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Ma X, Liang Y, Chen W, Zheng L, Lin H, Zhou T. The role of endothelin receptor antagonists in kidney disease. Ren Fail 2025; 47:2465810. [PMID: 40015728 PMCID: PMC11869344 DOI: 10.1080/0886022x.2025.2465810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 01/21/2025] [Accepted: 02/06/2025] [Indexed: 03/01/2025] Open
Abstract
Kidney diseases are among the most prevalent conditions worldwide, impacting over 850 million individuals. They are categorized into acute kidney injury and chronic kidney disease. Current preclinical and clinical trials have demonstrated that endothelin (ET) is linked to the onset and progression of kidney disease. In kidney diseases, pathological conditions such as hyperglycemia, acidosis, insulin resistance, and elevated angiotensin II levels lead to an increase in ET. This elevation activates endothelin receptor type A, resulting in harmful effects like proteinuria and a reduced glomerular filtration rate (GFR). Therefore, to slow the progression of kidney disease, endothelin receptor antagonists (ERAs) have been proposed as promising new therapies. Numerous studies have demonstrated the efficacy of ERAs in significantly reducing proteinuria and improving GFR, thereby slowing the progression of kidney diseases. This review discusses the mechanisms of action of ERAs in treating kidney disease, their efficacy and safety in preclinical and clinical studies, and explores future prospects for ERAs.
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Affiliation(s)
- Xiaoting Ma
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Yuyang Liang
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Wenmin Chen
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Lingqian Zheng
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Haishan Lin
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Tianbiao Zhou
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
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Nehus E, Mitsnefes M. Kidney consequences of obesity. Pediatr Nephrol 2025; 40:1879-1893. [PMID: 39680134 DOI: 10.1007/s00467-024-06623-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 11/15/2024] [Accepted: 11/15/2024] [Indexed: 12/17/2024]
Abstract
Herein, we review the devastating consequences of the worldwide obesity epidemic on kidney health and outcomes. We submit that the obesity epidemic is the most pressing public health crisis facing the nephrology community today. A historical approach has been undertaken, wherein major breakthroughs in the recognition and understanding of obesity-related kidney disease (ORKD) are highlighted. We begin with a description of the worldwide obesity epidemic followed by an account of the discovery and characterization of ORKD. A detailed summary of the pathophysiology of ORKD disease is presented, wherein we set forth the following two propositions: first, ORKD is due to a maladaptive response to caloric surplus; and second, this maladaptive response causes kidney damage via hemodynamic (hyperfiltration), hormonal (adipokine dysregulation), and lipotoxic pathways. Each of these pathways is described, with particular emphasis on the relatively recent discovery that the final stage of cellular injury in ORKD is mitochondrial oxidative damage. The prevention and treatment of ORKD are then discussed, including environmental, behavioral, pharmacologic, and surgical options. Finally, we conclude with suggestions for future research to improve early recognition and treatment of ORKD.
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Affiliation(s)
- Edward Nehus
- Department of Pediatrics, West Virginia University School of Medicine Charleston Campus, Charleston, WV, 25314, USA.
- Institute for Academic Medicine, Charleston Area Medical Center, Charleston, WV, USA.
| | - Mark Mitsnefes
- Division of Nephrology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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Yang Q, Huang D, Zhang Z, Gao H, Wu J, Zhong H, Guo X, Wang Y, Zhou H, Liu C, Duan X. Diabetes affects AD through plasma Aβ40: A Mendelian randomization study. Neuroscience 2025; 575:131-139. [PMID: 40233921 DOI: 10.1016/j.neuroscience.2025.04.025] [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: 01/08/2025] [Revised: 04/05/2025] [Accepted: 04/11/2025] [Indexed: 04/17/2025]
Abstract
Amyloid and tau proteins are important proteins in the pathological changes of Alzheimer's disease (AD), while Aβ pathology and tau pathology are the most critical factors contributing to the development of AD. Some studies have shown that there is a causal relationship between AD and diabetes mellitus, but there are no studies showing a causal relationship between diabetic traits and AD biomarkers, so further exploration is needed. We first summarized and analyzed the currently published literature on the link between diabetes and AD through a systematic review. Forest plots were used to observe whether there is an association between diabetes and AD. Then a two-sample Mendelian randomization (MR) analysis based on GWAS summary statistics was performed to verify the causal relationship between diabetic traits and AD biomarkers. Based on summary statistics from the GWAS, potential causal relationships between diabetic traits and AD biomarkers were explored separately. The results of the meta-analysis part showed that diabetes can increase the risk of AD. Meanwhile, our two-sample MR results showed a significant causal relationship between diabetes and plasma Aβ40. In addition, our two-sample MR results also showed a causal relationship between increased HbA1c and plasma APLP2. Other diabetic traits may have potential effects on different AD plasma markers.
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Affiliation(s)
- Qiumin Yang
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Delong Huang
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Zhaojing Zhang
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Haiyan Gao
- Department of Nuclear Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Junhao Wu
- Department of Nuclear Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Haoshu Zhong
- Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiaowei Guo
- School of Life Sciences, Southwest University, Chongqing, China
| | - Yiren Wang
- School of Nursing, Southwest Medical University, Luzhou, Sichuan, China
| | - Hemu Zhou
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Chengzhen Liu
- Faculty of Psychology, Southwest University, Chongqing, China
| | - Xiaodong Duan
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
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Sun M, Chen WM, Wu SY, Zhang J. Sarcopenia and adverse surgical outcomes following cholecystectomy. J Anesth 2025:10.1007/s00540-025-03512-y. [PMID: 40377658 DOI: 10.1007/s00540-025-03512-y] [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: 01/18/2025] [Accepted: 04/27/2025] [Indexed: 05/18/2025]
Abstract
PURPOSE Postoperative complications and mortality following cholecystectomy persist despite the procedural simplicity. We utilized a nationwide administrative database from Taiwan and conducted propensity score matching (PSM) to investigate the association between sarcopenia and major postoperative complications. PATIENTS AND METHODS This retrospective cohort study analyzed data from the Taiwan National Health Insurance Research Database from 2016 to 2020. Patients who underwent elective cholecystectomy under general anesthesia for gallstone disease were included. They were categorized into two groups: those with sarcopenia and those without. The cohorts were matched at a 1:4 ratio using PSM. RESULTS PSM yielded a final cohort of 13,330 surgical patients (10,664 without sarcopenia and 2666 with sarcopenia). Multivariate logistic regression demonstrated that sarcopenia was significantly associated with higher 30 day mortality (adjusted odds ratio [aOR] = 2.26, 95% confidence interval [CI] 1.61-3.18) and major complications, including acute renal failure (aOR = 1.71, 95% CI 1.02-2.84), pneumonia (aOR = 1.68, 95% CI 1.22-2.31), stroke (aOR = 1.13, 95% CI 1.06-1.57), and overall complications (aOR = 1.23, 95% CI 1.07-1.41). Sarcopenia also increased the risk of 90-day mortality (aOR = 2.09, 95% CI 1.58-2.76) and 90-day major complications, including acute renal failure (aOR = 1.61, 95% CI 1.01-2.56), pneumonia (aOR = 1.70, 95% CI 1.30-2.21), stroke (aOR = 1.28, 95% CI 1.04-1.58), and overall complications (aOR = 1.24, 95% CI 1.09-1.41). CONCLUSIONS We found that sarcopenia is an independent risk factor for increased postoperative complications and mortality following cholecystectomy. These findings highlight the importance of preoperative sarcopenia assessment to improve surgical outcomes.
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Affiliation(s)
- Mingyang Sun
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Wan-Ming Chen
- Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, Taipei, Taiwan
- Artificial Intelligence Development Center, Fu Jen Catholic University, Taipei, Taiwan
| | - Szu-Yuan Wu
- Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, Taipei, Taiwan.
- Artificial Intelligence Development Center, Fu Jen Catholic University, Taipei, Taiwan.
- Department of Food Nutrition and Health Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan.
- Big Data Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, No. 83, Nanchang St., Luodong Township, Yilan, 265, Taiwan.
- Division of Radiation Oncology, Department of Medicine, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, 265, Taiwan.
- Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan.
- Cancer Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan.
- Centers for Regional Anesthesia and Pain Medicine, Taipei Municipal Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
- Department of Management, College of Management, Fo Guang University, Yilan, Taiwan.
| | - Jiaqiang Zhang
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Electrophysiology, Henan Academy of Innovations in Medical Science, Zhenzhou, China
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Bansal A, Chonchol M. Metabolic dysfunction-associated kidney disease: pathogenesis and clinical manifestations. Kidney Int 2025:S0085-2538(25)00351-5. [PMID: 40379048 DOI: 10.1016/j.kint.2025.01.044] [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: 10/28/2024] [Revised: 01/14/2025] [Accepted: 01/30/2025] [Indexed: 05/19/2025]
Abstract
In recent years, there have been significant changes in the lifestyle and dietary habits of the population characterized by an increased intake of high-calorie food and a sedentary lifestyle without physical activity. The increased prevalence of overweight and obesity has led to metabolic dysfunction and related complications, such as cardiovascular disease and chronic kidney disease. The purpose of this review is to highlight the importance, clinical features, and pathogenesis of metabolic dysfunction-associated kidney disease (MDAKD). MDAKD is a term that describes kidney disease arising from metabolic dysfunction, often in the context of metabolic syndrome, and is characterized by the presence of chronic kidney disease in individuals with metabolic abnormalities such as obesity, insulin resistance, diabetes mellitus, dyslipidemia, and hypertension. MDAKD includes diabetic kidney disease, obesity-related kidney disease, and, increasingly, other less common kidney diseases where metabolic dysfunction may affect disease progression. MDAKD is part of a spectrum of diseases whose pathogenesis is driven by metabolic dysfunction and has recently led to the proposal of a new nomenclature including metabolic dysfunction-associated steatotic liver disease and cardio-kidney-metabolic syndrome. The new terminology of MDAKD places additional emphasis on the pathogenic role of metabolic dysfunction in kidney disease.
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Affiliation(s)
- Anip Bansal
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Michel Chonchol
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
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Hallab A. Mediating role of Interleukin-6 in the predictive association of diabetes with Hippocampus atrophy, Amyloid, Tau, and Neurofilament pathology at pre-clinical stages of diabetes-related cognitive impairment. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.05.06.25327092. [PMID: 40385439 PMCID: PMC12083567 DOI: 10.1101/2025.05.06.25327092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 05/20/2025]
Abstract
Introduction Type-2 diabetes (T 2 DM) has been associated with higher dementia risks, but the mechanisms are still unclear, and there is increasing evidence of the role of cytokines. Interleukin-6 (IL-6) mediating effect has never been explored. Methods The study included a subset of 1,927 participants from the Health and Aging Brain Study: Healthy Disparities (HABS-HD) cohort with complete data. Cross-sectional and longitudinal analyses were performed. Associations were studied using multivariable linear, logistic, and mediation analysis with non-parametric bootstrapping. Results T 2 DM and IL-6 were associated with worse executive function, Hippocampus atrophy, lower Aß 42 /Aß 40 ratio, and higher Aß 40 , Aß 42 , total Tau, and NfL levels. IL-6 mediated 5% of the association of T 2 DM with Aß 40 ([1.5%-10%], p- value<2×10 -16 ), 4% with Aß 42 ([0.7%-11%], p- value=0.014), 8% with TMT-B ([0.2%-35%], p- value=0.046), 11% with total Tau ([2.5%-40%], p- value=0.010), 5% with NfL ([1.6%-8%], p- value<2×10 -16 ), and 12% hippocampus atrophy ([3%-49%], p- value=0.004). The results, except TMT-B, were replicated in the longitudinal analysis of long-lasting T 2 DM on non-previously diagnosed cognitive impairment. Conclusions The study captured a pre-clinical stage of the T 2 DM-dementia association. The mediating effect of IL-6 is a novelty that has to be further explored and accounted for in risk stratification and preventive measures, particularly in ethnic minorities. Graphical abstract
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van Baar MJB, Muskiet MHA, Scholtes RA, Touw DJ, Nieuwdorp M, Kramer MHH, Joles JA, Cherney DZI, Bjornstad P, Krebber MM, van Raalte DH. Fasting and postprandial kidney haemodynamic effects of empagliflozin and linagliptin in mono- and combination therapy compared to gliclazide in overweight people with type 2 diabetes (RACELINES): A randomised, double-blind trial. Diabetes Obes Metab 2025. [PMID: 40326063 DOI: 10.1111/dom.16431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 04/07/2025] [Accepted: 04/17/2025] [Indexed: 05/07/2025]
Abstract
BACKGROUND Sodium-glucose cotransporter (SGLT) 2 inhibitors attenuate fasting glomerular hyperfiltration in people with type 2 diabetes (T2D). However, SGLT2-inhibition increases glucagon levels, which facilitate postprandial hyperfiltration. The impact of SGLT2 inhibition on protein-related hyperfiltration and postprandial (intra) kidney haemodynamic function is unclear. Moreover, the interaction with dipeptidyl-peptidase (DPP)-4 inhibitors, known to reduce glucagon levels and to affect meal-related factors modulating GFR, is unknown. AIMS We aimed to assess the effects of empagliflozin and linagliptin in mono- and combination therapy compared to the initiation and intensification of SU-derivative gliclazide treatment on fasting and postprandial kidney haemodynamic function. MATERIALS AND METHODS We compared three 16-week glucose-lowering strategies added to ongoing metformin monotherapy: (1) EMPA-LINA: 8-week empagliflozin 10 mg QD (EMPA0-8w) followed by the addition of 8-week linagliptin 5 mg QD (LINA8-16w); (2) LINA-EMPA: 8-week linagliptin (LINA0-8w) followed by the addition of 8-week empagliflozin (EMPA8-16w) versus (3) GLIC-GLIC: 8-week gliclazide 30 mg QD (GLIC0-8w) followed by the addition of 8-week gliclazide 30 mg (GLIC8-16w). We studied (intra) kidney haemodynamic interactions of this combination using iohexol and PAH clearance techniques to assess measured glomerular filtration rate (mGFR) and effective renal plasma flow (ERPF). RESULTS We studied n = 61 overweight people with T2D (HbA1c 62 + 11 mmol/mol, eGFR 89 [78-100] mL/min/1.73 m2 and urinary albumin-creatinine-ratio 1.0 [0.4-1.9] mg/mmol). In the fasting state, EMPA0-8w (-13.2; -21.3 to -5.1 mL/min) but not LINA0-8w reduced within-group mGFR. EMPA8-16w (-10.2; -16.5 to -4.0 mL/min) but not LINA8-16w reduced within-group mGFR. Following a proteinload, EMPA0-8w (-11.4; -20.2 to -2.6 mL/min) and EMPA8-16w (-16.2; -22.9 to -9.4 mL/min) but not LINA0-8w or LINA8-16w reduced within-group mGFR. Versus the comparatorarm, fasting mGFR EMPA0-8w, EMPA8-16w and EMPA-LINA and postprandial mGFR EMPA8-16w and LINA-EMPA, were significantly reduced. mGFR reductions resulted from intrakidney efferent vasodilation rather than afferent vasoconstriction. CONCLUSION In T2D people without CKD, the favourable kidney haemodynamic effects of empagliflozin persist in the postprandial state and are irrespective of concurrent use of linagliptin.
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Affiliation(s)
- Michaël J B van Baar
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Marcel H A Muskiet
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Rosalie A Scholtes
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Daan J Touw
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, The Netherlands
| | - Max Nieuwdorp
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Mark H H Kramer
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Jaap A Joles
- Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands
| | - David Z I Cherney
- Department of Medicine, University Health Network and University of Toronto, Toronto, Ontario, Canada
| | - Petter Bjornstad
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA
- Section of Endocrinology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Merle M Krebber
- Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands
| | - Daniël H van Raalte
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
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Navarro-Blackaller G, Benitez-Renteria AS, Hernández-Morales K, Rico-Fontalvo J, Daza-Arnedo R, Gómez-Ramírez GG, Camacho-Guerrero JR, Pérez-Venegas MA, Carmona-Morales J, Oseguera-González AN, Murguía-Soto C, Chávez-Alonso G, García-Peña F, Barrera-Torres CJ, Orozco-Chan E, Arredondo-Dubois M, Gallardo-González AM, Gómez-Fregoso JA, Rodríguez-García FG, Luquin-Arellano VH, Abundis-Mora G, Alcantar-Vallin L, Medina-González R, García-García G, Chávez-Iñiguez JS. Impact of HbA1c Reduction on Major Kidney Outcomes in Type 2 Diabetes With Poor Glycemic Control and Advanced CKD. Int J Endocrinol 2025; 2025:9919963. [PMID: 40352967 PMCID: PMC12066180 DOI: 10.1155/ije/9919963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 04/14/2025] [Accepted: 04/17/2025] [Indexed: 05/14/2025] Open
Abstract
Aims: In subjects with type 2 diabetes (DM), poor glycemic control, and advanced chronic kidney disease (CKD), the kidney benefit of the reduction of glycated hemoglobin (HbA1c) is not well established. Methods: In a retrospective cohort, we included patients with DM, CKD grade 3b-5, and HbA1c > 9% to evaluate the risk of developing major adverse kidney events (MAKE) defined as the start of kidney replacement therapy (KRT), ≥ 25% or ≥ 40% decline in the glomerular filtration rate (eGFR) from baseline, and death; patients were divided according to the HbA1c levels at the end of the follow-up into the following groups: > 75 mmol/mol (≥ 9.0%), 74-64 mmol/mol (8.9%-8.0%), 64-53 mmol/mol (7.9%-7.0%), and < 52 mmol/mol (< 7.0%). We described their characteristics and analyzed their risks, adjusting for confounding variables. Results: From 2015 to 2023, 111 patients were included. In 46 patients (41.4%), the HbA1c at the end of follow-up (60 months) was still > 75 mmol/mol (≥ 9%), and each patient had a mean of 4.9 HbA1c measurements. The mean age was 59 years, and 46% were male; the baseline eGFR was 25 mL/min/1.73 m2. MAKE occurred in 67% of cases. In a multivariate analysis, the risk of MAKE was not associated with the HbA1c groups, nor was it associated with any of the MAKE components individually, nor in certain subgroups. When evaluating the magnitude of percentage changes in HbA1 with the initiation of KRT, we did not find any association. Conclusions: With advanced CKD and poor glycemic control, changes in HbA1c during long follow-up are not associated with MAKE or its individual components.
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Affiliation(s)
- G. Navarro-Blackaller
- Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
- University of Guadalajara Health Sciences Center, Guadalajara, Jalisco, Mexico
| | | | - K. Hernández-Morales
- Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
- University of Guadalajara Health Sciences Center, Guadalajara, Jalisco, Mexico
| | - J. Rico-Fontalvo
- Kidney, Diabetes, and Metabolism Committee, Colombian Association of Nephrology and Hypertension, Bogotá, Colombia
- Departamento de Nefrología, Facultad de Medicina de la Universidad Simón Bolívar, Barranquilla, Colombia
| | - R. Daza-Arnedo
- Kidney, Diabetes, and Metabolism Committee, Colombian Association of Nephrology and Hypertension, Bogotá, Colombia
| | - G. G. Gómez-Ramírez
- Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
| | - J. R. Camacho-Guerrero
- Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
- University of Guadalajara Health Sciences Center, Guadalajara, Jalisco, Mexico
| | - M. A. Pérez-Venegas
- Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
- University of Guadalajara Health Sciences Center, Guadalajara, Jalisco, Mexico
| | - J. Carmona-Morales
- Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
- University of Guadalajara Health Sciences Center, Guadalajara, Jalisco, Mexico
| | - A. N. Oseguera-González
- Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
- University of Guadalajara Health Sciences Center, Guadalajara, Jalisco, Mexico
| | - C. Murguía-Soto
- Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
- University of Guadalajara Health Sciences Center, Guadalajara, Jalisco, Mexico
| | - G. Chávez-Alonso
- University of Guadalajara Health Sciences Center, Guadalajara, Jalisco, Mexico
| | - F. García-Peña
- Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
| | - C. J. Barrera-Torres
- Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
- University of Guadalajara Health Sciences Center, Guadalajara, Jalisco, Mexico
| | - E. Orozco-Chan
- Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
- University of Guadalajara Health Sciences Center, Guadalajara, Jalisco, Mexico
| | - M. Arredondo-Dubois
- Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
- University of Guadalajara Health Sciences Center, Guadalajara, Jalisco, Mexico
| | - A. Martínez Gallardo-González
- Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
- University of Guadalajara Health Sciences Center, Guadalajara, Jalisco, Mexico
| | - J. A. Gómez-Fregoso
- Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
| | - F. G. Rodríguez-García
- Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
| | - V. H. Luquin-Arellano
- Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
- University of Guadalajara Health Sciences Center, Guadalajara, Jalisco, Mexico
| | - G. Abundis-Mora
- University of Guadalajara Health Sciences Center, Guadalajara, Jalisco, Mexico
| | - L. Alcantar-Vallin
- Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
- University of Guadalajara Health Sciences Center, Guadalajara, Jalisco, Mexico
| | - R. Medina-González
- Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
| | - G. García-García
- University of Guadalajara Health Sciences Center, Guadalajara, Jalisco, Mexico
| | - J. S. Chávez-Iñiguez
- Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
- University of Guadalajara Health Sciences Center, Guadalajara, Jalisco, Mexico
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Kwok R, Kishore K, Zafari T, Koye DN, Hachem M, de Boer IH, Jeong TD, Min WK, Porrini E, Bjornstad P, MacIsaac RJ, Churilov L, Ekinci EI. Comparative performance of CKD-EPI equations in people with diabetes: An international pooled analysis of individual participant data. Diabetes Res Clin Pract 2025; 223:112104. [PMID: 40096945 DOI: 10.1016/j.diabres.2025.112104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 02/28/2025] [Accepted: 03/14/2025] [Indexed: 03/19/2025]
Abstract
AIM This study assessed the concordance and misclassification of chronic kidney disease (CKD) stages between directly measured glomerular filtration rate (mGFR) and estimates of GFR (eGFR) using the creatinine-based CKD-EPI-2009 and the CKD-EPI-2021 equations in individuals with diabetes. METHODS Data from 5,177 individuals across six international diabetes cohorts included mGFR measurements using exogenous filtration markers. We calculated an intra-class correlation coefficient (ICC), bias, precision and accuracy between mGFR and CKD-EPI estimates using a four-level mixed-effect linear variance component model. RESULTS The pooled cohort included people with type 1 (n = 1,748, median age: 33 years [IQR: 27, 40], mGFR = 104.2 ml/min per 1.73 m2) and type 2 diabetes (n = 3,429, median age: 66 years [IQR: 58, 73], mGFR = 58.4 ml/min per 1.73 m2). Both CKD-EPI equations showed good agreement (2009 ICC: 0.90; 2021 ICC: 0.87) but substantial bias (2009: 3.7 ml/min/1.73 m2; 2021: 8.6 ml/min/1.73 m2), low precision (2009: 12.4 ml/min/1.73 m2; 2021: 13.91 ml/min/1.73 m2), and limited accuracy (2009 p30: 77 %; 2021 p30: 70 %) compared to mGFR. CONCLUSION The use of CKD-EPI equations has the potential for misdiagnosis and suboptimal CKD management in people with diabetes. Alternative methods of estimating kidney function for people with diabetes are needed to optimally manage diabetes-related kidney disease.
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Affiliation(s)
- Rodney Kwok
- Department of Endocrinology, Austin Health, Melbourne, Australia; Department of Medicine Austin Health, Melbourne Medical School, The University of Melbourne, Australia; Australian Centre for Accelerating Diabetes Innovations, The University of Melbourne, Melbourne, Australia
| | - Kartik Kishore
- Department of Medicine Austin Health, Melbourne Medical School, The University of Melbourne, Australia; Australian Centre for Accelerating Diabetes Innovations, The University of Melbourne, Melbourne, Australia
| | - Tina Zafari
- Department of Endocrinology, Austin Health, Melbourne, Australia
| | - Digsu N Koye
- Australian Centre for Accelerating Diabetes Innovations, The University of Melbourne, Melbourne, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - Mariam Hachem
- Department of Endocrinology, Austin Health, Melbourne, Australia; Department of Medicine Austin Health, Melbourne Medical School, The University of Melbourne, Australia; Australian Centre for Accelerating Diabetes Innovations, The University of Melbourne, Melbourne, Australia
| | - Ian H de Boer
- Kidney Research Institute, University of Washington, Seattle, United States of America
| | - Tae-Dong Jeong
- Department of laboratory Medicine, Ewha Woman University College of Medicine, Seoul, Korea
| | - Won-Ki Min
- Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea
| | | | - Petter Bjornstad
- Department of Pediatrics and Department of Medicine, University of Washington, Seattle, WA, United States of America; University of Washington Medicine Diabetes Institute, University of Washington, Seattle, WA, United States of America; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Richard J MacIsaac
- Australian Centre for Accelerating Diabetes Innovations, The University of Melbourne, Melbourne, Australia; Department of Medicine, St Vincent's Hospital Melbourne, The University of Melbourne, Melbourne, Australia; Department of Endocrinology and Diabetes, St Vincent's Hospital Melbourne, Australia
| | - Leonid Churilov
- Australian Centre for Accelerating Diabetes Innovations, The University of Melbourne, Melbourne, Australia; Department of Medicine, Royal Melbourne Hospital, Melbourne Medical School, The University of Melbourne, Australia
| | - Elif I Ekinci
- Department of Endocrinology, Austin Health, Melbourne, Australia; Department of Medicine Austin Health, Melbourne Medical School, The University of Melbourne, Australia; Australian Centre for Accelerating Diabetes Innovations, The University of Melbourne, Melbourne, Australia.
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10
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Pang X, Dan W, Lin L, Li H, Rao X, Li S. Association of normal range of urinary albumin-to-creatinine ratio with all-cause mortality among diabetic adults with preserved kidney function: National Health and Nutrition Examination Survey (NHANES) 2003-2018. Diabetes Obes Metab 2025; 27:2670-2678. [PMID: 40000417 PMCID: PMC11965009 DOI: 10.1111/dom.16269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 01/16/2025] [Accepted: 01/28/2025] [Indexed: 02/27/2025]
Abstract
AIM To ascertain the connection between normal-range urinary albumin-to-creatinine ratio (UACR) and all-cause mortality (ACM) among diabetic adults with preserved eGFR. METHODS We used data from the 2003-2018 National Health and Nutrition Examination Survey. Nationally representative cross-sectional survey data linked with mortality outcomes from the National Death Index. Restricted cubic spline curves (RCS) and multivariable Cox regression models alongside subgroup analyses were utilised for estimating hazard ratios (HRs) and 95% confidence intervals (Cls) for UACR-ACM interplay, adjusting for demographic, socioeconomic, biochemical, medication and medical history factors. The UACR's predictive accuracy for survival outcomes was determined through receiver operating characteristic analysis. RESULTS The RCS regression analysis showcased that there was no significant evidence to support a nonlinear relationship between normal-range UACR and ACM (p = 0.080 for nonlinearity) in participants with diabetes mellitus (DM). In the model 2 adjusted for multiple confounding variables, the HR for ACM was 1.22 (95% CI, 1.06-1.40) per 10 mg/g raise in continuous UACR and 1.50 (95%CI, 1.18-1.91) for the high UACR tertile compared to the low. Kaplan-Meier analysis showed significantly lower survival rates in the medium and high UACR groups (p < 0.001). Subgroup analysis manifested a significant UACR-body mass index (BMI) interaction (p = 0.033 for interaction). CONCLUSIONS In DM adults without overt kidney dysfunction, elevated normal-range UACR was independently related to escalated ACM, particularly in those with normal BMI. To conclude, we underscore the significance of early risk assessment in DM patients with normal-range albuminuria, even without overt kidney dysfunction.
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Affiliation(s)
- Xiaoxia Pang
- Department of NephrologyGuang'anmen Hospital China Academy of Chinese Medical SciencesBeijingChina
| | - Wenchao Dan
- Department of Dermatology, Beijing Hospital of Traditional Chinese MedicineCapital Medical UniversityBeijingChina
| | - Lan Lin
- Department of NephrologyGuang'anmen Hospital China Academy of Chinese Medical SciencesBeijingChina
| | - Huimei Li
- Department of NephrologyGuang'anmen Hospital China Academy of Chinese Medical SciencesBeijingChina
| | - Xiangrong Rao
- Department of NephrologyGuang'anmen Hospital China Academy of Chinese Medical SciencesBeijingChina
| | - Shen Li
- Department of NephrologyGuang'anmen Hospital China Academy of Chinese Medical SciencesBeijingChina
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11
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Sun L, Wu Y, Sun T, Li P, Liang J, Yu X, Yang J, Meng N, Wang M, Chen C. Influence of diabetes mellitus on metabolic networks in lung cancer patients: an analysis using dynamic total-body PET/CT imaging. Eur J Nucl Med Mol Imaging 2025; 52:2145-2156. [PMID: 39831968 DOI: 10.1007/s00259-025-07081-w] [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: 08/30/2024] [Accepted: 01/07/2025] [Indexed: 01/22/2025]
Abstract
INTRODUCTION The intricate interplay between organs can give rise to a multitude of physiological conditions. Disruptions such as inflammation or tissue damage can precipitate the development of chronic diseases such as tumors or diabetes mellitus (DM). While both lung cancer and DM are the consequences of disruptions in homeostasis, the relationship between them is intricate. This study sought to investigate the potential influence of DM on lung cancer by employing total-body dynamic PET imaging. METHODS The present study proposes a framework for metabolic network analysis using total-body dynamic PET imaging of 20 lung cancer patients with DM (DM group) and 20 lung cancer patients without DM (Non-DM group), with the residuals of a third-order polynomial fit serving as an indicator of Pearson correlation. RESULTS The framework successfully captured the deviation of the DM group from the Non-DM group at both the edge and organ levels. At the edge level, there was a significant difference in the lesion- left ventricle (LV) between the DM and Non-DM groups (P < 0.05). Furthermore, we discovered a positive correlation between the absolute value of Z-score (ZCC) of lesion - LV and the duration of DM (R = 0.680, P < 0.001). At the organ level, there was a significant difference in the kidney, brain, and abdominal fat between the DM and Non-DM groups (P < 0.05). CONCLUSION This study demonstrated the feasibility of constructing metabolic networks to uncover complex alterations in lung cancer patients with DM. The findings contribute to understanding the systemic effects of DM on lung cancer metabolism and highlight the importance of personalized metabolic network analysis to comprehend the implications of concurrent diseases.
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Affiliation(s)
- Lubing Sun
- Department of Radiology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China
- Clinical Bioinformatics Experimental Center, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Yaping Wu
- Department of Radiology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Tao Sun
- Paul C. Lauterbur Research Center for Biomedical Imaging, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Panlong Li
- Department of Radiology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Junting Liang
- Clinical Bioinformatics Experimental Center, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China
| | - Xuan Yu
- Department of Radiology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Junpeng Yang
- Department of Endocrinology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China
| | - Nan Meng
- Department of Radiology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Meiyun Wang
- Department of Radiology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China.
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
| | - Chuanliang Chen
- Department of Radiology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China.
- Clinical Bioinformatics Experimental Center, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China.
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12
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Niendorf T, Gladytz T, Cantow K, Millward JM, Waiczies S, Seeliger E. Magnetic resonance imaging of renal oxygenation. Nat Rev Nephrol 2025:10.1038/s41581-025-00956-z. [PMID: 40269325 DOI: 10.1038/s41581-025-00956-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/20/2025] [Indexed: 04/25/2025]
Abstract
Renal hypoxia has a key role in the pathophysiology of many kidney diseases. MRI provides surrogate markers of oxygenation, offering a critical opportunity to detect renal hypoxia. However, studies that have assessed the diagnostic performance of oxygenation MRI for kidney disorders have provided inconsistent results because MRI metrics do not fully capture the complexity of renal oxygenation. Most oxygenation MRI studies are descriptive in nature and fail to detail the pathophysiological importance of the imaging findings. These limitations have restricted the clinical application of oxygenation MRI and the full potential of this technology to facilitate early diagnosis, risk prediction and treatment monitoring of kidney disease has not yet been realized. Understanding of the relationship between renal tissue oxygenation and MRI metrics, which is affected by kidney size, tubular volume fraction and renal blood volume fraction, and measurement of these factors using novel MR methods is imperative for correct physiological interpretation of renal MR oximetry findings. Next steps to enable the clinical adoption of MR oximetry should involve multidisciplinary collaboration to address standardization of acquisition and data analysis protocols and establish reference values of MRI metrics.
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Affiliation(s)
- Thoralf Niendorf
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Ultrahigh Field Facility (B.U.F.F.), Berlin, Germany.
- Experimental and Clinical Research Center, A joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
| | - Thomas Gladytz
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Ultrahigh Field Facility (B.U.F.F.), Berlin, Germany
- Experimental and Clinical Research Center, A joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Kathleen Cantow
- Institute of Translational Physiology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
| | - Jason M Millward
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Ultrahigh Field Facility (B.U.F.F.), Berlin, Germany
- Experimental and Clinical Research Center, A joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Sonia Waiczies
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Ultrahigh Field Facility (B.U.F.F.), Berlin, Germany
- Experimental and Clinical Research Center, A joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Erdmann Seeliger
- Institute of Translational Physiology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
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Oniki K, Shigaki T, Kajiwara-Morita A, Shigetome K, Yoshida A, Jinnouchi H, Saruwatari J. Quantitative assessment of metabolic memory and its prediction of renal function decline in patients with type 2 diabetes: A retrospective observational study. Diabetes Metab Syndr 2025; 19:103225. [PMID: 40239378 DOI: 10.1016/j.dsx.2025.103225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 04/07/2025] [Accepted: 04/11/2025] [Indexed: 04/18/2025]
Abstract
AIMS This study quantitatively assesses metabolic memory by modeling the relationship between hyperglycemic exposure and renal function decline in patients with type 2 diabetes (T2D). METHODS This retrospective longitudinal study included 381 Japanese patients with T2D. Hyperglycemic exposure was presented by calculating the area under the curve (AUC) for HbA1c ≥ 6 % (AUCHbA1c ≥ 6 %) during the observation period. A non-linear mixed-effects model was constructed to predict changes in estimated glomerular filtration rate (eGFR) based on AUCHbA1c ≥ 6 %. RESULTS The relationship between AUCHbA1c ≥ 6 % and eGFR changes was shown by a sigmoidal curve, with sex, age, diabetic retinopathy, dyslipidemia, and hypertension incorporated as covariates. The predictive utility of the model was validated using goodness-of-fit plot, visual predictive check, and bootstrap methods. CONCLUSIONS We developed an AUCHbA1c ≥ 6 %-based model to predict renal function decline in patients with T2D, showing that AUCHbA1c ≥ 6 % may serve as a quantitative indicator of metabolic memory.
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Affiliation(s)
- Kentaro Oniki
- Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
| | - Takuro Shigaki
- Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Ayami Kajiwara-Morita
- Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Diabetes Care Center, Jinnouchi Hospital, Kumamoto, Japan
| | - Keiichi Shigetome
- Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Akira Yoshida
- Diabetes Care Center, Jinnouchi Hospital, Kumamoto, Japan
| | | | - Junji Saruwatari
- Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
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Chen X, Zhang J, Lu F, Hu R, Du X, Xu C, Liang M, Chen L, Yao W, Ma Z, Zhong J, Wang M. Association between uric acid to high-density lipoprotein cholesterol ratio and chronic kidney disease in Chinese patients with type 2 diabetes mellitus: a cross-sectional study. Front Nutr 2025; 12:1582495. [PMID: 40297336 PMCID: PMC12034545 DOI: 10.3389/fnut.2025.1582495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Accepted: 03/28/2025] [Indexed: 04/30/2025] Open
Abstract
Objectives To examine the association between uric acid (UA) to high-density lipoprotein cholesterol (HDL-C) ratio (UHR) and chronic kidney disease (CKD) in type 2 diabetes mellitus (T2DM) patients in China. Methods The investigation stems from a survey conducted in the eastern Chinese province of Zhejiang, spanning from March to November 2018. A multivariable logistic regression model was employed to assess the relationship between UHR and CKD, while restricted cubic spline (RCS) analysis was used to evaluate the dose-response relationship. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal UHR cut-off value and assess its diagnostic performance for CKD. Model performance was further evaluated using net reclassification improvement (NRI) and integrated discrimination improvement (IDI) metrics. Sensitivity analyses, including propensity score matching (PSM) and k-means clustering, were conducted to enhance the robustness of the findings. Subgroup analyses were performed across various demographic and clinical categories to examine the consistency of the UHR-CKD association. Results This cross-sectional study included 1,756 Chinese patients with T2DM, among whom 485 (27.62%) were identified with CKD. Multivariable logistic regression analysis revealed a significant positive association between UHR and CKD. Per standard deviation (SD) increase in UHR was associated with a 40% higher odds of CKD (OR = 1.40, 95% CI: 1.23-1.60) after adjusting for potential covariates. When analyzed categorically, participants in the highest UHR tertile (T3) had 1.82-fold higher odds of CKD compared to the lowest tertile (T1) (95% CI: 1.32-2.50). RCS analysis demonstrated a consistent linear dose-response relationship between UHR and CKD across all models (all p for nonlinearity >0.05). ROC curve analysis identified an optimal UHR cut-off value of 12.28 for CKD prediction, with an area under the curve (AUC) of 0.710 (95% CI: 0.683-0.737) in the fully adjusted model. Subgroup analyses confirmed the robustness of the UHR-CKD association across most demographic and clinical variables, except for younger age groups (18-44 and 45-59 years) and smokers. Notably, BMI significantly modified the UHR-CKD relationship, with a nonlinear association observed in individuals with lower BMI (<24 kg/m2) and a linear association in those with higher BMI (≥24 kg/m2). Conclusion This study demonstrates a significant dose-response relationship between the UHR and CKD in Chinese patients with T2DM, highlighting UHR as a promising biomarker for CKD risk assessment. The identified UHR cut-off of 12.28 offers a practical threshold for early renal monitoring and targeted interventions. Future research should explore UHR-targeted therapies and its integration into personalized risk stratification models to improve CKD management in T2DM.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Meng Wang
- Department of Non-Communicable Disease Control and Prevention, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China
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15
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Ha HJ, Kang MK, Kim JH, Choi YH, Song TJ. Renal hyperfiltration is associated with a reduced incidence of hypertension in individuals younger than 70. Sci Rep 2025; 15:12573. [PMID: 40221499 PMCID: PMC11993564 DOI: 10.1038/s41598-025-97023-1] [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: 03/15/2024] [Accepted: 04/01/2025] [Indexed: 04/14/2025] Open
Abstract
Although the connection between decreased kidney function and hypertension is commonly acknowledged, there is insufficient research examining the relationship between renal hyperfiltration (higher-than-normal estimated glomerular filtration rate (eGFR)) and the incidence risk of hypertension. Therefore, through a nationwide longitudinal study, our research aimed to explore the relationship between the eGFR and the incidence risk of hypertension in the general population. This research used the cohort records for the National Health Insurance Service in Korea, analyzing records from 1,873,550 individuals between the ages of 20 and 79 who underwent health check-ups between 2010 and 2011. The eGFR levels, determined by applying the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, were employed to evaluate the renal function. An incidence of hypertension was confirmed when a diagnosis of (primary or secondary) hypertension (International Classification of Diseases (ICD)-10 codes I10-I11) was noted at least once per year during outpatient or inpatient care with a prescription for antihypertensive medication or at least one more surpassing 140/90 mmHg from a health examination after the index date after excluding diagnosis of secondary hypertension. The mean age of subjects was 46.03 ± 11.24 years. The 411,029 (21.9%) hypertension cases were identified over a median follow-up of 9.53 years. In the multivariable Cox regression analysis, compared with the 5th decile, the 10th eGFR deciles (≥ 115.58 mL/min/1.73 m²) (hazard ratio (HR): 0.87, 95% confidence interval (CI)(0.85-0.88), p < 0.001) demonstrated a significant association with a reduced incidence of hypertension. Moreover, an eGFR exceeding 120 mL/min/1.73 m² was linked to a lowered likelihood of hypertension (HR: 0.78, 95% CI (0.76-0.80), p < 0.001) compared to normal eGFR levels (90 ~ 120 mL/min/1.73 m²). In contrast, in the subgroup analysis of ages over 70 years old, renal hyperfiltration was not associated with a reduced incidence of hypertension. In our study, renal hyperfiltration were associated with a reduced risk of hypertension, and this association was particularly significant in those younger than 70 years old. The association between renal hyperfiltration and a lower risk of hypertension incidence was likely to vary with age.
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Affiliation(s)
- Hee-Jung Ha
- Department of Neurology, Seoul Hospital, Ewha Womans University College of Medicine, 260, Gonghang-daero, Gangseo-gu, Seoul, 07804, Republic of Korea
| | - Min Kyoung Kang
- Department of Neurology, Seoul Hospital, Ewha Womans University College of Medicine, 260, Gonghang-daero, Gangseo-gu, Seoul, 07804, Republic of Korea
- Department of Neurology, Seoul Chuk Hospital, Seoul, Republic of Korea
| | - Jeong Hwa Kim
- Department of Physiology, Ewha Womans University College of Medicine, Seoul, Republic of Korea
| | - Youn-Hee Choi
- Department of Physiology, Ewha Womans University College of Medicine, Seoul, Republic of Korea.
- Inflammation-Cancer Microenvironment Research Center, Ewha Womans University College of Medicine, 25, Magokdong-ro 2-gil, Gangseo-gu, 07804, Seoul, Seoul, Republic of Korea.
| | - Tae-Jin Song
- Department of Neurology, Seoul Hospital, Ewha Womans University College of Medicine, 260, Gonghang-daero, Gangseo-gu, Seoul, 07804, Republic of Korea.
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Wever BE, Scholtes RA, Mosterd CM, Hesp AC, Smits MM, Heerspink HJL, van Raalte DH. The systemic and kidney hemodynamic response to empagliflozin, losartan and their combination varies between individuals. J Nephrol 2025:10.1007/s40620-025-02289-3. [PMID: 40221573 DOI: 10.1007/s40620-025-02289-3] [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: 12/24/2024] [Accepted: 03/24/2025] [Indexed: 04/14/2025]
Abstract
BACKGROUND Renin-angiotensin system inhibitors (RASi) and sodium glucose cotransporter inhibitors (SGLT2i) are known for their kidney protective properties, but both show significant residual risk in large outcome trials. In these trials, SGLT2i were introduced on top of RASi; the individual response to each drug is currently unclear. We therefore aimed to investigate the individual reactions to the angiotensin II receptor blocker (ARB) losartan and the SGLT2i empagliflozin and their combination on measured GFR (mGFR) and systolic blood pressure (SBP). METHODS In this double-blind, randomized, 4-armed, crossover study, 24 participants received 7 days of empagliflozin 10 mg once daily, losartan 50 mg once daily, combination therapy or matching placebo. We visualized individual drug response variability. We further explored predictors of mGFR and SBP changes. RESULTS During empagliflozin administration, a greater than 10% reduction in mGFR was observed in 26% of participants receiving empagliflozin, in 30% of those receiving losartan, and in 39% among participants on combination therapy. In comparison, a greater than 10% reduction in SBP was observed in 35% of participants on empagliflozin, in 39% of those receiving losartan and in 43% on combination therapy. A large part of the participants who did not respond to one drug, did respond to the other drug or their combination. Monotherapy SGLT2i did not correlate with monotherapy ARB in mGFR change or SBP change. CONCLUSIONS Our data show large individual variability in response to treatment with the ARB losartan and the SGLT2i empagliflozin. Clinicians should monitor treatment responses in patients and consider switching from one kidney protective drug to another in non-responders.
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Affiliation(s)
- Britt Eveline Wever
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, Location VUMC, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
| | - Rosalie Annemien Scholtes
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, Location VUMC, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
| | - Charlotte Michelle Mosterd
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, Location VUMC, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
| | - Anne Clasien Hesp
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, Location VUMC, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
| | - Mark Martinus Smits
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, Location VUMC, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
| | - Hiddo Jan Lambers Heerspink
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, The Netherlands
| | - Daniël Henri van Raalte
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, Location VUMC, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
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Ruan AF, Zheng JW, Sun SQ, Liu XZ, Chen TL. The association of albumin-corrected anion gap and acute kidney injury in heart failure patients: a competing risk model analysis. BMC Cardiovasc Disord 2025; 25:277. [PMID: 40217175 PMCID: PMC11987305 DOI: 10.1186/s12872-025-04723-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Accepted: 04/01/2025] [Indexed: 04/15/2025] Open
Abstract
BACKGROUND The combination of heart failure (HF) and acute kidney injury (AKI) increases the mortality of patients. It is critical to identify HF patients who may have a high risk for AKI. Albumin-corrected anion gap (ACAG) is a new indicator, but there are no studies on ACAG and the risk of AKI in HF patients. METHODS Data for HF patients was obtained from the MIMIC-IV database. Receiver operating characteristic (ROC) analysis and decision curve analysis (DCA) were employed to evaluate the clinical value of ACAG in predicting AKI risk. Logistic regression analysis and restricted cubic spline (RCS) curve were conducted to explore the relationship between ACAG and AKI. A competing risk model was developed to further investigate the relationship between ACAG on AKI. RESULTS The study analyzed 5,972 HF patients, with 49.82% (2886/5972) suffering from AKI. The prediction performance of ACAG on AKI was good (AUC:0.656). Continuous ACAG was associated with AKI after adjusting for various significant variables (Model 1: OR = 1.094, 95%CI: 1.078-1.110; Model 2: OR = 1.150, 95%CI: 1.133-1.166; Model 3: OR = 1.035, 95%CI. 1.017-1.054). All High ACAG groups showed a higher risk of AKI (all P < 0.001). ACAG was also linked to in-hospital mortality (P < 0.001). The competing risks model revealed that high ACAG was still a risk factor for AKI when in-hospital mortality served as a competing risk event (P < 0.001). CONCLUSION High ACAG was associated with the risk of AKI in HF patients. Clinicians can risk-stratify HF patients by combining ACAG levels.
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Affiliation(s)
- Ai-Fang Ruan
- Department of cardiovascular medicine, Hangzhou Lin'an District Hospital of Traditional Chinese Medicine, Hangzhou, 311300, Zhejiang, China
| | - Jian-Wu Zheng
- Department of cardiovascular medicine, Hangzhou Hospital of Traditional Chinese Medicine, No.453 Stadium Road, Xihu District, Hangzhou, 310007, Zhejiang, China
| | - Shao-Qing Sun
- Department of cardiovascular medicine, Hangzhou Lin'an District Hospital of Traditional Chinese Medicine, Hangzhou, 311300, Zhejiang, China
| | - Xu-Zhu Liu
- Department of cardiovascular medicine, Hangzhou Lin'an District Hospital of Traditional Chinese Medicine, Hangzhou, 311300, Zhejiang, China
| | - Tie-Long Chen
- Department of cardiovascular medicine, Hangzhou Hospital of Traditional Chinese Medicine, No.453 Stadium Road, Xihu District, Hangzhou, 310007, Zhejiang, China.
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18
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Hansen AL, Christiansen CF, Brøns C, Engelhard LM, Hansen T, Nielsen JS, Vestergaard P, Højlund K, Jessen N, Olsen MH, Sørensen HT, Rossing P, Thomsen RW, Vaag A. Birthweight and risk of chronic kidney disease after a type 2 diabetes diagnosis in the DD2 cohort. Diabetologia 2025; 68:778-791. [PMID: 39891704 PMCID: PMC11950141 DOI: 10.1007/s00125-024-06357-4] [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: 09/04/2024] [Accepted: 12/10/2024] [Indexed: 02/03/2025]
Abstract
AIMS/HYPOTHESIS Low birthweight (LBW) is associated with younger age, less obesity and more hypertension among people recently diagnosed with type 2 diabetes, as well as increased cardiovascular morbidity and mortality risk. It is not known whether LBW is associated with an increased risk of incident chronic kidney disease (CKD) among people with a type 2 diabetes diagnosis. METHODS Original midwife records were retrieved for 5982 participants with recently diagnosed type 2 diabetes enrolled in the Danish Center for Strategic Research in Type 2 Diabetes (DD2) cohort between 2010 and 2024. They were followed until first incident CKD diagnosis, defined as either two eGFR measurements <60 ml/min per 1.73m2 or two urine albumin/creatinine ratio (UACR) measurements >3 mg/mmol, each 90-365 days apart. Confounder-standardised 10 year risks of CKD were estimated, with death considered as a competing risk. Adjusted hazard ratios (aHRs) for CKD were computed using Cox and spline regression analyses. All analyses were controlled for differences in sex, age at enrolment, calendar year at birth, family history of diabetes and born-at-term status. Mixed-effects models were used to examine the trajectories of eGFR and UACR following enrolment. RESULTS A total of 1501 incident CKD endpoints occurred, corresponding to an incidence rate of 42.4 per 1000 person-years over a median follow-up time of 8.3 years. Spline models with birthweight as a continuous measure showed progressively increasing aHRs for CKD with decreasing birthweight. The 10-year standardised risk of CKD was 36.0% in people with LBW (<2500 g) and 30.6% in people with a normal birthweight (2500-4000 g), yielding a risk difference (RD) of 5.5% (95% CI -0.5%, 11.8%) and an aHR of 1.23 (95% CI 0.98, 1.55). People with type 2 diabetes and high birthweight (>4000 g) had a similar 10-year standardised CKD risk compared with normal birthweight (33.1% and 30.6%, respectively). This yielded an RD of 2.5% (95% CI -1.6%, 6.7%) and an aHR of 1.10 (95% CI 0.93, 1.29). In mixed-effects models examining eGFR and UACR trajectories, each 1 kg decrease in birthweight was associated with a 6.6% (95% CI 1.9, 11.1) increase in UACR, whereas no association was found for eGFR. CONCLUSIONS/INTERPRETATION A history of LBW was associated with elevated risk of CKD among people with a recent type 2 diabetes diagnosis, although the precision of risk estimates was limited.
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Affiliation(s)
- Aleksander L Hansen
- Steno Diabetes Center Copenhagen, Herlev, Denmark.
- Department of Clinical Epidemiology, Aarhus University Hospital, and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
| | - Christian F Christiansen
- Department of Clinical Epidemiology, Aarhus University Hospital, and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | | | - Leonie M Engelhard
- Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Epidemiology, Aarhus University Hospital, and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Lund University Diabetes Center, Lund University, Lund, Sweden
| | - Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Jens S Nielsen
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
| | - Peter Vestergaard
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
| | - Kurt Højlund
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
| | - Niels Jessen
- Steno Diabetes Center, Aarhus University Hospital, Aarhus, Denmark
| | - Michael H Olsen
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Internal Medicine and Steno Diabetes Center Zealand, Holbæk Hospital, Holbæk, Denmark
| | - Henrik T Sørensen
- Department of Clinical Epidemiology, Aarhus University Hospital, and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Peter Rossing
- Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Reimar W Thomsen
- Department of Clinical Epidemiology, Aarhus University Hospital, and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Allan Vaag
- Steno Diabetes Center Copenhagen, Herlev, Denmark.
- Lund University Diabetes Center, Lund University, Lund, Sweden.
- Department of Endocrinology, Skåne University Hospital, Malmö, Sweden.
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Oba R, Ueno H, Oishi A, Nagahama K, Kanzaki G, Tsuboi N, Yokoo T, Nagase M. Upregulation of Piezo2 and increased extracellular matrix protein in diabetic kidney disease mice. Hypertens Res 2025; 48:1514-1528. [PMID: 39833555 DOI: 10.1038/s41440-024-02082-y] [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: 06/30/2024] [Revised: 12/16/2024] [Accepted: 12/21/2024] [Indexed: 01/22/2025]
Abstract
Mechanical forces such as glomerular hyperfiltration are crucial in the pathogenesis and progression of diabetic kidney disease. Piezo2 is a mechanosensitive cation channel and plays a major role in various biological and pathophysiological phenomena. We previously reported Piezo2 expression in mouse and rat kidneys and its alteration by dehydration and hypertension. To elucidate the alteration of Piezo2 expression and its consequences in a mouse model of diabetic kidney disease, we used high salt-fed male KK-Ay mice, an accelerated genetic model of diabetic kidney disease. KK-Ay mice exhibited marked obesity, hyperglycemia, elevated blood pressure, higher creatinine clearance, and overt albuminuria. Histopathological analysis revealed glomerular hypertrophy, mesangial expansion, macrophage infiltration, tubular vacuolization, and interstitial fibrosis. The mRNA and protein expression analyses revealed (1) increased fibronectin protein expression in the glomerular areas, (2) upregulated Piezo2 expression in the glomerular mesangial cells and interstitial region, (3) increased Piezo2 and the fibronectin-coding gene Fn1 mRNA, and (4) a strong correlation of Piezo2 expression with that of Fn1 in the kidneys of diabetic kidney disease mice. Piezo2 upregulation and fibronectin accumulation were alleviated by an angiotensin II receptor blocker. In accordance with these in vivo results, in vitro study demonstrated that Piezo2 overexpression increased fibronectin production in HEK293T cells. In conclusion, we demonstrated that Piezo2 expression was upregulated in glomerular mesangial cells in a mouse model of diabetic kidney disease. Our results suggest that Piezo2 contributes to the progression of diabetic kidney disease by mediating glomerular fibronectin production, leading to glomerulosclerosis. Hyperfiltration is crucial in the pathogenesis of diabetic kidney disease. We showed that Piezo2 expression is upregulated in mesangial cells of diabetic kidney disease mice with glomerular fibronectin accumulation. Piezo2 overexpression increased fibronectin production in HEK293T cells. Piezo2 may contribute to diabetic kidney disease progression by mediating glomerular fibronectin production.
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Affiliation(s)
- Rina Oba
- Department of Anatomy, Kyorin University School of Medicine, Mitaka, Tokyo, Japan
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
| | - Hitoshi Ueno
- Department of Anatomy, Kyorin University School of Medicine, Mitaka, Tokyo, Japan
| | - Atsuro Oishi
- Department of Anatomy, Kyorin University School of Medicine, Mitaka, Tokyo, Japan
| | - Kiyotaka Nagahama
- Department of Pathology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan
| | - Go Kanzaki
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
| | - Nobuo Tsuboi
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
| | - Takashi Yokoo
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
| | - Miki Nagase
- Department of Anatomy, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.
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20
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Gomes L, de Oliveira Carvalho H, Lopes GR, da Costa Furtado G, Gonçalves DES, Colares NND, Ferreira AM, da Costa Furtado C, da Silva HR, de L T Dos Santos AVT, do Nascimento AL, Lage TM, Pedro IDR, Teixeira TA, Carvalho JCT. The action of injectable nanodispersion of Bixa orellana (Chronic-in®) on arthritis in diabetic rats: pharmacological and histopathological studies. Inflammopharmacology 2025; 33:2109-2128. [PMID: 40067519 DOI: 10.1007/s10787-025-01703-3] [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: 01/19/2025] [Accepted: 02/18/2025] [Indexed: 04/13/2025]
Abstract
Diabetic arthritis (DA) is a microvascular complication associated with diabetes mellitus (DM), necessitating the exploration of innovative therapeutic approaches. The Amazon biome, rich in bioactive compounds, offers potential treatments; notably, Bixa orellana, which contains tocotrienol and geranylgeraniol, exhibits anti-inflammatory and antioxidant properties, particularly when formulated as a nanodispersion. OBJECTIVE This study aims to investigate the pharmacological effects of an injectable nanodispersion of Bixa orellana, termed Chronic-in®, in diabetic Wistar rats. METHOD Male Wistar rats were employed in the study, and DA was induced using an intraperitoneal injection of 100 mg/kg alloxan and an intraplantar administration of Freund's complete adjuvant. The animals were divided into five groups (n = 5): CON (normal rats treated with saline solution IM), CHR SC (DA rats treated with Chronic-in SC daily), SS (DA rats treated with saline solution IM), IND (DA rats treated with indomethacin orally), and CHR IM (DA rats treated with Chronic-in IM every 3 days). Treatment outcomes were assessed through various parameters, including changes in paw edema, Arthritic Index (AI), performance in the open field and Rotarod tests, radiographic evaluations using the Eichenholtz classification, Scanning Electron Microscopy (SEM) analysis of articular morphology, and hematological and biochemical assessments. RESULTS Significant reductions in edema were observed in the CHR SC, CHR IM, and IND groups (p < 0.001) compared to the SSA group. The AI showed significant differences among the CON, CHR SC, and CHR IM groups. Enhanced exploratory behavior was noted in the open field test for the Chronic-in-treated groups, particularly with IM administration. The Rotarod test demonstrated marked differences between the Chronic-in-treated, CON and SS groups. Radiographic and SEM evaluations indicated fewer bone alterations in the CHR IM and SC groups compared to the SSA and IND groups, along with preservation of articular surfaces. Histological assessments revealed thickened synovial membranes and pannus formation in the SS and IND groups. In contrast, CHR IM and CHR SC groups exhibited minimal loss of proteoglycans akin to the CON group. CONCLUSION Treatment with Chronic-in via both IM and SC routes effectively mitigated the inflammatory manifestations of diabetic neuropathic arthritis, demonstrating lower pain intensity during ambulation and protective effects against inflammation and joint integrity as evidenced in histological analyses. These findings suggest that Chronic-in represents a promising therapeutic option for diabetic arthritis.
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Affiliation(s)
- Lauana Gomes
- Laboratory of Drug Research, Department of Biological and Health Sciences, Federal University of Amapá, Rod. Josmar Chaves Pinto, Km 02, Jardim Marco Zero, Macapá, Amapá, 68903-419, Brazil
| | - Helison de Oliveira Carvalho
- Laboratory of Drug Research, Department of Biological and Health Sciences, Federal University of Amapá, Rod. Josmar Chaves Pinto, Km 02, Jardim Marco Zero, Macapá, Amapá, 68903-419, Brazil
| | - Gisele Rocha Lopes
- Laboratory of Drug Research, Department of Biological and Health Sciences, Federal University of Amapá, Rod. Josmar Chaves Pinto, Km 02, Jardim Marco Zero, Macapá, Amapá, 68903-419, Brazil
| | - Gabriel da Costa Furtado
- Laboratory of Drug Research, Department of Biological and Health Sciences, Federal University of Amapá, Rod. Josmar Chaves Pinto, Km 02, Jardim Marco Zero, Macapá, Amapá, 68903-419, Brazil
| | - Danna Emanuelle Santos Gonçalves
- Laboratory of Drug Research, Department of Biological and Health Sciences, Federal University of Amapá, Rod. Josmar Chaves Pinto, Km 02, Jardim Marco Zero, Macapá, Amapá, 68903-419, Brazil
| | - Nayara Nilcia Dias Colares
- Laboratory of Drug Research, Department of Biological and Health Sciences, Federal University of Amapá, Rod. Josmar Chaves Pinto, Km 02, Jardim Marco Zero, Macapá, Amapá, 68903-419, Brazil
| | - Adriana Maciel Ferreira
- Laboratory of Drug Research, Department of Biological and Health Sciences, Federal University of Amapá, Rod. Josmar Chaves Pinto, Km 02, Jardim Marco Zero, Macapá, Amapá, 68903-419, Brazil
| | - Crislany da Costa Furtado
- Laboratory of Drug Research, Department of Biological and Health Sciences, Federal University of Amapá, Rod. Josmar Chaves Pinto, Km 02, Jardim Marco Zero, Macapá, Amapá, 68903-419, Brazil
| | - Heitor Ribeiro da Silva
- Laboratory of Drug Research, Department of Biological and Health Sciences, Federal University of Amapá, Rod. Josmar Chaves Pinto, Km 02, Jardim Marco Zero, Macapá, Amapá, 68903-419, Brazil
| | - Abrahão Victor Tavares de L T Dos Santos
- Laboratory of Drug Research, Department of Biological and Health Sciences, Federal University of Amapá, Rod. Josmar Chaves Pinto, Km 02, Jardim Marco Zero, Macapá, Amapá, 68903-419, Brazil
- Innovation Pharmaceutical Program, Department of Biological and Health Sciences, Federal University of Amapá, Macapá, Amapá, Brazil
| | - Aline Lopes do Nascimento
- Laboratory of Drug Research, Department of Biological and Health Sciences, Federal University of Amapá, Rod. Josmar Chaves Pinto, Km 02, Jardim Marco Zero, Macapá, Amapá, 68903-419, Brazil
- Innovation Pharmaceutical Program, Department of Biological and Health Sciences, Federal University of Amapá, Macapá, Amapá, Brazil
| | - Tamiris Marques Lage
- Laboratory of Drug Research, Department of Biological and Health Sciences, Federal University of Amapá, Rod. Josmar Chaves Pinto, Km 02, Jardim Marco Zero, Macapá, Amapá, 68903-419, Brazil
| | - Irma Danielle Rodrigues Pedro
- Laboratory of Drug Research, Department of Biological and Health Sciences, Federal University of Amapá, Rod. Josmar Chaves Pinto, Km 02, Jardim Marco Zero, Macapá, Amapá, 68903-419, Brazil
| | - Thiago Afonso Teixeira
- Laboratory of Drug Research, Department of Biological and Health Sciences, Federal University of Amapá, Rod. Josmar Chaves Pinto, Km 02, Jardim Marco Zero, Macapá, Amapá, 68903-419, Brazil
- Innovation Pharmaceutical Program, Department of Biological and Health Sciences, Federal University of Amapá, Macapá, Amapá, Brazil
- University Hospital, Federal University of Amapá, Macapá, Amapá, Brazil
| | - José Carlos Tavares Carvalho
- Laboratory of Drug Research, Department of Biological and Health Sciences, Federal University of Amapá, Rod. Josmar Chaves Pinto, Km 02, Jardim Marco Zero, Macapá, Amapá, 68903-419, Brazil.
- Innovation Pharmaceutical Program, Department of Biological and Health Sciences, Federal University of Amapá, Macapá, Amapá, Brazil.
- University Hospital, Federal University of Amapá, Macapá, Amapá, Brazil.
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21
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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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22
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Tao Y, Liu M, Siebert G, Das-Earl P, Ibrahim D, Crowe N, Zheng S, Ma R. I-mfa, Mesangial Cell TRPC1 Channel, and Regulation of GFR. J Am Soc Nephrol 2025; 36:614-627. [PMID: 39446484 PMCID: PMC11975231 DOI: 10.1681/asn.0000000533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 10/17/2024] [Indexed: 10/26/2024] Open
Abstract
Key Points I-mfa is a multifunctional cytosolic protein and its function in kidney is unknown. The major finding in the present study was that I-mfa promoted glomerular filtration rate in both male and female mice. I-mfa suppressed contractile function of both human and mouse glomerular mesangial cells by decreasing TRPC1 channel protein abundance. Background Inhibitor of MyoD family A (I-mfa) is a cytosolic protein. Its function in the kidney is unknown. The aim of this study was to examine the regulatory role of I-mfa on GFR. Methods GFR was measured by transdermal measurement of fluorescein isothiocyanate–sinitrin clearance in conscious wild-type (WT) and I-mfa knockout (KO) mice. Cell contractility was assessed in a single human or mouse mesangial cell. Single-cell RNA sequence, Western blot, and Ca2+ imaging were used to evaluate the effects of I-mfa on transient receptor potential canonical (TRPCs) at messenger, protein, and functional levels in mesangial cells. Results In KO mice, GFR was significantly lower than that in WT mice. In WT mice, knocking down I-mfa selectively in mesangial cells using targeted nanoparticle/small interfering RNA delivery system significantly decreased GFR. In human mesangial cells, overexpression of I-mfa significantly blunted the angiotensin II (Ang II)-stimulated contraction, and knockdown of I-mfa significantly enhanced the contractile response. Consistently, the Ang II–induced contraction was significantly augmented in primary mesangial cells isolated from KO mice. The exaggerated response was restored by reintroducing I-mfa. Furthermore, single-cell RNA sequence showed an increase in trpc1 messenger, and Western blot showed an increase in TRPC1 protein abundance in I-mfa KO mouse mesangial cells. TRPC1 protein abundance was decreased in human embryonic kidney cells overexpressing I-mfa. Ca2+ imaging experiments showed that downregulation of I-mfa significantly enhanced Ang II–stimulated Ca2+ entry in human mesangial cells. Finally, TRPC1 inhibitor Pico145 significantly blunted Ang II–induced mesangial cell contraction. Conclusions I-mfa positively regulated GFR by decreasing mesangial cell contractile function through inhibition of TRPC1-mediated Ca2+ signaling.
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Affiliation(s)
- Yu Tao
- Department of Physiology and Anatomy, University of North Texas HSC, Fort Worth, Texas
| | - Muyi Liu
- Department of Microbiology, Immunology and Genetics, University of North Texas HSC, Fort Worth, Texas
| | - Garland Siebert
- Texas College of Osteopathic Medicine, University of North Texas HSC, Fort Worth, Texas
| | - Paromita Das-Earl
- Department of Physiology and Anatomy, University of North Texas HSC, Fort Worth, Texas
| | - Deena Ibrahim
- Department of Physiology and Anatomy, University of North Texas HSC, Fort Worth, Texas
| | - Nicole Crowe
- Department of Physiology and Anatomy, University of North Texas HSC, Fort Worth, Texas
| | - Suilan Zheng
- Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana
| | - Rong Ma
- Department of Physiology and Anatomy, University of North Texas HSC, Fort Worth, Texas
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23
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Yang Y, Li M, Zou H, Yang P, Wang L, Xu G. Dapagliflozin in diabetic kidney disease patients with different filtration status. Eur J Pharm Sci 2025; 207:107045. [PMID: 39961418 DOI: 10.1016/j.ejps.2025.107045] [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: 10/28/2024] [Revised: 02/13/2025] [Accepted: 02/14/2025] [Indexed: 02/23/2025]
Abstract
BACKGROUND Few studies have discussed the effects and mechanism of dapagliflozin on diabetic kidney disease (DKD) with different glomerular filtration rate (GFR) and systolic blood pressure (SBP). This study aimed to investigate the variation in the eGFR and proteinuria after dapagliflozin treatment in DKD patients with different filtration status and SBP levels. METHODS First, we conducted a cross-sectional study to determined hyperfiltration threshold for the DKD trial. Then, we enrolled 259 DKD patients with an eGFR greater than 70 mL/min/1.73m2 and an albumin-to-creatinine ratio (ACR) between 30 and 200 mg/g to receive treatment with dapagliflozin. Hyperfiltration was defined as the 95th percentile of eGFR above the age- and gender- specific in healthy subjects, DKD patients were divided into hyperfiltration and non-hyperfiltration groups, and SBP > 120 mmHg and ≤ 120 mmHg groups. The eGFR, ACR, and blood and urine electrolytes were measured before and after treatment. RESULTS The mean eGFR change at 2 weeks in the hyperfiltration with SBP > 120 mmHg group was greater than in the non-hyperfiltration with SBP ≤ 120 mmHg group (P = 0.048). The mean ACR reduction values were greater in the non-hyperfiltration with SBP ≤ 120 mmHg group than in the hyperfiltration with SBP > 120 mmHg group at 12 weeks (P = 0.042). There was no difference in other blood or urine electrolytes before and after treatment, except for the fractional excretion of sodium (FENa), which significantly increased after 2 weeks (P < 0.001) and recovered after 8 weeks (P = 0.305). CONCLUSION DKD with non-hyperfiltration with SBP ≤ 120 mmHg had a lower mean eGFR decline and greater decrease in the ACR after treatment. The initial increase in FENa and subsequent decrease after dapagliflozin treatment may be the main mechanism behind the eGFR variation.
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Affiliation(s)
- Yang Yang
- Department of Nephrology, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, PR China; Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, PR China
| | - Manna Li
- Department of Nephrology, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, PR China
| | - Honghong Zou
- Department of Nephrology, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, PR China
| | - Pingping Yang
- Department of endocrinology and metabolism, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, PR China
| | - Li Wang
- Department of Nephrology, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, PR China
| | - Gaosi Xu
- Department of Nephrology, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, PR China.
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Zhao N, Zhang Y, Liu P, Zhang X, Zhang Z, Ou W, Dong A, Chang Y, Chen S, Wang G, Wu S, Yang X. Association of changes in metabolic syndrome with new-onset and progression of chronic kidney disease. Endocrine 2025; 88:99-109. [PMID: 39616289 DOI: 10.1007/s12020-024-04119-1] [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: 07/19/2024] [Accepted: 11/23/2024] [Indexed: 03/25/2025]
Abstract
BACKGROUND Metabolic syndrome (MetS) is an independent risk factor for new-onset and progression of chronic kidney disease (CKD). However, whether changes in MetS are associated with the new-onset CKD and its progression remains unknown. METHODS A total of 36,571 participants from the Kailuan Study were enrolled in this study, including 27,072 without CKD and 9499 with CKD at baseline. According to the changes of MetS, 4 groups were divided as follows: MetS-free group, MetS-recovered group, MetS-developed group, and MetS-persistent group. Cox regression models were used to explore the association of changes in MetS with new-onset and progression of CKD. RESULTS During a median follow-up of 8.38 years, 3313 cases of new-onset CKD were identified in participants without CKD. Compared with the MetS-free group, the hazard ratio (HR) and 95% confidence interval (95% CI) for new-onset CKD in the MetS-recovered, MetS-developed and MetS-persistent groups was 1.34 (1.18-1.53), 1.46 (1.30-1.63) and 1.85 (1.69-2.02), respectively. Among 9499 participants with CKD, during a median follow-up of 8.18 years, a total of 2305 experienced CKD progression. Compared with the MetS-free group, the HR (95% CI) for CKD progression in each group were 1.05 (0.91-1.22), 1.34 (1.17-1.55) and 1.65 (1.49-1.83), respectively. Furthermore, the association between changes in MetS and new-onset CKD was stronger in younger and middle-aged participants (≤60 years old) compared with older participants. CONCLUSIONS Developed MetS and persistent MetS were both risk factors for the new-onset and progression of CKD. Even with recovery from MetS, an association of MetS with kidney damage remained.
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Affiliation(s)
- Naihui Zhao
- School of Public Health, North China University of Science and Technology, Caofeidian Eco-city, Tangshan, Hebei, China
| | - Yinggen Zhang
- Department of Nuclear Medicine, Kailuan General Hospital, Tangshan, Hebei, China
| | - Peipei Liu
- School of Public Health, North China University of Science and Technology, Caofeidian Eco-city, Tangshan, Hebei, China
| | - Xiaofu Zhang
- Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Caofeidian Eco-city, Tangshan, Hebei, China
| | - Zihao Zhang
- School of Public Health, North China University of Science and Technology, Caofeidian Eco-city, Tangshan, Hebei, China
| | - Wenli Ou
- School of Public Health, North China University of Science and Technology, Caofeidian Eco-city, Tangshan, Hebei, China
| | - Ao Dong
- School of Public Health, North China University of Science and Technology, Caofeidian Eco-city, Tangshan, Hebei, China
| | - Yanhe Chang
- Department of Nuclear Medicine, Kailuan General Hospital, Tangshan, Hebei, China
| | - Shuohua Chen
- Department of Cardiology, Kailuan General Hospital, Tangshan, Hebei, China
| | - Guodong Wang
- Department of Cardiology, Kailuan General Hospital, Tangshan, Hebei, China
| | - Shouling Wu
- Department of Cardiology, Kailuan General Hospital, Tangshan, Hebei, China.
| | - Xiuhong Yang
- School of Public Health, North China University of Science and Technology, Caofeidian Eco-city, Tangshan, Hebei, China.
- Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Caofeidian Eco-city, Tangshan, Hebei, China.
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25
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Tanaka M, Sato T, Gohda T, Kamei N, Murakoshi M, Ishiwata E, Endo K, Kawaharata W, Aida H, Nakata K, Akiyama Y, Kubota M, Sanuki M, Suzuki T, Suzuki Y, Furuhashi M. Urinary fatty acid-binding protein 4 is a promising biomarker for glomerular damage in patients with diabetes mellitus. J Diabetes Investig 2025; 16:670-679. [PMID: 39723798 PMCID: PMC11970305 DOI: 10.1111/jdi.14388] [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: 09/21/2024] [Revised: 12/02/2024] [Accepted: 12/04/2024] [Indexed: 12/28/2024] Open
Abstract
AIMS/INTRODUCTION Fatty acid-binding protein (FABP) 4, which acts as an adipokine secreted by adipocytes, macrophages, and capillary endothelial cells, is expressed in injured glomerular cells. It has been reported that urinary (U-) FABP4 is associated with renal dysfunction and proteinuria in several glomerular kidney diseases. However, the clinical significance of U-FABP4 in diabetic kidney disease (DKD) remains undetermined. MATERIALS AND METHODS Immunohistological analyses of FABP4 and FABP1 (liver-type FABP), an established biomarker for impaired proximal tubules, were performed in the kidneys of patients with DKD and nonobese diabetic mice (KK-Ta/Akita mice). The associations between U-FABP4 and U-FABP1 with kidney function and metabolic indices were also investigated in patients with type 1 diabetes (n = 57, mean age: 61 years) and patients with type 2 diabetes (n = 608, mean age: 65 years). RESULTS In both patients with diabetes and diabetic mice, FABP4 was expressed in injured glomeruli with increased markers of endoplasmic reticulum stress in addition to peritubular capillaries, whereas FABP1 was mainly expressed in proximal tubules. Levels of U-FABP4 and U-FABP1 were independently associated with each other, and both levels were independently associated with estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) after adjustment of age, sex, type of diabetes, duration of diabetes, and systolic blood pressure in patients with diabetes. CONCLUSIONS Urinary level of FABP4 derived from injured glomeruli with increased endoplasmic reticulum stress is independently associated with eGFR and UACR, suggesting a promising biomarker for glomerular damage in patients with diabetes.
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Affiliation(s)
- Marenao Tanaka
- Department of Cardiovascular, Renal and Metabolic MedicineSapporo Medical University School of MedicineSapporoJapan
- Tanaka Medical ClinicYoichiJapan
| | - Tatsuya Sato
- Department of Cardiovascular, Renal and Metabolic MedicineSapporo Medical University School of MedicineSapporoJapan
- Department of Cellular Physiology and Signal TransductionSapporo Medical University School of MedicineSapporoJapan
| | - Tomohito Gohda
- Department of NephrologyJuntendo University Faculty of MedicineTokyoJapan
| | - Nozomu Kamei
- Department of Endocrinology and MetabolismHiroshima Red Cross Hospital & Atomic‐bomb Survivors HospitalHiroshimaJapan
- Institute for Clinical ResearchNHO Kure Medical Center and Chugoku Cancer CenterKureJapan
| | - Maki Murakoshi
- Department of NephrologyJuntendo University Faculty of MedicineTokyoJapan
| | - Erika Ishiwata
- Department of Cardiovascular, Renal and Metabolic MedicineSapporo Medical University School of MedicineSapporoJapan
| | - Keisuke Endo
- Department of Cardiovascular, Renal and Metabolic MedicineSapporo Medical University School of MedicineSapporoJapan
| | - Wataru Kawaharata
- Department of Cardiovascular, Renal and Metabolic MedicineSapporo Medical University School of MedicineSapporoJapan
| | - Hiroki Aida
- Department of Cardiovascular, Renal and Metabolic MedicineSapporo Medical University School of MedicineSapporoJapan
| | - Kei Nakata
- Department of Cardiovascular, Renal and Metabolic MedicineSapporo Medical University School of MedicineSapporoJapan
| | - Yukinori Akiyama
- Department of NeurosurgerySapporo Medical University School of MedicineSapporoJapan
| | - Mitsunobu Kubota
- Department of Endocrinology and DiabetologyNHO Kure Medical Center and Chugoku Cancer CenterKureJapan
| | - Michiyoshi Sanuki
- Institute for Clinical ResearchNHO Kure Medical Center and Chugoku Cancer CenterKureJapan
| | - Toru Suzuki
- Natori Toru Internal Medicine and Diabetes ClinicNatoriJapan
| | - Yusuke Suzuki
- Department of NephrologyJuntendo University Faculty of MedicineTokyoJapan
| | - Masato Furuhashi
- Department of Cardiovascular, Renal and Metabolic MedicineSapporo Medical University School of MedicineSapporoJapan
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Chen X, Liang M, Zhang J, Xu C, Chen L, Hu R, Zhong J. The Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) to HDL-C Ratio (NHHR) and Its Association with Chronic Kidney Disease in Chinese Adults with Type 2 Diabetes: A Preliminary Study. Nutrients 2025; 17:1125. [PMID: 40218883 PMCID: PMC11990853 DOI: 10.3390/nu17071125] [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: 03/03/2025] [Revised: 03/17/2025] [Accepted: 03/23/2025] [Indexed: 04/14/2025] Open
Abstract
Objectives: The objective of this study was to examine the association between non-high-density lipoprotein cholesterol (non-HDL-C) to high-density lipoprotein cholesterol (HDL-C) ratio (NHHR) and chronic kidney disease (CKD) in Chinese adults with type 2 diabetes mellitus (T2DM). Methods: This study originated from a survey carried out in Zhejiang Province, located in eastern China, between March and November 2018. To explore the relationship between NHHR and CKD, a multivariable logistic regression model was employed. The dose-response relationship was assessed using restricted cubic spline (RCS) analysis, while generalized additive models (GAMs) were applied to examine the associations between NHHR and urinary albumin-to-creatinine ratio (UACR) as well as estimated glomerular filtration rate (eGFR). Subgroup analyses were performed across various demographic and clinical categories to assess the consistency of the NHHR-CKD association. The optimal NHHR cutoff for CKD diagnosis, its predictive accuracy, and its comparison with its components and HbA1c were determined through receiver operating characteristic (ROC) curve analysis. Results: The study enrolled 1756 participants, including 485 individuals with CKD and 1271 without CKD. Multivariable logistic regression revealed a significant positive association between NHHR and CKD, with each standard deviation (SD) increase in NHHR linked to a 23% higher odds of CKD (OR = 1.23, 95% CI: 1.09-1.37) after adjusting for potential confounders. When comparing quartiles, the fully adjusted ORs for Q2, Q3, and Q4 were 1.29 (0.92-1.79), 1.31 (0.94-1.83), and 1.87 (1.34-2.60), respectively, relative to Q1 (p for trend < 0.01). RCS analysis confirmed a linear dose-response relationship between NHHR and CKD in both sexes (p for nonlinearity > 0.05). GAMs indicated a significant positive correlation between NHHR and UACR (ρ = 0.109, p < 0.001) but no significant association with eGFR (ρ = -0.016, p = 0.502). Subgroup analyses demonstrated consistent associations across most subgroups, except for the 18-44 years age group, the well-controlled glycemic group, and the non-alcohol drinking group (p > 0.05). ROC curve analysis identified an optimal NHHR cutoff of 3.48 for CKD prediction, with an area under the curve (AUC) of 0.606 (95% CI: 0.577-0.635). Notably, NHHR outperformed its individual components and HbA1c in predictive performance. Conclusions: This study revealed a linear link between higher NHHR levels and increased CKD prevalence in Chinese T2DM patients. NHHR may also serve as a potential complementary biomarker for early CKD detection, though further prospective studies are needed to confirm its predictive value and clinical utility in high-risk T2DM populations.
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Affiliation(s)
| | | | | | | | | | | | - Jieming Zhong
- Department of Non-Communicable Disease Control and Prevention, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou 310051, China; (X.C.); (M.L.); (J.Z.); (C.X.); (L.C.); (R.H.)
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Crintea IN, Cindrea AC, Fulga TF, Trebuian CI, Marza AM, Petrica A, Mederle OA, Timar R. Obesity Class and Severity of Metabolic Emergencies: A Single-Center Retrospective Five-Year Study. Healthcare (Basel) 2025; 13:617. [PMID: 40150467 PMCID: PMC11942349 DOI: 10.3390/healthcare13060617] [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: 02/04/2025] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 03/29/2025] Open
Abstract
Background/Objectives: This study aims to investigate the impact of obesity severity on the prevalence and outcomes of acute metabolic emergencies in the emergency department (ED) setting, with a specific focus on obesity class stratification and associated metabolic complications. Methods: This retrospective, single-center study analyzed data from 433 patients admitted to the ED of the Timisoara Municipal Emergency Hospital between January 2019 and March 2024. Patients were classified according to WHO obesity grades (Class I: BMI 30.0-34.9 kg/m2, Class II: 35.0-39.9 kg/m2, Class III: ≥ 40.0 kg/m2). The prevalence and severity of metabolic emergencies, including hyperglycemic crises, acute kidney injury (AKI), and severe electrolyte imbalances, were compared across obesity classes. Results: Obese patients (37.2%) exhibited a significantly higher prevalence of metabolic emergencies than non-obese individuals (p < 0.001). Hyperglycemia was present in 27.9% of obese patients vs. 11.0% of non-obese patients (p < 0.001). AKI incidence nearly doubled in obese patients (12.4% vs. 5.5%, p = 0.01). Logistic regression identified Class III obesity as an independent risk factor for metabolic emergencies (adjusted OR = 3.2, 95% CI: 2.1-4.9, p < 0.001). Conclusions: The severity of metabolic emergencies increases with increasing obesity class, emphasizing the need for obesity-specific risk stratification in ED settings. Routine monitoring of metabolic markers and early intervention strategies should be prioritized for high-risk obese patients.
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Affiliation(s)
- Iulia Najette Crintea
- Department of Surgery, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (I.N.C.); (A.C.C.); (A.M.M.)
- Emergency Department, Emergency Clinical Municipal Hospital, 300079 Timisoara, Romania
| | - Alexandru Cristian Cindrea
- Department of Surgery, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (I.N.C.); (A.C.C.); (A.M.M.)
- Emergency Department, Emergency Clinical Municipal Hospital, 300079 Timisoara, Romania
| | - Teodor Florin Fulga
- Faculty of Cybernetics, Statistics and Economic Informatics, The Bucharest University of Economic Studies, 010374 Bucharest, Romania;
| | - Cosmin Iosif Trebuian
- Department of Surgery, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (I.N.C.); (A.C.C.); (A.M.M.)
- Department of Anesthesia and Intensive Care, Emergency County Hospital, 320210 Resita, Romania
| | - Adina Maria Marza
- Department of Surgery, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (I.N.C.); (A.C.C.); (A.M.M.)
- Emergency Department, Emergency Clinical Municipal Hospital, 300079 Timisoara, Romania
| | - Alina Petrica
- Department of Surgery, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (I.N.C.); (A.C.C.); (A.M.M.)
- Emergency Department, “Pius Brinzeu” Emergency Clinical County Hospital, 300736 Timisoara, Romania
| | - Ovidiu Alexandru Mederle
- Department of Surgery, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (I.N.C.); (A.C.C.); (A.M.M.)
- Emergency Department, Emergency Clinical Municipal Hospital, 300079 Timisoara, Romania
| | - Romulus Timar
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania;
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
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Kumar N, Kumar B, Ashique S, Yasmin S, Venkatesan K, Islam A, Ghosh S, Sahu A, Bhui U, Ansari MY. A critical review on SGLT2 inhibitors for diabetes mellitus, renal health, and cardiovascular conditions. Diabetes Res Clin Pract 2025; 221:112050. [PMID: 39965722 DOI: 10.1016/j.diabres.2025.112050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/03/2025] [Accepted: 02/11/2025] [Indexed: 02/20/2025]
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were originally formulated to reduce blood glucose levels in individuals with diabetes. Recent clinical trials indicate that this compound can be repurposed for other critical conditions. A literature search was performed on PubMed, Scopus, Embase, ProQuest, and Google Scholar, utilizing key terms such as SGLT2i, diabetes, and oxidative stress. SGLT2i has significant beneficial effects not only in cardiovascular disease but also in renal dysfunction. SGLT2i therapy can mitigate critical cardiovascular complications like heart attacks, strokes, mortality rates, and hospitalization duration, as well as delay the necessity for dialysis irrespective of diabetic condition. Evidence supports potential advantages of SGLT2 inhibitors for individuals with renal problems and heart failure, regardless of diabetes status. In addition to diabetic mellitus, this analysis explores the latest updates on SGLT2i and the therapeutic advantages it offers in many renal and cardiovascular diseases (CVDs).
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Affiliation(s)
- Nitish Kumar
- SRM Modinagar College of Pharmacy, SRM Institute of Science and Technology (Deemed to be University), Delhi-NCR Campus, Modinagar, Ghaziabad, Uttar Pradesh 201204, India
| | - Bimlesh Kumar
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Sumel Ashique
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India.
| | - Sabina Yasmin
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Kumar Venkatesan
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Anas Islam
- Faculty of Pharmacy, Integral University, Lucknow 226026, Uttar Pradesh, India
| | - Suman Ghosh
- Division of Pharmaceutical Chemistry, Guru Nanak Institute of Pharmaceutical Science and Technology, 157/F, Nilgunj Road, Kolkata, West Bengal 700114, India
| | - Anwesha Sahu
- Division of Pharmacology, Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India
| | - Utpal Bhui
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Mohammad Yousuf Ansari
- MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana 133207, India; Ibne Seena College of Pharmacy, Azmi Vidya Nagri Anjhi Shahabad, Hardoi, Uttar Pradesh (U.P.) 241124, India.
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29
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Yoo SA, Sayo MIA, Lee JH. Association between chronic renal disease and psoriasis risk in diabetes patients: A Korean population-based study. Indian J Dermatol Venereol Leprol 2025; 91:152-157. [PMID: 38899413 DOI: 10.25259/ijdvl_669_2023] [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: 06/27/2023] [Accepted: 12/18/2023] [Indexed: 06/21/2024]
Abstract
Background Several studies have reported that psoriasis has a positive correlation with type 2 diabetes mellitus (DM). Understanding the risk of psoriasis in diabetic patients is significant because it allows for early intervention and potential insights into the common pathways between the two conditions. Objectives We analysed the risk of psoriasis according to the estimated glomerular filtration rate (eGFR) and proteinuria level in DM patients using Korean population-based data. Methods This study was a retrospective cohort study using data collected from the country in the form of exploratory data analysis. A total of 927,234 participants diagnosed with DM were enrolled. Patients under the age of 20 with existing psoriasis or psoriasis developed within 1 year and missing data were excluded. The development of psoriasis was the primary outcome within a follow-up period of 7.83 ± 1.68 years. Results Of the 840,395 final participants, 28,010 (3.33%) patients developed psoriasis. In multivariate-adjusted Cox proportional hazards regression models, the DM patients with eGFR < 30 had a higher risk of psoriasis after adjustment (eGFR 60-90, hazard ratio [HR] 1 (Ref.); eGFR < 30, HR 1.173, 95% CI 1.089-1.264). In addition, there was an increased psoriatic risk of patients with DM and proteinuria after adjustment (negative, HR 1 (Ref.); 2+, HR 1.164, 95% CI 1.080-1.254; 3+, HR 1.433, 95% CI 1.273-1.613; 4+, HR 1.508, 95% CI 1.177-1.931). Limitations The severity of psoriasis was not measured since the occurrence of psoriasis was the outcome. Details of oral hypoglycaemic agents such as type and dose were not investigated. Conclusion This study showed that a decrease in eGFR and aggravation of proteinuria increase the risk of psoriasis in diabetic patients. Therefore, by using eGFR and proteinuria as predictive risk factors of psoriasis in DM patients, early and proactive treatment may play a vital role in managing diabetic patients.
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Affiliation(s)
- Seung Ah Yoo
- Department of Dermatology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Republic of Korea
| | | | - Ji Hyun Lee
- Department of Dermatology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Republic of Korea
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30
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Eisinger F, Neumann M, Wörn M, Fritsche A, Heyne N, Peter A, Birkenfeld AL, von Schwartzenberg RJ, Artunc F. Comparison of GFR estimation in patients with diabetes mellitus using the EKFC and CKD-EPI equations. J Nephrol 2025; 38:707-716. [PMID: 39792299 PMCID: PMC11961541 DOI: 10.1007/s40620-024-02202-4] [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: 08/10/2024] [Accepted: 12/15/2024] [Indexed: 01/12/2025]
Abstract
BACKGROUND The estimation of glomerular filtration rate (eGFR) is essential in the early detection of diabetic nephropathy. We herein compare the performance of common eGFR formulas against a gold standard measurement of GFR in patients with diabetes mellitus. METHODS GFR was measured in 93 patients with diabetes mellitus using iohexol clearance as the reference standard. The performance of the creatinine- and cystatin C-based EKFC formulas (2021, 2023) and the CKD-EPI formulas (2009, 2012) was compared against measured GFR. RESULTS Sixty patients with type 2 diabetes mellitus and 33 patients with type 1 diabetes mellitus were included. The creatinine-based EKFC formula showed lower bias and higher accuracy than the CKD-EPI formula. No significant difference was observed between the cystatin C-based formulas. The combined creatinine- and cystatin C-based formulas had the highest accuracy and lowest bias. Body fat or diabetes type did not significantly influence the accuracy of the cystatin C-based formulas. CONCLUSIONS Our study demonstrated a slight advantage of the creatinine-based EKFC formula over the CKD-EPI formula in patients with diabetes. However, both for the CKD-EPI and the EKFC formula, the best performance was achieved by the combined creatinine- and cystatin C-based formulas.
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Affiliation(s)
- Felix Eisinger
- Department of Diabetology, Endocrinology, Nephrology, University of Tuebingen, Tuebingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
- German Center for Diabetes Research (DZD E.V.), Neuherberg, Germany
| | - Mareike Neumann
- Department of Diabetology, Endocrinology, Nephrology, University of Tuebingen, Tuebingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
- German Center for Diabetes Research (DZD E.V.), Neuherberg, Germany
| | - Matthias Wörn
- Department of Diabetology, Endocrinology, Nephrology, University of Tuebingen, Tuebingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
- German Center for Diabetes Research (DZD E.V.), Neuherberg, Germany
| | - Andreas Fritsche
- Department of Diabetology, Endocrinology, Nephrology, University of Tuebingen, Tuebingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
- German Center for Diabetes Research (DZD E.V.), Neuherberg, Germany
| | - Nils Heyne
- Department of Diabetology, Endocrinology, Nephrology, University of Tuebingen, Tuebingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
- German Center for Diabetes Research (DZD E.V.), Neuherberg, Germany
| | - Andreas Peter
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
- German Center for Diabetes Research (DZD E.V.), Neuherberg, Germany
- Department for Diagnostic Laboratory Medicine, Institute for Clinical Chemistry and Pathobiochemistry, University Hospital of Tuebingen, Tuebingen, Germany
| | - Andreas L Birkenfeld
- Department of Diabetology, Endocrinology, Nephrology, University of Tuebingen, Tuebingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
- German Center for Diabetes Research (DZD E.V.), Neuherberg, Germany
| | - Reiner Jumpertz von Schwartzenberg
- Department of Diabetology, Endocrinology, Nephrology, University of Tuebingen, Tuebingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
- German Center for Diabetes Research (DZD E.V.), Neuherberg, Germany
| | - Ferruh Artunc
- Department of Diabetology, Endocrinology, Nephrology, University of Tuebingen, Tuebingen, Germany.
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany.
- German Center for Diabetes Research (DZD E.V.), Neuherberg, Germany.
- Southwest Clinic Network, Hospital Sindelfingen, Section Nephrology, Sindelfingen, Germany.
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31
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Kishi S. Redefining glomerular hyperfiltration: pathophysiology, clinical implications, and novel perspectives. Hypertens Res 2025; 48:1176-1178. [PMID: 39814970 DOI: 10.1038/s41440-024-02092-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 12/21/2024] [Indexed: 01/18/2025]
Affiliation(s)
- Seiji Kishi
- Department of Nephrology and Hypertension, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.
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Huber A, Aslam I, Crowe L, Pruijm M, de Perrot T, de Seigneux S, Vallée JP, Berchtold L. T1 mapping magnetic resonance imaging predicts decline of kidney function. Clin Kidney J 2025; 18:sfaf032. [PMID: 40123968 PMCID: PMC11926595 DOI: 10.1093/ckj/sfaf032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Indexed: 03/25/2025] Open
Abstract
Background Renal cortical interstitial fibrosis, typically assessed by biopsy, is crucial for kidney function prognosis. Magnetic resonance imaging (MRI) is a promising method to assess fibrosis non-invasively. Diffusion-weighted (DW) MRI correlates with renal fibrosis and predicts kidney function decline in chronic kidney disease (CKD) and kidney allograft patients. This study evaluates whether T1 and T2 mapping predict kidney function decline and if their simultaneous use enhances the predictive power of a DW-MRI-based model. Methods We prospectively included 197 patients (42 CKD, 155 allograft kidneys). Each underwent a biopsy followed by multiparametric MRI without contrast within 1 week. Over a median follow-up of 2.2 years, laboratory parameters were recorded. The primary endpoint was a rapid decline in kidney function [glomerular filtration rate (GFR) reduction >30%] or replacement therapy initiation. The ability of T1 and T2 mapping sequences to predict poor renal outcome was examined using multivariable Cox regression models, incorporating MRI-derived parameters, estimated GFR (eGFR) and proteinuria. Results Renal outcome occurred in 54 patients after a median of 1.1 years (interquartile range 0.9-2.1). Univariable survival analysis showed cortical T1 was associated with poor renal outcome {hazard ratio [HR] 3.02 [95% confidence interval (CI) 1.44-6.33]}, while T2 sequences had no significant predictive value. Adding cortical T1 to the established model (ΔADC, eGFR, proteinuria) did not improve the HR [from 4.62 (95% CI 1.56-13.67) to 4.36 (95% CI 1.46-13.02)] and marginally increased Harrell's C-index (0.77 to 0.79). Adjusting the regression model for ΔT2 yielded no enhancement in predictive power. Conclusions Cortical T1 is strongly associated with poor renal outcome but did not enhance prognostic power of the DW-MRI-based model.
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Affiliation(s)
- Aurélie Huber
- Department of Medicine, Division of Nephrology and Hypertension, University Hospitals of Geneva, Geneva, Switzerland
| | - Ibtisam Aslam
- Department of Diagnostics, Division of Radiology, University Hospitals of Geneva and Faculty of Medicine of the Geneva University, Geneva, Switzerland
| | - Lindsey Crowe
- Department of Diagnostics, Division of Radiology, University Hospitals of Geneva and Faculty of Medicine of the Geneva University, Geneva, Switzerland
| | - Menno Pruijm
- Department of Medicine, Division of Nephrology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Thomas de Perrot
- Department of Diagnostics, Division of Radiology, University Hospitals of Geneva and Faculty of Medicine of the Geneva University, Geneva, Switzerland
| | - Sophie de Seigneux
- Department of Medicine, Division of Nephrology and Hypertension, University Hospitals of Geneva, Geneva, Switzerland
| | - Jean-Paul Vallée
- Department of Diagnostics, Division of Radiology, University Hospitals of Geneva and Faculty of Medicine of the Geneva University, Geneva, Switzerland
| | - Lena Berchtold
- Department of Medicine, Division of Nephrology and Hypertension, University Hospitals of Geneva, Geneva, Switzerland
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Apperloo EM, Tuttle KR, Pavo I, Haupt A, Taylor R, Wiese RJ, Hemmingway A, Cherney DZ, Sattar N, Heerspink HJ. Tirzepatide Associated With Reduced Albuminuria in Participants With Type 2 Diabetes: Pooled Post Hoc Analysis From the Randomized Active- and Placebo-Controlled SURPASS-1-5 Clinical Trials. Diabetes Care 2025; 48:430-436. [PMID: 39746157 PMCID: PMC11870291 DOI: 10.2337/dc24-1773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 12/03/2024] [Indexed: 01/04/2025]
Abstract
OBJECTIVE Tirzepatide, a long-acting, glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor agonist, reduced urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) decline in people with type 2 diabetes and high cardiovascular risk in the SURPASS-4 trial. To examine the generalizability of these findings, we assessed change from baseline in UACR for tirzepatide (5, 10, and 15 mg) compared with active and placebo treatment in a broad population from the SURPASS-1-5 trials. RESEARCH DESIGN AND METHODS This post hoc analysis examined data from the overall pooled SURPASS-1-5 population and subgroups defined by baseline UACR ≥30 mg/g. A mixed model for repeated measures was used to analyze on-treatment data from baseline to the end-of-treatment visit. Study identifier was included in the model as a covariate. RESULTS The adjusted mean percent change from baseline in UACR for tirzepatide 5, 10, or 15 mg compared with all pooled comparators was -19.3% (95% CI -25.5, -12.5), -22.0% (-28.1, -15.3), and -26.3 (-32.0, -20.0), respectively, at week 40/42. Results were similar across pooled placebo, active, and insulin comparator studies. UACR lowering appeared more pronounced in subgroups with UACR ≥30 mg/g. Mediation analysis findings suggested that approximately one-half of the reduction in albuminuria associated with tirzepatide may be weight loss related. There was no difference in eGFR between tirzepatide and pooled comparators at week 40/42. CONCLUSIONS In this post hoc analysis in people with type 2 diabetes, including those with chronic kidney disease, tirzepatide was associated with a clinically relevant decreased UACR versus comparators, suggesting a potential kidney-protective effect.
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Affiliation(s)
- Ellen M. Apperloo
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Katherine R. Tuttle
- Providence Medical Research Center, Providence Inland Northwest Health, Spokane, WA
- Nephrology Division and Kidney Research Institute, University of Washington School of Medicine, Seattle, WA
| | - Imre Pavo
- Eli Lilly and Company, Indianapolis, IN
| | | | | | | | | | - David Z.I. Cherney
- Division of Nephrology, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Naveed Sattar
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, U.K
| | - Hiddo J.L. Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- The George Institute for Global Health, Sydney, New South Wales, Australia
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Antoniadou C, Gavriilidis E, Ritis K, Tsilingiris D. Anemia in diabetes mellitus: Pathogenetic aspects and the value of early erythropoietin therapy. Metabol Open 2025; 25:100344. [PMID: 39886103 PMCID: PMC11780985 DOI: 10.1016/j.metop.2024.100344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Accepted: 12/30/2024] [Indexed: 02/01/2025] Open
Abstract
Anemia is a frequent, yet increasingly recognized, comorbidity in diabetes mellitus (DM), with prevalence often driven by multifactorial mechanisms. Hematinic deficiencies, common in this population, may arise from associated comorbidities or medications, such as metformin, as well as other drugs commonly employed for DM-related conditions. Among contributing factors, diabetic kidney disease (DKD) plays a pivotal role, with anemia developing more frequently and being more pronounced in earlier stages, than in CKD of other causes. This enhanced susceptibility stems primarily from the combined impact of impaired renal oxygen sensing and deficient erythropoietin (EPO) production linked to tubulointerstitial fibrosis. Additional mechanisms comprise glomerular dysfunction, shortened erythrocyte lifespan, uremia-induced bone marrow suppression, and increased bleeding risk. DM is also recognized as a chronic low-grade inflammatory condition, with its inflammatory burden driving iron maldistribution, suppression of erythropoiesis, and resistance to EPO. The diagnostic approach of anemia in DM mirrors that in the general population. Addressing modifiable causes such as hematinic deficiencies, and other chronic conditions, such as DKD and bone marrow disorders, is paramount. In total, the underlying pathophysiology of anemia in DM primarily reflects a state of absolute or relative EPO deficiency and/or diminished bone marrow responsiveness, effectively corresponding to 'anemia of chronic disease. Early initiation of EPO therapy, even in DM patients without overt DKD, may mitigate disease progression and improve outcomes. Future research should focus on diabetes-specific strategies integrating optimal EPO use, potentially implementing targeted management of renal and inflammatory contributors to anemia.
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Affiliation(s)
- Christina Antoniadou
- First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
- Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Efstratios Gavriilidis
- First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
- Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Konstantinos Ritis
- First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
- Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Dimitrios Tsilingiris
- First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
- Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
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Jeong S, Doo M, Sung K, Kim YJ, Lee JH, Ha JH. Aruncus Dioicus Var. Kamtschaticus Extract Prevents Ocular Endoplasmic Reticulum Stress, Inflammation, and Oxidative Stress In Vitro. J Med Food 2025; 28:281-293. [PMID: 39973273 DOI: 10.1089/jmf.2024.k.0240] [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: 02/21/2025] Open
Abstract
The aim of this study was to determine the anti-inflammatory and anti-endoplasmic reticulum (ER) stress effects of Aruncus dioicus var. kamtschaticus (ADK) extract on ARPE-19 cells. Pretreatment with ADK effectively mitigated thapsigargin (Tg)-induced increases in vascular endothelial growth factor protein secretion and intracellular calcium levels. Furthermore, pretreatment with ADK suppressed ocular ER stress-related protein expression in a dose-dependent manner, inhibited the loss of tight junctions, and suppressed interleukin-6 gene expression. Moreover, ADK pretreatment significantly prevented lipopolysaccharide-inducible proinflammatory cytokine gene expression at the transcription level and the phosphorylation of proteins involved in the mitogen-activated protein kinase-nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) axis at the posttranslational level. Additionally, ADK extract enhanced antioxidant activity, as evidenced by increased heme oxygenase-1 protein expression and increased 2,2-diphenyl-1-picrylhydrazyl radical scavenging and ferric-reducing antioxidant power. In conclusion, ADK extract effectively protected ARPE-19 cells from ocular ER stress, inflammation, and oxidative stress, demonstrating its potential as a nutraceutical intervention for ocular diseases.
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Affiliation(s)
- Sunyoung Jeong
- Bioanalytical and Pharmacokinetic Research Group, Korea Institute of Toxicology, Daejeon, Korea
- Department of Human and Environmental Toxicology, University of Science and Technology, Daejeon, Korea
| | - Miae Doo
- Department of Food and Nutrition, Kunsan National University, Gunsan, Korea
| | - Kihun Sung
- Department of Food Science and Nutrition, Dankook University, Cheonan, Korea
| | - Young Jun Kim
- Department of Food and Biotechnology, Korea University, Sejong, Korea
| | - Jong-Hwa Lee
- Bioanalytical and Pharmacokinetic Research Group, Korea Institute of Toxicology, Daejeon, Korea
- Department of Human and Environmental Toxicology, University of Science and Technology, Daejeon, Korea
| | - Jung-Heun Ha
- Department of Food Science and Nutrition, Dankook University, Cheonan, Korea
- Research Center for Industrialization of Natural Neutralization, Dankook University, Yongin, Korea
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Chung SM, Jung I, Lee DY, Park SY, Yu JH, Moon JS, Seo JA, Han KD, Kim NH. Effect of Glomerular Hyperfiltration on Incident Cardiovascular Disease in Patients with Type 2 Diabetes Mellitus. Clin J Am Soc Nephrol 2025; 20:410-419. [PMID: 39786936 PMCID: PMC11906009 DOI: 10.2215/cjn.0000000618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 01/06/2025] [Indexed: 01/12/2025]
Abstract
Key Points Patients with type 2 diabetes mellitus who had glomerular hyperfiltration (GHF) were younger and had fewer comorbid metabolic disorders, despite poor glycemic control. The relationship between eGFR and incident cardiovascular disease showed an inverted J-shaped pattern, which was highest among low filtration, followed by GHF. GHF was associated with a higher risk of cardiovascular disease, particularly myocardial infarction and heart failure. Background The effects of glomerular hyperfiltration (GHF) on cardiovascular disease (CVD) risk in patients with type 2 diabetes mellitus were explored. Methods This retrospective cohort study enrolled 1,952,053 patients with type 2 diabetes mellitus from the Korean National Health Insurance Service database between 2015 and 2016. On the basis of age- and sex-specific eGFR percentiles, patients were classified into five groups: <5 (low filtration), 5–40, 40–60, 60–95, and >95 (GHF). Patients with incident CVD (myocardial infarction [MI], stroke, and hospitalization for heart failure) were followed up until December 2022. Results CVD occurred in 214,111 patients (11%). The incidence rates were 36.1, 20.8, 18.3, 18.7, and 19.3 per 1000 person-years for the eGFR groups, respectively. Low filtration (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.53 to 1.59) and GHF (HR, 1.13; 95% CI, 1.10 to 1.15) were associated with higher CVD risk adjusted for covariates than that of the eGFR 40–60 percentile, showing an inverted J-shaped relationship. GHF was associated with a higher risk of MI (HR, 1.06; 95% CI, 1.01 to 1.11) and heart failure (HR, 1.17; 95% CI, 1.14 to 1.20) and with a higher risk of stroke. eGFR was associated with CVD risk across subgroups of age, sex, obesity, hypertension, and dyslipidemia. The effect of GHF on CVD may be greater in younger patients (HR=1.30, 1.17, and 1.05 in <40, 40–60, and ≥65 years old, respectively). Conclusions GHF was associated with CVD, particularly MI and heart failure. Screening for GHF in the early stages of type 2 diabetes mellitus may be beneficial.
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Affiliation(s)
- Seung Min Chung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Inha Jung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea
| | - Da Young Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea
| | - So Young Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea
| | - Ji Hee Yu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea
| | - Jun Sung Moon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Ji A. Seo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea
| | - Kyung-Do Han
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea
| | - Nan Hee Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea
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Liu C, Chen H, Ma Y, Zhang L, Chen L, Huang J, Zhao Z, Jiang H, Kong J. Clinical metabolomics in type 2 diabetes mellitus: from pathogenesis to biomarkers. Front Endocrinol (Lausanne) 2025; 16:1501305. [PMID: 40070584 PMCID: PMC11893406 DOI: 10.3389/fendo.2025.1501305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 01/21/2025] [Indexed: 03/14/2025] Open
Abstract
As a multidimensional metabolic disorder, the disability and death rate of type 2 diabetes mellitus (T2DM) has increased over time. T2DM covers a wide range of pathological manifestations ranging from hyperglycemia to multi-organ failure, and it has the potential to evolve into acute complications, including ketosis and chronic complications such as peripheral neuropathy, retinopathy, and nephropathy. T2DM mainly occurs in microvascular and large vessels and thus it is restricted for the clinician to diagnose and prescribe. However, the pathological mechanism and clinical diagnosis are inadequate. High-throughput metabolomics, characterized by non-invasive diagnostic techniques to identify potential biomarkers and distinct stages of T2DM, has been increasingly recognized as a vigorous tool with latent capacity for clinical translation. The pathological stratification of T2DM can significantly reduce disability and mortality rates. By tracing the metabolome and associated pathways from impaired fasting blood glucose or impaired glucose tolerance to severe organ failure, the chief contributions of large, independent population-based cohorts are summarized herein. These results facilitate understanding the pathophysiology and mechanism and supports research in accurate diagnosis, risk prediction, curative effect, distinct stages, and prognosis judgment of T2DM.
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Affiliation(s)
- Chuanxin Liu
- Luoyang Key Laboratory of Clinical Multiomics and Translational Medicine, Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Hetao Chen
- Luoyang Key Laboratory of Clinical Multiomics and Translational Medicine, Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
- Department of Clinical Laboratory, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Yujin Ma
- Luoyang Key Laboratory of Clinical Multiomics and Translational Medicine, Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Lei Zhang
- Department of Integrative Medicine, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Lulu Chen
- Luoyang Key Laboratory of Clinical Multiomics and Translational Medicine, Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
- Department of Clinical Laboratory, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Jiarui Huang
- Department of Critical Care Medicine, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Zizhe Zhao
- Luoyang Key Laboratory of Clinical Multiomics and Translational Medicine, Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Hongwei Jiang
- Luoyang Key Laboratory of Clinical Multiomics and Translational Medicine, Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Jiao Kong
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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Viggiano D, Joshi R, Borriello G, Cacciola G, Gonnella A, Gigliotti A, Nigro M, Gigliotti G. SGLT2 Inhibitors: The First Endothelial-Protector for Diabetic Nephropathy. J Clin Med 2025; 14:1241. [PMID: 40004772 PMCID: PMC11856817 DOI: 10.3390/jcm14041241] [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: 01/06/2025] [Revised: 02/05/2025] [Accepted: 02/07/2025] [Indexed: 02/27/2025] Open
Abstract
Sodium-glucose co-transporter type 2 inhibitors (SGLT2i) have emerged as a class of agents relevant for managing diabetic nephropathy and cardiopathy. In a previous report, we noticed that these drugs share, with other drugs with "nephroprotective" effects, the ability to reduce the glomerular filtration rate (GFR), thus suggesting the kidney hemodynamic effect as a proxy for optimal drug dosage. We also noticed that all known nephroprotective drugs exert cardioprotective functions, suggesting the possibility of activities not mediated by the kidney. Finally, we observe that nephroprotective drugs can be grouped according to their effects on hemoglobin levels, thus suggesting their mechanism of action. While the primary mechanism of SGLT2i involves glycosuria and natriuria, growing evidence suggests broader therapeutic effects beyond hemodynamic modulation. Specifically, the evidence that SGLT2 can be expressed in several atypical regions under pathological conditions, supports the possibility that its inhibition has several extratubular effects. Evidence supports the hypothesis that SGLT2i influence mitochondrial function in various cell types affected by diabetes, particularly in the context of diabetic nephropathy. Notably, in SGLT2i-treated patients, the extent of albumin-creatinine ratio (ACR) reduction post-treatment may be correlated with mitochondrial staining intensity in glomerular endothelial cells. This implies that the anti-proteinuric effects of SGLT2i could involve direct actions on glomerular endothelial cell. Our investigation into the role of SGLT2 inhibitors (SGLT2i) in endothelial function suggests that the aberrant expression of SGLT2 in endothelial cells in T2DM would lead to intracellular accumulation of glucose; therefore, SGLT2i are the first type of endothelial protective drugs available today, with potential implications for ageing-related kidney disease. The review reveals two major novel findings: SGLT2 inhibitors are the first known class of endothelial-protective drugs, due to their ability to prevent glucose accumulation in endothelial cells where SGLT2 is aberrantly expressed in Type 2 Diabetes. Additionally, the research demonstrates that SGLT2 inhibitors share a GFR-reducing effect with other nephroprotective drugs, suggesting both a mechanism for optimal drug dosing and potential broader applications in ageing-related kidney disease through their effects on mitochondrial function and glomerular endothelial cells.
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Affiliation(s)
- Davide Viggiano
- Department Translational Medical Sciences, University of Campania, 80138 Naples, Italy; (R.J.); (G.B.); (G.C.)
| | - Rashmi Joshi
- Department Translational Medical Sciences, University of Campania, 80138 Naples, Italy; (R.J.); (G.B.); (G.C.)
| | - Gianmarco Borriello
- Department Translational Medical Sciences, University of Campania, 80138 Naples, Italy; (R.J.); (G.B.); (G.C.)
| | - Giovanna Cacciola
- Department Translational Medical Sciences, University of Campania, 80138 Naples, Italy; (R.J.); (G.B.); (G.C.)
| | - Annalisa Gonnella
- Department Nephrology, Eboli Hospital, 84025 Eboli, Italy; (A.G.); (A.G.); (M.N.); (G.G.)
| | - Andrea Gigliotti
- Department Nephrology, Eboli Hospital, 84025 Eboli, Italy; (A.G.); (A.G.); (M.N.); (G.G.)
| | - Michelangelo Nigro
- Department Nephrology, Eboli Hospital, 84025 Eboli, Italy; (A.G.); (A.G.); (M.N.); (G.G.)
| | - Giuseppe Gigliotti
- Department Nephrology, Eboli Hospital, 84025 Eboli, Italy; (A.G.); (A.G.); (M.N.); (G.G.)
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Ma L, Wang J, Ma L, Wang XM. The link between hyperuricemia and diabetes: insights from a quantitative analysis of scientific literature. Front Endocrinol (Lausanne) 2025; 15:1441503. [PMID: 39991045 PMCID: PMC11842261 DOI: 10.3389/fendo.2024.1441503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 12/30/2024] [Indexed: 02/25/2025] Open
Abstract
Background Hyperuricemia (HUA) is a significant public health issue, ranking second only to diabetes in prevalence. While existing research demonstrates a robust correlation between these two conditions, the precise etiological mechanisms remain inadequately elucidated. This study utilized scientometric analysis to investigate the global association between HUA and diabetes. Methods Data on HUA and diabetes were retrieved from the Web of Science Core Collection database, encompassing the period from its inception until September 30, 2024. Collaboration networks were examined using VOSviewer, cluster analysis was executed with CiteSpace, and systematic mapping was conducted using Bibliometrix. Results By September 30, 2024, 1,464 studies indicated a consistent yearly increase in publications connecting HUA and diabetes despite some fluctuations. The lead authors were Richard J. Johnson, Miguel A. Lanaspa, and Masanari Kuwabara, with most contributors from China, the United States, and Japan. Key institutions include China Medical University, Shanghai Jiao Tong University, and Capital Medical University. The most published journal was Nutrition, Metabolism and Cardiovascular Diseases (CVDs), whereas the most cited journal was Diabetes Care. The reference network from 1987 to September 30, 2024, identified 19 clusters highlighting key research areas in HUA and diabetes, such as metabolic syndrome, uropathology, chronic kidney disease (CKD), and CVD. Exploring pathological mechanisms and pharmacological interventions linked to diabetes concomitant with HUA has emerged as a focal point of research and a burgeoning trend within the field. Conclusion This study is the first scientometric analysis to synthesize research trends on HUA and diabetes, revealing molecular mechanisms and treatment strategies and providing theoretical insights for future clinical use.
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Affiliation(s)
- Lili Ma
- Department of Internal Medicine, Shengzhou Hospital of Traditional Chinese Medicine, Shaoxing, China
| | - Jing Wang
- Xinjiang Laboratory of Respiratory Disease Research, Hospital of Traditional Chinese Medicine Affiliated to Xinjiang Medical University, Urumqi, China
| | - Li Ma
- Department of Endocrinology, Affiliated Hospital of Traditional Chinese Medicine, Xinjiang Medical University, Urumqi, China
| | - Xian Min Wang
- Department of Scientific Research Management, Affiliated Hospital of Traditional Chinese Medicine, Xinjiang Medical University, Urumqi, China
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Crintea IN, Cindrea AC, Mederle OA, Fulga TF, Marza AM, Petrica A, Trebuian CI, Timar R. Obesity as a Risk Factor for Hyperglycemia, Electrolyte Disturbances, and Acute Kidney Injury in the Emergency Department. Biomedicines 2025; 13:349. [PMID: 40002762 PMCID: PMC11853456 DOI: 10.3390/biomedicines13020349] [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: 01/13/2025] [Revised: 01/31/2025] [Accepted: 02/03/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: Obesity is a global health challenge linked to a higher risk of metabolic and cardiovascular complications. This study investigates the role of cardiovascular markers in predicting metabolic crises in obese patients, focusing on the prevalence and clinical implications of these markers. Methods: This retrospective cohort study included 433 patients presenting with metabolic crises at the Emergency Department of Timișoara Municipal Emergency Hospital between 2019 and 2024. Patients were classified into obese (n = 161) and non-obese (n = 272) groups, with obesity further stratified into four grades based on body mass index (BMI). Cardiovascular markers, including NT-proBNP, troponin I, CRP, CK-MB, and D-dimer, alongside metabolic parameters, were analyzed. Results: Metabolic crises were significantly more prevalent in obese patients in all metabolic emergencies: hyperglycemia (27.9% vs. 11.0%, p < 0.001), electrolyte imbalance (23.6% vs. 9.2%, p < 0.001), and acute kidney injury (AKI) (12.4% vs. 5.5%, p = 0.01). NT-proBNP levels independently predicted AKI in obese patients (adjusted OR: 1.14 per 1000 pg/mL, 95% CI: 1.10-1.19, p < 0.001), with excellent discriminatory power (AUC: 0.88). Troponin I and D-dimer were higher in hyperglycemia and electrolyte imbalance, respectively, emphasizing the role of cardiac stress and pro-thrombotic states. Inflammatory markers such as CRP were significantly associated with metabolic disturbances, supporting the contribution of systemic inflammation. Comorbidities, particularly heart failure and atrial fibrillation, further increased the risk of metabolic crises. Conclusions: Cardiovascular markers suggest potential utility for early risk stratification of metabolic crises in obese patients. However, further studies are needed to validate their clinical applicability and to establish standardized approaches for integrating these biomarkers into routine practice, especially in patients with advanced obesity grades.
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Affiliation(s)
- Iulia Najette Crintea
- Department of Surgery, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (I.N.C.); (A.C.C.); (A.M.M.); (A.P.); (C.I.T.)
- Emergency Department, Emergency Clinical Municipal Hospital, 300079 Timisoara, Romania
| | - Alexandru Cristian Cindrea
- Department of Surgery, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (I.N.C.); (A.C.C.); (A.M.M.); (A.P.); (C.I.T.)
- Emergency Department, Emergency Clinical Municipal Hospital, 300079 Timisoara, Romania
| | - Ovidiu Alexandru Mederle
- Department of Surgery, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (I.N.C.); (A.C.C.); (A.M.M.); (A.P.); (C.I.T.)
- Emergency Department, Emergency Clinical Municipal Hospital, 300079 Timisoara, Romania
| | - Teodor Florin Fulga
- Faculty of Cybernetics, Statistics and Economic Informatics, The Bucharest University of Economic Studies, 010374 Bucharest, Romania;
| | - Adina Maria Marza
- Department of Surgery, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (I.N.C.); (A.C.C.); (A.M.M.); (A.P.); (C.I.T.)
- Emergency Department, Emergency Clinical Municipal Hospital, 300079 Timisoara, Romania
| | - Alina Petrica
- Department of Surgery, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (I.N.C.); (A.C.C.); (A.M.M.); (A.P.); (C.I.T.)
- Emergency Department, “Pius Brinzeu” Emergency Clinical County Hospital, 300736 Timisoara, Romania
| | - Cosmin Iosif Trebuian
- Department of Surgery, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (I.N.C.); (A.C.C.); (A.M.M.); (A.P.); (C.I.T.)
- Department of Anesthesia and Intensive Care, Emergency County Hospital, 320210 Resita, Romania
| | - Romulus Timar
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania;
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
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Hill C, McKnight AJ, Smyth LJ. Integrated multiomic analyses: An approach to improve understanding of diabetic kidney disease. Diabet Med 2025; 42:e15447. [PMID: 39460977 PMCID: PMC11733670 DOI: 10.1111/dme.15447] [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: 06/06/2024] [Revised: 09/17/2024] [Accepted: 09/20/2024] [Indexed: 10/28/2024]
Abstract
AIM Diabetes is increasing in prevalence worldwide, with a 20% rise in prevalence predicted between 2021 and 2030, bringing an increased burden of complications, such as diabetic kidney disease (DKD). DKD is a leading cause of end-stage kidney disease, with significant impacts on patients, families and healthcare providers. DKD often goes undetected until later stages, due to asymptomatic disease, non-standard presentation or progression, and sub-optimal screening tools and/or provision. Deeper insights are needed to improve DKD diagnosis, facilitating the identification of higher-risk patients. Improved tools to stratify patients based on disease prognosis would facilitate the optimisation of resources and the individualisation of care. This review aimed to identify how multiomic approaches provide an opportunity to understand the complex underlying biology of DKD. METHODS This review explores how multiomic analyses of DKD are improving our understanding of DKD pathology, and aiding in the identification of novel biomarkers to detect disease earlier or predict trajectories. RESULTS Effective multiomic data integration allows novel interactions to be uncovered and empathises the need for harmonised studies and the incorporation of additional data types, such as co-morbidity, environmental and demographic data to understand DKD complexity. This will facilitate a better understanding of kidney health inequalities, such as social-, ethnicity- and sex-related differences in DKD risk, onset and progression. CONCLUSION Multiomics provides opportunities to uncover how lifetime exposures become molecularly embodied to impact kidney health. Such insights would advance DKD diagnosis and treatment, inform preventative strategies and reduce the global impact of this disease.
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Affiliation(s)
- Claire Hill
- Centre for Public Health, School of Medicine, Dentistry and Biomedical ScienceQueen's University BelfastBelfastUK
| | - Amy Jayne McKnight
- Centre for Public Health, School of Medicine, Dentistry and Biomedical ScienceQueen's University BelfastBelfastUK
| | - Laura J. Smyth
- Centre for Public Health, School of Medicine, Dentistry and Biomedical ScienceQueen's University BelfastBelfastUK
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42
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Romagnani P, Agarwal R, Chan JCN, Levin A, Kalyesubula R, Karam S, Nangaku M, Rodríguez-Iturbe B, Anders HJ. Chronic kidney disease. Nat Rev Dis Primers 2025; 11:8. [PMID: 39885176 DOI: 10.1038/s41572-024-00589-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/19/2024] [Indexed: 02/01/2025]
Abstract
Chronic kidney disease (CKD) is defined by persistent abnormalities of kidney function or structure that have consequences for the health. A progressive decline of excretory kidney function has effects on body homeostasis. CKD is tightly associated with accelerated cardiovascular disease and severe infections, and with premature death. Kidney failure without access to kidney replacement therapy is fatal - a reality in many regions of the world. CKD can be the consequence of a single cause, but CKD in adults frequently relates rather to sequential injuries accumulating over the life course or to the presence of concomitant risk factors. The shared pathomechanism of CKD progression is the irreversible loss of kidney cells or nephrons together with haemodynamic and metabolic overload of the remaining nephrons, leading to further loss of kidney cells or nephrons. The management of patients with CKD focuses on early detection and on controlling all modifiable risk factors. This approach includes reducing the overload of the remaining nephrons with inhibitors of the renin-angiotensin system and the sodium-glucose transporter 2, as well as disease-specific drug interventions, if available. Hypertension, anaemia, metabolic acidosis and secondary hyperparathyroidism contribute to cardiovascular morbidity and reduced quality of life, and require diagnosis and treatment.
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Affiliation(s)
- Paola Romagnani
- Nephrology and Dialysis Unit, Meyer Children's Hospital IRCCS, Florence, Italy
- Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Rajiv Agarwal
- Richard L. Roudebush VA Medical Center and Indiana University, Indianapolis, IN, USA
| | - Juliana C N Chan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences and Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
| | - Adeera Levin
- Division of Nephrology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
- BC Renal, Provincial Health Services Authority, Vancouver, British Columbia, Canada
| | - Robert Kalyesubula
- African Community Center for Social Sustainability, Nakaseke District, Uganda
- Department of Physiology, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Sabine Karam
- Division of Nephrology and Hypertension, University of Minnesota, Minneapolis, MN, USA
- Department of Internal Medicine, Division of Nephrology and Hypertension, American University of Beirut, Beirut, Lebanon
| | - Masaomi Nangaku
- Division of Nephrology and Endocrinology, The University of Tokyo, Bunkyo City, Tokyo, Japan
| | | | - Hans-Joachim Anders
- Division of Nephrology, Department of Medicine IV, Hospital of the Ludwig-Maximilians University, Munich, Germany.
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Pallauf M, Brönimann S, Rezaee ME, Kohn TP, Fletcher SA, McNamara M, Enikeev D, Shariat SF, Hoffman-Censits J, Smith AK, Singla N. Metformin intake and risk of metabolic acidosis after radical cystectomy with urinary diversion: A comparative study using data from the TriNetX research network. Urol Oncol 2025:S1078-1439(24)01055-X. [PMID: 39848843 DOI: 10.1016/j.urolonc.2024.12.275] [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: 10/27/2024] [Revised: 12/22/2024] [Accepted: 12/28/2024] [Indexed: 01/25/2025]
Abstract
PURPOSE To investigate the association of diabetes mellitus and metformin use with metabolic acidosis risk after radical cystectomy (RC) and urinary diversion for bladder cancer. MATERIALS AND METHODS This retrospective cohort study used TriNetX Research Network data. Patients undergoing RC with continent diversion or ileal conduit for bladder cancer were identified using International Classification of Diseases, 10th Revision (ICD-10) and ICD-10 Procedure Coding System (ICD-10-PCS) codes. The primary outcome was acidosis between 1 month and 3 years postsurgery. Risk ratios (RR) and odds ratios (OR) were calculated based on diabetes and metformin use, stratified by diversion type and chronic kidney disease stage. Propensity score matching balanced potential confounders. RESULTS We identified 1,986 patients who underwent continent diversion and 11,184 who underwent ileal conduit reconstruction. In matched analyses, diabetes patients had higher acidosis risk (continent diversion: RR 1.87, 95% confidence interval [CI] 1.39-2.51; ileal conduit: RR 1.94, 95% CI 1.66-2.27). The risk was highest for diabetes patients with metformin prescription (continent diversion: RR 2.06, 95% CI 1.63-2.61; ileal conduit: RR 2.13, 95% CI 1.84-2.47). However, among patients with diabetes, metformin use did not significantly affect acidosis rates in most analyses. Continent diversion patients had higher acidosis risk than ileal conduit patients (RR 1.89, 95% CI 1.58-2.26). CONCLUSION Diabetes significantly increases metabolic acidosis risk after RC with urinary diversion, especially in continent diversion patients. While metformin may contribute to metabolic acidosis risk, its impact appears less significant than that of diabetes. Careful monitoring and appropriate metformin adjustments are crucial in this population.
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Affiliation(s)
- Maximilian Pallauf
- Department of Urology, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria; The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Stephan Brönimann
- The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Michael E Rezaee
- The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Taylor P Kohn
- The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Sean A Fletcher
- The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Meghan McNamara
- The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD; Johns Hopkins Urologic Oncology at Sibley Memorial Hospital, Washington, DC
| | - Dmitry Enikeev
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Division of Urology, Rabin Medical Center, Petah Tikva, Israel; Faculty of Medicine, Tel Aviv University, Israel; Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Shahrokh F Shariat
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria; Department of Urology, Weill Cornell Medical College, New York, NY; Department of Urology, University of Texas Southwestern, Dallas, TX; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; Division of Urology, Department of Special Surgery, Jordan University Hospital, The University of Jordan, Amman, Jordan; Research Center for Evidence Medicine, Urology Department Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jean Hoffman-Censits
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Armine K Smith
- The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD; Johns Hopkins Urologic Oncology at Sibley Memorial Hospital, Washington, DC
| | - Nirmish Singla
- The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD.
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Kleibert M, Tkacz K, Winiarska K, Małyszko J, Cudnoch-Jędrzejewska A. The role of hypoxia-inducible factors 1 and 2 in the pathogenesis of diabetic kidney disease. J Nephrol 2025; 38:37-47. [PMID: 39648258 PMCID: PMC11903585 DOI: 10.1007/s40620-024-02152-x] [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: 05/29/2024] [Accepted: 10/30/2024] [Indexed: 12/10/2024]
Abstract
According to the 10th edition of the IDF Diabetes Atlas, 537 million people suffered from diabetes in 2021, and this number will increase by 47% by 2045. It is estimated that even 30-40% of these individuals may develop diabetic kidney disease (DKD) in the course of diabetes. DKD is one of the most important complications of diabetes, both in terms of impact and magnitude. It leads to high morbidity and mortality, which subsequently impacts on quality of life, and it carries a high financial burden. Diabetic kidney disease is considered a complex and heterogeneous entity involving disturbances in vascular, glomerular, podocyte, and tubular function. It would appear that hypoxia-inducible factors (HIF)-1 and HIF-2 may be important players in the pathogenesis of this disease. However, their exact role is still not fully investigated. In this article, we summarize the current knowledge about HIF signaling and its role in DKD. In addition, we focus on the possible effects of nephroprotective drugs on HIF expression and activity in various tissues.
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Affiliation(s)
- Marcin Kleibert
- Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, 02-097, Warsaw, Poland.
| | - Kamil Tkacz
- Department of Diabetology and Internal Diseases, Medical University of Warsaw, 02-097, Warsaw, Poland
| | - Katarzyna Winiarska
- Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096, Warsaw, Poland
| | - Jolanta Małyszko
- Department of Nephrology, Dialysis and Internal Medicine, Medical University of Warsaw, Banacha 1A, 02-097, Warsaw, Poland
| | - Agnieszka Cudnoch-Jędrzejewska
- Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, 02-097, Warsaw, Poland
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Wang Y, Pang Z, He W, Ren P, He Q, Jin J. LncRNA HOXB3OS improves high glucose-mediated podocyte damage and progression of diabetic kidney disease through enhancing SIRT1 mRNA stability. Biomed Pharmacother 2025; 182:117770. [PMID: 39693905 DOI: 10.1016/j.biopha.2024.117770] [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: 08/06/2024] [Revised: 12/05/2024] [Accepted: 12/13/2024] [Indexed: 12/20/2024] Open
Abstract
High glucose (HG)-mediated podocyte damage can be ameliorated by lncRNA HOXB3OS, and exosomes derived from adipose-derived mesenchymal stem cells (ADSCs-Exo) can ameliorate the progression of diabetic kidney disease (DKD) dependening on RNA. To investigate the mechanism by which HOXB3OS improves podocyte injury and the effects of engineered ADSCs-Exo with a high abundance of HOXB3OS on DKD progression, MPC5 cells stimulated with HG and db/db mice were used to develop a podocyte injury model and type II DKD mouse model, respectively. HOXB3OS expression and mRNA level of SIRT1 were detected by qRT-PCR. The protein content of SIRT1 and Ythdc2 was measured through WB, IHC, and IF assays. CCK-8 assay and flow cytometry assay were used to detect cell viability and apoptosis rate of MPC5 cells. RIP assay was used to investigate the binding capacity of Ythdc2 to HOXB3OS or SIRT1 mRNA. Albuminuria, renal function and glomerular structure were observed by kits and PAS, respectively. Consequently, we found that HOXB3OS combined with Ythdc2 and inhibited the binding of Ythdc2 to SIRT1 mRNA, hence inhibiting SIRT1 mRNA degradation. SIRT1 siRNA inhibited the effect of Ythdc2 siRNA on HOXB3OS knock-down or HG-induced podocyte injury. ADSCs-Exo with a high content of HOXB3OS ameliorated HG-mediated podocyte damage and DKD progression. This suggests that engineered ADSCs-Exo with HOXB3OS can suppress Ythdc2-mediated SIRT1 mRNA degradation by disturbing the binding of Ythdc2 to SIRT1 mRNA as well as reverse SIRT1 down-regulation induced by HG, thereby ameliorating podocyte injury and DKD progression.
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Affiliation(s)
- Yifei Wang
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China; Provincial Key Laboratory for Research and Translation on the Syndrome of Kidney Deficiency Accompanied by Blood Stasis and Turbidity, China
| | - Zhengyi Pang
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China; Provincial Key Laboratory for Research and Translation on the Syndrome of Kidney Deficiency Accompanied by Blood Stasis and Turbidity, China
| | - Wenfang He
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China; Provincial Key Laboratory for Research and Translation on the Syndrome of Kidney Deficiency Accompanied by Blood Stasis and Turbidity, China
| | - Peiyao Ren
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China; Provincial Key Laboratory for Research and Translation on the Syndrome of Kidney Deficiency Accompanied by Blood Stasis and Turbidity, China
| | - Qiang He
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China; Provincial Key Laboratory for Research and Translation on the Syndrome of Kidney Deficiency Accompanied by Blood Stasis and Turbidity, China.
| | - Juan Jin
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China; Provincial Key Laboratory for Research and Translation on the Syndrome of Kidney Deficiency Accompanied by Blood Stasis and Turbidity, China.
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León-Jiménez D, Sridhar VS, López-Mendoza M, Scholtes RA, Schmieder RE, Cherney DZI, van Raalte DH, Toro-Prieto FJ, Miramontes-González JP, van Bommel EJM. Kidney hemodynamic effects of sodium-glucose cotransporter 2 inhibitors in diabetes: physiology and clinical implications. Clin Kidney J 2025; 18:sfae370. [PMID: 40008354 PMCID: PMC11852268 DOI: 10.1093/ckj/sfae370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Indexed: 02/27/2025] Open
Abstract
The progressive loss of kidney function in diabetes mellitus is partly attributable to the occurrence of glomerular hyperfiltration. Consequently, therapeutic interventions that lower intra-glomerular pressure are a cornerstone of treatment in diabetic kidney disease. Sodium-glucose cotransporter 2 (SGLT2) inhibitors consistently reduce glomerular filtration rate (GFR) and calculated intraglomerular pressures across studies. However, the net effect on arteriolar tone that leads to acute GFR declines may differ between cohorts. While pre-glomerular vasoconstriction appears to be the dominant mechanism responsible for GFR dipping in patients with type 1 diabetes (T1D) and glomerular hyperfiltration, other factors, including post-glomerular vasodilation, may contribute to the acute GFR decline in normofilterering individuals with T1D and type 2 diabetes. Regardless of the responsible mechanisms, acute changes in GFR are associated with long-term kidney function preservation-a relationship that may reflect an underlying protective decline in glomerular hypertension.
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Affiliation(s)
- David León-Jiménez
- Vascular Risk Unit, Internal Medicine Department, Virgen del Rocío University Hospital, University of Seville, Instituto de Biomedicina de Sevilla (IBIS), Seville, Spain
| | - Vikas S Sridhar
- Division of Nephrology, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Manuel López-Mendoza
- Nephrology Department, Virgen del Rocío University Hospital, University of Seville, Spain
| | - Rosalie A Scholtes
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, VU University Medical Center, Amsterdam, The Netherlands
| | - Roland E Schmieder
- Department of Internal Medicine, Nephrology and Hypertension, Friedrich-Alexander University Erlangen, Erlangen, Germany
| | - David Z I Cherney
- Division of Nephrology, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Daniël H van Raalte
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, VU University Medical Center, Amsterdam, The Netherlands
| | | | - José Pablo Miramontes-González
- Internal Medicine, Institute of Biomedical Research of Salamanca (IBSAL), Río Hortega University Hospital, Valladolid, Spain
| | - Erik J M van Bommel
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, VU University Medical Center, Amsterdam, The Netherlands
- Radboud University Medical Center, Department of Internal Medicine, Nijmegen, The Netherlands
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Goyal K, Afzal M, Altamimi ASA, Babu MA, Ballal S, Kaur I, Kumar S, Kumar MR, Chauhan AS, Ali H, Shahwan M, Gupta G. Chronic kidney disease and aging: dissecting the p53/p21 pathway as a therapeutic target. Biogerontology 2024; 26:32. [PMID: 39725742 DOI: 10.1007/s10522-024-10173-z] [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: 11/09/2024] [Accepted: 12/14/2024] [Indexed: 12/28/2024]
Abstract
Chronic kidney diseases (CKD) are a group of multi-factorial disorders that markedly impair kidney functions with progressive renal deterioration. Aging contributes to age-specific phenotypes in kidneys, which undergo several structural and functional alterations, such as a decline in regenerative capacity and increased fibrosis, inflammation, and tubular atrophy, all predisposing them to disease and increasing their susceptibility to injury while impeding their recovery. A central feature of these age-related processes is the activation of the p53/p21 pathway signaling. The pathway is a key player in cellular senescence, apoptosis, and cell cycle regulation, which are all key to maintaining the health of the kidney. P53 is a transcription factor and a tumor suppressor protein that responds to cell stress and damage. Persistent activation of cell p53 can lead to the expression of p21, an inhibitor of the cell cycle known as a cyclin-dependent kinase. This causes cells to cease dividing and leads to senescence, where cells can no longer increase. The accumulation of senescent cells in the aging kidney impairs kidney function by altering the microenvironment. As the number of senescent cells increases, the capacity of the kidney to recover from injury decreases, accelerating the progression of end-stage renal disease. This article review extensively explores the relationship between the p53/p21 pathway and cellular senescence within an aging kidney and the emerging therapeutic strategies that target it to overcome the impacts of cellular senescence on CKD.
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Affiliation(s)
- Kavita Goyal
- Department of Biotechnology, Graphic Era (Deemed to Be University), Clement Town, Dehradun, 248002, India
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, 21442, Jeddah, Saudi Arabia
| | | | - M Arockia Babu
- Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Irwanjot Kaur
- Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan, 303012, India
| | - Sachin Kumar
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, India
| | - M Ravi Kumar
- Chandigarh Pharmacy College, Chandigarh Group of College, Jhanjeri, Mohali, Punjab, 140307, India
| | - Ashish Singh Chauhan
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, 531162, India
| | - Haider Ali
- Uttaranchal Institute of Pharmaceutical Sciences, Division of Research and Innovation, Uttaranchal University, Dehradun, India
| | - Moyad Shahwan
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Gaurav Gupta
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
- Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates.
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India.
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Liu M, Yang W, Qu S, Zhao T, Jiang S, Peng S, Zhang M, Xuan J, Liu Z, Zen K. Loss of glomerular aldolase B in diabetic nephropathy promotes renal fibrosis via activating Akt/GSK/β-catenin axis. J Adv Res 2024:S2090-1232(24)00605-2. [PMID: 39725005 DOI: 10.1016/j.jare.2024.12.027] [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: 08/17/2024] [Revised: 11/13/2024] [Accepted: 12/16/2024] [Indexed: 12/28/2024] Open
Abstract
OBJECTIVE Diabetic nephropathy (DN), characterized by a complex and multifaceted pathogenesis, stands as the foremost catalyst behind end-stage renal disease (ESRD). This study aims to analyze the level and non-metabolic role of glomerular aldolase B (ALDOB) in DN progression. METHODS Glomerular proteomics and transcriptome are analyzed from 50 DN patients and 25 controls, respectively. Human kidney biopsy, cultured podocytes and mouse models are employed to study ALDOB levels and function. RESULTS ALDOB is strongly downregulated in DN-affected glomeruli, as well as in human and murine podocytes exposed to inflammatory cytokines. ALDOB reduction increases podocyte injury, while adenovirus-mediated ALDOB overexpression leads to substantial alleviation of renal injuries in a diabetic mouse model. Mechanistically, ALDOB reduction triggers the Akt/GSK/β-catenin signaling cascade within podocytes. CONCLUSION Our findings reveal a novel non-metabolic role of glomerular ALDOB in protecting against podocyte injury and renal fibrosis.
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Affiliation(s)
- Minghui Liu
- School of Pharmaceutical Science, Nanjing Tech University, 30 South Puzhu Road, Nanjing, Jiangsu 211816, China; State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Drum Tower Hospital, Nanjing University, School of Life Sciences, Nanjing, Jiangsu 210093, China
| | - Wenwen Yang
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Drum Tower Hospital, Nanjing University, School of Life Sciences, Nanjing, Jiangsu 210093, China
| | - Shuang Qu
- Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu 210024, China
| | - Tingting Zhao
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, China
| | - Song Jiang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, China
| | - Suming Peng
- School of Life Science and Technology, Chinese Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Mingchao Zhang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, China
| | - Ji Xuan
- Department of Gastroenterology, Jinling Hospital, Nanjing University, School of Medicine, Nanjing, Jiangsu 210002, China.
| | - Zhihong Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, China.
| | - Ke Zen
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Drum Tower Hospital, Nanjing University, School of Life Sciences, Nanjing, Jiangsu 210093, China.
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Li X, Zhang H, Hu H, Song X, Leng B. Association between type 2 diabetes mellitus and Klebsiella pneumoniae colonization: construction of nomogram model. Am J Transl Res 2024; 16:7633-7644. [PMID: 39822526 PMCID: PMC11733326 DOI: 10.62347/dzkv8669] [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: 08/29/2024] [Accepted: 11/20/2024] [Indexed: 01/19/2025]
Abstract
OBJECTIVE To investigate the association between the basic and clinical characteristics of patients with type 2 diabetes mellitus (T2DM) and their susceptibility to Klebsiella pneumoniae colonization (KPC). Additionally, a clinical prediction model was developed to identify high-risk patients for KPC. METHODS Data from 486 T2DM patients who visited Shanghai Fifth People's Hospital from December 2020 to December 2022 were retrospectively collected. Patients were classified into the KPC group and normal group based on their Klebsiella pneumoniae test results. Differences between the two groups were analyzed using t-test and chi-square test. Logistic regression was performed to identify factors influencing KPC susceptibility in T2DM patients, with odds ratios (ORs) calculated. A clinical prediction model was constructed using a nomogram and evaluated through the area under the receiver operating characteristic (ROC) curve (AUC), Hosmer-Lemeshow test, calibration curve, and decision curve analysis (DCA). RESULTS Of the 486 T2DM patients, 124 were found to have KPC, with a colonization rate of 25.51%. Logistic regression analysis revealed that hospitalization within the past six months, elevated white blood cell count, decreased hemoglobin, and elevated ferritin levels were independent risk factors for KPC. Thyroid and liver function indicators were also associated with KPC susceptibility. The clinical prediction model achieved an AUC of 0.74 (95% CI: 0.68-0.80). The calibration curve indicated no significant differences between observed and predicted values, suggesting that the model effectively identifies high-risk KPC patients. CONCLUSION T2DM patients are at an increased risk of secondary KPC. Identifying key risk factors for KPC in T2DM patients has significant clinical implications for early identification, targeted interventions, and individualized treatment strategies.
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Affiliation(s)
- Xiaoying Li
- Department of Infectious Diseases, Shanghai Fifth People’s HospitalShanghai 200240, China
| | - Hui Zhang
- Department of Laboratory Medicine, Shanghai Fifth People’s HospitalShanghai 200240, China
| | - Huili Hu
- Department of Infectious Diseases, Shanghai Fifth People’s HospitalShanghai 200240, China
| | - Xiaolei Song
- Department of Infectious Diseases, Shanghai Fifth People’s HospitalShanghai 200240, China
| | - Beizheng Leng
- Department of Infectious Diseases, Shanghai Fifth People’s HospitalShanghai 200240, China
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Adamczak M, Kurnatowska I, Naumnik B, Stompór T, Tylicki L, Krajewska M. Pharmacological Nephroprotection in Chronic Kidney Disease Patients with Type 2 Diabetes Mellitus-Clinical Practice Position Statement of the Polish Society of Nephrology. Int J Mol Sci 2024; 25:12941. [PMID: 39684653 PMCID: PMC11641270 DOI: 10.3390/ijms252312941] [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: 10/17/2024] [Revised: 11/20/2024] [Accepted: 11/26/2024] [Indexed: 12/18/2024] Open
Abstract
Both chronic kidney disease (CKD) and type 2 diabetes (T2D) are modern epidemics worldwide and have become a severe public health problem. Chronic kidney disease progression in T2D patients is linked to the need for dialysis or kidney transplantation and represents the risk factor predisposing to serious cardiovascular complications. In recent years, important progress has occurred in nephroprotective pharmacotherapy in CKD patients with T2D. In the current position paper, we described a nephroprotective approach in CKD patients with T2D based on the five following pillars: effective antihyperglycemic treatment, SGLT2 inhibitor or semaglutide, antihypertensive therapy, use of RASi (ARB or ACEi), and in selected patients, finerenone, as well as sodium bicarbonate in patients with metabolic acidosis. We thought that the current statement is comprehensive and up-to-date and addresses multiple pathways of nephroprotection in patients with CKD and T2D.
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Affiliation(s)
- Marcin Adamczak
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, 40-027 Katowice, Poland
| | - Ilona Kurnatowska
- Department of Internal Diseases and Transplant Nephrology, Medical University of Lodz, 90-153 Lodz, Poland
| | - Beata Naumnik
- 1st Department of Nephrology, Transplantation and Internal Medicine with Dialysis Unit, Medical University of Bialystok, 15-540 Bialystok, Poland;
| | - Tomasz Stompór
- Department of Nephrology, Hypertension and Internal Medicine, University of Warmia and Mazury in Olsztyn, 10-516 Olsztyn, Poland;
| | - Leszek Tylicki
- Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdansk, 80-952 Gdansk, Poland
| | - Magdalena Krajewska
- Department of Non-Surgical Clinical Sciences, Wroclaw University of Science and Technology, 50-370 Wroclaw, Poland;
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