of Catania, Italy; European Medical Association, Brussels, Belgium.
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9
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Johnson MJ, Tommerdahl KL, Vinovskis C, Waikar S, Reinicke T, Parikh CR, Obeid W, Nelson RG, van Raalte DH, Pyle L, Nadeau KJ, Bjornstad P. Relationship between biomarkers of tubular injury and intrarenal hemodynamic dysfunction in youth with type 1 diabetes. Pediatr Nephrol 2022; 37:3085-3092. [PMID: 35286453 PMCID: PMC9470783 DOI: 10.1007/s00467-022-05487-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 01/29/2022] [Accepted: 01/31/2022] [Indexed: 01/10/2023]
Abstract
BACKGROUND Early identification of youth with type 1 diabetes (T1D) at risk for diabetic kidney disease may improve clinical outcomes. We examined the cross-sectional relationship between kidney biomarkers neutrophil gelatinase-associated lipocalin (NGAL), copeptin, interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), chitinase-3-like protein-1 (YKL-40), and monocyte chemoattractant protein-1 (MCP-1) and intrarenal hemodynamic function in adolescents with T1D. METHODS Urine albumin-to-creatinine ratio (UACR), renal vascular resistance (RVR), glomerular filtration rate (GFR), intraglomerular pressure (PGLO), efferent arteriole resistance (RE), afferent arteriolar resistance (RA), and renal plasma flow (RPF), and the above indicated biomarkers were assessed in youth aged 12-21 years with and without T1D of < 10 years duration. RESULTS Fifty adolescents with T1D (16.1 ± 3.0 years, HbA1c 8.6 ± 1.2%) and 20 adolescents of comparable BMI without T1D (16.1 ± 2.9 years, HbA1c 5.2 ± 0.2%) were enrolled. Adolescents with T1D demonstrated significantly higher GFR, RPF, RE, and PGLO than controls (39%, 33%, 74%, and 29%, respectively, all p < 0.0001). Adolescents with T1D also exhibited significantly lower RVR and RA than controls (25% and 155%, respectively, both p < 0.0001). YKL-40 and KIM-1 concentrations, respectively, were positively associated with GFR (r: 0.43, p = 0.002; r: 0.41, p = 0.003), RPF (r: 0.29, p = 0.08; r: 0.34, p = 0.04), UACR (r: 0.33, p = 0.02; r: 0.50, p = 0.0002), and PGLO (r: 0.45, p = 0.006; r: 0.52, p = 0.001) in adolescents with T1D. CONCLUSIONS Higher concentrations of biomarkers YKL-40 and KIM-1 may help define the risk for intraglomerular hemodynamic dysfunction in youth with T1D. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
- Melissa J Johnson
- Department of Pediatrics, Section of Pediatric Endocrinology, Children's Hospital Colorado and University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Kalie L Tommerdahl
- Department of Pediatrics, Section of Pediatric Endocrinology, Children's Hospital Colorado and University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
- Ludeman Center for Women's Health Research, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Carissa Vinovskis
- Department of Pediatrics, Section of Pediatric Endocrinology, Children's Hospital Colorado and University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Sushrut Waikar
- Section of Nephrology, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA
| | - Trenton Reinicke
- Department of Pediatrics, Section of Pediatric Endocrinology, Children's Hospital Colorado and University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Chirag R Parikh
- Division of Nephrology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Wassim Obeid
- Division of Nephrology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Robert G Nelson
- Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, USA
| | - Daniel H van Raalte
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, location VUMC, Amsterdam, The Netherlands
| | - Laura Pyle
- Department of Biostatistics, Colorado School of Public Health, Aurora, CO, USA
| | - Kristen J Nadeau
- Department of Pediatrics, Section of Pediatric Endocrinology, Children's Hospital Colorado and University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Ludeman Center for Women's Health Research, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Petter Bjornstad
- Department of Pediatrics, Section of Pediatric Endocrinology, Children's Hospital Colorado and University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
- Ludeman Center for Women's Health Research, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
- Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, 13123 E. 16th AveBox B265, Aurora, CO, USA.
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10
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Lytvyn Y, Albakr R, Bjornstad P, Lovblom LE, Liu H, Lovshin JA, Boulet G, Farooqi MA, Weisman A, Keenan HA, Brent MH, Paul N, Bril V, Perkins BA, Cherney DZI. Renal hemodynamic dysfunction and neuropathy in longstanding type 1 diabetes: Results from the Canadian study of longevity in type 1 diabetes. J Diabetes Complications 2022; 36:108320. [PMID: 36201892 PMCID: PMC10187942 DOI: 10.1016/j.jdiacomp.2022.108320] [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: 12/21/2021] [Revised: 08/29/2022] [Accepted: 09/23/2022] [Indexed: 11/28/2022]
Abstract
AIMS To determine the relationship between renal hemodynamic function and neuropathy in adults with ≥50-years of type 1 diabetes (T1D) compared to nondiabetic controls. METHODS Glomerular filtration rate (GFR, inulin), effective renal plasma flow (ERPF, p-aminohippurate), modified Toronto Clinical Neuropathy Score (mTCNS), corneal confocal microscopy, nerve conduction, and heart rate variability (autonomic function) were measured; afferent (RA) and efferent (RE) arteriolar resistances were estimated using the Gomez equations in 74 participants with T1D and in 75 controls. Diabetic kidney disease (DKD) non-resistors were defined by eGFRMDRD < 60 ml/min/1.73 m2 or 24-h urine albumin excretion >30 mg/day. Linear regression was applied to examine the relationships between renal function (dependent variable) and neuropathy measures (independent variable), adjusted for age, sex, HbA1c, systolic blood pressure, low density lipoprotein cholesterol, and 24-h urine albumin to creatinine ratio. RESULTS Higher mTCNS associated with lower renal blood flow (β ± SE:-9.29 ± 4.20, p = 0.03) and greater RE (β ± SE:32.97 ± 15.43, p = 0.04) in participants with T1D, but not in controls. DKD non-resistors had a higher mTCNS and worse measures of corneal nerve morphology compared to those without DKD. Renal hemodynamic parameters did not associate with autonomic nerve function. CONCLUSIONS Although neurological dysfunction in the presence of diabetes may contribute to impaired renal blood flow resulting in ischemic injury in patients with T1D, early autonomic dysfunction does not appear to be associated with kidney function changes.
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Affiliation(s)
- Yuliya Lytvyn
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Rehab Albakr
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada; Division of Nephrology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Petter Bjornstad
- Department of Pediatrics, Division of Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Leif Erik Lovblom
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Hongyan Liu
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Julie A Lovshin
- Department of Medicine, Division of Endocrinology and Metabolism, Mount Sinai 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
| | - Alanna Weisman
- Department of Medicine, Division of Endocrinology and Metabolism, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | | | - 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
- Division of Neurology, Department of Medicine, 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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11
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Renal Denervation Influences Angiotensin II Types 1 and 2 Receptors. Int J Nephrol 2022; 2022:8731357. [PMID: 36262553 PMCID: PMC9576444 DOI: 10.1155/2022/8731357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 09/05/2022] [Accepted: 09/12/2022] [Indexed: 11/17/2022] Open
Abstract
The sympathetic and renin-angiotensin systems (RAS) are two critical regulatory systems in the kidney which affect renal hemodynamics and function. These two systems interact with each other so that angiotensin II (Ang II) has the presynaptic effect on the norepinephrine secretion. Another aspect of this interaction is that the sympathetic nervous system affects the function and expression of local RAS receptors, mainly Ang II receptors. Therefore, in many pathological conditions associated with an increased renal sympathetic tone, these receptors' expression changes and renal denervation can normalize these changes and improve the diseases. It seems that the renal sympathectomy can alter Ang II receptors expression and the distribution of RAS receptors in the kidneys, which influence renal functions.
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12
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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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13
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Sharma M, Singh V, Sharma R, Koul A, McCarthy ET, Savin VJ, Joshi T, Srivastava T. Glomerular Biomechanical Stress and Lipid Mediators during Cellular Changes Leading to Chronic Kidney Disease. Biomedicines 2022; 10:407. [PMID: 35203616 PMCID: PMC8962328 DOI: 10.3390/biomedicines10020407] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 01/31/2022] [Accepted: 02/04/2022] [Indexed: 02/04/2023] Open
Abstract
Hyperfiltration is an important underlying cause of glomerular dysfunction associated with several systemic and intrinsic glomerular conditions leading to chronic kidney disease (CKD). These include obesity, diabetes, hypertension, focal segmental glomerulosclerosis (FSGS), congenital abnormalities and reduced renal mass (low nephron number). Hyperfiltration-associated biomechanical forces directly impact the cell membrane, generating tensile and fluid flow shear stresses in multiple segments of the nephron. Ongoing research suggests these biomechanical forces as the initial mediators of hyperfiltration-induced deterioration of podocyte structure and function leading to their detachment and irreplaceable loss from the glomerular filtration barrier. Membrane lipid-derived polyunsaturated fatty acids (PUFA) and their metabolites are potent transducers of biomechanical stress from the cell surface to intracellular compartments. Omega-6 and ω-3 long-chain PUFA from membrane phospholipids generate many versatile and autacoid oxylipins that modulate pro-inflammatory as well as anti-inflammatory autocrine and paracrine signaling. We advance the idea that lipid signaling molecules, related enzymes, metabolites and receptors are not just mediators of cellular stress but also potential targets for developing novel interventions. With the growing emphasis on lifestyle changes for wellness, dietary fatty acids are potential adjunct-therapeutics to minimize/treat hyperfiltration-induced progressive glomerular damage and CKD.
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Affiliation(s)
- Mukut Sharma
- Research and Development Service, Kansas City VA Medical Center, Kansas City, MO 64128, USA;
- Midwest Veterans’ Biomedical Research Foundation, Kansas City, MO 64128, USA; (A.K.); (V.J.S.); (T.S.)
- Department of Internal Medicine, The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, MO 66160, USA;
| | - Vikas Singh
- Neurology, Kansas City VA Medical Center, Kansas City, MO 64128, USA;
| | - Ram Sharma
- Research and Development Service, Kansas City VA Medical Center, Kansas City, MO 64128, USA;
| | - Arnav Koul
- Midwest Veterans’ Biomedical Research Foundation, Kansas City, MO 64128, USA; (A.K.); (V.J.S.); (T.S.)
| | - Ellen T. McCarthy
- Department of Internal Medicine, The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, MO 66160, USA;
| | - Virginia J. Savin
- Midwest Veterans’ Biomedical Research Foundation, Kansas City, MO 64128, USA; (A.K.); (V.J.S.); (T.S.)
| | - Trupti Joshi
- Department of Health Management and Informatics, University of Missouri, Columbia, MO 65201, USA;
| | - Tarak Srivastava
- Midwest Veterans’ Biomedical Research Foundation, Kansas City, MO 64128, USA; (A.K.); (V.J.S.); (T.S.)
- Section of Nephrology, Children’s Mercy Hospital and University of Missouri, Kansas City, MO 64108, USA
- Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri, Kansas City, MO 64108, USA
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14
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Gronda E, Lopaschuk GD, Arduini A, Santoro A, Benincasa G, Palazzuoli A, Gabrielli D, Napoli C. Mechanisms of action of SGLT2 inhibitors and their beneficial effects on the cardiorenal axis. Can J Physiol Pharmacol 2022; 100:93-106. [PMID: 35112597 DOI: 10.1139/cjpp-2021-0399] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Large clinical studies conducted with sodium-glucose co-transporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes and heart failure with reduced ejection fraction have demonstrated their ability to achieve both cardiac and kidney benefits. Although there is huge evidence on SGLT2i-mediated clinical benefits both in diabetic and non-diabetic patients, the pathophysiological mechanisms underlying their efficacy are still poorly understood. Some favorable mechanisms are likely due to the prompt glycosuric action which is associated with natriuretic effects leading to hemodynamic benefits as well as a reduction in glomerular hyperfiltration and renin-angiotensin-aldosterone system activation. In addition to the renal mechanisms, SGLT2i may play a relevant role in cardiorenal axis protection by improving the cardiomyocyte metabolism, by exerting anti-fibrotic and anti-inflammatory actions, and by increasing cardioprotective adipokine expression. New studies will be needed to better understand the specific molecular mechanisms that mediate the SGLT2i favorable effects in patients suffering diabetes. Our aim is to first discuss about the molecular mechanisms underlying the cardiovascular benefits of SGLT2i in each of the main organs involved in the cardiorenal axis. Furthermore, we update on the most recent clinical trials evaluating the beneficial effects of SGLT2i in treatment of both diabetic and non-diabetic patients suffering heart failure.
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Affiliation(s)
- Edoardo Gronda
- Dipartimento di Medicina e Specialità Mediche, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico di Milano UOC di Nefrologia, Dialisi e Trapianto Renale dell'adulto, Milan, Italy
| | - Gary D Lopaschuk
- Cardiovascular Research Centre, University of Alberta, 423 Heritage Medical Research Centre, Edmonton, AB T6G 2S2, Canada
| | - Arduino Arduini
- Department of Research and Development, CoreQuest Sagl, Tecnopolo, 6934 Bioggio, Switzerland
| | - Antonio Santoro
- Nephrology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Italy
| | - Giuditta Benincasa
- Clinical Department of Internal Medicine and Specialistic Units, Azienda Ospedaliera Universitaria and Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Alberto Palazzuoli
- Cardiovascular Diseases Unit, Department of Medical Sciences, Le Scotte Hospital University of Siena, Italy
| | - Domenico Gabrielli
- Division of Cardiology, San Camillo Hospital, Rome, Italy and Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO)
| | - Claudio Napoli
- Clinical Department of Internal Medicine and Specialistic Units, Azienda Ospedaliera Universitaria and Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
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15
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Kuczeriszka M, Dobrowolski L, Walkowska A, Baranowska I, Sitek JD, Kompanowska-Jezierska E. Role of Ang1-7 in renal haemodynamics and excretion in streptozotocin diabetic rats. Clin Exp Pharmacol Physiol 2021; 49:432-441. [PMID: 34870864 DOI: 10.1111/1440-1681.13618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 11/12/2021] [Accepted: 11/24/2021] [Indexed: 11/28/2022]
Abstract
The contribution of angiotensin (1-7) (Ang1-7) to control of extrarenal and renal function may be modified in diabetes. We investigated the effects of Ang1-7 supplementation on blood pressure, renal circulation and intrarenal reactivity (IVR) to vasoactive agents in normoglycaemic (NG) and streptozotocin diabetic rats (DM). In Sprague Dawley DM and NG rats, 3 weeks after streptozotocin (60 mg/kg i.p.) or solvent injection, Ang1-7 was administered (400 ng/min) over the next 2 weeks using subcutaneously implanted osmotic minipumps. For a period of 5 weeks, blood pressure (BP), 24 h water intake and diuresis were determined weekly. In anaesthetised rats, BP, renal total and cortical (CBF), outer (OMBF) and inner medullary (IMBF) perfusion and urine excretion were determined. To check IVR, a short-time infusion of acetylcholine or norepinephrine was randomly given to the renal artery. Unexpectedly, BP did not differ between NG and DM, and this was not modified by Ang-1-7 supplementation. Baseline IMBF was higher in NG vs. DM, and Ang1-7 treatment did not change it in NG but decreased it in DM. In the latter, Ang1-7 increased cortical IVR to vasoconstrictor and vasodilator stimuli. IMBF decrease after high acetylcholine dose seen in untreated NG was reverted to an increase in Ang1-7 treated rats. Irrespective of the glycaemia level, Ang1-7 did not modify BP. However, it impaired medullary circulation in DM, whereas in NG it rendered the medullary vasculature more sensitive to vasodilators. Possibly, the medullary hypoperfusion in DM was mediated by Ang1-7 activation of angiotensin AT-1 receptors which are upregulated by hyperglycaemia.
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Affiliation(s)
- Marta Kuczeriszka
- Department of Renal and Body Fluid Physiology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Leszek Dobrowolski
- Department of Renal and Body Fluid Physiology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Agnieszka Walkowska
- Department of Renal and Body Fluid Physiology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Iwona Baranowska
- Department of Renal and Body Fluid Physiology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Joanna D Sitek
- Department of Renal and Body Fluid Physiology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Elżbieta Kompanowska-Jezierska
- Department of Renal and Body Fluid Physiology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
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16
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Liu T, Li R, Wang X, Gao X, Zhang X. Benefits of SGLT2 inhibitors combining with renin-angiotensin-system blockers on cardiovascular outcomes in chronic kidney disease patients: A systemic review and meta-analysis. Med Clin (Barc) 2021; 159:65-72. [PMID: 34872768 DOI: 10.1016/j.medcli.2021.09.031] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 08/28/2021] [Accepted: 09/02/2021] [Indexed: 01/01/2023]
Abstract
BACKGROUND AND OBJECTIVE Efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors in combination with renin-angiotensin-system (RAS) blockers for CKD remains controversial. We conducted this meta-analysis to explore the effect of SGLT2 inhibitors combining with RAS blockers on cardiovascular outcomes in chronic kidney disease (CKD) patients. METHODS We searched Embase, PubMed, Web of Science, and Cochrane Library databases with the following keywords. "Renal Insufficiency, Chronic" or "Diabetic Nephropathies" and "Sodium-glucose cotransporter 2 inhibitors". We included randomized controlled trials (RCTs) based on angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy. The outcome events included cardiac and renal outcomes and other adverse events. This study is registered with PROSPERO: CRD42020218337. RESULTS Ten RCTs including 16,983 CKD patients met the inclusion criteria. Compared with placebo plus RAS blockers, SGLT2 inhibitors plus RAS blockers significantly reduced cardiovascular mortality and heart failure-related hospitalization rates (RR=0.78, 95% CI: 0.66-0.91, p=0.002; RR=0.7, 95% CI: 0.61-0.8, p=0.000). We also performed trials sequential analysis (TSA) and the results indicated that our results are reliable. Additionally, it significantly reduced the 24-h urinary albumin excretion rate (24hUAE) and the creatinine elevation rate (WMD=-0.19, 95% CI: -0.24 to -0.14; RR=0.61, 95% CI: 0.51-0.74, p=0.000), delayed progression to end-stage renal disease (ESRD) (RR=0.69, 95% CI: 0.59-0.81, p=0.000). Further, it had no significant effect on the incidence of renal-related adverse events or renal-related mortality. Although it decreased the estimated glomerular filtration rate (eGFR) (WMD=-5.4, 95% CI: -7.24 to -3.57), this effect was reversible. CONCLUSIONS These data provide a well-document testimonial of the benefits of the combined use of SGLT2 inhibitors and RAS blockers for cardiovascular and renal outcomes in CKD patients.
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Affiliation(s)
- Ting Liu
- Department of Nephrology, The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Rui Li
- Shanxi Medical University, Taiyuan, China
| | | | | | - Xiaodong Zhang
- Department of Nephrology, The First Hospital of Shanxi Medical University, Taiyuan, China.
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17
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Ricciardi CA, Gnudi L. Kidney disease in diabetes: From mechanisms to clinical presentation and treatment strategies. Metabolism 2021; 124:154890. [PMID: 34560098 DOI: 10.1016/j.metabol.2021.154890] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 09/08/2021] [Accepted: 09/16/2021] [Indexed: 12/24/2022]
Abstract
Metabolic and haemodynamic perturbations and their interaction drive the development of diabetic kidney disease (DKD) and its progression towards end stage renal disease (ESRD). Increased mitochondrial oxidative stress has been proposed as the central mechanism in the pathophysiology of DKD, but other mechanisms have been implicated. In parallel to increased oxidative stress, inflammation, cell apoptosis and tissue fibrosis drive the relentless progressive loss of kidney function affecting both the glomerular filtration barrier and the renal tubulointerstitium. Alteration of glomerular capillary autoregulation is at the basis of glomerular hypertension, an important pathogenetic mechanism for DKD. Clinical presentation of DKD can vary. Its classical presentation, often seen in patients with type 1 diabetes (T1DM), features hyperfiltration and albuminuria followed by progressive fall in renal function. Patients can often also present with atypical features characterised by progressive reduction in renal function without albuminuria, others in conjunction with non-diabetes related pathologies making the diagnosis, at times, challenging. Metabolic, lipid and blood pressure control with lifestyle interventions are crucial in reducing the progressive renal function decline seen in DKD. The prevention and management of DKD (and parallel cardiovascular disease) is a huge global challenge and therapies that target haemodynamic perturbations, such as inhibitors of the renin-angiotensin-aldosterone system (RAAS) and SGLT2 inhibitors, have been most successful.
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Affiliation(s)
| | - Luigi Gnudi
- School of Cardiovascular Medicine & Science, King's College London, London, UK.
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18
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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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19
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Nangaku M. Founding papers of current nephrology: from acute kidney injury to diabetic kidney disease. Kidney Int 2021; 98:6-9. [PMID: 32571493 DOI: 10.1016/j.kint.2020.03.040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 03/26/2020] [Indexed: 01/12/2023]
Affiliation(s)
- Masaomi Nangaku
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
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20
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Assessment of nephron number and single-nephron glomerular filtration rate in a clinical setting. Hypertens Res 2021; 44:605-617. [PMID: 33526913 DOI: 10.1038/s41440-020-00612-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 12/02/2020] [Accepted: 12/08/2020] [Indexed: 01/31/2023]
Abstract
Total nephron counts vary widely between individuals and may affect susceptibility to certain diseases, including hypertension and chronic kidney disease. Detailed analyses of whole kidneys collected from autopsy patients remain the only method for accurately counting nephrons in humans, with no equivalent option in living subjects. Current technological advances have enabled estimations of nephron numbers in vivo, particularly the use of total nephron number and whole-kidney glomerular filtration rate to estimate the mean single-nephron glomerular filtration rate. The use of this method would allow physicians to detect dynamic changes in filtration function at the single-nephron level rather than to simply count the number of nephrons that appear to be functioning. Currently available methods for estimating total nephron number in clinical practice have the potential to overcome limitations associated with autopsy analyses and may therefore pave the way for new therapeutic interventions and improved clinical outcomes.
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21
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Thomson SC, Vallon V. Effects of SGLT2 inhibitor and dietary NaCl on glomerular hemodynamics assessed by micropuncture in diabetic rats. Am J Physiol Renal Physiol 2021; 320:F761-F771. [PMID: 33645318 PMCID: PMC8174804 DOI: 10.1152/ajprenal.00552.2020] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/09/2021] [Accepted: 02/19/2021] [Indexed: 01/10/2023] Open
Abstract
Inhibitors of the main proximal tubular Na-glucose cotransporter (SGLT2) mitigate diabetic glomerular hyperfiltration and have been approved by the United States Food and Drug Administration for slowing the progression of diabetic kidney disease. It has been proposed that SGLT2 inhibitors improve hard renal outcomes by reducing glomerular capillary pressure (PGC) via a tubuloglomerular feedback (TGF) response to a decrease in proximal reabsorption (Jprox). However, the effect of SGLT2 inhibition on PGC has not been measured. Here, we studied the effects of acute SGLT2 blockade (ertugliflozin) on Jprox and glomerular hemodynamics in two-period micropuncture experiments using streptozotocin-induced diabetic rats fed high- or low-NaCl diets. PGC was measured by direct capillary puncture or computed from tubular stop-flow pressure (PSF). TGF is intact while measuring PGC directly but rendered inoperative when measuring PSF. Acute SGLT2 inhibitor reduced Jprox by ∼30%, reduced PGC by 5-8 mmHg, and reduced glomerular filtration rate (GFR) by ∼25% (all P < 0.0001) but had no effect on PSF. The decrease in PGC was larger with the low-NaCl diet (8 vs. 5 mmHg, P = 0.04) where PGC was higher to begin with (54 vs. 50 mmHg, P = 0.003). Greater decreases in PGC corresponded, unexpectedly, to lesser decreases in GFR (P = 0.04). In conclusion, these results confirm expectations that PGC would decline in response to acute SGLT2 inhibition and that a functioning TGF system is required for this. We infer a contribution of postglomerular vasorelaxation to the TGF responses where decreases in PGC were large and decreases in GFR were small.NEW & NOTEWORTHY It has been theorized that Na-glucose cotransporter (SGLT2) blockade slows progression of diabetic kidney disease by reducing physical strain on the glomerulus. This is the first direct measurement of intraglomerular pressure during SGLT2 blockade. Findings confirmed that SGLT2 blockade does reduce glomerular capillary pressure, that this is mediated through tubuloglomerular feedback, and that the tubuloglomerular feedback response to SGLT2 blockade involves preglomerular vasoconstriction and postglomerular vasorelaxation.
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Affiliation(s)
- Scott Culver Thomson
- Division of Nephrology-Hypertension, Department of Medicine, University of California, San Diego, California; and Veterans Affairs San Diego Healthcare System, La Jolla, California
| | - Volker Vallon
- Division of Nephrology-Hypertension, Department of Medicine, University of California, San Diego, California; and Veterans Affairs San Diego Healthcare System, La Jolla, California
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22
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Angiotensin-neprilysin inhibition confers renoprotection in rats with diabetes and hypertension by limiting podocyte injury. J Hypertens 2021; 38:755-764. [PMID: 31790054 DOI: 10.1097/hjh.0000000000002326] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVES Combined angiotensin receptor--neprilysin inhibition (ARNI) reduces glomerulosclerosis better than single angiotensin receptor blockade (ARB) in diabetic, hypertensive rats. The renoprotective mechanism remains unknown, but may depend on superior blood pressure control, improved renal hemodynamics, suppressed renal inflammation or prevention of podocyte loss. METHODS To address this, TGR(mREN2)27 rats (a model of angiotensin II-dependent hypertension) were made diabetic for 12 weeks and treated with vehicle (n = 10), valsartan (ARB; n = 7) or sacubitril/valsartan (ARNI; n = 8) for the final 3 weeks. Arterial pressure was measured via radiotelemetry. RESULTS Sacubitril/valsartan lowered mean arterial pressure by -50 ± 4 mmHg and valsartan by -43 ± 4 mmHg (P = 0.3). Both treatments lowered albuminuria, but only sacubitril/valsartan maintained high urinary atrial natriuretic peptide, improved glycemic control and protected podocyte integrity, reflected by increased nephrin expression and suppression of transient receptor potential canonical 6 and regulator of calcineurin 1. This resulted in markedly reduced glomerulosclerosis (P < 0.05 vs. control and valsartan). Despite higher effective renal plasma flow and glomerular filtration rates, sacubitril/valsartan did neither improve filtration fraction nor renal immune cell infiltration. CONCLUSION Sacubitril/valsartan offers drug-class-specific renoprotection in a preclinical model of diabetes and hypertension. Renoprotection is unrelated to antihypertensive efficacy, renal hemodynamics or inflammation, but may be related to protective effects of natriuretic peptides on podocyte integrity.
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23
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Hinden L, Kogot-Levin A, Tam J, Leibowitz G. Pathogenesis of diabesity-induced kidney disease: role of kidney nutrient sensing. FEBS J 2021; 289:901-921. [PMID: 33630415 DOI: 10.1111/febs.15790] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/09/2021] [Accepted: 02/24/2021] [Indexed: 12/11/2022]
Abstract
Diabetes kidney disease (DKD) is a major healthcare problem associated with increased risk for developing end-stage kidney disease and high mortality. It is widely accepted that DKD is primarily a glomerular disease. Recent findings however suggest that kidney proximal tubule cells (KPTCs) may play a central role in the pathophysiology of DKD. In diabetes and obesity, KPTCs are exposed to nutrient overload, including glucose, free-fatty acids and amino acids, which dysregulate nutrient and energy sensing by mechanistic target of rapamycin complex 1 and AMP-activated protein kinase, with subsequent induction of tubular injury, inflammation, and fibrosis. Pharmacological treatments that modulate nutrient sensing and signaling in KPTCs, including cannabinoid-1 receptor antagonists and sodium glucose transporter 2 inhibitors, exert robust kidney protective effects. Shedding light on how nutrients are sensed and metabolized in KPTCs and in other kidney domains, and on their effects on signal transduction pathways that mediate kidney injury, is important for understanding the pathophysiology of DKD and for the development of novel therapeutic approaches in DKD and probably also in other forms of kidney disease.
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Affiliation(s)
- Liad Hinden
- Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
| | - Aviram Kogot-Levin
- Diabetes Unit and Endocrine Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Joseph Tam
- Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
| | - Gil Leibowitz
- Diabetes Unit and Endocrine Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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24
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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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Cai J, Liu B, Guo T, Zhang Y, Wu X, Leng J, Zhu N, Guo J, Zhou Y. Effects of thromboxane prostanoid receptor deficiency on diabetic nephropathy induced by high fat diet and streptozotocin in mice. Eur J Pharmacol 2020; 882:173254. [PMID: 32553735 DOI: 10.1016/j.ejphar.2020.173254] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 05/14/2020] [Accepted: 06/05/2020] [Indexed: 02/05/2023]
Abstract
Diabetic nephropathy (DN), one of the main causes of end-stage renal disease, still remains as a challenge of clinical management. This study aimed to determine whether deficiency of the thromboxane (TX) prostanoid receptor (TP), which mediates the contractile activities of all prostanoids, alleviates the development of DN and if so, to examine the underlying mechanism(s). Diabetes was induced by high fat diet and streptozotocin injection in wild-type (WT) mice and those with TP deficiency (TP-/-). Here we show that WT and TP-/- mice developed diabetes with a similar blood glucose level; however, signs of renal functional impairments and pathologies occurred to a lesser extent in TP-/- than in WT mice. Also, the extent of an increase in the expression level of transforming growth factor-β1 (TGF-β1), a common pathological mediator of DN, in diabetic renal cortexes of TP-/- mice was lower than that of WT counterparts. Moreover, we noted that expression levels of cyclooxygenase (COX)-2 and calcium-dependent phospholipase A2 (cPLA2) as well as levels of prostaglandin E2 and TXA2 in diabetic renal cortexes were increased as compared to those of non-diabetic conditions. These results thus demonstrate that possibly due to up-regulated cPLA2 and COX-2 that lead to increased prostanoid syntheses in diabetic renal cortexes, TP-/- alleviates DN development. In addition, our results suggest that such an effect of TP-/- might be related to the suppression of TGF-β1 up-regulation that is commonly associated with the disease condition.
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Affiliation(s)
- Juyu Cai
- Department of Medicine, Medical College of Jiaying University, Meizhou, China; Cardiovascular Research Center, Shantou University Medical College, Shantou, China
| | - Bin Liu
- Cardiovascular Research Center, Shantou University Medical College, Shantou, China
| | - Tingting Guo
- Cardiovascular Research Center, Shantou University Medical College, Shantou, China
| | - Yingzhan Zhang
- Cardiovascular Research Center, Shantou University Medical College, Shantou, China
| | - Xiangzhong Wu
- Cardiovascular Research Center, Shantou University Medical College, Shantou, China
| | - Jing Leng
- Cardiovascular Research Center, Shantou University Medical College, Shantou, China
| | - Ningxia Zhu
- Cardiovascular Research Center, Shantou University Medical College, Shantou, China
| | - Jinwei Guo
- Cardiovascular Research Center, Shantou University Medical College, Shantou, China
| | - Yingbi Zhou
- Cardiovascular Research Center, Shantou University Medical College, Shantou, China.
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26
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Understanding Diabetic Neuropathy: Focus on Oxidative Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:9524635. [PMID: 32832011 PMCID: PMC7422494 DOI: 10.1155/2020/9524635] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 07/22/2020] [Indexed: 02/06/2023]
Abstract
Diabetic neuropathy is one of the clinical syndromes characterized by pain and substantial morbidity primarily due to a lesion of the somatosensory nervous system. The burden of diabetic neuropathy is related not only to the complexity of diabetes but also to the poor outcomes and difficult treatment options. There is no specific treatment for diabetic neuropathy other than glycemic control and diligent foot care. Although various metabolic pathways are impaired in diabetic neuropathy, enhanced cellular oxidative stress is proposed as a common initiator. A mechanism-based treatment of diabetic neuropathy is challenging; a better understanding of the pathophysiology of diabetic neuropathy will help to develop strategies for the new and correct diagnostic procedures and personalized interventions. Thus, we review the current knowledge of the pathophysiology in diabetic neuropathy. We focus on discussing how the defects in metabolic and vascular pathways converge to enhance oxidative stress and how they produce the onset and progression of nerve injury present in diabetic neuropathy. We discuss if the mechanisms underlying neuropathy are similarly operated in type I and type II diabetes and the progression of antioxidants in treating diabetic neuropathy.
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Ullah MM, Ow CPC, Evans RG, Hilliard Krause LM. Impact of choice of kinetic model for the determination of transcutaneous FITC-sinistrin clearance in rats with streptozotocin-induced type 1 diabetes. Clin Exp Pharmacol Physiol 2020; 47:1158-1168. [PMID: 32160333 DOI: 10.1111/1440-1681.13301] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 03/08/2020] [Indexed: 11/28/2022]
Abstract
Transcutaneous assessment of fluorescein isothiocyanate (FITC)-sinistrin clearance using an optical device was recently validated for determination of glomerular filtration rate (GFR) in conscious animals. In the current study, we compared four available kinetic models for calculating FITC-sinistrin clearance, to provide further insight into whether the choice of model might influence findings generated using this device. Specifically, we calculated the excretion half-life of FITC-sinistrin (minutes), rate constant (minute-1 ) and GFR indexed to bodyweight in control rats and rats with streptozotocin-induced diabetes across a 4-week experimental period using standard one-compartment (1-COM), two-compartment (2-COM) and three-compartment (3-COM) kinetic models (1-COM), and a three-compartment kinetic model with baseline correction (3-COMB). Glomerular hyperfiltration was detected in STZ-induced diabetic rats with the 2-COM or 3-COMB at day 14 and with the 3-COM at day 3 and 14 after induction of diabetes, but not at any time point using the 1-COM. From a theoretical perspective, we reasoned that the 3-COMB model provides a better estimate of t1/2 than the other models. Linear regression analysis of data generated using the 3-COMB showed a significant relationship between blood glucose and calculated GFR at the day 14 (P = .004) and day 28 (P = .01) time points, and a strong tendency for a relationship at the day 3 time point (P = .06). We conclude that hyperfiltration is an early and sustained characteristic of STZ-induced diabetes in rats. Furthermore, we propose that the 3-COMB model provides the most valid t1/2 for estimation of GFR via transcutaneous detection of FITC-sinistrin clearance.
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Affiliation(s)
- Md Mahbub Ullah
- Cardiovascular Disease Program, Department of Physiology, Biomedicine Discovery Institute, Monash University, Melbourne, Vic., Australia
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Connie P C Ow
- Cardiovascular Disease Program, Department of Physiology, Biomedicine Discovery Institute, Monash University, Melbourne, Vic., Australia
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
| | - Roger G Evans
- Cardiovascular Disease Program, Department of Physiology, Biomedicine Discovery Institute, Monash University, Melbourne, Vic., Australia
| | - Lucinda M Hilliard Krause
- Cardiovascular Disease Program, Department of Physiology, Biomedicine Discovery Institute, Monash University, Melbourne, Vic., Australia
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Han DC, Ziyadeh FN. Favorable Treatment Outcome with Neutralizing anti Transforming Growth Factor I:} Antibodies in Experimental Diabetic Kidney Disease. Perit Dial Int 2020. [DOI: 10.1177/089686089901902s39] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Affiliation(s)
- Dong Cheol Han
- Renal-Electrolyte and Hypertension Division, and Penn Center for Molecular Studies of Kidney Diseases, Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, U.S.A
| | - Fuad N. Ziyadeh
- Renal-Electrolyte and Hypertension Division, and Penn Center for Molecular Studies of Kidney Diseases, Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, U.S.A
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Sasaki T, Tsuboi N, Okabayashi Y, Haruhara K, Kanzaki G, Koike K, Takahashi H, Ikegami M, Shimizu A, Yokoo T. Synergistic Impact of Diabetes and Hypertension on the Progression and Distribution of Glomerular Histopathological Lesions. Am J Hypertens 2019; 32:900-908. [PMID: 31044221 DOI: 10.1093/ajh/hpz059] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 03/25/2019] [Accepted: 04/25/2019] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Diabetes and hypertension share renal histopathological features, such as arterial lesions and glomerular hypertrophy, that have not been investigated in relation to the blood pressure status of diabetic subjects. The severity of glomerular lesions varies across locations of the renal cortex, which may be further affected by diabetes and/or hypertension. METHODS Histopathological lesions in different parts of the renal cortex of autopsy kidneys were evaluated and analyzed based on medical histories of diabetes and hypertension. RESULTS This study included a total of 82 Japanese autopsies composed of normotensive nondiabetics (n = 31), hypertensive nondiabetics (n = 28), normotensive diabetics (n = 14), and hypertensive diabetics (n = 9). There were no differences in age, sex, renal function, or body size among groups. In both the superficial and juxtamedullary cortices, increased glomerular volume (GV) was significantly associated with either diabetes or hypertension. In addition, diabetes and hypertension showed a significant interaction with GV regardless of the cortical location. Values for global glomerulosclerosis (GGS) and arteriolar hyalinosis (AH) were associated with diabetes but not with hypertension. Only values for GGS consistently showed cortical surface superiority. The zonal distribution of AH, GV, or other diabetic glomerular lesions differed among the lesions depending on the presence or absence of hypertension. CONCLUSIONS These results imply that diabetes and hypertension synergistically enhance glomerular hypertrophy across all layers of the human renal cortex. The process is closely associated with the severity of GGS and AH predominantly associated with diabetes.
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Affiliation(s)
- Takaya Sasaki
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Nobuo Tsuboi
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Yusuke Okabayashi
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kotaro Haruhara
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Go Kanzaki
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kentaro Koike
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Hiroyuki Takahashi
- Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan
| | - Masahiro Ikegami
- Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan
| | - Akira Shimizu
- Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan
| | - Takashi Yokoo
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
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Sun HJ, Wu ZY, Cao L, Zhu MY, Liu TT, Guo L, Lin Y, Nie XW, Bian JS. Hydrogen Sulfide: Recent Progression and Perspectives for the Treatment of Diabetic Nephropathy. Molecules 2019; 24:molecules24152857. [PMID: 31390847 PMCID: PMC6696501 DOI: 10.3390/molecules24152857] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 07/29/2019] [Accepted: 08/05/2019] [Indexed: 02/06/2023] Open
Abstract
Diabetic kidney disease develops in approximately 40% of diabetic patients and is a major cause of chronic kidney diseases (CKD) and end stage kidney disease (ESKD) worldwide. Hydrogen sulfide (H2S), the third gasotransmitter after nitric oxide (NO) and carbon monoxide (CO), is synthesized in nearly all organs, including the kidney. Though studies on H2S regulation of renal physiology and pathophysiology are still in its infancy, emerging evidence shows that H2S production by renal cells is reduced under disease states and H2S donors ameliorate kidney injury. Specifically, aberrant H2S level is implicated in various renal pathological conditions including diabetic nephropathy. This review presents the roles of H2S in diabetic renal disease and the underlying mechanisms for the protective effects of H2S against diabetic renal damage. H2S may serve as fundamental strategies to treat diabetic kidney disease. These H2S treatment modalities include precursors for H2S synthesis, H2S donors, and natural plant-derived compounds. Despite accumulating evidence from experimental studies suggests the potential role of the H2S signaling pathway in the treatment of diabetic nephropathy, these results need further clinical translation. Expanding understanding of H2S in the kidney may be vital to translate H2S to be a novel therapy for diabetic renal disease.
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Affiliation(s)
- Hai-Jian Sun
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Zhi-Yuan Wu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Lei Cao
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Meng-Yuan Zhu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Teng-Teng Liu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Lei Guo
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Ye Lin
- School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou 213164, China
| | - Xiao-Wei Nie
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Jin-Song Bian
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
- National University of Singapore (Suzhou) Research Institute, Suzhou 215000, China.
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Kelly JT, Campbell KL, Carrero JJ. Primary Versus Secondary Prevention of Chronic Kidney Disease: The Case of Dietary Protein. J Ren Nutr 2019; 28:225-228. [PMID: 29935606 DOI: 10.1053/j.jrn.2018.04.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 04/18/2018] [Indexed: 12/30/2022] Open
Affiliation(s)
- Jaimon T Kelly
- Faculty of Health Sciences and Medicine, Bond University, Australia
| | | | - Juan J Carrero
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
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Mottl AK, Hostetter TH, Derebail VK. Glomerular Filtration: Too Much of a Good Thing? Am J Kidney Dis 2019; 73:756-758. [DOI: 10.1053/j.ajkd.2019.01.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 01/27/2019] [Indexed: 11/11/2022]
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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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Devries MC, Sithamparapillai A, Brimble KS, Banfield L, Morton RW, Phillips SM. Changes in Kidney Function Do Not Differ between Healthy Adults Consuming Higher- Compared with Lower- or Normal-Protein Diets: A Systematic Review and Meta-Analysis. J Nutr 2018; 148:1760-1775. [PMID: 30383278 PMCID: PMC6236074 DOI: 10.1093/jn/nxy197] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Revised: 11/01/2017] [Accepted: 07/24/2018] [Indexed: 01/09/2023] Open
Abstract
Background Higher-protein (HP) diets are advocated for several reasons, including mitigation of sarcopenia, but their effects on kidney function are unclear. Objective This meta-analysis was conducted to determine the effect of HP intakes on kidney function in healthy adults. Methods We conducted a systematic review and meta-analysis of trials comparing HP (≥1.5 g/kg body weight or ≥20% energy intake or ≥100 g protein/d) with normal- or lower-protein (NLP; ≥5% less energy intake from protein/d compared with HP group) intakes on kidney function. Medline and EMBASE databases were searched. Randomized controlled trials comparing the effects of HP with NLP (>4 d duration) intakes on glomerular filtration rate (GFR) in adults without kidney disease were included. Results A total of 2144 abstracts were reviewed, with 40 articles selected for full-text review; 28 of these were analyzed and included data from 1358 participants. Data were analyzed using random-effects meta-analysis (RevMan 5; The Cochrane Collaboration), meta-regression (STATA; StataCorp), and dose-response analysis (Prism; GraphPad). Analyses were conducted using postintervention (post) GFR and the change in GFR from preintervention to post. The post-only comparison showed a trivial effect for GFR to be higher after HP intakes [standardized mean difference (SMD): 0.19; 95% CI: 0.07, 0.31; P = 0.002]. The change in GFR did not differ between interventions (SMD: 0.11; 95% CI: -0.05, 0.27; P = 0.16). There was a linear relation between protein intake and GFR in the post-only comparison (r = 0.332, P = 0.03), but not between protein intake and the change in GFR (r = 0.184, P = 0.33). The main limitation of the current analysis is the unclear risk of selection bias of the included trials. Conclusions Postintervention GFR comparisons indicate that HP diets result in higher GFRs; however, when changes in GFR were compared, dietary protein had no effect. Our analysis indicates that HP intakes do not adversely influence kidney function on GFR in healthy adults.
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Affiliation(s)
- Michaela C Devries
- Department of Kinesiology, Faculty of Applied Health Sciences, University of Waterloo, Waterloo, Canada
| | | | | | - Laura Banfield
- Health Sciences Library, Faculty of Health Sciences, McMaster University, Hamilton, Canada
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Amelioration of renal structural changes in STZ-induced diabetic mice with ethanolic extract of Allium saralicum R.M. Fritsch. ACTA ACUST UNITED AC 2018. [DOI: 10.1007/s00580-018-2674-9] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Geraci S, Chacon-Caldera J, Cullen-McEwen L, Schad LR, Sticht C, Puelles VG, Bertram JF, Gretz N. Combining new tools to assess renal function and morphology: a holistic approach to study the effects of aging and a congenital nephron deficit. Am J Physiol Renal Physiol 2017; 313:F576-F584. [PMID: 28490528 DOI: 10.1152/ajprenal.00329.2015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Revised: 04/28/2017] [Accepted: 05/09/2017] [Indexed: 01/17/2023] Open
Abstract
Recently, new methods for assessing renal function in conscious mice (transcutaneous assessment) and for counting and sizing all glomeruli in whole kidneys (MRI) have been described. In the present study, these methods were used to assess renal structure and function in aging mice, and in mice born with a congenital low-nephron endowment. Age-related nephron loss was analyzed in adult C57BL/6 mice (10-50 wk of age), and congenital nephron deficit was assessed in glial cell line-derived neurotrophic factor heterozygous (GDNF HET)-null mutant mice. Renal function was measured through the transcutaneous quantitation of fluorescein isothiocyanate-sinistrin half-life (t1/2) in conscious mice. MRI was used to image, count, and size cationic-ferritin labeled glomeruli in whole kidneys ex vivo. Design-based stereology was used to validate the MRI measurements of glomerular number and mean volume. In adult C57BL/6 mice, older age was associated with fewer and larger glomeruli, and a rightward shift in the glomerular size distribution. These changes coincided with a decrease in renal function. GNDF HET mice had a congenital nephron deficit that was associated with glomerular hypertrophy and exacerbated by aging. These findings suggest that glomerular hypertrophy and hyperfiltration are compensatory processes that can occur in conjunction with both age-related nephron loss and congenital nephron deficiency. The combination of measurement of renal function in conscious animals and quantitation of glomerular number, volume, and volume distribution provides a powerful new tool for investigating aspects of renal aging and functional changes.
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Affiliation(s)
- Stefania Geraci
- Medical Research Centre, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Jorge Chacon-Caldera
- Computer Assisted Clinical Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; and
| | - Luise Cullen-McEwen
- Cardiovascular Program, Monash Biomedicine Discovery Institute, and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia
| | - Lothar R Schad
- Computer Assisted Clinical Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; and
| | - Carsten Sticht
- Medical Research Centre, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Victor G Puelles
- Cardiovascular Program, Monash Biomedicine Discovery Institute, and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia
| | - John F Bertram
- Cardiovascular Program, Monash Biomedicine Discovery Institute, and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia
| | - Norbert Gretz
- Medical Research Centre, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany;
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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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Dumont V, Tolvanen TA, Kuusela S, Wang H, Nyman TA, Lindfors S, Tienari J, Nisen H, Suetsugu S, Plomann M, Kawachi H, Lehtonen S. PACSIN2 accelerates nephrin trafficking and is up-regulated in diabetic kidney disease. FASEB J 2017; 31:3978-3990. [PMID: 28550045 PMCID: PMC5572687 DOI: 10.1096/fj.201601265r] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 05/01/2017] [Indexed: 01/07/2023]
Abstract
Nephrin is a core component of podocyte (glomerular epithelial cell) slit diaphragm and is required for kidney ultrafiltration. Down-regulation or mislocalization of nephrin has been observed in diabetic kidney disease (DKD), characterized by albuminuria. Here, we investigate the role of protein kinase C and casein kinase 2 substrate in neurons 2 (PACSIN2), a regulator of endocytosis and recycling, in the trafficking of nephrin and development of DKD. We observe that PACSIN2 is up-regulated and nephrin mislocalized in podocytes of obese Zucker diabetic fatty (ZDF) rats that have altered renal function. In cultured podocytes, PACSIN2 and nephrin colocalize and interact. We show that nephrin is endocytosed in PACSIN2-positive membrane regions and that PACSIN2 overexpression increases both nephrin endocytosis and recycling. We identify rabenosyn-5, which is involved in early endosome maturation and endosomal sorting, as a novel interaction partner of PACSIN2. Interestingly, rabenosyn-5 expression is increased in podocytes in obese ZDF rats, and, in vitro, its overexpression enhances the association of PACSIN2 and nephrin. We also show that palmitate, which is elevated in diabetes, enhances this association. Collectively, PACSIN2 is up-regulated and nephrin is abnormally localized in podocytes of diabetic ZDF rats. In vitro, PACSIN2 enhances nephrin turnover apparently via a mechanism involving rabenosyn-5. The data suggest that elevated PACSIN2 expression accelerates nephrin trafficking and associates with albuminuria.—Dumont, V., Tolvanen, T. A., Kuusela, S., Wang, H., Nyman, T. A., Lindfors, S., Tienari, J., Nisen, H., Suetsugu, S., Plomann, M., Kawachi, H., Lehtonen, S. PACSIN2 accelerates nephrin trafficking and is up-regulated in diabetic kidney disease.
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Affiliation(s)
- Vincent Dumont
- Department of Pathology, University of Helsinki, Helsinki, Finland
| | | | - Sara Kuusela
- Department of Pathology, University of Helsinki, Helsinki, Finland
| | - Hong Wang
- Department of Pathology, University of Helsinki, Helsinki, Finland
| | - Tuula A Nyman
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Sonja Lindfors
- Department of Pathology, University of Helsinki, Helsinki, Finland
| | - Jukka Tienari
- Department of Pathology, Helsinki University Hospital, Hyvinkää, Finland.,Department of Pathology, Helsinki University Hospital, Hyvinkää, Finland
| | - Harry Nisen
- Department of Urology, Helsinki University Hospital, Helsinki, Finland
| | - Shiro Suetsugu
- Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Japan
| | | | - Hiroshi Kawachi
- Department of Cell Biology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Sanna Lehtonen
- Department of Pathology, University of Helsinki, Helsinki, Finland;
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Hagh-Nazari L, Goodarzi N, Zangeneh MM, Zangeneh A, Tahvilian R, Moradi R. Stereological study of kidney in streptozotocin-induced diabetic mice treated with ethanolic extract of Stevia rebaudiana (bitter fraction). ACTA ACUST UNITED AC 2017. [DOI: 10.1007/s00580-016-2398-7] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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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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Awad Allah RS, Dkhil MA, Danfour MA. Structural Alterations of the Glomerular Wall and Vessels in Early Stages of Diabetes Mellitus (Light and Transmission Electron Microscopic Study). Libyan J Med 2016. [DOI: 10.3402/ljm.v2i3.4713] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Affiliation(s)
- R S Awad Allah
- Department of Anatomy, Faculty of Medicine, Al-Azhar University, Egypt
| | - M A Dkhil
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Egypt
| | - M A Danfour
- Faculty of Medicine, 7th of October University, Misurata, Libya
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DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol 2016; 13:11-26. [PMID: 27941935 DOI: 10.1038/nrneph.2016.170] [Citation(s) in RCA: 381] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The kidney has a pivotal role in maintaining glucose homeostasis by using glucose as a metabolic fuel, by producing glucose through gluconeogenesis, and by reabsorbing all filtered glucose through the sodium-glucose cotransporters SGLT1 and SGLT2 located in the proximal tubule. In patients with diabetes, the maximum glucose reabsorptive capacity (TmG) of the kidney, as well as the threshold for glucose spillage into the urine, are elevated, contributing to the pathogenesis of hyperglycaemia. By reducing the TmG and, more importantly, the threshold of glucosuria, SGLT2 inhibitors enhance glucose excretion, leading to a reduction in fasting and postprandial plasma glucose levels and improvements in both insulin secretion and insulin sensitivity. The beneficial effects of SGLT2 inhibition extend beyond glycaemic control, however, with new studies demonstrating that inhibition of renal glucose reabsorption reduces blood pressure, ameliorates glucotoxicity and induces haemodynamic effects that lead to improved cardiovascular and renal outcomes in patients with type 2 diabetes mellitus. In this Review we examine the role of SGLT2 and SGLT1 in the regulation of renal glucose reabsorption in health and disease and the effect of SGLT2 inhibition on renal function, glucose homeostasis, and cardiovascular disease.
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Affiliation(s)
- Ralph A DeFronzo
- Diabetes Division, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78229, USA
| | - Luke Norton
- Diabetes Division, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78229, USA
| | - Muhammad Abdul-Ghani
- Diabetes Division, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78229, USA
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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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Brakeman P, Miao S, Cheng J, Lee CZ, Roy S, Fissell WH, Ferrell N. A modular microfluidic bioreactor with improved throughput for evaluation of polarized renal epithelial cells. BIOMICROFLUIDICS 2016; 10:064106. [PMID: 27917253 PMCID: PMC5116024 DOI: 10.1063/1.4966986] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Accepted: 10/23/2016] [Indexed: 05/16/2023]
Abstract
Most current microfluidic cell culture systems are integrated single use devices. This can limit throughput and experimental design options, particularly for epithelial cells, which require significant time in culture to obtain a fully differentiated phenotype. In addition, epithelial cells require a porous growth substrate in order to fully polarize their distinct apical and basolateral membranes. We have developed a modular microfluidic system using commercially available porous culture inserts to evaluate polarized epithelial cells under physiologically relevant fluid flow conditions. The cell-support for the bioreactor is a commercially available microporous membrane that is ready to use in a 6-well format, allowing for cells to be seeded in advance in replicates and evaluated for polarization and barrier function prior to experimentation. The reusable modular system can be easily assembled and disassembled using these mature cells, thus improving experimental throughput and minimizing fabrication requirements. The bioreactor consists of an apical microfluidic flow path and a static basolateral chamber that is easily accessible from the outside of the device. The basolateral chamber acts as a reservoir for transport across the cell layer. We evaluated the effect of initiation of apical shear flow on short-term intracellular signaling and mRNA expression using primary human renal epithelial cells (HRECs). Ten min and 5 h after initiation of apical fluid flow over a stable monolayer of HRECs, cells demonstrated increased phosphorylation of extracellular signal-related kinase and increased expression of interleukin 6 (IL-6) mRNA, respectively. This bioreactor design provides a modular platform with rapid experimental turn-around time to study various epithelial cell functions under physiologically meaningful flow conditions.
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Affiliation(s)
- Paul Brakeman
- Department of Pediatrics, University of California , San Francisco, San Francisco, California 94143, USA
| | - Simeng Miao
- Department of Biomedical Engineering, Vanderbilt University , Nashville, Tennessee 37232, USA
| | - Jin Cheng
- Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, USA
| | - Chao-Zong Lee
- Department of Pediatrics, University of California , San Francisco, San Francisco, California 94143, USA
| | - Shuvo Roy
- Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, San Francisco, California 94143, USA
| | - William H Fissell
- Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, USA
| | - Nicholas Ferrell
- Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, USA
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Bjornstad P, Škrtić M, Lytvyn Y, Maahs DM, Johnson RJ, Cherney DZI. The Gomez' equations and renal hemodynamic function in kidney disease research. Am J Physiol Renal Physiol 2016; 311:F967-F975. [PMID: 27605583 PMCID: PMC6347069 DOI: 10.1152/ajprenal.00415.2016] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 09/02/2016] [Indexed: 12/16/2022] Open
Abstract
Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease. A major challenge in preventing DKD is the difficulty in identifying high-risk patients at an early, pre-clinical stage. Albuminuria and eGFR as measures of renal function in DKD research and clinical practice are limited by regression of one-third of patients with microalbuminuria to normoalbuminuria and eGFR is biased and imprecise in the normal-elevated range. Moreover, existing methods that are used to assess renal function do not give detailed insight into the location of the renal hemodynamic effects of pharmacological agents at the segmental level. To gain additional information about the intrarenal circulation in-vivo in humans, mathematical equations were developed by Gomez et al in the 1950s. These equations used measurements of GFR, renal blood flow (RBF), effective renal plasma flow (ERPF), renal vascular resistance (RVR), hematocrit and serum protein to calculate afferent and efferent arteriolar resistances, glomerular hydrostatic pressure and filtration pressure. Although indirect and based on physiological assumptions, these techniques have the potential to improve researchers' ability to identify early pre-clinical changes in renal hemodynamic function in patients with a variety of conditions including DKD, thereby offering tremendous potential in mechanistic human research studies. In this review, we focus on the application of Gomez' equations and summarize the potential and limitations of this technique in DKD research. We also summarize illustrative data derived from Gomez' equations in patients with type 1 (T1D) and type 2 diabetes (T2D) and hypertension.
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Lytvyn Y, Škrtić M, Yang GK, Lai V, Scholey JW, Yip PM, Perkins BA, Cherney DZI. Plasma uric acid effects on glomerular haemodynamic profile of patients with uncomplicated Type 1 diabetes mellitus. Diabet Med 2016; 33:1102-11. [PMID: 26670339 DOI: 10.1111/dme.13051] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/07/2015] [Indexed: 12/30/2022]
Abstract
AIMS Increased plasma uric acid (PUA) levels are associated with impaired renal function in patients with Type 1 diabetes, but the mechanisms are not well understood. Our aim was to evaluate whether higher PUA levels are associated with increased afferent arteriolar resistance in patients with Type 1 diabetes vs. healthy controls, thereby influencing renal function. METHODS PUA, GFR (inulin) and effective renal plasma flow (ERPF; para-aminohippurate) were measured in 70 otherwise healthy patients with Type 1 diabetes and 60 healthy controls. Gomez's equations were used to estimate afferent (RA ) and efferent (RE ) arteriolar resistances, glomerular hydrostatic pressure (PGLO ) and filtration pressure (ΔPF ). The relationships between PUA and glomerular haemodynamic parameters were evaluated by univariable linear regression correlation coefficients. RESULTS In patients with Type 1 diabetes, higher PUA correlated with lower PGLO (P = 0.002) and ΔPF (P = 0.0007), with higher RA (P = 0.001), but not with RE (P = 0.55). These associations were accompanied by correlations between higher PUA with lower GFR (P = 0.0007), ERPF (P = 0.008), RBF (P = 0.047) and higher RVR (P = 0.021). There were no significant correlations between PUA and renal haemodynamic parameters in the healthy controls. CONCLUSIONS The association between higher PUA with lower GFR and lower ERPF in patients with Type 1 diabetes is driven by alterations in the estimated RA . PUA-mediated RA may be caused by increased tone or thickening of the afferent renal arteriole, which might potentiate renal injury by causing ischaemia to the renal microcirculation.
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Affiliation(s)
- Y 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
| | - M Škrtić
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - G K Yang
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - V Lai
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - J W Scholey
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - P M Yip
- University Health Network, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - B A Perkins
- Department of Medicine, Division of Endocrinology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - D Z I Cherney
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
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Chacon-Caldera J, Geraci S, Krämer P, Cullen-McEwen L, Bertram JF, Gretz N, Schad LR. Fast glomerular quantification of whole ex vivo mouse kidneys using Magnetic Resonance Imaging at 9.4 Tesla. Z Med Phys 2016; 26:54-62. [DOI: 10.1016/j.zemedi.2015.12.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Revised: 12/13/2015] [Accepted: 12/14/2015] [Indexed: 11/28/2022]
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Impact of Iodinated Contrast on Renal Function and Hemodynamics in Rats with Chronic Hyperglycemia and Chronic Kidney Disease. BIOMED RESEARCH INTERNATIONAL 2016; 2016:3019410. [PMID: 27034930 PMCID: PMC4789389 DOI: 10.1155/2016/3019410] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 01/26/2016] [Accepted: 02/04/2016] [Indexed: 12/19/2022]
Abstract
Iodinated contrast (IC) is clinically used in diagnostic and interventional procedures, but its use can result in contrast-induced acute kidney injury (CI-AKI). Chronic kidney disease (CKD) and chronic hyperglycemia (CH) are important predisposing factors to CI-AKI. The aim of this study was to investigate the impact of iodinated contrast on the renal function and hemodynamics in rats with chronic hyperglycemia and chronic kidney disease. A total of 30 rats were divided into six groups; Sham: control of chronic renal disease; Citrate: control of chronic hyperglycemia (CH); Nx5/6: rats with 5/6 nephrectomy; Chronic Hyperglycemia: rats receiving Streptozotocin 65 mg/kg; Nx5/6 + IC: rats Nx5/6 received 6 mL/kg of IC; CH + IC: Chronic hyperglycemia rats receiving 6 mL/kg of IC. Renal function (inulin clearance; urinary neutrophil gelatinase-associated lipocalin, NGAL) and hemodynamics (arterial blood pressure; renal blood flow; renal vascular resistance) were evaluated. Iodinated contrast significantly increased urinary NGAL and reduced inulin clearance, while the hemodynamics parameters showed changes in arterial blood pressure, renal blood flow, and renal vascular resistance in both CKD and CH groups. The results suggest that the iodinated contrast in risk factors models has important impact on renal function and hemodynamics. NGAL was confirmed to play a role of highlight in diagnosis of CI-AKI.
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Renal Damage Frequency in Patients with Solitary Kidney and Factors That Affect Progression. Int J Nephrol 2016; 2015:876907. [PMID: 26783458 PMCID: PMC4689961 DOI: 10.1155/2015/876907] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 10/27/2015] [Indexed: 01/27/2023] Open
Abstract
Background. The aim of this study is to assess renal damage incidence in patients with solitary kidney and to detect factors associated with progression. Methods. Medical records of 75 patients with solitary kidney were investigated retrospectively and divided into two groups: unilateral nephrectomy (group 1) and unilateral renal agenesis/dysplasia (group 2). According to the presence of kidney damage, each group was divided into two subgroups: group 1a/b and group 2a/b. Results. Patients in group 1 were older than those in group 2 (p = 0.001). 34 patients who comprise group 1a had smaller kidney size (p = 0.002) and higher uric acid levels (p = 0.028) than those in group 1b at presentation. Uric acid levels at first and last visit were associated with renal damage progression (p = 0.004, 0.019). 18 patients who comprise group 2a were compared with those in group 2b in terms of presence of DM (p = 0.038), HT (p = 0.003), baseline proteinuria (p = 0.014), and uric acid (p = 0.032) levels and group 2a showed higher rates for each. Progression was more common in patients with DM (p = 0.039), HT (p = 0.003), higher initial and final visit proteinuria (p = 0.014, for both), and higher baseline uric acid levels (p = 0.047). Conclusions. The majority of patients with solitary kidney showed renal damage at presentation. Increased uric acid level is a risk factor for renal damage and progression. For early diagnosis of renal damage and reducing the risk of progression, patients should be referred to a nephrologist as early as possible.
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Pathak JV, Dass EE. A retrospective study of the effects of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in diabetic nephropathy. Indian J Pharmacol 2016; 47:148-52. [PMID: 25878372 PMCID: PMC4386121 DOI: 10.4103/0253-7613.153420] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 07/25/2014] [Accepted: 01/20/2015] [Indexed: 12/17/2022] Open
Abstract
Objective: Till date, several studies have compared angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in terms of delaying the progression of diabetic nephropathy. But the superiority of one drug class over the other remains unsettled. This study has retrospectively compared the effects of ACE inhibitors and ARBs in diabetic nephropathy. The study aims to compare ACE inhibitors and ARBs in terms of delaying or preventing the progression of diabetic nephropathy, association between blood pressure (B.P) and urinary albumin and also B.P and serum creatinine with ACE inhibitor and ARB, know the percentage of hyperkalemia in patients of diabetic nephropathy receiving ACE inhibitor or ARB. Settings and Design: A total of 134 patients diagnosed with diabetic nephropathy during the years 2001–2010 and having a complete follow-up were studied, out of which 99 were on ARB (63 patients of Losartan and 36 of Telmisartan) and 35 on ACE inhibitor (Ramipril). Subjects and Methods: There was at least 1-month of interval between each observation made and also between the date of treatment started and the first reading that is, the observation of the 1st month. In total, three readings were taken that is, of the 1st, 2nd and 3rd month after the treatment started. Comparison of the 1st and 3rd month after the treatment started was done. Mean ± standard deviation, Paired t-test, and Chi-square were used for the analysis of the data. Results: The results reflect that ARBs (Losartan and Telmisartan) when compared to ACE inhibitor (Ramipril) are more effective in terms of delaying the progression of diabetic nephropathy and also in providing renoprotection. Also, ARBs have the property of simultaneously decreasing the systolic B.P and albuminuria when compared to ACE inhibitor (Ramipril). Conclusions: Angiotensin receptor blockers are more renoprotective than ACE inhibitors and also provide better cardioprotection.
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Affiliation(s)
- Jahnavi V Pathak
- Department of Pharmacology, Smt. Bhikhiben Kanjibhai Shah Medical Institute and Research Centre, Sumandeep Vidyapeeth University, Vadodara, Gujarat, India
| | - Ervilla E Dass
- Department of Pharmacology, Smt. Bhikhiben Kanjibhai Shah Medical Institute and Research Centre, Sumandeep Vidyapeeth University, Vadodara, Gujarat, India
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