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Sellasie SW, Pecchioli C, Cersosimo K, Nardone I, Zaccaria S, Centi A, Di Perna P, Tatangelo P, Sperti P, Schifano G, Giurato L, Bellia A, Palumbo R, Uccioli L. Attending an integrated nephrology and diabetology outpatient service can improve diabetic kidney disease treatment: a single-center experience. Acta Diabetol 2025:10.1007/s00592-024-02423-w. [PMID: 39982508 DOI: 10.1007/s00592-024-02423-w] [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: 07/16/2024] [Accepted: 11/23/2024] [Indexed: 02/22/2025]
Abstract
BACKGROUND Glucose-lowering medications with established reno-protective effects are still underused in Italy. We explored whether attending an integrated nephrology and diabetology (NPD) outpatient service can improve clinical outcomes and adherence to treatment guidelines for diabetic kidney disease (DKD). METHODS We retrospectively included 110 DKD patients (aged 71.1 ± 10.1 years; 74.5% males) having attended the NPD outpatient service of CTO Hospital (Rome) between June and November 2023. Age- and gender-matched control group included DKD patients attending regular Diabetology outpatient service. Drugs prescriptions, clinical and biochemical parameters related to routine evaluation of DKD were collected at first and 6-months control visit. RESULTS This DKD population was made of 28.2% of patients with urine albumin-creatinine ratio (UACR) > 30 mg/gr, 33.6% with glomerular filtration rate (GFR) < 60 ml/min, 38.2% with both abnormalities. Proportion of patients prescribed with most recent anti-diabetic medications significantly increased after attending the NPD service (for SGLT-2 inhibitors, 54.5 vs. 25.5%, p < 0.01; for GLP1-R agonists, 28.3 vs. 21.8%, p = 0.01), as well as for statins (p < 0.01) and calcium channel-blockers (p = 0.01). During the same observation period we registered significant reduction in LDL cholesterol (p = 0.01) and UACR levels (p = 0.007), with a trend toward improvement in HbA1c and eGFR. Conversely, no significant differences in drugs prescriptions were reported in the control group, except for SGLT-2 inhibitors. CONCLUSIONS Enhanced real-time interaction and collaborative decision-making in an outpatient setting that integrates both diabetology and nephrology expertise can lead to better clinical outcomes and greater adherence to DKD management guidelines, ultimately providing a more comprehensive strategy for cardio-renal risk reduction.
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Affiliation(s)
- S Wolde Sellasie
- Division of Endocrinology and Diabetes, Department of Biomedicine and Prevention, CTO Andrea Alesini Hospital, University of Rome Tor Vergata, 00133, Rome, Italy
- PhD School of Applied Medical-Surgical Sciences, University of Rome Tor Vergata, 00133, Rome, Italy
| | - C Pecchioli
- Division of Endocrinology and Diabetes, Department of Biomedicine and Prevention, CTO Andrea Alesini Hospital, University of Rome Tor Vergata, 00133, Rome, Italy
| | - K Cersosimo
- Unit of Nephrology, Sant' Eugenio Hospital, 00144, Rome, Italy
| | - I Nardone
- Division of Endocrinology and Diabetes, Department of Biomedicine and Prevention, CTO Andrea Alesini Hospital, University of Rome Tor Vergata, 00133, Rome, Italy
- PhD School of Applied Medical-Surgical Sciences, University of Rome Tor Vergata, 00133, Rome, Italy
| | - S Zaccaria
- Division of Endocrinology and Diabetes, Department of Biomedicine and Prevention, CTO Andrea Alesini Hospital, University of Rome Tor Vergata, 00133, Rome, Italy
- PhD School of Applied Medical-Surgical Sciences, University of Rome Tor Vergata, 00133, Rome, Italy
| | - A Centi
- Unit of Nephrology, Sant' Eugenio Hospital, 00144, Rome, Italy
| | - P Di Perna
- Division of Endocrinology and Diabetes, Department of Biomedicine and Prevention, CTO Andrea Alesini Hospital, University of Rome Tor Vergata, 00133, Rome, Italy
| | - P Tatangelo
- Unit of Nephrology, Sant' Eugenio Hospital, 00144, Rome, Italy
| | - P Sperti
- Division of Endocrinology and Diabetes, Department of Biomedicine and Prevention, CTO Andrea Alesini Hospital, University of Rome Tor Vergata, 00133, Rome, Italy
| | - G Schifano
- School of Specialization in Food Sciences, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
| | - L Giurato
- Division of Endocrinology and Diabetes, Department of Biomedicine and Prevention, CTO Andrea Alesini Hospital, University of Rome Tor Vergata, 00133, Rome, Italy
| | - A Bellia
- Department of Systems Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.
| | - R Palumbo
- Unit of Nephrology, Sant' Eugenio Hospital, 00144, Rome, Italy
| | - L Uccioli
- Division of Endocrinology and Diabetes, Department of Biomedicine and Prevention, CTO Andrea Alesini Hospital, University of Rome Tor Vergata, 00133, Rome, Italy
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Deng S, Peng L. Triglyceride Glucose Index and the Risk of Diabetic Nephropathy in Patients with Type 2 Diabetes: A Meta-Analysis. Horm Metab Res 2025; 57:106-116. [PMID: 39236743 DOI: 10.1055/a-2376-6044] [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] [Indexed: 09/07/2024]
Abstract
Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in patients with type 2 diabetes mellitus (T2DM). This meta-analysis aims to evaluate the association between the triglyceride glucose (TyG) index, a novel marker reflecting insulin resistance, and the risk of developing DN in patients with T2DM. We conducted a comprehensive literature search in PubMed, Embase, and Web of Science databases up to May 12, 2024. Studies assessing the TyG index in relation to DN risk among T2DM patients were included. The pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model. A total of eight longitudinal follow-up studies encompassing 15 889 patients with T2DM were included. The pooled analysis revealed a significant association between a higher TyG index and an increased risk of DN in patients with T2DM (RR=1.53, 95% CI: 1.37-1.71, p<0.001; I2=35%). The results of meta-regression analysis suggested that the cutoff of TyG index was positively associated with the RR for the association between TyG index and DN. Subgroup analyses demonstrated that the association was stronger in studies with cutoff of TyG index ≥9.5 as compared to those with the cutoff <9.5 (RR: 1.73 vs. 1.40, p for subgroup difference <0.05). The association was not significantly affected by study design, mean age of the patients, proportion of men, or follow-up durations. In conclusion, higher TyG index is significantly associated with an increased risk of DN in patients with T2DM.
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Affiliation(s)
- Sheng Deng
- Department of Medical Laboratory, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Ling Peng
- Department of Nephrology, Xiangya Hospital Central South University, Changsha, China
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Rendell M. Lessons learned from early-stage clinical trials for diabetic nephropathy. Expert Opin Investig Drugs 2024; 33:287-301. [PMID: 38465470 DOI: 10.1080/13543784.2024.2326025] [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: 08/13/2023] [Accepted: 02/28/2024] [Indexed: 03/12/2024]
Abstract
INTRODUCTION The evolution of treatment for diabetic nephropathy illustrates how basic biochemistry and physiology have led to new agents such as SGLT2 inhibitors and mineralocorticoid blockers. Conversely, clinical studies performed with these agents have suggested new concepts for investigational drug development. We reviewed currently available treatments for diabetic nephropathy and then analyzed early clinical trials of new agents to assess the potential for future treatment modalities. AREAS COVERED We searched ClinicalTrials.gov for new agents under study for diabetic nephropathy in the past decade. Once we have identified investigation trials of new agents, we then used search engines and Pubmed.gov to find publications providing insight on these drugs. Current treatments have shown benefit in both cardiac and renal disease. In our review, we found 51 trials and 43 pharmaceuticals in a number of drug classes: mineralocorticoid blockers, anti-inflammatory, anti-fibrosis, nitric oxide stimulatory, and podocyte protection, and endothelin inhibitors. EXPERT OPINION It is difficult to predict which early phase treatments will advance to confirmatory clinical trials. Current agents are thought to improve hemodynamic function. However, the coincident benefit of both myocardial function and the glomerulus argues for primary effects at the subcellular level, and we follow the evolution of agents which modify fundamental cellular processes.
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Affiliation(s)
- Marc Rendell
- The Association of Diabetes Investigators, Newport Coast, CA, USA
- The Rose Salter Medical Research Foundation, Newport Coast, CA, USA
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Shibata M, Sato KK, Koh H, Shibata I, Okamura K, Takeuchi Y, Oue K, Morimoto M, Hayashi T. The Relationship of Alcohol Consumption and Drinking Pattern to the Risk of Glomerular Hyperfiltration in Middle-aged Japanese Men: The Kansai Healthcare Study. J Epidemiol 2024; 34:137-143. [PMID: 37211396 PMCID: PMC10853046 DOI: 10.2188/jea.je20220312] [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: 11/02/2022] [Accepted: 03/31/2023] [Indexed: 05/23/2023] Open
Abstract
BACKGROUND Glomerular hyperfiltration has been reported to be associated with adverse renal outcomes in the general population. It is not known whether drinking pattern is associated with the risk of glomerular hyperfiltration in healthy individuals. METHODS We prospectively followed middle-aged 8,640 Japanese men with normal renal function, no proteinuria, no diabetes, and no use of antihypertensive medications at entry. Data on alcohol consumption were gathered by questionnaire. Glomerular hyperfiltration was defined as estimated glomerular filtration rate (eGFR) ≥117 mL/min/1.73 m2, which was the upper 2.5th percentile value of eGFR in the entire cohort. RESULTS During 46,186 person-years of follow-up, 330 men developed glomerular hyperfiltration. In a multivariate model, for men who consumed alcohol on 1-3 days per week, alcohol consumption of ≥69.1 g ethanol/drinking day was significantly associated with the risk of glomerular hyperfiltration (hazard ratio [HR] 2.37; 95% confidence interval [CI], 1.18-4.74) compared with non-drinkers. For those who consumed alcohol on 4-7 days per week, higher alcohol consumption per drinking day was associated with a higher risk of glomerular hyperfiltration: the HRs for alcohol consumption of 46.1-69.0, and ≥69.1 g ethanol/drinking day were 1.55 (95% CI, 1.01-2.38), and 1.78 (95% CI, 1.02-3.12), respectively. CONCLUSION For high drinking frequency per week, more alcohol intake per drinking day was associated with an increased risk of glomerular hyperfiltration, while for low drinking frequency per week, only very high alcohol intake per drinking day was associated with an increased risk of glomerular hyperfiltration in middle-aged Japanese men.
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Affiliation(s)
- Mikiko Shibata
- Preventive Medicine and Environmental Health, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Kyoko Kogawa Sato
- Preventive Medicine and Environmental Health, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Hideo Koh
- Preventive Medicine and Environmental Health, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Izumi Shibata
- Preventive Medicine and Environmental Health, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Kaori Okamura
- Preventive Medicine and Environmental Health, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yuka Takeuchi
- Preventive Medicine and Environmental Health, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Keiko Oue
- Health Administration Center (Kansai region), Nippon Telegraph and Telephone West Corporation, Osaka, Japan
| | - Michio Morimoto
- Health Administration Center (Kansai region), Nippon Telegraph and Telephone West Corporation, Osaka, Japan
| | - Tomoshige Hayashi
- Preventive Medicine and Environmental Health, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
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Liu M, Yang Y, Liu Y, Peng X, Hou Y, Zhang X, Sun H, Shan C. Serum branched chain amino acids: an effective indicator of diabetic kidney disease. Front Endocrinol (Lausanne) 2023; 14:1269633. [PMID: 38089615 PMCID: PMC10711269 DOI: 10.3389/fendo.2023.1269633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 10/13/2023] [Indexed: 12/18/2023] Open
Abstract
Introduction In recent years, there has been a growing association between elevated circulating levels of branched-chain amino acids (BCAA) and diabetes mellitus. However, the relationship between serum BCAA levels and diabetic kidney disease (DKD) remains ambiguous. This study aims to investigate serum BCAA levels in DKD patients at various stages and assess the correlation between BCAA and clinical characteristics. Materials and methods We enrolled patients with type 2 diabetes mellitus (T2DM) who were admitted to our hospital and categorized them into three groups based on different DKD stages: normal proteinuria, microproteinuria, and macroalbuminuria groups. Forty healthy volunteers were included as the control group, and we measured serum BCAA concentrations using liquid chromatography-mass spectrometry (LC-MS). Subsequently, we conducted correlation and regression analyses to assess the associations between BCAA and clinical indicators. Results Serum BCAA levels were significantly elevated in T2DM patients compared to healthy controls. However, these levels exhibited a gradual decline with the progression of DKD. Furthermore, after adjusting for age, gender, and disease duration, we observed an independent association between serum albumin, urinary transferrin, and urinary microalbumin with BCAA. Discussion Our findings suggest a noteworthy decline in serum BCAA levels alongside the advancement of DKD. Additionally, serum BCAA exhibits an independent correlation with renal function indicators. These observations point to the possibility that serum BCAA concentrations in individuals with T2DM hold promise as a crucial predictor for both the initiation and progression of DKD.
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Affiliation(s)
- Min Liu
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, China
| | - Yanhui Yang
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, China
| | - Yajin Liu
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, China
| | - Xiaoyue Peng
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, China
| | - Yi Hou
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, China
| | - Xuejiao Zhang
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, China
| | - Haipeng Sun
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, China
| | - Chunyan Shan
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, China
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Yan M, Li W, Wei R, Li S, Liu Y, Huang Y, Zhang Y, Lu Z, Lu Q. Identification of pyroptosis-related genes and potential drugs in diabetic nephropathy. J Transl Med 2023; 21:490. [PMID: 37480090 PMCID: PMC10360355 DOI: 10.1186/s12967-023-04350-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: 04/28/2023] [Accepted: 07/11/2023] [Indexed: 07/23/2023] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is one of the serious microvascular complications of diabetes mellitus (DM). A growing body of research has demonstrated that the inflammatory state plays a critical role in the incidence and development of DN. Pyroptosis is a new way of programmed cell death, which has the particularity of natural immune inflammation. The inhibition of inflammatory cytokine expression and regulation of pathways related to pyroptosis may be a novel strategy for DN treatment. The aim of this study is to identify pyroptosis-related genes and potential drugs for DN. METHODS DN differentially expressed pyroptosis-related genes were identified via bioinformatic analysis Gene Expression Omnibus (GEO) dataset GSE96804. Dataset GSE30528 and GSE142025 were downloaded to verify pyroptosis-related differentially expressed genes (DEGs). Least absolute shrinkage and selection operator (LASSO) regression analysis was used to construct a pyroptosis-related gene predictive model. A consensus clustering analysis was performed to identify pyroptosis-related DN subtypes. Subsequently, Gene Set Variation Analysis (GSVA), Gene Ontology (GO) function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted to explore the differences between DN clusters. A protein-protein interaction (PPI) network was used to select hub genes and DGIdb database was utilized to screen potential therapeutic drugs/compounds targeting hub genes. RESULTS A total of 24 differentially expressed pyroptosis-related genes were identified in DN. A 16 gene predictive model was conducted via LASSO regression analysis. According to the expression level of these 16 genes, DN cases were divided into two subtypes, and the subtypes are mainly associated with inflammation, activation of immune response and cell metabolism. In addition, we identified 10 hub genes among these subtypes, and predicted 65 potential DN therapeutics that target key genes. CONCLUSION We identified two pyroptosis-related DN clusters and 65 potential therapeutical agents/compounds for DN, which might shed a light on the treatment of DN.
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Affiliation(s)
- Meng Yan
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China.
- Department of Clinical Pharmacology, School of Pharmacy, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
| | - Wenwen Li
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Rui Wei
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Shuwen Li
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Yan Liu
- Jiangsu Key Laboratory of Brain Disease and Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Genetic Foundation and Clinical Application, Department of Genetics, Xuzhou Engineering Research Center of Medical Genetics and Transformation, Xuzhou Medical University, Xuzhou, China
| | - Yuqian Huang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Yunye Zhang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Zihao Lu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Qian Lu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China.
- Department of Clinical Pharmacology, School of Pharmacy, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
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Bae J, Lee BW. Significance of Diabetic Kidney Disease Biomarkers in Predicting Metabolic-Associated Fatty Liver Disease. Biomedicines 2023; 11:1928. [PMID: 37509567 PMCID: PMC10377561 DOI: 10.3390/biomedicines11071928] [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: 06/15/2023] [Revised: 07/04/2023] [Accepted: 07/06/2023] [Indexed: 07/30/2023] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD) and diabetic kidney disease (DKD) share various pathophysiological factors, and epidemiological evidence suggests that these two diseases are associated. Albuminuria and the estimated glomerular filtration rate, which are conventional biomarkers of DKD, are reportedly associated with the risk or severity of MAFLD. Recently, novel DKD biomarkers reflecting renal tubular injury have been introduced to complement conventional DKD markers. In this article, we looked at previous studies that showed an association between MAFLD and DKD, and also reviewed the significance of DKD biomarkers as predictive risk factors for MAFLD.
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Affiliation(s)
- Jaehyun Bae
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Catholic Kwandong University College of Medicine, International St. Mary's Hospital, Incheon 22711, Republic of Korea
| | - Byung-Wan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
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Katsimardou A, Patoulias D, Zografou I, Tegou Z, Imprialos K, Stavropoulos K, Toumpourleka M, Karagiannis A, Petidis K, Doumas M. The Associations between Kidney Function and Sexual Dysfunction among Males and Females with Type 2 Diabetes Mellitus. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:medicina59050969. [PMID: 37241201 DOI: 10.3390/medicina59050969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/04/2023] [Accepted: 05/16/2023] [Indexed: 05/28/2023]
Abstract
Background and Objectives: Diabetic kidney disease (DKD), expressed either as albuminuria, low estimated glomerular filtration rate (eGFR) or both, and sexual dysfunction (SD), are common complications among type 2 diabetes mellitus (T2DM) patients. This study aims to assess whether an association exists between DKD and SD, erectile dysfunction (ED) or female sexual dysfunction (FSD) in a T2DM population. Materials and Methods: A cross-sectional study was designed and conducted among T2DM patients. The presence of SD was assessed using the International Index of Erectile Function and the Female Sexual Function Index questionnaires for males and females, respectively, and patients were evaluated for DKD. Results: Overall, 80 patients, 50 males and 30 females, agreed to participate. Sexual dysfunction was present in 80% of the study population. Among the participants, 45% had DKD, 38.5% had albuminuria and/or proteinuria and 24.1% had an eGFR below 60 mL/min/1.73 m2. The eGFR was associated with SD, ED and FSD. Moreover, SD and ED were proven as significant determinants for lower eGFR values in multiple linear regression analyses. DKD was associated with lower lubrication scores and eGFR was associated with lower desire, arousal, lubrication and total scores; however, the multivariate linear regression analyses showed no significant associations between them. Older age resulted in significantly lower arousal, lubrication, orgasm and total FSFI scores. Conclusions: SD is commonly encountered in older T2DM patients and DKD affects almost half of them. The eGFR has been significantly associated with SD, ED and FSD, while SD and ED were proven to be significant determinants for the eGFR levels.
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Affiliation(s)
- Alexandra Katsimardou
- 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital "Hippokration", 54642 Thessaloniki, Greece
| | - Dimitrios Patoulias
- 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital "Hippokration", 54642 Thessaloniki, Greece
| | - Ioanna Zografou
- 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital "Hippokration", 54642 Thessaloniki, Greece
| | - Zoi Tegou
- 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital "Hippokration", 54642 Thessaloniki, Greece
| | - Konstantinos Imprialos
- 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital "Hippokration", 54642 Thessaloniki, Greece
| | - Konstantinos Stavropoulos
- 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital "Hippokration", 54642 Thessaloniki, Greece
| | - Maria Toumpourleka
- 3rd Department of Cardiology, Aristotle University of Thessaloniki, General Hospital "Hippokration", 54642 Thessaloniki, Greece
| | - Asterios Karagiannis
- 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital "Hippokration", 54642 Thessaloniki, Greece
| | - Konstantinos Petidis
- 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital "Hippokration", 54642 Thessaloniki, Greece
| | - Michael Doumas
- 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital "Hippokration", 54642 Thessaloniki, Greece
- Veterans Affairs Medical Center, George Washington University, Washington, DC 20422, USA
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Development of a metabolite-based deep learning algorithm for clinical precise diagnosis of the progression of diabetic kidney disease. Biomed Signal Process Control 2023. [DOI: 10.1016/j.bspc.2023.104625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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Scilletta S, Di Marco M, Miano N, Filippello A, Di Mauro S, Scamporrino A, Musmeci M, Coppolino G, Di Giacomo Barbagallo F, Bosco G, Scicali R, Piro S, Purrello F, Di Pino A. Update on Diabetic Kidney Disease (DKD): Focus on Non-Albuminuric DKD and Cardiovascular Risk. Biomolecules 2023; 13:biom13050752. [PMID: 37238622 DOI: 10.3390/biom13050752] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 04/25/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023] Open
Abstract
The classic description of diabetic kidney disease (DKD) involves progressive stages of glomerular hyperfiltration, microalbuminuria, proteinuria, and a decline in the estimated glomerular filtration rate (eGFR), leading to dialysis. In recent years, this concept has been increasingly challenged as evidence suggests that DKD presents more heterogeneously. Large studies have revealed that eGFR decline may also occur independently from the development of albuminuria. This concept led to the identification of a new DKD phenotype: non-albuminuric DKD (eGFR < 60 mL/min/1.73 m2, absence of albuminuria), whose pathogenesis is still unknown. However, various hypotheses have been formulated, the most likely of which is the acute kidney injury-to-chronic kidney disease (CKD) transition, with prevalent tubular, rather than glomerular, damage (typically described in albuminuric DKD). Moreover, it is still debated which phenotype is associated with a higher cardiovascular risk, due to contrasting results available in the literature. Finally, much evidence has accumulated on the various classes of drugs with beneficial effects on DKD; however, there is a lack of studies analyzing the different effects of drugs on the various phenotypes of DKD. For this reason, there are still no specific guidelines for therapy in one phenotype rather than the other, generically referring to diabetic patients with CKD.
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Affiliation(s)
- Sabrina Scilletta
- Department of Clinical and Experimental Medicine, University of Catania, 95122 Catania, Italy
| | - Maurizio Di Marco
- Department of Clinical and Experimental Medicine, University of Catania, 95122 Catania, Italy
| | - Nicoletta Miano
- Department of Clinical and Experimental Medicine, University of Catania, 95122 Catania, Italy
| | - Agnese Filippello
- Department of Clinical and Experimental Medicine, University of Catania, 95122 Catania, Italy
| | - Stefania Di Mauro
- Department of Clinical and Experimental Medicine, University of Catania, 95122 Catania, Italy
| | - Alessandra Scamporrino
- Department of Clinical and Experimental Medicine, University of Catania, 95122 Catania, Italy
| | - Marco Musmeci
- Department of Clinical and Experimental Medicine, University of Catania, 95122 Catania, Italy
| | - Giuseppe Coppolino
- Department of Clinical and Experimental Medicine, University of Catania, 95122 Catania, Italy
| | | | - Giosiana Bosco
- Department of Clinical and Experimental Medicine, University of Catania, 95122 Catania, Italy
| | - Roberto Scicali
- Department of Clinical and Experimental Medicine, University of Catania, 95122 Catania, Italy
| | - Salvatore Piro
- Department of Clinical and Experimental Medicine, University of Catania, 95122 Catania, Italy
| | - Francesco Purrello
- Department of Clinical and Experimental Medicine, University of Catania, 95122 Catania, Italy
| | - Antonino Di Pino
- Department of Clinical and Experimental Medicine, University of Catania, 95122 Catania, Italy
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11
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Kamli-Salino SEJ, Brown PAJ, Haschler TN, Liang L, Feliers D, Wilson HM, Delibegovic M. Induction of experimental diabetes and diabetic nephropathy using anomer-equilibrated streptozotocin in male C57Bl/6J mice. Biochem Biophys Res Commun 2023; 650:109-116. [PMID: 36774688 DOI: 10.1016/j.bbrc.2023.01.089] [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: 01/10/2023] [Revised: 01/20/2023] [Accepted: 01/28/2023] [Indexed: 02/08/2023]
Abstract
Streptozotocin (STZ) is widely used to induce experimental diabetes in murine models. However, the ability to induce diabetic nephropathy (DN) is more challenging. It has been recommended to inject STZ at multiple low doses within 15 min after dissolution due to its alleged instability. However, some studies suggest that STZ is stable for days due to equilibration of its two anomers (α and β), 90 min after dissolution, and that this anomer-equilibrated STZ leads to higher survival rates and persistent hyperglycaemia with minimal weight loss. The aim of this study was to determine an optimal dose of anomer-equilibrated STZ to induce kidney tubular damage and compare it with the more commonly used freshly prepared STZ. We hypothesised that anomer-equilibrated STZ provides a better, reproducible experimental model of diabetes-induced kidney damage with improved animal welfare. Body measurements, fasting glycaemia, insulinemia and renal histology were assessed in male C57Bl/6J at two and six months of age treated with fresh (50 mg/kg) or anomer-equilibrated (dose ranging 35-50 mg/kg) STZ or vehicle control. We demonstrated a dose-dependent effect of anomer-equilibrated STZ on the induction of hypo-insulinaemia and hyperglycaemia, as well as body weight in two-month-old mice. Interestingly, in six-month-old mice STZ leads to body weight loss, independently of STZ preparation mode. Anomer-equilibrated STZ provoked moderate to severe kidney tubule structural damage, resulting in significant kidney hypertrophy, whereas freshly prepared STZ only caused mild alterations. In conclusion, our study proposes that anomer-equilibrated STZ provides a robust murine model of diabetes and early-stage diabetic nephropathy, which can be used to test therapeutic approaches to treat and/or prevent renal damage.
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Affiliation(s)
- Sarah E J Kamli-Salino
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK; Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Aberdeen, UK.
| | - Paul A J Brown
- Department of Pathology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, Scotland, UK
| | - Timo N Haschler
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal & Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Lihuan Liang
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal & Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Denis Feliers
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal & Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Heather M Wilson
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK; Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Aberdeen, UK
| | - Mirela Delibegovic
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK; Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Aberdeen, UK
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12
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He P, Li H, Zhang Z, Zhang Y, Lin T, Song Y, Liu L, Liang M, Nie J, Wang B, Huo Y, Hou FF, Xu X, Qin X. Change in the Estimated Glomerular Filtration Rate Over Time and Risk of First Stroke in Hypertensive Patients. J Epidemiol 2023; 33:142-149. [PMID: 35400712 PMCID: PMC9909174 DOI: 10.2188/jea.je20210242] [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] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND The association between changes in estimated glomerular filtration rate (eGFR) over time and the risk of stroke remains inconclusive. We aimed to evaluate the relation of eGFR change during the China Stroke Primary Prevention Trial (CSPPT) with the risk of first stroke during the subsequent post-trial follow-up. METHODS A total of 11,742 hypertensive participants with two eGFR measurements (median measure interval, 4.4; interquartile range, 4.2-4.6 years) and without a history of stroke from the CSPPT were included in this analysis. RESULTS Over a median post-trial follow-up of 4.4 years, 729 first strokes were identified, of which 635 were ischemic, 88 were hemorrhagic, and 6 were uncertain types of strokes. Compared with those with 1 to <2% per year increase in eGFR (with the lowest stroke risk), those with an increase in eGFR of ≥4% per year had significantly increased risks of first stroke (adjusted hazard ratio [HR] 1.96; 95% confidence interval [CI], 1.10-3.50) and first ischemic stroke (adjusted HR 2.14; 95% CI, 1.17-3.90). Similarly, those with a decline in eGFR of ≥5% per year also had significantly increased first stroke (adjusted HR 2.13; 95% CI, 1.37-3.31) and first ischemic stroke (adjusted HR 1.89; 95% CI, 1.19-3.02) risk. However, there was no significant association between eGFR change and first hemorrhagic stroke. A similar result was found when the change in eGFR was quantified as an absolute annual change. CONCLUSION In Chinese hypertensive patients, both the decline and increase of eGFR levels were independently associated with the risks of first stroke or first ischemic stroke.
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Affiliation(s)
- Panpan He
- Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory
| | - Huan Li
- Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory
| | - Zhuxian Zhang
- Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory
| | - Yuanyuan Zhang
- Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory
| | - Tengfei Lin
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University
| | - Yun Song
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University.,Institute of Biomedicine, Anhui Medical University
| | - Lishun Liu
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University
| | - Min Liang
- Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory
| | - Jing Nie
- Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory
| | - Binyan Wang
- Institute of Biomedicine, Anhui Medical University.,Shenzhen Evergreen Medical Institute
| | - Yong Huo
- Department of Cardiology, Peking University First Hospital
| | - Fan Fan Hou
- Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory
| | - Xiping Xu
- Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University
| | - Xianhui Qin
- Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory
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13
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Genetic Polymorphism in Angiotensinogen and Its Association with Cardiometabolic Diseases. Metabolites 2022; 12:metabo12121291. [PMID: 36557328 PMCID: PMC9785123 DOI: 10.3390/metabo12121291] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 11/30/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Angiotensinogen (AGT) is one of the most significant enzymes of the renin-angiotensin-aldosterone system (RAAS) which is involved in the regulation and maintenance of blood pressure. AGT is involved in the production of angiotensin I which is then converted into angiotensin II that leads to renal homeostasis. However, various genetic polymorphisms in AGT have been discovered in recent times which have shown an association with various diseases. Genetic polymorphism increases the level of circulating AGT in blood which exaggerates the effects produced by AGT. The associated diseases occur due to various effects produced by increased AGT levels. Several cardiovascular diseases including myocardial infarction, coronary heart disease, heart failure, hypertrophy, etc. are associated with AGT polymorphism. Other diseases such as depression, obesity, diabetic nephropathy, pre-eclampsia, and liver injury are also associated with some variants of AGT gene. The most common variants of AGT polymorphism are M235T and T174M. The two variants are associated with many diseases. Some other variants such as G-217A, A-6G, A-20C and G-152A, are also present but they are not as significant as that of M235T and T174M variants. These variants increase the level of circulating AGT and are associated with prevalence of different diseases. These diseases occur through various pathological pathways, but the initial reason remains the same, i.e., increased level of AGT in the blood. In this article, we have majorly focused on how genetic polymorphism of different variants of AGT gene is associated with the prevalence of different diseases.
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14
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Mok H, Al-Jumaily A, Lu J. Plasmacytoma Variant Translocation 1 (PVT1) Gene as a Potential Novel Target for the Treatment of Diabetic Nephropathy. Biomedicines 2022; 10:2711. [PMID: 36359234 PMCID: PMC9687488 DOI: 10.3390/biomedicines10112711] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/08/2022] [Accepted: 10/21/2022] [Indexed: 01/29/2024] Open
Abstract
Introduction: Diabetic nephropathy (DN), a severe microvascular complication in patients with diabetes, is clinically characterized by progressive decline in glomerular filtration rate (GFR). DN is the most common cause of end-stage renal disease (ESRD), and has a consistently high mortality rate. Despite the fact that the prevalence of DN is increasing worldwide, the molecular mechanism underlying the pathogenesis of DN is not fully understood. Previous studies indicated PVT1 as a key determinant of ESRD as well as a mediator of extracellular matrix (ECM) accumulation in vitro. More investigations into the role of PVT1 in DN development are needed. Objectives: To study the effect of PVT1 silencing on progression of DN in diabetic male C57BL/6 mice at early, intermediate and relatively advanced ages. Methods: Diabetic mice were treated with either scramble-siRNA (DM + siRNA (scramble)) or PVT1-siRNA (DM + siRNA (PVT1)), whereas the control mice were normal mice without siRNA injection (Control). Blood, urine and kidney were collected at the age of 9 (young), 16 (middle-aged) or 24 (old) weeks old. Kidney function, histology and molecular gene expression were evaluated. Results: Our findings showed that silencing of PVT1 reduced kidney hypertrophy, proteinuria (UAE, UACR, UPE, UPCR), serum creatinine, serum TGF-β1, serum insulin decline, glomerular and mesangial areas, and increased creatinine clearance in diabetic mice to levels closer to the age-matched controls. Also, silencing of PVT1 markedly suppressed the upregulation of PAI-1, TGF-β1, FN1, COL4A1, and downregulation of BMP7. Conclusion: Silencing of PVT1 ameliorates DN in terms of kidney function and histology in diabetic mice. The renoprotection is attributed to the reduction in ECM accumulation, TGF-β1 elevation and insulin decline. PVT1 is suggested to play an important role in ECM accumulation which makes it a possible target for the treatment of DN.
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Affiliation(s)
- Helen Mok
- School of Science, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland 1142, New Zealand
| | - Ahmed Al-Jumaily
- School of Engineering, Computer and Mathematical Sciences, Faculty of Design and Creative Technologies, Auckland University of Technology, Auckland 1142, New Zealand
| | - Jun Lu
- School of Science, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland 1142, New Zealand
- Maurice Wilkins Centre for Molecular Discovery, Auckland 1142, New Zealand
- College of Food Science and Technology, Nanchang University, Nanchang 330031, China
- College of Food Engineering and Nutrition Sciences, Shaanxi Normal University, Xi’an 710119, China
- School of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai 201418, China
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15
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Liu G, Ren X, Li Y, Li H. Midkine promotes kidney injury in diabetic kidney disease by increasing neutrophil extracellular traps formation. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:693. [PMID: 35845498 PMCID: PMC9279803 DOI: 10.21037/atm-22-2382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 05/31/2022] [Indexed: 12/02/2022]
Abstract
Background We sought to investigate the role of midkine (MK) on neutrophil extracellular trap formation (NETosis) and diabetic kidney disease (DKD) progression. Methods The expression of MK and NETosis in the renal tissue of DKD patients was examined by immunohistochemistry and immunofluorescence, respectively. Neutrophils extracted from mouse bone marrow by gradient centrifugation were treated with MK for this in-vitro study. A mouse diabetes model was induced by a high-fat diet combined with an intraperitoneal injection of streptozocin (STZ). Antisense oligodeoxynucleotide (ODN) for MK inhibition was administered via tail vein injection. Results We found that the expression of MK was increased in the kidney tissue of DKD patients. Additionally, a greater number of neutrophils were primed toward NETosis in the kidney tissue of DKD patients, which was manifested by the increased expression of NETosis biomarkers citrullinated histone H3 (H3Cit) and myeloperoxidase (MPO). In vitro, MK treatment concentration-dependently increased neutrophil proliferation (cell counting kit-8). Further, western blot and enzyme-linked immunosorbent assays showed that MK (100 ng/mL) significantly promoted NETosis and the expression of inflammatory factors interleukin (IL)-1 and IL-6 secretion in high-glucose treated neutrophils. In the mouse diabetes model, MK promoted the pathological damage and fibrosis of kidney tissue, as demonstrated by the reversion of the pathological damage and fibrosis by the MK antisense ODN [diabetes mellitus (DM) + MK – ODN] treatment. Additionally, the inhibition of MK reduced the formation of NETs. Conclusions MK promotes DKD progression by increasing NETosis.
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Affiliation(s)
- Gaohong Liu
- Department of Nephrology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.,Department of Nephrology, Shanxi Provincial People's Hospital, Taiyuan, China
| | - Xiaojun Ren
- Department of Nephrology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Yousong Li
- Department of Traditional Chinese Medicine, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Han Li
- Department of Nephrology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
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16
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Kim HJ, Kim SS, Song SH. Glomerular filtration rate as a kidney outcome of diabetic kidney disease: a focus on new antidiabetic drugs. Korean J Intern Med 2022; 37:502-519. [PMID: 35368179 PMCID: PMC9082447 DOI: 10.3904/kjim.2021.515] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 02/17/2022] [Indexed: 11/27/2022] Open
Abstract
Diabetes has reached epidemic proportions, both in Korea and worldwide and is associated with an increased risk of chronic kidney disease and kidney failure (KF). The natural course of kidney function among people with diabetes (especially type 2 diabetes) may be complex in real-world situations. Strong evidence from observational data and clinical trials has demonstrated a consistent association between decreased estimated glomerular filtration rate (eGFR) and subsequent development of hard renal endpoints (such as KF or renal death). The disadvantage of hard renal endpoints is that they require a long follow-up duration. In addition, there are many patients with diabetes whose renal function declines without the appearance of albuminuria, measurement of the eGFR is emphasized. Many studies have used GFR-related parameters, such as its change, decline, or slope, as clinical endpoints for kidney disease progression. In this respect, understanding the trends in GFR changes could be crucial for developing clinical management strategies for the prevention of diabetic complications. This review focuses on the clinical implication of the eGFR-related parameters that have been used so far in diabetic kidney disease. We also discuss the use of recently developed new antidiabetic drugs for kidney protection, with a focus on the GFR as clinical endpoints.
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Affiliation(s)
- Hyo Jin Kim
- Division of Nephrology, Department of Internal Medicine, Pusan National University Hospital, Busan,
Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan,
Korea
| | - Sang Soo Kim
- Biomedical Research Institute, Pusan National University Hospital, Busan,
Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Hospital, Busan,
Korea
| | - Sang Heon Song
- Division of Nephrology, Department of Internal Medicine, Pusan National University Hospital, Busan,
Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan,
Korea
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17
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Granata A, Pesce F, Iacoviello M, Anzaldi M, Amico F, Catalano M, Leonardi G, Gatta C, Costanza G, Corrao S, Gesualdo L. SGLT2 Inhibitors: A Broad Impact Therapeutic Option for the Nephrologist. FRONTIERS IN NEPHROLOGY 2022; 2:867075. [PMID: 37674992 PMCID: PMC10479658 DOI: 10.3389/fneph.2022.867075] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/17/2022] [Indexed: 09/08/2023]
Abstract
Since their introduction as antidiabetic drugs, SGLT2 inhibitors (SGLT2i) have come a long way, proving to be beneficial on cardiovascular and renal outcomes independently of diabetes status. The benefits go far beyond glycemic control, and both the cardio- and nephroprotection are underpinned by diverse mechanisms. From the activation of tubule glomerular feedback and the consequent reduction in hyperfiltration to the improvement of hypoxia and oxidative stress in the renal cortex, SGLT2i have also been shown to inhibit hepcidin and limit podocyte damage. Likewise, they improve cardiac metabolism and bioenergetics, and reduce necrosis and cardiac fibrosis and the production of adipokines, cytokines, and epicardial adipose tissue mass. In terms of outcomes, the efficacy has been demonstrated on blood pressure control, BMI, albuminuria, stroke, heart disease, and mortality rate due to cardiovascular events. Patients with chronic kidney disease and proteinuria, with or without diabetes, treated with some SGLT2i have a reduced risk of progression. The analysis of subgroups of individuals with specific diseases such as IgA nephropathy has confirmed this solid effect on renal outcomes. Given these overarching activities on such a broad pathophysiological background and the favorable safety profile that goes with the use of SGLT2i, it is now certain that they are changing our approach to clinical interventions for important outcomes with an impressive impact.
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Affiliation(s)
- Antonio Granata
- Nephrology and Dialysis Unit, “Cannizzaro” Emergency Hospital, Catania, Italy
| | - Francesco Pesce
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Massimo Iacoviello
- Cardiology Unit, Department of Medical and Surgical Science, University of Foggia, Foggia, Italy
| | | | - Francesco Amico
- Cardiology Unit, “Cannizzaro” Emergency Hospital, Catania, Italy
| | - Maria Catalano
- Cardiology Unit, “Cannizzaro” Emergency Hospital, Catania, Italy
| | - Giuseppe Leonardi
- Cardiology Unit, Azienda Ospedaliera Universitaria (A.O.U.) “Policlinico-San Marco”, Catania, Italy
| | - Carmela Gatta
- Internal Medicine Unit, Azienda Ospedaliera Universitaria (A.O.U.) “Policlinico-San Marco”, Catania, Italy
| | - Giusy Costanza
- Nephrology and Dialysis, “Vittorio Emanuele” Hospital, Gela, Italy
| | - Salvatore Corrao
- Department of Internal Medicine, “Azienda di Rilievo Nazionale ed Alta Specializzazione (ARNAS) Civico, Di Cristina e Benfratelli”, Palermo, Italy
| | - Loreto Gesualdo
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
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18
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Low-grade proteinuria and atherosclerotic cardiovascular disease: A transition study of patients with diabetic kidney disease. PLoS One 2022; 17:e0264568. [PMID: 35213636 PMCID: PMC8880428 DOI: 10.1371/journal.pone.0264568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 02/11/2022] [Indexed: 11/21/2022] Open
Abstract
Diabetic kidney disease (DKD) is heterogeneous in terms of proteinuria. Patients with DKD who present with low-grade proteinuria are more likely to have nephrosclerosis rather than traditional diabetic nephropathy. The amount of proteinuria might reflect the underlying pathology of renal failure and influence the prognosis after dialysis initiation. Clinical implications of proteinuria at the start of dialysis have not been confirmed, while greater proteinuria is associated with higher risk of cardiovascular disease (CVD) in the predialysis stages of chronic kidney disease. We performed a retrospective multicenter cohort study enrolling incident hemodialysis patients with diabetes. Patients were stratified using proteinuria quartiles. We examined the association of proteinuria quartiles with types of subsequent CVD. Among the enrolled 361 patients, the estimated mean glomerular filtration rate and proteinuria was 5.4 mL/min/1.73 m2 and 6.3 g/gCr, respectively. Lower quartile of proteinuria (cut-offs: 3.0, 5.4, and 8.8 g/gCr) was significantly associated with male, older age, and history of atherosclerotic CVD including coronary artery disease, peripheral arterial disease, and cerebral infarction (Ptrend<0.05). Kidney size was smaller in patients with lower levels of proteinuria. Patients with higher levels of proteinuria were more likely to have proliferative diabetic retinopathy (Ptrend<0.05). Multivariate competing risk analysis revealed that the first quartile of proteinuria was associated with a greater risk of atherosclerotic CVD than the third quartile (subhazard ratio [95% confidence interval]: 2.04 [1.00–4.14]). This association was attenuated after additional adjustments for history of atherosclerotic CVD. Furthermore, patients with lower quartiles of proteinuria were more likely to die of atherosclerotic CVD than those with non-atherosclerotic CVD (Ptrend = 0.01). Diabetic patients with lower proteinuria at dialysis initiation were characterized by severer macroangiopathy, as shown by a more atrophic kidney and higher prevalence of past atherosclerotic CVD. Hence, they are at a high risk of developing atherosclerotic CVD.
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19
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Deng L, Li W, Xu G. Update on pathogenesis and diagnosis flow of normoalbuminuric diabetes with renal insufficiency. Eur J Med Res 2021; 26:144. [PMID: 34895352 PMCID: PMC8665546 DOI: 10.1186/s40001-021-00612-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 11/16/2021] [Indexed: 12/11/2022] Open
Abstract
In recent decades, the prevalence of diabetic kidney disease has remained stable and appears to be a wide heterogeneity. Normoalbuminuric diabetes with renal insufficiency, which is characterized by a decline in the glomerular filtration rate in the absence of albuminuria, has been identified as an albuminuria-independent phenotype of diabetic kidney disease. Epidemiological data demonstrate that normoalbuminuric phenotype is prevalent. Compared to albuminuric phenotype, normoalbuminuric phenotype has distinct clinical characteristics and a wide heterogeneity of pathological features. Currently, the pathogenesis of normoalbuminuric phenotype remains unclear. Additionally, the flow of diagnosing normoalbuminuric phenotype is not perfect. In this article, we review the latest studies addressing the epidemiology, clinical characteristics, and pathology of normoalbuminuric phenotype. Based on the studies of clinical features and renal histopathologic changes, we attempt to propose an underlying pathogenesis model and a flow chart for diagnosing normoalbuminuric phenotype.
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Affiliation(s)
- Le Deng
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Donghu District, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Wenjie Li
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Donghu District, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Gaosi Xu
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Donghu District, Nanchang, Jiangxi, 330006, People's Republic of China.
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20
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Middleton TL, Chadban S, Molyneaux L, D'Souza M, Constantino MI, Yue DK, McGill M, Wu T, Twigg SM, Wong J. Young adult onset type 2 diabetes versus type 1 diabetes: Progression to and survival on renal replacement therapy. J Diabetes Complications 2021; 35:108023. [PMID: 34481713 DOI: 10.1016/j.jdiacomp.2021.108023] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 08/12/2021] [Accepted: 08/12/2021] [Indexed: 11/21/2022]
Abstract
BACKGROUND Young-onset type 2 diabetes is an aggressive disease characterized by development of diabetic complications, including nephropathy, early in the disease course. However, within the cohort of young-onset type 1 and type 2 diabetes there are limited comparative data regarding progression to ESKD requiring renal replacement therapy or renal-related death (RRT/RRD). METHODS Probabilistic linkage of data from the RPAH Diabetes Centre, National Death Index and Australian and New Zealand Dialysis and Transplant Registry was undertaken. Cumulative Incidence Competing Risk and Cox Proportional Hazards Modelling approaches were utilized to examine progression to ESKD in young-onset type 1 and type 2 diabetes (age of diagnosis 15-35 years). FINDINGS Unadjusted incidence rates (95% CI) of RRT/RRD in young-onset type 1 and type 2 diabetes were 3.1 (2.3-4.0) and 4.6 (3.7-5.7) per 1000 person years respectively. After adjustment for gender, ethnicity and duration of diabetes, the HR (95% CI) of RRT/RRD in young-onset type 2 diabetes was 2.0 (1.4-2.9). The HR remained higher after further adjustment for first available cholesterol, HbA1c and systolic blood pressure but not BMI. For those who progressed to RRT, prognosis was similar irrespective of diabetes type; cumulative incidence of mortality was 40% in both young-onset type 1 and type 2 diabetes after 6 years of dialysis. INTERPRETATION Progression to RRT/RRD is greater in young-onset type 2 diabetes than in young-onset type 1 diabetes. The increased progression is associated with increased BMI. However, once ESKD is reached, individuals with young-onset type 1 and type 2 diabetes do equally poorly.
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Affiliation(s)
- Timothy L Middleton
- Diabetes Centre, RPA Hospital, Camperdown, NSW 2050, Australia; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia.
| | - Steven Chadban
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia; Department of Renal Medicine, RPA Hospital, Camperdown, NSW 2050, Australia; Australia and New Zealand Dialysis and Transplant Registry, Adelaide, SA 5001, Australia
| | - Lynda Molyneaux
- Diabetes Centre, RPA Hospital, Camperdown, NSW 2050, Australia
| | - Mario D'Souza
- Sydney Local Health District Clinical Research Centre, Camperdown, NSW 2050, Australia
| | - Maria I Constantino
- Diabetes Centre, RPA Hospital, Camperdown, NSW 2050, Australia; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia
| | - Dennis K Yue
- Diabetes Centre, RPA Hospital, Camperdown, NSW 2050, Australia; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia
| | - Margaret McGill
- Diabetes Centre, RPA Hospital, Camperdown, NSW 2050, Australia; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia
| | - Ted Wu
- Diabetes Centre, RPA Hospital, Camperdown, NSW 2050, Australia
| | - Stephen M Twigg
- Diabetes Centre, RPA Hospital, Camperdown, NSW 2050, Australia; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia
| | - Jencia Wong
- Diabetes Centre, RPA Hospital, Camperdown, NSW 2050, Australia; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia
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21
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Hong X, Huang L, Zhang Y, Shen X, Weng S, Zeng F, Zhao F, Yan S. Stronger Association of Albuminuria with the Risk of Vascular Complications than Estimated Glomerular Filtration Rate in Type 2 Diabetes. Kidney Blood Press Res 2021; 46:550-562. [PMID: 34428770 DOI: 10.1159/000515163] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 02/10/2021] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Albuminuria is a risk factor for macro- and microvascular complications of type 2 diabetes (T2D).With an increasing trend of normoalbuminuria, however, of the 2 predictors - estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) - which one is a better predictor of vascular complications of T2D is not clear. OBJECTIVE This study aimed to compare the impacts of albuminuria and eGFR on patients with T2D associated with micro- and macrovascular complications. METHODS This retrospective study recruited 4,715 patients with T2D and grouped them based on the values of UACR (high UACR: ≥30 mg/g, low UACR: <30 mg/g) and eGFR (mL/[min × 1.73 m2]) (G1: eGFR ≥ 90; G2: eGFR = 60-89; G3-5: eGFR < 60) from April 2008 to November 2018. Logistic regression analysis was carried out for risk factors in patients with diabetic retinopathy (DR), diabetic peripheral neuropathy (DPN), peripheral arterial disease (PAD), left ventricular remodeling, diastolic disorders, and carotid atherosclerotic plaque in 6 different groups: low UACR + G1 (control group), low UACR + G2, low UACR + G3-5, high UACR + G1, high UACR + G2, and high UACR + G3-5. Patients were grouped according to the change in the UACR value (UACR-decreased group: ≤-30%, UACR-stable group: -30 to 30%, and UACR-increased group ≥30%), eGFR value (eGFR-decreased group: >3%, and eGFR-stable group: ≤3%) and followed up. RESULTS Compared with the control group, patients with higher albuminuria and lower eGFR had higher adjusted odds ratio (OR) trends of complications, especially in the high UACR + G3-5 group. The OR of 2.010, 3.444, 1.633, 2.742, and 3.014 were obtained for DR, DPN, PAD, left ventricular remodeling, and diastolic disorders, respectively. No statistically significant difference was found in the risk of complications within each one of 2 phenotypes, regardless of the change in the eGFR. After grouping by eGFR, the regression analysis of the urinary protein level in each stage revealed that a majority of complications had a statistically significant difference, except for DR and PAD in the high UACR + G3-5 group. DR in the follow-up study had a higher risk in the UACR-stable/increased group than the UACR-decreased group (UACR stable: OR = 2.568; 95% confidence interval (CI): 1.128-5.849; p = 0.025; UACR increased: OR = 2.489; 95% CI: 1.140-5.433; p = 0.022). CONCLUSION UACR is a more predictive risk factor for diabetic complications compared with a reduced eGFR.
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Affiliation(s)
- Xinyu Hong
- Department of Endocrinology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Province Clinical Research Center for Metabolic Diseases, Fuzhou, China.,Diabetes Research Institute of Fujian Province, Fuzhou, China.,Metabolic Diseases Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Lingning Huang
- Department of Endocrinology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Province Clinical Research Center for Metabolic Diseases, Fuzhou, China.,Diabetes Research Institute of Fujian Province, Fuzhou, China.,Metabolic Diseases Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Yongze Zhang
- Department of Endocrinology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Province Clinical Research Center for Metabolic Diseases, Fuzhou, China.,Diabetes Research Institute of Fujian Province, Fuzhou, China.,Metabolic Diseases Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Ximei Shen
- Department of Endocrinology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Province Clinical Research Center for Metabolic Diseases, Fuzhou, China.,Diabetes Research Institute of Fujian Province, Fuzhou, China.,Metabolic Diseases Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Suiyan Weng
- Department of Endocrinology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Province Clinical Research Center for Metabolic Diseases, Fuzhou, China.,Diabetes Research Institute of Fujian Province, Fuzhou, China.,Metabolic Diseases Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Feihui Zeng
- Department of Endocrinology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Province Clinical Research Center for Metabolic Diseases, Fuzhou, China.,Diabetes Research Institute of Fujian Province, Fuzhou, China.,Metabolic Diseases Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Fengying Zhao
- Department of Endocrinology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Province Clinical Research Center for Metabolic Diseases, Fuzhou, China.,Diabetes Research Institute of Fujian Province, Fuzhou, China.,Metabolic Diseases Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Sunjie Yan
- Department of Endocrinology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Province Clinical Research Center for Metabolic Diseases, Fuzhou, China.,Diabetes Research Institute of Fujian Province, Fuzhou, China.,Metabolic Diseases Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
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22
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Takahashi Y, Suzuki Y, Dohmae S, Murayama H. Intermittent Diabetes Care and the Risk of Diabetic Kidney Disease in Patients with Type 2 Diabetes Mellitus: Findings from Data Analysis of Local Governmental Claims Data. JMA J 2021; 4:284-288. [PMID: 34414325 PMCID: PMC8355720 DOI: 10.31662/jmaj.2020-0106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 03/17/2021] [Indexed: 11/22/2022] Open
Affiliation(s)
- Yuta Takahashi
- Health and Welfare Bureau, City of Yokohama, Kanagawa, Japan
| | - Yukio Suzuki
- Medical Care Bureau, City of Yokohama, Kanagawa, Japan.,Department of Obstetrics and Gynecology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
| | - Soshi Dohmae
- Medical Care Bureau, City of Yokohama, Kanagawa, Japan
| | - Hiroshi Murayama
- Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
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23
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Cao Y, Yang Z, Chen Y, Jiang S, Wu Z, Ding B, Yang Y, Jin Z, Tang H. An Overview of the Posttranslational Modifications and Related Molecular Mechanisms in Diabetic Nephropathy. Front Cell Dev Biol 2021; 9:630401. [PMID: 34124032 PMCID: PMC8193943 DOI: 10.3389/fcell.2021.630401] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 04/12/2021] [Indexed: 01/14/2023] Open
Abstract
Diabetic nephropathy (DN), a common diabetic microvascular complication, is characterized by its complex pathogenesis, higher risk of mortality, and the lack of effective diagnosis and treatment methods. Many studies focus on the diagnosis and treatment of diabetes mellitus (DM) and have reported that the pathophysiology of DN is very complex, involving many molecules and abnormal cellular activities. Given the respective pivotal roles of NF-κB, Nrf2, and TGF-β in inflammation, oxidative stress, and fibrosis during DN, we first review the effect of posttranslational modifications on these vital molecules in DN. Then, we describe the relationship between these molecules and related abnormal cellular activities in DN. Finally, we discuss some potential directions for DN treatment and diagnosis. The information reviewed here may be significant in the design of further studies to identify valuable therapeutic targets for DN.
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Affiliation(s)
- Yu Cao
- Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, The Air Force Medical University, Xi'an, China
| | - Zhao Yang
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ying Chen
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shuai Jiang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Zhen Wu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Baoping Ding
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Yang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Zhenxiao Jin
- Department of Cardiovascular Surgery, Xijing Hospital, The Air Force Medical University, Xi'an, China
| | - Haifeng Tang
- Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, The Air Force Medical University, Xi'an, China
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24
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Fu H, Chu D, Geng X. Downregulation of miR-17 suppresses TGF-β1-mediated renal fibrosis through targeting Smad7. Mol Cell Biochem 2021; 476:3051-3064. [PMID: 33797702 DOI: 10.1007/s11010-021-04140-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 03/13/2021] [Indexed: 12/15/2022]
Abstract
MiR-17 is found upregulated in diabetic mice; however, its effect(s) on renal fibrosis of diabetic nephropathy remain(s) unknown. This study aimed to explore the mechanism underlying the downregulation of miR-17 in renal fibrosis of diabetic nephropathy (DN). Patients with diabetes mellitus (DM) and DN and normal healthy individual controls, mice (db/db, db/m), and human mesangial cells (HMCs) and human proximal tubule epithelial cells (HK-2) were used as research subjects in the study. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to measure the expression of miR-17 in the serum samples, renal tissues and cells. Acid-Schiff (PAS) and Masson staining experiments were performed to detect glomerular mesangial matrix and collagen deposition. Levels of fibrosis-related proteins (E-Cadherin (E-cad), vimentin, fibronectin and collagen I) were measured by Western blot (WB). The target gene of miR-17 was predicted by TargetScan 7.2 and confirmed by dual-luciferase reporter analysis. The study found that miR-17 expression was elevated in the serums of DN patients as well as in the serums and kidney tissues of db/db mice. db/db mice showed a severe renal fibrosis condition. The levels of E-cad in db/db mice, HMC and HK-2 cells were increased by downregulating miR-17 expression, while expressions of vimentin, fibronectin and collagen I were reduced. Smad7 was predicted to be the target gene of miR-17, and its expression was promoted by downregulation of miR-17. Moreover, the reduced Smad7 expression could inhibit the expressions of fibrosis-related proteins, which, however, can be ameliorated by the downregulation of miR-17. In addition, downregulation of miR-17 could suppress renal fibrosis mediated by TGF-β1 through targeting Smad7, which might be a clinical therapeutic target for patients with DN.
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Affiliation(s)
- Haixia Fu
- Department of Nephrology, Qingdao Municipal Hospital, No.5, Middle Donghai Road, Qingdao, 266071, Shandong, China
| | - Debo Chu
- Department of Nephrology, Qingdao Haici Med Ctr, Qingdao, China
| | - Xiuli Geng
- Department of Emergency, Qingdao Municipal Hospital, Qingdao, China.
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25
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Bae J, Won YJ, Lee BW. Non-Albumin Proteinuria (NAP) as a Complementary Marker for Diabetic Kidney Disease (DKD). Life (Basel) 2021; 11:life11030224. [PMID: 33802211 PMCID: PMC7998887 DOI: 10.3390/life11030224] [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: 02/16/2021] [Revised: 03/06/2021] [Accepted: 03/06/2021] [Indexed: 11/16/2022] Open
Abstract
Diabetic kidney disease (DKD) is one of the most common forms of chronic kidney disease. Its pathogenic mechanism is complex, and it can affect entire structures of the kidney. However, conventional approaches to early stage DKD have focused on changes to the glomerulus. Current standard screening tools for DKD, albuminuria, and estimated glomerular filtration rate are insufficient to reflect early tubular injury. Therefore, many tubular biomarkers have been suggested. Non-albumin proteinuria (NAP) contains a wide range of tubular biomarkers and is convenient to measure. We reviewed the clinical meanings of NAP and its significance as a marker for early stage DKD.
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Affiliation(s)
- Jaehyun Bae
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Catholic Kwandong University College of Medicine, International St. Mary’s Hospital, Incheon KS006, Korea; (J.B.); (Y.J.W.)
| | - Young Jun Won
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Catholic Kwandong University College of Medicine, International St. Mary’s Hospital, Incheon KS006, Korea; (J.B.); (Y.J.W.)
| | - Byung-Wan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul KS013, Korea
- Correspondence:
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26
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Roles of mTOR in Diabetic Kidney Disease. Antioxidants (Basel) 2021; 10:antiox10020321. [PMID: 33671526 PMCID: PMC7926630 DOI: 10.3390/antiox10020321] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/13/2021] [Accepted: 02/18/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and the number of patients affected is increasing worldwide. Thus, there is a need to establish a new treatment for DKD to improve the renal prognosis of diabetic patients. Recently, it has shown that intracellular metabolic abnormalities are involved in the pathogenesis of DKD. In particular, the activity of mechanistic target of rapamycin complex 1 (mTORC1), a nutrient-sensing signaling molecule, is hyperactivated in various organs of diabetic patients, which suggests the involvement of excessive mTORC1 activation in the pathogenesis of diabetes. In DKD, hyperactivated mTORC1 may be involved in the pathogenesis of podocyte damage, which causes proteinuria, and tubular cell injury that decreases renal function. Therefore, elucidating the role of mTORC1 in DKD and developing new therapeutic agents that suppress mTORC1 hyperactivity may shed new light on DKD treatments in the future.
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27
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Lv L, Zhou Y, Chen X, Gong L, Wu J, Luo W, Shen Y, Han S, Hu J, Wang Y, Li Q, Wang Z. Relationship Between the TyG Index and Diabetic Kidney Disease in Patients with Type-2 Diabetes Mellitus. Diabetes Metab Syndr Obes 2021; 14:3299-3306. [PMID: 34305401 PMCID: PMC8296712 DOI: 10.2147/dmso.s318255] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/02/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Diabetic kidney disease (DKD) lacks a simple and relatively accurate predictor. The Triglyceride-Glucose (TyG) Index is a proxy of insulin resistance, but the association between the TyG Index and DKD is less certain. We investigated if the TyG Index can predict DKD onset effectively. MATERIALS AND METHODS Cross-sectional and longitudinal analyses were undertaken. In total, 1432 type-2 diabetes mellitus (T2DM) patients were included in the cross-sectional analysis. The TyG Index (calculated by ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]) was split into three tertiles. Associations of the TyG Index with microalbuminuria and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 were calculated. Longitudinally, 424 patients without DKD at baseline were followed up for 21 (range, 12-24) months. The main outcome was DKD prevalence as defined with eGFR <60 mL/min/1.73 m2 or continuously increased urinary microalbuminuria: creatinine ratio (>30 mg/mL) over 3 months. Cox regression was used to analyze the association between the TyG Index at baseline and DKD. Receiver operating characteristics curve (ROC) analysis was used to assess the sensitivity and specificity of the TyG Index in predicting DKD. RESULTS In cross-sectional analysis, patients with a higher TyG Index had a higher risk of microalbuminuria (OR = 2.342, 95% CI = 1.744-3.144, p < 0.001), and eGFR <60 mL/min/1.73 m2 (1.696, 95% CI =1.096-2.625, p = 0.018). Longitudinally, 94 of 424 participants developed DKD. After confounder adjustment, patients in the high tertile of the TyG Index at baseline had a greater risk to developing DKD than those in the low tertile (HR = 1.727, 95% CI = 1.042-2.863, p = 0.034). The area under the ROC curve was 0.69 (0.63-0.76). CONCLUSION The TyG Index is a potential predictor for DKD in T2DM patients. CLINICAL TRIAL Clinical Trials identification number = NCT03692884.
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Affiliation(s)
- Liangjing Lv
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Yangmei Zhou
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Xiangjun Chen
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Lilin Gong
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Jinshan Wu
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Wenjin Luo
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Yan Shen
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Shichao Han
- Department of Statistics, University of California, Berkeley, CA, USA
| | - Jinbo Hu
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Yue Wang
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Qifu Li
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Zhihong Wang
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
- Correspondence: Zhihong Wang Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Yuzhong District, Chongqing, People’s Republic of ChinaTel/Fax +86-023-89011552 Email
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Giorgino F, Vora J, Fenici P, Solini A. Renoprotection with SGLT2 inhibitors in type 2 diabetes over a spectrum of cardiovascular and renal risk. Cardiovasc Diabetol 2020; 19:196. [PMID: 33222693 PMCID: PMC7680601 DOI: 10.1186/s12933-020-01163-9] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 10/29/2020] [Indexed: 02/07/2023] Open
Abstract
Approximately half of all patients with type 2 diabetes (T2D) develop a certain degree of renal impairment. In many of them, chronic kidney disease (CKD) progresses over time, eventually leading to end-stage kidney disease (ESKD) requiring dialysis and conveying a substantially increased risk of cardiovascular morbidity and mortality. Even with widespread use of renin-angiotensin system blockers and tight glycemic control, a substantial residual risk of nephropathy progression remains. Recent cardiovascular outcomes trials investigating sodium-glucose cotransporter 2 (SGLT2) inhibitors have suggested that these therapies have renoprotective effects distinct from their glucose-lowering action, including the potential to reduce the rates of ESKD and acute kidney injury. Although patients in most cardiovascular outcomes trials had higher prevalence of existing cardiovascular disease compared with those normally seen in clinical practice, the proportion of patients with renal impairment was similar to that observed in a real-world context. Patient cardiovascular risk profiles did not relevantly impact the renoprotective benefits observed in these studies. Benefits were observed in patients across a spectrum of renal risk, but were evident also in those without renal damage, suggesting a role for SGLT2 inhibition in the prevention of CKD in people with T2D. In addition, recent studies such as CREDENCE and DAPA-CKD offer a greater insight into the renoprotective effects of SGLT2 inhibitors in patients with moderate-to-severe CKD. This review outlines the evidence that SGLT2 inhibitors may prevent the development of CKD and prevent and delay the worsening of CKD in people with T2D at different levels of renal risk.
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Affiliation(s)
- Francesco Giorgino
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Policlinico, Piazza Giulio Cesare, 11, 70124, Bari, Italy.
| | - Jiten Vora
- Diabetes and Endocrinology, University of Liverpool, Liverpool, UK
| | | | - Anna Solini
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy
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Vitale M, Haxhi J, Cirrito T, Pugliese G. Renal protection with glucagon-like peptide-1 receptor agonists. Curr Opin Pharmacol 2020; 54:91-101. [PMID: 33027748 DOI: 10.1016/j.coph.2020.08.018] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/31/2020] [Accepted: 08/31/2020] [Indexed: 02/07/2023]
Abstract
There is an unmet need for renoprotective drugs for more pronounced reduction of albuminuria beyond that provided by renin-angiotensin system (RAS) blockers and for effective slowdown of eGFR decline independent of albuminuria. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have proven effective in reducing prespecified secondary composite kidney outcomes in cardiovascular outcome trials. However, GLP-1 RAs showed a prevailing anti-albuminuric effect, additional to that of RAS blockers, and a non-significant risk reduction in worsening of kidney function, at variance with sodium-glucose cotransporter 2 inhibitors. Mechanisms underlying renal protection with GLP-1 RAs are porly understood. Though treatment with GLP-1 RAs resulted in better glycaemic, blood pressure and body weight control versus placebo, correction for on-trial changes in these parameters did not significantly affect results. Anti-inflammatory/anti-oxidant effects via intracellular signalling through protein kinase A, natriuretic effect via inhibition of sodium-hydrogen exchanger 3 and reduction of hyperfiltration have been proposed as direct renoprotective effects.
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Affiliation(s)
- Martina Vitale
- Department of Clinical and Molecular Medicine, "La Sapienza" University, and Endocrine and Metabolic Unit, Sant'Andrea University Hospital, Rome, Italy
| | - Jonida Haxhi
- Department of Clinical and Molecular Medicine, "La Sapienza" University, and Endocrine and Metabolic Unit, Sant'Andrea University Hospital, Rome, Italy
| | - Tiziana Cirrito
- Department of Clinical and Molecular Medicine, "La Sapienza" University, and Endocrine and Metabolic Unit, Sant'Andrea University Hospital, Rome, Italy
| | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, and Endocrine and Metabolic Unit, Sant'Andrea University Hospital, Rome, Italy.
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30
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Faselis C, Katsimardou A, Imprialos K, Deligkaris P, Kallistratos M, Dimitriadis K. Microvascular Complications of Type 2 Diabetes Mellitus. Curr Vasc Pharmacol 2020; 18:117-124. [PMID: 31057114 DOI: 10.2174/1570161117666190502103733] [Citation(s) in RCA: 269] [Impact Index Per Article: 53.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 11/06/2018] [Accepted: 11/12/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is a chronic, non communicable, multisystem disease that has reached epidemic proportions. Chronic exposure to hyperglycaemia affects the microvasculature, eventually leading to diabetic nephropathy, retinopathy and neuropathy with high impact on the quality of life and overall life expectancy. Sexual dysfunction is an often-overlooked microvascular complication of T2DM, with a complex pathogenesis originating from endothelial dysfunction. OBJECTIVE The purpose of this review is to present current definitions, epidemiological data and risk factors for diabetic retinopathy, nephropathy, neuropathy and sexual dysfunction. We also describe the clinical and laboratory evaluation that is mandatory for the diagnosis of these conditions. METHODS A comprehensive review of the literature was performed to identify data from clinical studies for the prevalence, risk factors and diagnostic methods of microvascular complications of T2DM. RESULTS Diabetic nephropathy and retinopathy affect approximately 25% of patients with T2DM; diabetic neuropathy is encountered in almost 50% of the diabetic population, while the prevalence of erectile dysfunction ranges from 35-90% in diabetic men. The duration of T2DM along with glycemic, blood pressure and lipid control are common risk factors for the development of these complications. Criteria for the diagnosis of these conditions are well established, but exclusion of other causes is mandatory. CONCLUSION Early detection of microvascular complications associated with T2DM is important, as early intervention leads to better outcomes. However, this requires awareness of their definition, prevalence and diagnostic modalities.
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Affiliation(s)
| | - Alexandra Katsimardou
- 2nd Prop Department of Internal Medicine, Aristotle University, Thessaloniki, Greece
| | | | - Pavlos Deligkaris
- Department of Neurology, Hippokrateion Hospital, Thessaloniki, Greece
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31
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Transcriptomic Analysis Reveals the Protection of Astragaloside IV against Diabetic Nephropathy by Modulating Inflammation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:9542165. [PMID: 32855769 PMCID: PMC7443226 DOI: 10.1155/2020/9542165] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 06/23/2020] [Accepted: 07/15/2020] [Indexed: 12/17/2022]
Abstract
Background Diabetic nephropathy (DN) is one of the leading causes of end-stage kidney disease. Recently, there is no specific drug available to block the kidney damage. Astragaloside IV (AS-IV) is a major active component of Astragalus membranaceus (Fisch) Bge and has been demonstrated to benefit the kidney functions. This study explores the potential pharmacological action of AS-IV in DN of rats. Methods Male Sprague-Dawley rats were fed with high-fat diet and injected with streptozotocin to induce diabetes. The diabetic rats were randomized and treated with vehicle or AS-IV (80 mg/kg) daily by gavage for 12 weeks as the DN or AS-IV group, respectively. The normal control rats were fed with normal chow and injected with vehicles (n = 8 per group). These rats were monitored for diabetes- and kidney function-related measures. The expression profiles of gene mRNA transcripts in the kidney tissues were analyzed by RNA-seq and quantitative RT-PCR. The levels of advanced glycation end products (AGEs), IL-1β, and IL-18 in the serum samples and kidney tissues were quantified by ELISA. The levels of collagen IV (COL-4) and fibronectin (FN) expression in kidney tissues were examined by immunohistochemistry and Western blot. Results In comparison with the DN group, AS-IV treatment significantly reduced blood glucose levels, food and water consumption, 24 h urine, renal index values, 24 h urine total proteins, blood urea nitrogen (BUN) levels, and creatinine clearance rates (CCR), accompanied by minimizing the DN-induced early kidney damages, fibrosis, and microstructural changes. Furthermore, AS-IV treatment significantly modulated the DN-altered gene transcription profiles in the kidney of rats, particularly for inflammation-related genes, including the nucleotide-binding oligomerization domain-like receptor signaling, which was validated by quantitative RT-PCR. AS-IV treatment significantly decreased the levels of serum and kidney AGEs, IL-1β, and IL-18 expression and fibrosis indexes in the kidney of rats. Conclusion AS-IV treatment ameliorated the severity of DN by inhibiting inflammation-related gene expression in the kidney of rats.
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Menini S, Iacobini C, Vitale M, Pugliese G. The Inflammasome in Chronic Complications of Diabetes and Related Metabolic Disorders. Cells 2020; 9:E1812. [PMID: 32751658 PMCID: PMC7464565 DOI: 10.3390/cells9081812] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/24/2020] [Accepted: 07/28/2020] [Indexed: 12/14/2022] Open
Abstract
Diabetes mellitus (DM) ranks seventh as a cause of death worldwide. Chronic complications, including cardiovascular, renal, and eye disease, as well as DM-associated non-alcoholic fatty liver disease (NAFLD) account for most of the morbidity and premature mortality in DM. Despite continuous improvements in the management of late complications of DM, significant gaps remain. Therefore, searching for additional strategies to prevent these serious DM-related conditions is of the utmost importance. DM is characterized by a state of low-grade chronic inflammation, which is critical in the progression of complications. Recent clinical trials indicate that targeting the prototypic pro-inflammatory cytokine interleukin-1β (IL-1 β) improves the outcomes of cardiovascular disease, which is the first cause of death in DM patients. Together with IL-18, IL-1β is processed and secreted by the inflammasomes, a class of multiprotein complexes that coordinate inflammatory responses. Several DM-related metabolic factors, including reactive oxygen species, glyco/lipoxidation end products, and cholesterol crystals, have been involved in the pathogenesis of diabetic kidney disease, and diabetic retinopathy, and in the promoting effect of DM on the onset and progression of atherosclerosis and NAFLD. These metabolic factors are also well-established danger signals capable of regulating inflammasome activity. In addition to presenting the current state of knowledge, this review discusses how the mechanistic understanding of inflammasome regulation by metabolic danger signals may hopefully lead to novel therapeutic strategies targeting inflammation for a more effective treatment of diabetic complications.
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Affiliation(s)
| | | | | | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy; (S.M.); (C.I.); (M.V.)
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Saiki A, Otsuki M, Tamada D, Kitamura T, Shimomura I, Kurihara I, Ichijo T, Takeda Y, Katabami T, Tsuiki M, Wada N, Yanase T, Ogawa Y, Kawashima J, Sone M, Inagaki N, Yoshimoto T, Okamoto R, Takahashi K, Kobayashi H, Tamura K, Kamemura K, Yamamoto K, Izawa S, Kakutani M, Yamada M, Tanabe A, Naruse M. Diabetes Mellitus Itself Increases Cardio-Cerebrovascular Risk and Renal Complications in Primary Aldosteronism. J Clin Endocrinol Metab 2020; 105:5818654. [PMID: 32275055 DOI: 10.1210/clinem/dgaa177] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 04/09/2020] [Indexed: 11/19/2022]
Abstract
CONTEXT The prevalence of diabetes mellitus (DM) in patients with primary aldosteronism (PA) is higher than in those with essential hypertension and the general population. Although DM is a common major risk factor for cardio-cerebrovascular (CCV) diseases and renal complications, details of its effects in PA have not been demonstrated. OBJECTIVE The aim of this study was to determine the effects of coexistent DM on the risk of CCV events and progression of renal complications in PA patients. DESIGN A multi-institutional, cross-sectional study was conducted. PATIENTS AND METHODS PA patients experienced between January 2006 and October 2016 and with available data of CCV events and DM were enrolled from the Japan PA registry of the Japan Primary Aldosteronism Study/Japan Rare Intractable Adrenal Diseases Study (n = 2524). CCV events and renal complications were compared between a DM group and a non-DM group by logistic and liner-regression analysis. RESULTS DM significantly increased the odds ratio (OR) of CCV events (OR 1.59, 95% CI: 1.05-2.41) and that of proteinuria (OR 2.25, 95% CI: 1.59-3.16). DM correlated significantly with declines in estimated glomerular filtration rate (β = .05, P = .02). CONCLUSIONS This the first report to demonstrate the presence of DM as an independent risk factor for CCV events and renal complications, even in PA patients. Management of DM should be considered in addition to the specific treatment of PA.
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Affiliation(s)
- Aya Saiki
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Michio Otsuki
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Daisuke Tamada
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tetsuhiro Kitamura
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Isao Kurihara
- Department of Endocrinology, Metabolism, and Nephrology, School of Medicine, Keio University, Tokyo, Japan
| | - Takamasa Ichijo
- Department of Endocrinology and Metabolism, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan
| | - Yoshiyu Takeda
- Department of Internal Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Takuyuki Katabami
- Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine, Yokohama City Seibu Hospital, Yokohama, Japan
| | - Mika Tsuiki
- Department of Endocrinology and Metabolism, National Hospital Organization Kyoto Medical Center, Kyoto, Japan
| | - Norio Wada
- Department of Diabetes and Endocrinology, Sapporo City General Hospital, Sapporo, Japan
| | | | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Junji Kawashima
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Masakatsu Sone
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takanobu Yoshimoto
- Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Diabetes and Endocrinology, Tokyo Metropolitan Hiroo Hospital Tokyo, Tokyo, Japan
| | - Ryuji Okamoto
- Department of Cardiology, Mie University Hospital, Mie, Japan
| | | | - Hiroki Kobayashi
- Division of Nephrology, Hypertension, and Endocrinology, Nihon University School of Medicine, Tokyo, Japan
| | - Kouichi Tamura
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | | | - Koichi Yamamoto
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Shoichiro Izawa
- Department of Endocrinology and Metabolism, Tottori University Hospital, Yonago, Japan
| | - Miki Kakutani
- Division of Diabetes, Endocrinology, and Clinical Immunology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Masanobu Yamada
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Akiyo Tanabe
- Division of Endocrinology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Mitsuhide Naruse
- Department of Endocrinology and Metabolism, National Hospital Organization Kyoto Medical Center, Kyoto, Japan
- Endocrine Center, Ijinkai Takeda General Hospital, Kyoto, Japan
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Punicalagin Protects Diabetic Nephropathy by Inhibiting Pyroptosis Based on TXNIP/NLRP3 Pathway. Nutrients 2020; 12:nu12051516. [PMID: 32456088 PMCID: PMC7284711 DOI: 10.3390/nu12051516] [Citation(s) in RCA: 111] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/14/2020] [Accepted: 05/20/2020] [Indexed: 12/11/2022] Open
Abstract
Diabetic nephropathy is a diabetic complication caused by chronic inflammation. As the primary polyphenol in pomegranate, punicalagin is believed to have significant anti-inflammatory properties. In this study, we established a mice model for diabetes induced by high-fat diet (HFD)/ streptozotocin (STZ) to verify the protective effect of punicalagin in vivo. The results show that the blood urea nitrogen (BUN), serum creatinine (CREA), and the urine albumin to creatinine ratio (UACR) were significantly decreased in diabetic mice after punicalagin intervention, and the symptoms of glomerular interstitial hyperplasia and glomerular hypertrophy were alleviated. Pyroptosis is an essential manner of programmed cell death in the inflammatory response; the expression of pyroptosis-related proteins such as interleukin-1 (IL-1β), cysteinyl aspartate-specific protease-1 (caspase-1), gasdermin D (GSDMD), and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing protein 3 (NLRP3) was decreased in our study, which proved that the administration of punicalagin for eight weeks can significantly inhibit pyroptosis in mice. In addition, punicalagin reduced high glucose-mediated protein expressions of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) and alleviated mitochondria damage. Low expression of NOX4 inhibits the dissociation of thioredoxin (Trx) and thioredoxin-interacting protein (TXNIP) and the suppression of NLRP3 inflammasome activation. To summarize, our study provided evidence that punicalagin can alleviate diabetic nephropathy, and the effect is associated with downregulating the expression of NOX4, inhibiting TXNIP/NLRP3 pathway-mediated pyroptosis, suggesting its therapeutic implications for complications of diabetes.
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Yokoyama H, Araki SI, Kawai K, Yamazaki K, Shirabe SI, Sugimoto H, Minami M, Miyazawa I, Maegawa H. The Prognosis of Patients With Type 2 Diabetes and Nonalbuminuric Diabetic Kidney Disease Is Not Always Poor: Implication of the Effects of Coexisting Macrovascular Complications (JDDM 54). Diabetes Care 2020; 43:1102-1110. [PMID: 32144168 DOI: 10.2337/dc19-2049] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 01/25/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Nonalbuminuric diabetic kidney disease (DKD) has become the prevailing phenotype in patients with type 2 diabetes. However, it remains unclear whether its prognosis is poorer than that of other DKD phenotypes. RESEARCH DESIGN AND METHODS A total of 2,953 Japanese patients with type 2 diabetes and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, enrolled in an observational cohort study in 2004, were followed until 2015. On the basis of albuminuria (>30 mg/g creatinine) and reduced eGFR (<60 mL/min/1.73 m2) at baseline, participants were classified into the four DKD phenotypes-no-DKD, albuminuric DKD without reduced eGFR, nonalbuminuric DKD with reduced eGFR, and albuminuric DKD with reduced eGFR-to assess the risks of mortality, cardiovascular disease (CVD), and renal function decline. RESULTS During the mean follow-up of 9.7 years, 113 patients died and 263 developed CVD. In nonalbuminuric DKD, the risks of death or CVD were not higher than those in no-DKD (adjusted hazard ratio 1.02 [95% CI 0.66, 1.60]) and the annual decline in eGFR was slower than in other DKD phenotypes. The risks of death or CVD in nonalbuminuric DKD without prior CVD were similar to those in no-DKD without prior CVD, whereas the risks in nonalbuminuric DKD with prior CVD as well as other DKD phenotypes were higher. CONCLUSIONS Nonalbuminuric DKD did not have a higher risk of mortality, CVD events, or renal function decline than the other DKD phenotypes. In nonalbuminuric DKD, the presence of macrovascular complications may be a main determinant of prognosis rather than the renal phenotype.
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Affiliation(s)
| | - Shin-Ichi Araki
- Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
| | | | | | | | | | | | - Itsuko Miyazawa
- Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
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Haraguchi R, Kohara Y, Matsubayashi K, Kitazawa R, Kitazawa S. New Insights into the Pathogenesis of Diabetic Nephropathy: Proximal Renal Tubules Are Primary Target of Oxidative Stress in Diabetic Kidney. Acta Histochem Cytochem 2020; 53:21-31. [PMID: 32410750 PMCID: PMC7212204 DOI: 10.1267/ahc.20008] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 04/09/2020] [Indexed: 12/15/2022] Open
Abstract
Diabetic nephropathy is a major source of end-stage renal failure, affecting about one-third cases of diabetes mellitus. It has long been accepted that diabetic nephropathy is mainly characterized by glomerular defects, while clinical observations have implied that renal tubular damage is closely linked to kidney dysfunction at the early stages of diabetic nephropathy. In this study, we conducted pathohistological analyses focusing on renal tubular lesions in the early-stage diabetic kidney with the use of a streptozotocin (STZ)-induced diabetes mellitus mouse model. The results revealed that histological alterations in renal tubules, shown by a vacuolar nucleic structure, accumulations of PAS-positive substance, and accelerated restoration stress, occur initially without the presence of glomerular lesions in the early-stage diabetic kidney, and that these tubular defects are localized mainly in proximal renal tubules. Moreover, enhanced expression of RAGE, suggesting an aberrant activation of AGEs-RAGE signaling pathway, and accumulation of oxidative modified mitochondria through the impaired autophagy/lysosome system, were also seen in the damaged diabetic proximal renal tubules. Our findings indicate that proximal tubular defects are the initial pathological events increasingly linked to the progression of diabetic nephropathy, and that controlling renal tubular damage could be an effective therapeutic strategy for the clinical treatment of diabetic nephropathy.
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Affiliation(s)
- Ryuma Haraguchi
- Department of Molecular Pathology, Ehime University Graduate School of Medicine
| | - Yukihiro Kohara
- Department of Molecular Pathology, Ehime University Graduate School of Medicine
| | - Kanako Matsubayashi
- Department of Molecular Pathology, Ehime University Graduate School of Medicine
| | - Riko Kitazawa
- Department of Molecular Pathology, Ehime University Graduate School of Medicine
- Department of Diagnostic Pathology, Ehime University Hospital
| | - Sohei Kitazawa
- Department of Molecular Pathology, Ehime University Graduate School of Medicine
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Bae J, Hong N, Lee BW, Kang ES, Cha BS, Lee YH. Comparison of Renal Effects of Ezetimibe-Statin Combination versus Statin Monotherapy: A Propensity-Score-Matched Analysis. J Clin Med 2020; 9:E798. [PMID: 32183405 PMCID: PMC7141215 DOI: 10.3390/jcm9030798] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/09/2020] [Accepted: 03/10/2020] [Indexed: 01/13/2023] Open
Abstract
Neither lowering of blood lipid levels nor treatment with statins definitively improves renal outcomes. Ezetimibe, a non-statin antilipidemic agent, is known to not only decrease blood lipid levels but also reduce inflammatory response and activate autophagy. We evaluated the effect of adding ezetimibe to a statin on renal outcome compared with statin monotherapy by analyzing longitudinal data of 4537 patients treated with simvastatin 20 mg plus ezetimibe 10 mg (S + E) or simvastatin 20 mg alone (S) for more than 180 days. A propensity-score-based process was used to match baseline characteristics, medical history, and estimated glomerular filtration rate (eGFR) between S + E and S groups. Changes in serum creatinine and incidence of renal events, defined as doubling of serum creatinine to ≥1.5 mg/dL or occurrence of end-stage renal disease after the first day of treatment initiation, were compared between the groups. Among 3104 well-matched patients with a median follow-up of 4.2 years, the S + E group showed a significantly lower risk of renal events than the S group (hazard ratio 0.58; 95% CI 0.35-0.95, P = 0.032). In addition, the S + E group tended to preserve renal function compared with the S group throughout follow-up, as assessed by serum creatinine changes (P-values for time-group interactions <0.001). These data support the beneficial effects on renal function when combining ezetimibe with a statin.
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Affiliation(s)
- Jaehyun Bae
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (J.B.); (N.H.); (B.-W.L.); (E.S.K.); (B.-S.C.)
| | - Namki Hong
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (J.B.); (N.H.); (B.-W.L.); (E.S.K.); (B.-S.C.)
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Byung-Wan Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (J.B.); (N.H.); (B.-W.L.); (E.S.K.); (B.-S.C.)
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Eun Seok Kang
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (J.B.); (N.H.); (B.-W.L.); (E.S.K.); (B.-S.C.)
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Bong-Soo Cha
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (J.B.); (N.H.); (B.-W.L.); (E.S.K.); (B.-S.C.)
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Yong-ho Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (J.B.); (N.H.); (B.-W.L.); (E.S.K.); (B.-S.C.)
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul 03722, Korea
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Pugliese G, Penno G, Natali A, Barutta F, Di Paolo S, Reboldi G, Gesualdo L, De Nicola L. Diabetic kidney disease: new clinical and therapeutic issues. Joint position statement of the Italian Diabetes Society and the Italian Society of Nephrology on "The natural history of diabetic kidney disease and treatment of hyperglycemia in patients with type 2 diabetes and impaired renal function". J Nephrol 2020; 33:9-35. [PMID: 31576500 PMCID: PMC7007429 DOI: 10.1007/s40620-019-00650-x] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
AIMS This joint document of the Italian Diabetes Society and the Italian Society of Nephrology reviews the natural history of diabetic kidney disease (DKD) in the light of the recent epidemiological literature and provides updated recommendations on anti-hyperglycemic treatment with non-insulin agents. DATA SYNTHESIS Recent epidemiological studies have disclosed a wide heterogeneity of DKD. In addition to the classical albuminuric phenotype, two new albuminuria-independent phenotypes have emerged, i.e., "nonalbuminuric renal impairment" and "progressive renal decline", suggesting that DKD progression toward end-stage kidney disease (ESKD) may occur through two distinct pathways, albuminuric and nonalbuminuric. Several biomarkers have been associated with decline of estimated glomerular filtration rate (eGFR) independent of albuminuria and other clinical variables, thus possibly improving ESKD prediction. However, the pathogenesis and anatomical correlates of these phenotypes are still unclear. Also the management of hyperglycemia in patients with type 2 diabetes and impaired renal function has profoundly changed during the last two decades. New anti-hyperglycemic drugs, which do not cause hypoglycemia and weight gain and, in some cases, seem to provide cardiorenal protection, have become available for treatment of these individuals. In addition, the lowest eGFR safety thresholds for some of the old agents, particularly metformin and insulin secretagogues, have been reconsidered. CONCLUSIONS The heterogeneity in the clinical presentation and course of DKD has important implications for the diagnosis, prognosis, and possibly treatment of this complication. The therapeutic options for patients with type 2 diabetes and impaired renal function have substantially increased, thus allowing a better management of these individuals.
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Affiliation(s)
- Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Rome, Italy.
- Endocrine and Metabolic Unit, Sant'Andrea University Hospital, Rome, Italy.
| | - Giuseppe Penno
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Diabetes Unit, University Hospital, Pisa, Italy
| | - Andrea Natali
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Unit of Internal Medicine, University Hospital, Pisa, Italy
| | - Federica Barutta
- Department of Medical Sciences, University of Turin, Turin, Italy
| | | | | | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, "Aldo Moro" University, Bari, Italy
- Nephrology, Dialysis and Transplantation Unit, "Policlinico" University Hospital, Bari, Italy
| | - Luca De Nicola
- Nephrology and Dialysis Unit, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
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Korbut AI, Klimontov VV, Vinogradov IV, Romanov VV. Risk factors and urinary biomarkers of non-albuminuric and albuminuric chronic kidney disease in patients with type 2 diabetes. World J Diabetes 2019; 10:517-533. [PMID: 31798788 PMCID: PMC6885724 DOI: 10.4239/wjd.v10.i11.517] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 10/06/2019] [Accepted: 10/18/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND A number of recent studies indicate a transformation in the natural course of chronic kidney disease (CKD) in type 2 diabetes (T2D) patients: an increasing prevalence of declined renal function without proceeding to the accompanying elevation of albuminuria. It has been suggested that albuminuric and non-albuminuric CKD patterns could be different in their phenotypes and pathogenic mechanisms.
AIM To identify the risk factors and biomarkers of albuminuric and non-albuminuric patterns of CKD in patients with T2D.
METHODS Three hundred sixty patients with T2D duration ≥ 10 years were included in this observational cross-sectional study. The associations of a panel of demographic and clinical characteristics, complications, comorbidities, and metabolic and hematology parameters with albuminuric and non-albuminuric CKD patterns were analyzed. The urinary excretion of nephrin and podocin, two podocyte-specific markers, and WAP-four-disulfide core domain protein 2 (WFDC-2), a marker of tubulointerstitial fibrosis, was determined by ELISA in comparison with healthy controls.
RESULTS Non-albuminuric CKD was associated with age ≥ 65 years (P = 0.0001), female sex (P = 0.04), diabetes duration ≥ 15 years (P = 0.0009), and the use of diuretics (P = 0.0005). Male sex (P = 0.01), smoking (P = 0.01), waist-to-hip ratio >1.0 (P = 0.01) and hemoglobin A1c (HbA1c) > 8.0% (P = 0.005) were risk factors for elevated albuminuria not accompanied by a decrease in estimated glomerular filtration rate (eGFR). Duration of diabetes ≥ 15 years and the use of calcium channel blockers were risk factors for albuminuria with decreased eGFR (both P = 0.01). In multivariate logistic regression analysis, age, HbA1c, female sex and diuretics were significant predictors for reduced eGFR, while waist-to-hip ratio, HbA1c and male sex were associated with elevated urinary albumin-to-creatinine ratio (UACR). Excretion of nephrin and podocin was increased in patients with albuminuria, regardless of decline in renal function (P < 0.001), correlating positively with UACR. The urinary excretion of WFDC-2 was markedly higher in men than in women (P < 0.000001). Men with T2D demonstrated increased WFDC-2 levels independently of the CKD pattern (all P < 0.05). In T2D women, WFDC-2 excretion was increased in those with reduced renal function (P ≤ 0.01), correlating negatively with eGFR.
CONCLUSION The data provide further evidence that albuminuric and non-albuminuric CKD phenotypes correspond to different pathways of diabetic kidney disease progression.
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Affiliation(s)
- Anton I Korbut
- Laboratory of Endocrinology, Research Institute of Clinical and Experimental Lymphology – Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL – Branch of IC&G SB RAS), Novosibirsk 630060, Russia
| | - Vadim V Klimontov
- Laboratory of Endocrinology, Research Institute of Clinical and Experimental Lymphology – Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL – Branch of IC&G SB RAS), Novosibirsk 630060, Russia
| | - Ilya V Vinogradov
- Clinical Laboratory, “MBU-Technology” ltd., Novosibirsk 630090, Russia
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Pugliese G, Penno G, Natali A, Barutta F, Di Paolo S, Reboldi G, Gesualdo L, De Nicola L. Diabetic kidney disease: New clinical and therapeutic issues. Joint position statement of the Italian Diabetes Society and the Italian Society of Nephrology on "The natural history of diabetic kidney disease and treatment of hyperglycemia in patients with type 2 diabetes and impaired renal function". Nutr Metab Cardiovasc Dis 2019; 29:1127-1150. [PMID: 31586514 DOI: 10.1016/j.numecd.2019.07.017] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 07/18/2019] [Accepted: 07/18/2019] [Indexed: 02/06/2023]
Abstract
AIMS This joint document of the Italian Diabetes Society and the Italian Society of Nephrology reviews the natural history of diabetic kidney disease (DKD) in the light of the recent epidemiological literature and provides updated recommendations on anti-hyperglycemic treatment with non-insulin agents. DATA SYNTHESIS Recent epidemiological studies have disclosed a wide heterogeneity of DKD. In addition to the classical albuminuric phenotype, two new albuminuria-independent phenotypes have emerged, i.e., "nonalbuminuric renal impairment" and "progressive renal decline", suggesting that DKD progression toward end-stage kidney disease (ESKD) may occur through two distinct pathways, albuminuric and nonalbuminuric. Several biomarkers have been associated with decline of estimated glomerular filtration rate (eGFR) independent of albuminuria and other clinical variables, thus possibly improving ESKD prediction. However, the pathogenesis and anatomical correlates of these phenotypes are still unclear. Also the management of hyperglycemia in patients with type 2 diabetes and impaired renal function has profoundly changed during the last two decades. New anti-hyperglycemic drugs, which do not cause hypoglycemia and weight gain and, in some cases, seem to provide cardiorenal protection, have become available for treatment of these individuals. In addition, the lowest eGFR safety thresholds for some of the old agents, particularly metformin and insulin secretagogues, have been reconsidered. CONCLUSIONS The heterogeneity in the clinical presentation and course of DKD has important implications for the diagnosis, prognosis, and possibly treatment of this complication. The therapeutic options for patients with type 2 diabetes and impaired renal function have substantially increased, thus allowing a better management of these individuals.
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Affiliation(s)
- Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Endocrine and Metabolic Unit, Sant'Andrea University Hospital, Rome, Italy.
| | - Giuseppe Penno
- Department of Clinical and Experimental Medicine, University of Pisa, Diabetes Unit, University Hospital, Pisa, Italy
| | - Andrea Natali
- Department of Clinical and Experimental Medicine, University of Pisa, Unit of Internal Medicine, University Hospital, Pisa, Italy
| | - Federica Barutta
- Department of Medical Sciences, University of Turin, Turin, Italy
| | | | | | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, "Aldo Moro" University, Nephrology, Dialysis and Transplantation Unit, "Policlinico" University Hospital, Bari, Italy
| | - Luca De Nicola
- Nephrology and Dialysis Unit, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
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Minutolo R, Gabbai FB, Provenzano M, Chiodini P, Borrelli S, Garofalo C, Sasso FC, Santoro D, Bellizzi V, Conte G, De Nicola L. Cardiorenal prognosis by residual proteinuria level in diabetic chronic kidney disease: pooled analysis of four cohort studies. Nephrol Dial Transplant 2019; 33:1942-1949. [PMID: 29509925 DOI: 10.1093/ndt/gfy032] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 01/21/2018] [Indexed: 11/13/2022] Open
Abstract
Background No study has assessed whether the prognosis of coexisting diabetes mellitus and chronic kidney disease (DM-CKD) is dictated by DM per se or by the extent of proteinuria. Methods In this pooled analysis of four prospective studies in CKD patients treated with drugs inhibiting the renin-angiotensin system, we compared the risk of all-cause mortality, fatal and non-fatal cardiovascular (CV) events and end-stage renal disease (ESRD) between patients with (n = 693) and without diabetes (n = 1481) stratified by proteinuria level (<0.15, 0.15-0.49, 0.5-1 and >1 g/day). Results The group with DM-CKD was older (69 ± 11 versus 65 ± 15 years), had a higher body mass index (29.6 ± 5.4 versus 27.5 ± 4.8 kg/m2) and systolic blood pressure (143 ± 19 versus 136 ± 18 mmHg), prevalent CV disease (48% versus 29%) and lower estimated glomerular filtration rate (34.5 ± 17.9 versus 36.6 ± 19.0 mL/min/1.73 m2). During 4.07 years of follow-up, there were 466 patients with ESRD, 334 deaths and 401 CV events occurred. In the subgroup with urine protein <0.15 g/day (N = 662), the risks of ESRD, CV events and mortality were similar in diabetic and non-diabetic patients. Conversely, in DM-CKD patients, the mortality risk was higher in proteinuric patients {hazard ratio 1.92 [95% confidence interval (CI) 1.25-2.95); 1.99 (1.26-3.15) and 1.98 (1.28-3.06) for proteinuria 0.15-0.49, 0.5-1 and >1 g/day, respectively}, whereas in non-diabetics the mortality risk increased only for proteinuria 0.5-1 g/day [HR 1.60 (95% CI 1.07-2.40)] and >1 g/day [HR 1.69 (95% CI1.20-2.55)]. In both groups, CV risk had a trend similar to that of mortality. ESRD risk increased progressively across strata >0.5 g/day independent of diabetic status. Conclusions We provide evidence that patients with non-proteinuric DM-CKD are not exposed to higher cardiorenal risk. In contrast, in the presence of moderate proteinuria and diabetes per se is associated with a higher risk of mortality and CV events, whereas the entity of abnormal proteinuria modulates ESRD risk independent of diabetes.
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Affiliation(s)
- Roberto Minutolo
- Division of Nephrology, University of Campania, Luigi Vanvitelli, Italy
| | - Francis B Gabbai
- Department of Medicine, VA San Diego Healthcare System and University of California at San Diego Medical School, San Diego, CA, USA
| | | | - Paolo Chiodini
- Medical Statistics Unit, University of Campania, Luigi Vanvitelli, Italy
| | - Silvio Borrelli
- Division of Nephrology, University of Campania, Luigi Vanvitelli, Italy
| | - Carlo Garofalo
- Division of Nephrology, University of Campania, Luigi Vanvitelli, Italy
| | - Ferdinando C Sasso
- Department of Internal and Experimental Medicine "Magrassi - Lanzara", University of Campania, Luigi Vanvitelli, Italy
| | - Domenico Santoro
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Vincenzo Bellizzi
- Nephrology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona", Salerno, Italy
| | - Giuseppe Conte
- Division of Nephrology, University of Campania, Luigi Vanvitelli, Italy
| | - Luca De Nicola
- Division of Nephrology, University of Campania, Luigi Vanvitelli, Italy
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Zheng M, Wang D, Chen L, Chen MN, Wang W, Ye SD. The association between thyroid dysfunction (TD) and diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM). Int J Clin Pract 2019; 73:e13415. [PMID: 31508877 DOI: 10.1111/ijcp.13415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 08/23/2019] [Accepted: 08/31/2019] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Epidemiological studies have identified an association between thyroid dysfunction (TD) and various kidney diseases. In this study, the prevalence of TD in type 2 diabetic mellitus (T2DM) patients with diabetic kidney disease (DKD) was evaluated to analyse the potential association between TD and DKD in T2DM patients. METHODOLOGY A total of 2108 T2DM patients from Anhui Provincial Hospital were recruited in this study. Demographic and clinical characteristics were collected from 834 T2DM patients with DKD and 1274 T2DM patients without DKD (non-DKD). All patients were stratified into a number of groups based on UACR (urine albumin-to-creatinine ratio) or eGFR (estimated glomerular filtration rate): (a) A1: normoalbuminuria (<30), A2: microalbuminuria (30-300) and A3: macroalbuminuria (>300); (b) F1: normal filtration (60-139), F2: hyper filtration (≥140) and F3: low filtration (<60). RESULTS Significant differences were observed between the non-DKD and DKD groups (P < .05) in age, sex ratio, duration, systolic blood pressure, total cholesterol, low density lipoprotein cholesterol, serum creatinine, blood urea nitrogen, free triiodothyronine (FT3), free thyroxine (FT4) and sensitive thyrotropin hormone (sTSH). The macroalbuminuira and low filtration groups had the lowest levels of FT3 and FT4 and the highest level of sTSH, compared with all other groups (P < .0167). The prevalence of subclinical hypothyroidism in the DKD group was significantly higher than that in the non-DKD group (χ2 = 13.92, P < .01). Logistic regression analysis showed that hypothyroidism was associated with increased UACR or reduced eGFR in T2DM patients. Compared with controls, T2DM patients with hypothyroidism exhibited a higher UACR and urinary excretion of transferrin, as well as a lower excretion of urinary Tamm-Horsfall protein (THP) (P < .0167). CONCLUSION Subclinical hypothyroidism is more prevalent in T2DM patients with DKD than in T2DM patients without DKD. Hypothyroidism is associated with albuminuria and decreased eGFR in T2DM patients.
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Affiliation(s)
- Mao Zheng
- Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, P. R. China
| | - Dong Wang
- Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, P. R. China
| | - Li Chen
- Department of Endocrinology, The Third Affiliated Hospital of AHMU (The First People's Hospital of Hefei City), Hefei, P. R. China
| | - Mei-Nan Chen
- Ethics Committee on Clinical Research, The First Affiliated Hospital of USTC, Hefei, P. R. China
| | - Wei Wang
- Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, P. R. China
| | - Shan-Dong Ye
- Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, P. R. China
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Wang H, Lou Y, Ma Y, Shan X. Estimating the glomerular filtration rate and tubular dysfunction in an elderly population with normoalbuminuria in China. Clin Chim Acta 2019; 495:377-381. [DOI: 10.1016/j.cca.2019.05.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 05/07/2019] [Accepted: 05/07/2019] [Indexed: 10/26/2022]
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Afkarian M, Polsky S, Parsa A, Aronson R, Caramori ML, Cherney DZ, Crandall JP, de Boer IH, Elliott TG, Galecki AT, Goldfine AB, Haw JS, Hirsch IB, Karger AB, Lingvay I, Maahs DM, McGill JB, Molitch ME, Perkins BA, Pop-Busui R, Pragnell M, Rosas SE, Rossing P, Senior P, Sigal RJ, Spino C, Tuttle KR, Umpierrez GE, Wallia A, Weinstock RS, Wu C, Mauer M, Doria A. Preventing Early Renal Loss in Diabetes (PERL) Study: A Randomized Double-Blinded Trial of Allopurinol-Rationale, Design, and Baseline Data. Diabetes Care 2019; 42:1454-1463. [PMID: 31186299 PMCID: PMC6647051 DOI: 10.2337/dc19-0342] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 05/08/2019] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Higher serum uric acid (SUA) is associated with diabetic kidney disease (DKD). Preventing Early Renal Loss in Diabetes (PERL) evaluates whether lowering SUA with allopurinol slows glomerular filtration rate (GFR) loss in people with type 1 diabetes (T1D) and mild to moderate DKD. We present the PERL rationale, design, and baseline characteristics. RESEARCH DESIGN AND METHODS This double-blind, placebo-controlled, multicenter trial randomized 530 participants with T1D, estimated GFR (eGFR) of 40-99.9 mL/min/1.73 m2, SUA ≥4.5 m/dL, and micro- to macroalbuminuric DKD or normoalbuminuria with declining kidney function (NDKF) (defined as historical eGFR decline ≥3 mL/min/1.73 m2/year) to allopurinol or placebo. The primary outcome is baseline-adjusted iohexol GFR (iGFR) after 3 years of treatment plus a 2-month washout period. RESULTS Participants are 66% male and 84% white. At baseline, median age was 52 years and diabetes duration was 35 years, 93% of participants had hypertension, and 90% were treated with renin-angiotensin system inhibitors (median blood pressure 127/71 mmHg). Median HbA1c was 8%, SUA 5.9 mg/dL, iGFR 68 mL/min/1.73 m2, and historical eGFR slope -3.5 mL/min/1.73 m2/year. Compared with participants with albuminuria (n = 419), those with NDKF (n = 94) were significantly older (56 vs. 52 years), had lower HbA1c (7.7 vs. 8.1%) and SUA (5.4 vs. 6.0 mg/dL), and had higher eGFR (82 vs. 74 mL/min/1.73 m2) and historical eGFR loss (-4.7 vs. -2.5 mL/min/1.73 m2/year). These differences persisted when comparing groups with similar rates of historical eGFR loss. CONCLUSIONS PERL will determine the effect of allopurinol on mild to moderate DKD in T1D, with or without albuminuria. Participants with normoalbuminuria and rapid GFR loss manifested many DKD risk factors of those with albuminuria, but with less severity.
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Affiliation(s)
- Maryam Afkarian
- Division of Nephrology, Department of Medicine, University of California, Davis, Davis, CA
| | - Sarit Polsky
- Barbara Davis Center for Diabetes, University of Colorado, Aurora, CO
| | - Afshin Parsa
- Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD
| | | | - Maria Luiza Caramori
- Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, MN
| | - David Z Cherney
- Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Jill P Crandall
- Department of Medicine, Albert Einstein College of Medicine, New York, NY
| | - Ian H de Boer
- Department of Medicine, University of Washington, Seattle, WA
| | | | - Andrzej T Galecki
- Division of Geriatrics, Institute of Gerontology, University of Michigan, Ann Arbor, MI.,Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI
| | - Allison B Goldfine
- Research Division, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, MA
| | - J Sonya Haw
- Department of Medicine, Emory University, Atlanta, GA
| | - Irl B Hirsch
- Department of Medicine, University of Washington, Seattle, WA
| | - Amy B Karger
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN
| | - Ildiko Lingvay
- Department of Internal Medicine and Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX
| | - David M Maahs
- Department of Pediatrics, Stanford University, Palo Alto, CA
| | - Janet B McGill
- Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Mark E Molitch
- Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Bruce A Perkins
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, and Division of Endocrinology and Metabolism, University of Toronto, Toronto, Ontario, Canada
| | - Rodica Pop-Busui
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
| | | | - Sylvia E Rosas
- Research Division, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, MA
| | - Peter Rossing
- Steno Diabetes Center Copenhagen, Gentofte, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Peter Senior
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Ronald J Sigal
- Departments of Medicine, Cardiac Sciences, and Community Health Sciences, Faculties of Medicine and Kinesiology, University of Calgary, Calgary, Alberta, Canada
| | - Catherine Spino
- Statistical Analysis of Biomedical and Educational Research, Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI
| | - Katherine R Tuttle
- Providence Health Care, Spokane, WA.,Institute of Translational Health Sciences, Kidney Research Institute, and Division of Nephrology, University of Washington, Seattle, WA
| | | | - Amisha Wallia
- Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Ruth S Weinstock
- Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY
| | - Chunyi Wu
- Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI
| | - Michael Mauer
- Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, MN
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Kopel J, Pena-Hernandez C, Nugent K. Evolving spectrum of diabetic nephropathy. World J Diabetes 2019; 10:269-279. [PMID: 31139314 PMCID: PMC6522757 DOI: 10.4239/wjd.v10.i5.269] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 05/13/2019] [Accepted: 05/13/2019] [Indexed: 02/05/2023] Open
Abstract
Diabetes remains an important health issue as more patients with chronic and uncontrolled diabetes develop diabetic nephropathy (DN), which classically presents with proteinuria followed by a progressive decrease in renal function. However, an increasing proportion of DN patients have a decline in kidney function and vascular complications without proteinuria, known as non-proteinuric DN (NP-DN). Despite the increased incidence of NP-DN, few clinical or experimental studies have thoroughly investigated the pathophysiological mechanisms and targeted treatment for this form of DN. In this review, we will examine the differences between conventional DN and NP-DN and consider potential pathophysiological mechanisms, diagnostic markers, and treatment for both DN and NP-DN. The investigation of the pathophysiology of NP-DN should provide additional insight into the cardiovascular factors influencing renal function and disease and provide novel treatments for the vascular complications seen in diabetic patients.
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Affiliation(s)
- Jonathan Kopel
- Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79416, United States
| | - Camilo Pena-Hernandez
- Department of Internal Medicine, Division of Nephrology, Lubbock, TX 79430, United States
| | - Kenneth Nugent
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, United States
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Wang Y, Yang S, Zhou Q, Zhang H, Yi B. Effects of Vitamin D Supplementation on Renal Function, Inflammation and Glycemic Control in Patients with Diabetic Nephropathy: a Systematic Review and Meta-Analysis. Kidney Blood Press Res 2019; 44:72-87. [PMID: 30808855 DOI: 10.1159/000498838] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/05/2019] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS Vitamin D (VD) is widely recognized as renal protective. However, whether VD supplementation provides benefit to patients with diabetic nephropathy (DN) remains controversial. Here, we performed a meta-analysis to systematically evaluate the impact of VD supplementation on indexes of renal function, inflammation and glycemic control in DN patients, and to explore the potential renal protective mechanism of VD. METHODS We searched Pubmed, Embase, Cochrane Library, and three major Chinese biomedical databases (CNKI, WANGFANG and VIP) for randomized controlled trials (RCTs) examining the effects of VD or its analogs in DN patients, published between September 2007 and July 2018. Quality assessment and data extraction were performed independently by two authors, according to the Cochrane systematic review methods. Meta-analysis based on the extracted results were performed via Revman 5.2 software. RESULTS We included 20 RCTs representing 1,464 patients with DN in this meta-analysis. VD supplementation significantly reduced 24-hour urine protein [MD = -0.26; 95% CI (-0.34, -0.17); P < 0.00001; I2 = 95%], UAER [MD = -67.36; 95% CI (-91.96, -42.76); P < 0.00001; I2 = 97%], hs-CRP [MD = -0.69; 95% CI (-0.86,-0.53); P < 0.00001; I2 = 0%], TNF-α [MD = -56.79; 95% CI (-77.05, -36.52); P < 0.00001; I2 = 89%] and IL-6 [MD = -0.73; 95% CI(-1.03, -0.44); P < 0.00001; I2 = 0%]. However, VD supplementation failed to decrease SCr [MD = -0.83; 95% CI (-3.67,2.02); P = 0.57; I2 = 0%] or increase eGFR [MD = 2.13; 95% CI (-2.06, 6.32); P = 0.32; I2 = 0%]. In addition, VD supplementation showed no impact on indexes of glycemic control, such as HbA1c [MD = 0.01; 95% CI (-0.09, 0.11); P = 0.84; I2 = 0%] and FBG [MD = -0.05; 95% CI (-0.29, 0.20); P = 0.70; I2 = 0%]. Analysis of 24-hour urine protein, SCr, eGFR, hs-CRP or HbA1c revealed no difference between subgroups based on the type of VD supplementation, including calcitriol, alfacalcidol and vitamin D3, and the dose or duration of calcitriol usage. CONCLUSION In patients with DN, VD supplementation provides beneficial effects on 24-hour urine protein and inflammation indexes, but not on SCr, eGFR or glycemic control indexes. More RCTs that comprehensively evaluate the impact of VD supplementation on indexes of renal function, inflammation and glycemic control in DN atients are required in order to reach conclusive results.
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Affiliation(s)
- Yangyang Wang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Shikun Yang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Qianying Zhou
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Hao Zhang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Bin Yi
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, China,
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Erianin protects against high glucose-induced oxidative injury in renal tubular epithelial cells. Food Chem Toxicol 2019; 126:97-105. [PMID: 30763685 DOI: 10.1016/j.fct.2019.02.021] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 01/17/2019] [Accepted: 02/08/2019] [Indexed: 01/02/2023]
Abstract
Erianin is the major bibenzyl compound found in Dendrobium chrysotoxum Lindl. The current study was designed to investigate the protective effects of erianin on high glucose-induced injury in cultured renal tubular epithelial cells (NRK-52E cells) and determine the possible mechanisms for its effects. NRK-52E cells were pretreated with erianin (5, 10, 25 or 50 nmol/L) for 1 h followed by further exposure to high glucose (30 mmol/L, HG) for 48 h. Erianin concentration dependently enhanced cell viability followed by HG treatment in NRK-52E cells. HG induced reactive oxygen species (ROS) generation, malondialdehyde production, and glutathione deficiency were recovered in NRK-52E cells pretreated with erianin. HG triggered cell apoptosis via the loss of mitochondrial membrane potential, depletion of adenosine triphosphate, upregulation of caspases 9 and 3, enhancement of cytochrome c release, and subsequent interruption of the Bax/Bcl-2 balance. These detrimental effects were ameliorated by erianin. HG also induced activation of p53, JNK, p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) in NRK-52E cells, which were blocked by erianin. The results suggest that treatment NRK-52E cells with erianin halts HG-induced renal dysfunction through the suppression of the ROS/MAPK/NF-κB signaling pathways. Our findings provide novel therapeutic targets for diabetic nephropathy.
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Wang W, Sun W, Cheng Y, Xu Z, Cai L. Role of sirtuin-1 in diabetic nephropathy. J Mol Med (Berl) 2019; 97:291-309. [PMID: 30707256 PMCID: PMC6394539 DOI: 10.1007/s00109-019-01743-7] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 12/29/2018] [Accepted: 01/09/2019] [Indexed: 02/06/2023]
Abstract
Diabetic nephropathy (DN) is a research priority for scientists around the world because of its high prevalence and poor prognosis. Although several mechanisms have been shown to be involved in its pathogenesis and many useful drugs have been developed, the management of DN remains challenging. Increasing amounts of evidence show that silent information regulator 2 homolog 1 (sirtuin-1), a nicotinamide adenine dinucleotide (NAD+)–dependent protein deacetylase, plays a crucial role in the pathogenesis and development of DN. Clinical data show that gene polymorphisms of sirtuin-1 affect patient vulnerability to DN. In addition, upregulation of sirtuin-1 attenuates DN in various experimental models of diabetes and in renal cells, including podocytes, mesangial cells, and renal proximal tubular cells, incubated with high concentrations of glucose or advanced glycation end products. Mechanistically, sirtuin-1 has its renoprotective effects by modulating metabolic homeostasis and autophagy, resisting apoptosis and oxidative stress, and inhibiting inflammation through deacetylation of histones and the transcription factors p53, forkhead box group O, nuclear factor-κB, hypoxia-inducible factor-1α, and others. Furthermore, some microRNAs have been implicated in the progression of DN because they target sirtuin-1 mRNA. Several synthetic drugs and natural compounds have been identified that upregulate the expression and activity of sirtuin-1, which protects against DN. The present review will summarize advances in knowledge regarding the role of sirtuin-1 in the pathogenesis of DN. The available evidence implies that sirtuin-1 has great potential as a clinical target for the prevention and treatment of diabetes.
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Affiliation(s)
- Wanning Wang
- Department of Nephrology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021 Jilin Province China
- Pediatric Research Institute, Department of Pediatrics, The University of Louisville School of Medicine, Louisville, KY 40292 USA
| | - Weixia Sun
- Department of Nephrology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021 Jilin Province China
| | - Yanli Cheng
- Department of Nephrology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021 Jilin Province China
| | - Zhonggao Xu
- Department of Nephrology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021 Jilin Province China
| | - Lu Cai
- Pediatric Research Institute, Department of Pediatrics, The University of Louisville School of Medicine, Louisville, KY 40292 USA
- Departments of Radiation Oncology, Pharmacology and Toxicology, The University of Louisville School of Medicine, 570 S. Preston Str., Baxter I, Suite 304F, Louisville, KY 40292 USA
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Klimontov VV, Korbut AI. Albuminuric and non-albuminuric patterns of chronic kidney disease in type 2 diabetes. Diabetes Metab Syndr 2019; 13:474-479. [PMID: 30641747 DOI: 10.1016/j.dsx.2018.11.014] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Accepted: 11/02/2018] [Indexed: 12/17/2022]
Abstract
A growing body of evidence supports a shift in the natural history of chronic kidney disease (CKD) in subjects with diabetes. Specifically, normoalbuminuric chronic kidney disease (NA-CKD), which is characterized by a decline in the glomerular filtration rate in the absence of a preceding or accompanying elevation of albuminuria, has become a widely prevalent variant of renal impairment in diabetes. Diabetic women and nonsmoking individuals with better glycemic control have a better chance of preserving normoalbuminuria, even in the case of declining renal function. The wide use of renin-angiotensin system blockers, advances in antihyperglycemic, antihypertensive, and hypolipidemic therapy, and smoking cessation are suspected to be responsible for an increasing proportion of NA-CKD among diabetic subjects with renal impairment. Significant differences in the sets of risk factors, renal morphology, comorbidity, and outcomes were found between the albuminuric and normoalbuminuric CKD patterns. NA-CKD, even if a more favorable option in terms of the risk of end-stage renal disease, is clearly associated with cardiovascular disease and its risk factors. The presence of NA-CKD in patients with diabetes increases the risk of myocardial infarction, stroke, and cardiovascular death. The study of the molecular pathways, clinical course, and outcomes of NA-CKD in diabetic subjects and the search for more specific diagnostic and treatment options are challenges for future research.
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Affiliation(s)
- Vadim V Klimontov
- Laboratory of Endocrinology, Research Institute of Clinical and Experimental Lymphology, Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russian Federation.
| | - Anton I Korbut
- Laboratory of Endocrinology, Research Institute of Clinical and Experimental Lymphology, Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russian Federation
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