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Xiong Y, Li W, Jin S, Wan S, Wu S. Inflammation in glomerular diseases. Front Immunol 2025; 16:1526285. [PMID: 40103820 PMCID: PMC11913671 DOI: 10.3389/fimmu.2025.1526285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 02/12/2025] [Indexed: 03/20/2025] Open
Abstract
The structural and functional integrity of glomerular cells is critical for maintaining normal kidney function. Glomerular diseases, which involve chronic histological damage to the kidney, are related to injury to glomerular cells such as endothelial cells, mesangial cells (MCs), and podocytes. When faced with pathogenic conditions, these cells release pro-inflammatory cytokines such as chemokines, inflammatory factors, and adhesion factors. These substances interact with glomerular cells through specific inflammatory pathways, resulting in damage to the structure and function of the glomeruli, ultimately causing glomerular disease. Although the role of inflammation in chronic kidney diseases is well known, the specific molecular pathways that result in glomerular diseases remain largely unclear. For a long time, it has been believed that only immune cells can secrete inflammatory factors. Therefore, targeted therapies against immune cells were considered the first choice for treating inflammation in glomerular disease. However, emerging research indicates that non-immune cells such as glomerular endothelial cells, MCs, and podocytes can also play a role in renal inflammation by releasing inflammatory factors. Similarly, targeted therapies against glomerular cells should be considered. This review aims to uncover glomerular diseases related to inflammation and pathways in glomerular inflammation, and for the first time summarized that non-immune cells in the glomerulus can participate in glomerular inflammatory damage by secreting inflammatory factors, providing valuable references for future strategies to prevent and treat glomerular diseases. More importantly, we emphasized targeted glomerular cell therapy, which may be a key direction for the future treatment of glomerular diseases.
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Affiliation(s)
- Yongqing Xiong
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, China
| | - Wei Li
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, China
| | - Songzhi Jin
- School of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Shujing Wan
- School of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Suzhen Wu
- School of Basic Medicine, Gannan Medical University, Ganzhou, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, China
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El-Tahir F, Esh A, Ghorab A, Shendi AM. Chemerin, TNF - α and the degree of albuminuria in patients with diabetic kidney disease. Cytokine 2024; 184:156772. [PMID: 39366065 DOI: 10.1016/j.cyto.2024.156772] [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: 02/16/2024] [Revised: 05/08/2024] [Accepted: 09/26/2024] [Indexed: 10/06/2024]
Abstract
BACKGROUND Chronic inflammation has been increasingly recognized as an essential pathogenic mechanism for the development and progression of diabetic kidney disease (DKD). Chemerin is an adipokine which has been suggested to be related to inflammation and has been correlated with the development of diabetic complications. We aimed to explore the potential links between chemerin, TNF - α, as a marker of systemic inflammation, and the level of albuminuria in patients with type 2 diabetes mellitus (T2DM). METHOD The study included 84 patients with T2DM and 10 normoalbuminuric non-diabetic controls. Demographic, clinical and laboratory data including chemerin and TNF-α levels were collected. RESULTS A total of 84 diabetic patients were enrolled, 32 males (38.1 %), with mean age 57.9 ± 10.7 years. They were divided into 3 groups: A1: 14 with normalbuminuria, A2: 27 with microalbuminuria, and A3: 43 with macroalbuminuria (uACR < 30, 30-300 and > 300 mg/gm respectively). Chemerin and TNF-α levels increased with the progress of albuminuria (control: 21.3 (14.7 -77), A1: 794 (683-925), A2: 1150 (962.9 - 1221.5) and A3: 1466 (1197.5 - 2002.5) ng/ml; p < 0.001) and (control: 77.9 (59 - 96.8), A1: 85.2 (71-116.3), A2: 87.3 (81 - 97.5) and A3: 99 (85.1 - 142.5) pg/ml; p = 0.009) respectively. Among the diabetics, a significant association was evident between serum chemerin and serum TNF-α (r = 0.53; p < 0.001). On linear stepwise regression analysis, chemerin was significantly associated with TNF-α and HbA1c (unstandardized β 10.881 and 272.68 respectively, p < 0.001); and TNF-α was significantly correlated with chemerin, uACR (unstandardized β 0.059 and 0.004 respectively, p < 0.001) and HbA1c (unstandardized β -13.699, p = 0.014). CONCLUSION Our findings suggest a potential role of chemerin and TNF-α in the development and progression of DKD, and thus support the role of the inflammatory pathway. Larger follow up studies are warranted to further explore the potential links between chemerin, inflammation and DKD.
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Affiliation(s)
- Fatima El-Tahir
- Nephrology unit, Internal Medicine Department, Faculty of Medicine, Zagazig University, Egypt
| | - Asmaa Esh
- Clinical Pathology Department, Faculty of Medicine, Zagazig University, Egypt
| | - Adel Ghorab
- Nephrology unit, Internal Medicine Department, Faculty of Medicine, Zagazig University, Egypt
| | - Ali M Shendi
- Nephrology unit, Internal Medicine Department, Faculty of Medicine, Zagazig University, Egypt; Organ Transplant Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
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Zhang M, Ye S, Li J, Zhang M, Tan L, Wang Y, Xie P, Peng H, Li S, Chen S, Wen Q, Chan KW, Tang SCW, Li B, Chen W. Association of systemic immune-inflammation index with all-cause and cardio-cerebrovascular mortality in individuals with diabetic kidney disease: evidence from NHANES 1999-2018. Front Endocrinol (Lausanne) 2024; 15:1399832. [PMID: 39659615 PMCID: PMC11628304 DOI: 10.3389/fendo.2024.1399832] [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: 03/12/2024] [Accepted: 11/11/2024] [Indexed: 12/12/2024] Open
Abstract
Background Emerging evidence suggests a potential role of immune response and inflammation in the pathogenesis of diabetic kidney disease (DKD). The systemic immune-inflammation index (SII) offers a comprehensive measure of inflammation; however, its relationship with the prognosis of DKD patients remains unclear. Methods Using data from the National Health and Nutrition Examination Survey (NHANES) spanning 1999 to 2018, this cross-sectional study involved adults diagnosed with DKD. Cox proportional hazards models were utilized to assess the associations between SII and all-cause or cardio-cerebrovascular disease mortality. Additionally, restricted cubic spline, piecewise linear regression, and subgroup analyses were performed. Results Over a median follow-up duration of 6.16 years, 1338 all-cause deaths were recorded. After adjusting for covariates, elevated SII levels were significantly associated with increased risks of all-cause and cardio-cerebrovascular disease mortality. Specifically, per one-unit increment in natural log-transformed SII (lnSII), there was a 29% increased risk of all-cause mortality (P < 0.001) and a 23% increased risk of cardio-cerebrovascular disease mortality (P = 0.01) in the fully adjusted model. Similar results were observed when SII was analyzed as a categorical variable (quartiles). Moreover, nonlinear association was identified between SII and all-cause mortality (P < 0.001) through restricted cubic spline analysis, with threshold value of 5.82 for lnSII. The robustness of these findings was confirmed in subgroup analyses. Likewise, the statistically significant correlation between SII levels and cardio-cerebrovascular disease mortality persisted in individuals with DKD. Conclusion Increased SII levels, whether examined as continuous variables or categorized, demonstrate a significant association with elevated risks of all-cause and cardio-cerebrovascular disease mortality among DKD patients. These findings imply that maintaining SII within an optimal range could be crucial in reducing mortality risk.
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Affiliation(s)
- Manhuai Zhang
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- National Health Commission (NHC) Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Siyang Ye
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- National Health Commission (NHC) Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Jianbo Li
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- National Health Commission (NHC) Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Meng Zhang
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- National Health Commission (NHC) Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Li Tan
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- National Health Commission (NHC) Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Yiqin Wang
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- National Health Commission (NHC) Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Peichen Xie
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- National Health Commission (NHC) Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Huajing Peng
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- National Health Commission (NHC) Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Suchun Li
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- National Health Commission (NHC) Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Sixiu Chen
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- National Health Commission (NHC) Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Qiong Wen
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- National Health Commission (NHC) Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Kam Wa Chan
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
| | - Sydney C. W. Tang
- Division of Nephrology, Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Bin Li
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- National Health Commission (NHC) Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Wei Chen
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- National Health Commission (NHC) Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
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Jin Z, Zhang Q, Liu K, Wang S, Yan Y, Zhang B, Zhao L. The association between interleukin family and diabetes mellitus and its complications: An overview of systematic reviews and meta-analyses. Diabetes Res Clin Pract 2024; 210:111615. [PMID: 38513987 DOI: 10.1016/j.diabres.2024.111615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 02/26/2024] [Accepted: 03/11/2024] [Indexed: 03/23/2024]
Abstract
OBJECTIVE To evaluate and summarize the association between interleukin (IL) concentrations and diabetes mellitus (DM) and its complications. METHODS Meta-analyses and eligible individual studies of observational studies investigating the associations between IL and DM and its complications were included. The random-effects model was used to estimate the summary effect, and the heterogeneity among studies was assessed using the Q-statistic and the I2 metric; The Egger's regression and the χ2 test were used to test for small study effects and excess significance bias. RESULTS This overview identified 34 meta-analyses that investigated the association between IL concentrations and DM and its complications. Meta-analyses of prospective studies indicated that elevated circulating IL-6 and IL-1β had predictive value for the incident of type 2 diabetes mellitus (T2DM), type 1 diabetes mellitus (T1DM) as well as gestational diabetes mellitus (GDM), and the overall Hazard Ratio (HR) of T2DM was 1.28 (95 % CI: 1.17, 1.40; P＜0.001) per 1 log pg/ml increment in IL-6 levels, however, there was no correlation between circulating IL-10 levels and DM. Meanwhile, the increased level of IL-6 was significantly associated several diabetic complications (Diabetic kidney disease[DKD], diabetic peripheral neuropathy[DPN], and cognitive impairment[CI]), and for the diabetic retinopathy (DR), the levels of IL-1β, IL-8 and IL-10 in the aqueous humor and vitreous humor, but not the blood were significantly correlated with it. CONCLUSION Multiple ILs, such as the IL-6 and IL-1β, are definitively linked to DM and its complications, and they may be new targets for the diagnosis and treatment, but stronger evidence needs to be confirmed by prospective studies with larger sample sizes and longer observation periods.
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Affiliation(s)
- Zishan Jin
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China; Beijing University of Chinese Medicine, Beijing 100105, China
| | - Qiqi Zhang
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ke Liu
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Sicheng Wang
- Beijing University of Chinese Medicine, Beijing 100105, China
| | - Yan Yan
- Health Construction Administration Center, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Boxun Zhang
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Linhua Zhao
- Beijing University of Chinese Medicine, Beijing 100105, China.
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Quan KY, Yap CG, Jahan NK, Pillai N. Review of early circulating biomolecules associated with diabetes nephropathy - Ideal candidates for early biomarker array test for DN. Diabetes Res Clin Pract 2021; 182:109122. [PMID: 34742785 DOI: 10.1016/j.diabres.2021.109122] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 07/26/2021] [Accepted: 10/31/2021] [Indexed: 01/08/2023]
Abstract
BACKGROUND Diabetic nephropathy (DN) is one of the catastrophic complications of type 2 diabetes mellitus (T2DM). 45% of DN patients progressed to End Stage Renal Disease (ESRD) which robs casualties of the quality of live. The challenge in early diagnosis of DN is it is asymptomatic in the early phase. Current gold standard test for screening and diagnosis of DN are nonspecific and are not sensitive in detecting DN early enough and subsequently monitor renal function during management and intervention plans. Recent studies reported various biomolecules which are associated with the onset of DN in T2DM using cutting-edge technologies. These biomolecules could be potential early biomarkers for DN. This review selectively identified potential early serum biomolecules which are potential candidates for developing an Early Biomarker Array Test for DN. METHODS An advanced literature search was conducted on 4 online databases. Search terms used were "Diabetes Mellitus, Type 2", "Diabetic nephropathy", "pathogenesis" and "early biomarker. Filters were applied to capture articles published from 2010 to 2020, written in English, human or animal models and focused on serum biomolecules associated with DN. RESULTS Five serum biomolecules have been evidently described as contributing pivotal roles in the pathophysiology of DN. MiR-377, miR-99b, CYP2E1, TGF-β1 and periostin are potential candidates for designing an early biomarker array for screening and diagnosis of early stages of DN. The five shortlisted biomolecules originates from endogenous biochemical processes which are specific to the progressive pathophysiology of DN. CONCLUSION miR-377, miR-99b, CYP2E1, TGF-β1 and periostin are potential candidate biomolecules for diagnosing DN at the early phases and can be developed into a panel of endogenous biomarkers for early detection of DN in patients with T2DM. The outcomes of this study will be a stepping stone towards planning and developing an early biomarker array test for diabetic nephropathy. The proposed panel of early biomarkers for DN has potential of stratifying the stages of DN because each biomolecule appears at distinct stages in the pathophysiology of DN.
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Affiliation(s)
- Kok Ying Quan
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Kuala Lumpur, Malaysia
| | - Christina Gertrude Yap
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Kuala Lumpur, Malaysia.
| | - Nowrozy Kamar Jahan
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Kuala Lumpur, Malaysia.
| | - Naganathan Pillai
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Kuala Lumpur, Malaysia.
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Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study. Genome Med 2020; 12:109. [PMID: 33261667 PMCID: PMC7708171 DOI: 10.1186/s13073-020-00806-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 11/11/2020] [Indexed: 01/04/2023] Open
Abstract
Background The rising prevalence of type 2 diabetes (T2D) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2D can be observed in easily accessible tissues such as blood. Additionally, large-scale human studies are required to further our understanding of the putative inflammatory component of insulin resistance and T2D. Here we used transcriptomics data from individuals with (n = 789) and without (n = 2127) T2D from the IMI-DIRECT cohorts to describe the co-expression structure of whole blood that mainly reflects processes and cell types of the immune system, and how it relates to metabolically relevant clinical traits and T2D. Methods Clusters of co-expressed genes were identified in the non-diabetic IMI-DIRECT cohort and evaluated with regard to stability, as well as preservation and rewiring in the cohort of individuals with T2D. We performed functional and immune cell signature enrichment analyses, and a genome-wide association study to describe the genetic regulation of the modules. Phenotypic and trans-omics associations of the transcriptomic modules were investigated across both IMI-DIRECT cohorts. Results We identified 55 whole blood co-expression modules, some of which clustered in larger super-modules. We identified a large number of associations between these transcriptomic modules and measures of insulin action and glucose tolerance. Some of the metabolically linked modules reflect neutrophil-lymphocyte ratio in blood while others are independent of white blood cell estimates, including a module of genes encoding neutrophil granule proteins with antibacterial properties for which the strongest associations with clinical traits and T2D status were observed. Through the integration of genetic and multi-omics data, we provide a holistic view of the regulation and molecular context of whole blood transcriptomic modules. We furthermore identified an overlap between genetic signals for T2D and co-expression modules involved in type II interferon signaling. Conclusions Our results offer a large-scale map of whole blood transcriptomic modules in the context of metabolic disease and point to novel biological candidates for future studies related to T2D.
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Hashimoto Y, Hamaguchi M, Kaji A, Sakai R, Kitagawa N, Fukui M. Serum levels of mac-2 binding protein are associated with diabetic microangiopathy and macroangiopathy in people with type 2 diabetes. BMJ Open Diabetes Res Care 2020; 8:8/1/e001189. [PMID: 32847841 PMCID: PMC7451284 DOI: 10.1136/bmjdrc-2020-001189] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 07/04/2020] [Accepted: 07/18/2020] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Non-alcoholic fatty liver disease is reportedly associated with type 2 diabetes and progressive liver fibrosis, as evaluated by transient elastography, and has been linked with micro- and macroangiopathy in people with type 2 diabetes. The purpose of this cross-sectional study was to investigate the association between serum mac-2 binding protein glycosylation isomer (M2BPGi) levels and diabetic complications in people with type 2 diabetes. RESEARCH DESIGN AND METHODS Serum M2BPGi levels were measured in terms of cut-off index (C.O.I.) units. Urinary albumin excretion (UAE) was calculated and nephropathy was graded as normoalbuminuria, microalbuminuria, or macroalbuminuria. Retinopathy was divided into three groups: no-diabetic retinopathy (NoDR), non-proliferative-diabetic retinopathy (NPDR), or proliferative-diabetic retinopathy (PDR) . RESULTS The mean age for the 363 studied subjects (212 males) was 66.4±10.6 years, the median serum M2BPGi level was 0.77 (0.57-1.04) C.O.I., and the median UAE was 22 (9-82.1) mg/g creatinine. M2BPGi levels in microalbuminuria (0.83 (0.61 to 1.18) C.O.I.) and macroalbuminuria (0.88 (0.67 to 1.22) C.O.I.) cases were higher than those in normoalbuminuria cases (0.71 (0.54 to 0.92) C.O.I.). M2BPGi levels in NPDR (0.93 (0.68 to 1.28) C.O.I.) and PDR (0.95 (0.71 to 1.31) C.O.I.) cases were higher than in cases with NoDR (0.73 (0.56 to 0.99) C.O.I.). Furthermore, M2BPGi levels in subjects with a history of cardiovascular diseases were higher than in those with no such history (0.82 (0.65 to 1.22) vs 0.76 (0.55 to 1.03) C.O.I., p=0.019). The logarithm of (M2BPGi+1) was associated with the logarithm of UAE values after adjusting for covariates (standardized β=0.107, p=0.031). CONCLUSIONS This study reveals a close association between serum M2BPGi levels and diabetic microangiopathy and macroangiopathy in people with type 2 diabetes. The results also show that liver fibrosis, evaluated by M2BPGi, is independently associated with an increased risk of albuminuria.
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Affiliation(s)
- Yoshitaka Hashimoto
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Masahide Hamaguchi
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Ayumi Kaji
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Ryosuke Sakai
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Noriyuki Kitagawa
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
- Department of Diabetology, Kameoka Municipal Hospital, Kameoka, Japan
| | - Michiaki Fukui
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
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Kitagawa N, Hashimoto Y, Hamaguchi M, Osaka T, Fukuda T, Yamazaki M, Fukui M. Liver Stiffness Is Associated With Progression of Albuminuria in Adults With Type 2 Diabetes: Nonalcoholic Fatty Disease Cohort Study. Can J Diabetes 2020; 44:428-433. [PMID: 32616276 DOI: 10.1016/j.jcjd.2020.03.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 02/12/2020] [Accepted: 03/10/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Previous studies have shown the association between liver fibrosis and albuminuria. However, the effect of liver fibrosis on change in albuminuria is unclear. Thus, we investigated the effect of liver fibrosis on change in albuminuria in patients with type 2 diabetes. METHODS In this retrospective cohort study, we assessed 105 patients with type 2 diabetes concomitant with nonalcoholic fatty disease. A change in urinary albumin excretion (UAE) was defined as follows: change in UAE=(logarithm [UAE+1] at follow-up examination minus logarithm [UAE+1] at baseline examination) / follow-up duration (1 year in this study). Elastography was performed to assess controlled attenuation parameter (dB/m) and liver stiffness measurement (LSM; kPa) values. RESULTS Mean (standard deviation) data were as follows: age, 63.3 (12.1) years; body mass index, 25.4 (4.3) kg/m2; controlled attenuation parameter, 273.1 (53.0) dB/m; and LSM, 6.2 (3.4) kPa. Median UAE value (interquartile range) was 16 (6 to 43) mg/g creatinine. LSM was associated with changes in UAE (r=0.27, p=0.005). Multiple regression analysis demonstrated that LSM was associated with change in UAE (β=0.28, p=0.015) after adjusting for sex, age, duration of diabetes, smoking status, exercise habits, glycated hemoglobin, body mass index, estimated glomerular filtration rate, systolic blood pressure, logarithm (UAE+1) at baseline examination, use of renin‒angiotensin system inhibitors, new use of sodium glucose cotransporter-2 inhibitors and glucagon-like peptide-1 and controlled attenuation parameter. CONCLUSIONS Liver stiffness is an independent risk factor for the progression of albuminuria in patients with type 2 diabetes.
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Affiliation(s)
- Nobuko Kitagawa
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshitaka Hashimoto
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Masahide Hamaguchi
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takafumi Osaka
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Endocrinology and Diabetology, Ayabe city Hospital, Ayabe, Japan
| | - Takuya Fukuda
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Masahiro Yamazaki
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Michiaki Fukui
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
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Liu KZ, Tian G, Ko ACT, Geissler M, Brassard D, Veres T. Detection of renal biomarkers in chronic kidney disease using microfluidics: progress, challenges and opportunities. Biomed Microdevices 2020; 22:29. [PMID: 32318839 DOI: 10.1007/s10544-020-00484-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Chronic kidney disease (CKD) typically evolves over many years in a latent period without clinical signs, posing key challenges to detection at relatively early stages of the disease. Accurate and timely diagnosis of CKD enable effective management of the disease and may prevent further progression. However, long turn-around times of current testing methods combined with their relatively high cost due to the need for established laboratory infrastructure, specialized instrumentation and trained personnel are drawbacks for efficient assessment and monitoring of CKD, especially in underserved and resource-poor locations. Among the emerging clinical laboratory approaches, microfluidic technology has gained increasing attention over the last two decades due to the possibility of miniaturizing bioanalytical assays and instrumentation, thus potentially improving diagnostic performance. In this article, we review current developments related to the detection of CKD biomarkers using microfluidics. A general trend in this emerging area is the search for novel, sensitive biomarkers for early detection of CKD using technology that is improved by means of microfluidics. It is anticipated that these innovative approaches will be soon adopted and utilized in both clinical and point-of-care settings, leading to improvements in life quality of patients.
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Affiliation(s)
- Kan-Zhi Liu
- Medical Devices Research Centre, National Research Council Canada, 435 Ellice Avenue, Winnipeg, MB, R3B1Y6, Canada.
| | - Ganghong Tian
- Medical Devices Research Centre, National Research Council Canada, 435 Ellice Avenue, Winnipeg, MB, R3B1Y6, Canada
| | - Alex C-T Ko
- Medical Devices Research Centre, National Research Council Canada, 435 Ellice Avenue, Winnipeg, MB, R3B1Y6, Canada
| | - Matthias Geissler
- Medical Devices Research Centre, National Research Council Canada, 75 de Mortagne Boulevard, Boucherville, QC, J4B6Y4, Canada
| | - Daniel Brassard
- Medical Devices Research Centre, National Research Council Canada, 75 de Mortagne Boulevard, Boucherville, QC, J4B6Y4, Canada
| | - Teodor Veres
- Medical Devices Research Centre, National Research Council Canada, 75 de Mortagne Boulevard, Boucherville, QC, J4B6Y4, Canada
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10
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Lampropoulou IT, Stangou Μ, Sarafidis P, Gouliovaki A, Giamalis P, Tsouchnikas I, Didangelos T, Papagianni Α. TNF-α pathway and T-cell immunity are activated early during the development of diabetic nephropathy in Type II Diabetes Mellitus. Clin Immunol 2020; 215:108423. [PMID: 32304735 DOI: 10.1016/j.clim.2020.108423] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 04/13/2020] [Accepted: 04/14/2020] [Indexed: 02/07/2023]
Abstract
Aim of the present study was to investigate the possible involvement of TNF-α signaling pathway and T-lymphocyte activation in DN. Eighty-two diabetic patients [39 male, age 69.5(56-78)years] were divided into three groups, according to Albumin/Creatinine ratio (ACR) levels, Group I (ACR < 30 μg/mg), Group II (ACR 30-300 μg/mg), Group III (ACR > 300 μg/mg). Urinary Tumor Necrosis Factor-α (TNF-α), and serum TNF-α, ΤNF-receptor 1 (TNFR1), TNFR2, B7-1, CD28, Cytoxic T-Lymphocyte-Associated protein-4 (CTLA4), were estimated. There were significant differences between Groups I, II, III regarding the concentration of urinary TNF-α (p < .001), serum TNFR1 (p < .001), serum TNFR2(p < .001), CTLA4 (p < .001) and CD28(p = .034). In multivariate analysis, independent parameters correlated with ACR were serum TNFR1 (p = .003), TNFR2 (p = .012) and urinary TNF-α (p = .015) levels. There was a significant correlation between markers of T-cell activation and TNF-α signaling pathway activation. Activation of TNF-α signaling pathway and T-lymphocytes seem to synergize and participate in the development of DN in type II DM.
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Affiliation(s)
| | - Μaria Stangou
- Department of Nephrology, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece.
| | - Pantelis Sarafidis
- Department of Nephrology, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
| | | | - Panagiotis Giamalis
- Department of Nephrology, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
| | - Ioannis Tsouchnikas
- Department of Nephrology, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
| | - Triantafillos Didangelos
- Diabetes Center, First Department of Internal Medicine, Medical School, AHEPA Hospital, Aristotle University, Thessaloniki, Greece
| | - Αikaterini Papagianni
- Department of Nephrology, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
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11
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Yan L, Sun A, Xu X. Zafirlukast, a Cysteinyl Leukotriene Receptor 1 Antagonist, Reduces the Effect of Advanced Glycation End-Products in Rat Renal Mesangial Cells In Vitro. Med Sci Monit 2019; 25:8753-8763. [PMID: 31745068 PMCID: PMC6880630 DOI: 10.12659/msm.918187] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Zafirlukast is an antagonist of cysteinyl leukotriene receptor 1 (CysLTR1). Advanced glycation end-products (AGEs) are formed by the glycation of lipids and proteins in hyperglycemia, including diabetes mellitus. Zafirlukast has not previously been studied in diabetic nephropathy. This study aimed to investigate the effects of zafirlukast on rat renal mesangial cells cultured with AGEs in vitro. Material/Methods Mesangial cells were cultured in AGEs (0, 20, 50, 100 μg/ml), and with AGEs (100 μg/ml) and zafirlukast (2.5 μm, 5 μm, and 100 μm). An enzyme-linked immunoassay (ELISA) was used to measure the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and monocyte chemoattractant protein-1 (MCP-1). Reactive oxygen species (ROS) were assessed by intracellular fluorescence measurement of 2′-7′-dichlorodihydrofluorescein diacetate (DCFH-DA), and detection kits were used to measure malondialdehyde (MDA), lactate dehydrogenase (LDH), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD). Cell apoptosis was assessed by flow cytometry, and Western blot was used to measure protein levels. Results In mesangial cells cultured with AGEs, markers of inflammation, oxidative stress, and apoptosis and levels of CysLTR1 increased, and these effects were reduced by zafirlukast in a dose-dependent manner. The effects of zafirlukast as a CysLTR1 antagonist protected mesangial cells from the effects of AGE in vitro. Conclusions Zafirlukast, a CysLTR1 antagonist, reduced the levels of inflammatory cytokines, markers of oxidative stress, and cell apoptosis induced by AGE in mesangial cells in a dose-dependent way. Future in vivo studies are needed to investigate the potential role for zafirlukast in models of diabetic nephropathy.
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Affiliation(s)
- Liping Yan
- Administration Division, Weifang People's Hospital, Weifang, Shandong, China (mainland)
| | - Ani Sun
- Infection Control Office, Weifang People's Hospital, Weifang, Shandong, China (mainland)
| | - Xinwei Xu
- Nephrology Department, Weifang People's Hospital, Weifang, Shandong, China (mainland)
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12
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Meng Y, Bai H, Yu Q, Yan J, Zhao L, Wang S, Li Z, Wang Q, Chen L. High–Resistant Starch, Low-Protein Flour Intervention on Patients With Early Type 2 Diabetic Nephropathy: A Randomized Trial. J Ren Nutr 2019; 29:386-393. [DOI: 10.1053/j.jrn.2018.12.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 12/02/2018] [Accepted: 12/12/2018] [Indexed: 11/11/2022] Open
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13
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Zhang D, Ye S, Pan T. The role of serum and urinary biomarkers in the diagnosis of early diabetic nephropathy in patients with type 2 diabetes. PeerJ 2019; 7:e7079. [PMID: 31218128 PMCID: PMC6568248 DOI: 10.7717/peerj.7079] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 05/04/2019] [Indexed: 12/15/2022] Open
Abstract
Background Previous studies have shown that a variety of biomarkers are closely related to the occurrence and development of early-stage diabetic nephropathy (DN) in patients. The aim of this study was to evaluate the role of multiple sera and urinary biomarkers in the diagnosis of early-stage DN in patients with type 2 diabetes. Methods We enrolled 287 patients with type 2 diabetes, who were classified into normoalbuminuria (n = 144), microalbuminuria (n = 94), or macroalbuminuria (n = 49) groups based on their urine albumin to creatinine ratios (UACR), along with 42 healthy controls. We assessed 13 biomarkers, including transferrin (Tf), immunoglobulin G (IgG), podocalyxin, neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-beta-glucosaminidase, α-1-microglobulin, 8-hydroxy-deoxyguanosine, tumor necrosis factor-alpha (TNF-α), and interleukin-18 in urine samples, along with cystatin C, total bilirubin, and uric acid in sera samples, to evaluate their diagnostic roles. From the measurements, the blood neutrophil to lymphocyte ratio was also calculated. Results Urinary Tf, IgG, NGAL, and TNF-α were significantly related to the UACR. We calculated the area under the receiver operating characteristic curves (area under the curve) and found that urinary IgG (0.894), NGAL (0.875), Tf (0.861), TNF-α (0.763), and the combination of urinary Tf + IgG + TNF-α + NGAL (0.922) showed good diagnostic value for early-stage DN. Conclusions Urinary Tf, IgG, NGAL, TNF-α, and the combination of all four biomarkers demonstrated excellent diagnostic value for early-stage DN in patients with type 2 diabetes.
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Affiliation(s)
- Deyuan Zhang
- School of Medicine, Shandong University, Jinan, Shandong, China.,Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Shandong Ye
- School of Medicine, Shandong University, Jinan, Shandong, China.,Department of Endocrinology, Anhui Provincial Hospital, Hefei, Anhui, China
| | - Tianrong Pan
- Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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14
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Walker A, Nissen E, Geiger A. Migratory, metabolic and functional alterations of fibrocytes in type 2 diabetes. IUBMB Life 2018; 70:1122-1132. [PMID: 30184318 DOI: 10.1002/iub.1920] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 07/03/2018] [Accepted: 07/05/2018] [Indexed: 12/16/2022]
Abstract
Fibrocytes are bloodborne mesenchymal progenitor cells that are recruited to injured tissue sites and contribute to the repair process by acquiring a myofibroblast-like phenotype and producing extracellular matrix components and growth factors. Treatment with normal fibrocytes or their exosomes restores the ability of genetically diabetic mice to heal skin wounds, suggesting the existence of dysfunctional alterations in diabetic fibrocytes. This study compared the migratory, metabolic and functional characteristics of fibrocytes from patients with type 2 diabetes (T2DPs) and healthy controls (HCs). It was found that the frequency of these cells was abnormally low in the peripheral blood of T2DPs. Diabetic fibrocytes showed reduced expression of the C-X-C motif and C-C motif chemokine receptors (CXCR)4, (CCR)5, and CCR7, and demonstrated reduced migration in response to their ligands (CXCL)12, (CCL)5, and CCL21. They exhibited increased expression of the receptor for advanced glycation end product, suppression of the alternative AGE receptor 1, increased intracellular concentrations of AGEs, decreased expression of sirtuin-1 and elevated oxidative stress. In short-term cultures, fibrocytes from T2DPs released larger amounts of proinflammatory cytokines than those from HCs. Unlike normal fibrocytes, diabetic fibrocytes did not exhibit increased expression of type I collagen and α-smooth muscle actin on stimulation with transforming growth factor (TGF)-β1 and this abnormal response was associated with downregulation of TGF-β1 type II receptor on the cell surface. Study findings uncover multiple migratory and functional alterations of diabetic fibrocytes that may contribute to explain why T2DPs experience impaired wound healing and chronic ulcers. © 2018 IUBMB Life, 70(11):1122-1132, 2018.
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Affiliation(s)
- Audrey Walker
- Proteomics & Metabolomics Laboratory, DreiRosen Pharma GmbH, Berlin, Germany
| | - Erwin Nissen
- Proteomics & Metabolomics Laboratory, DreiRosen Pharma GmbH, Berlin, Germany
| | - Adolf Geiger
- Technology Development, DreiRosen Pharma GmbH, Berlin, Germany
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15
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Seo C, Kim S, Lee M, Cha MU, Kim H, Park S, Yun HR, Jhee JH, Kee YK, Han SH, Yoo TH, Kang SW, Park JT. THYROID HORMONE REPLACEMENT REDUCES THE RISK OF CARDIOVASCULAR DISEASES IN DIABETIC NEPHROPATHY PATIENTS WITH SUBCLINICAL HYPOTHYROIDISM. Endocr Pract 2018; 24:265-272. [PMID: 29547051 DOI: 10.4158/ep-2017-0017] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVE Patients with diabetic nephropathy (DMN) have an increased risk of cardiovascular disease (CVD). However, strategies to reduce this risk are limited. Thyroid hormone replacement therapy (THRT) in patients with hypothyroidism has been shown to reduce several surrogate markers of CVD. Therefore, we performed a study to determine if THRT would reduce CVD risk in patients with subclinical hypothyroidism (SCH) and DMN. METHODS This was a retrospective, nonrandomized study of patients with type 2 diabetes, DMN, and SCH. Those with known thyroid dysfunction or taking THRT at baseline were excluded. Patients receiving THRT for at least 180 days were included in the THRT group, while the remaining patients were assigned to the non-THRT group. The primary outcome was CVD events, which included coronary syndrome, cerebrovascular events, and peripheral artery diseases. RESULTS Among the 257 patients, 83 (32.3%) were in the THRT group. The mean ages were 62.7 ± 12.3 and 66.8 ± 12.4 years in the THRT and non-THRT groups, respectively. The corresponding numbers of male patients were 32 (40.0%) and 94 (53.1%). During a mean follow-up of 38.0 ± 29.2 months, 98 CVD events were observed. Acute coronary syndrome and cerebrovascular event prevalence rates were lower in the THRT group than the non-THRT group, but there was no difference for peripheral artery diseases. Multivariate Cox analysis revealed that THRT was independently associated with a decreased CVD event risk. CONCLUSION THRT may decrease the risk of CVD in DMN patients with SCH. Randomized trials are needed to verify this finding. ABBREVIATIONS CV = cardiovascular DMN = diabetic nephropathy eGFR = estimated glomerular filtration rate fT4 = free thyroxine HbA1c = glycosylated hemoglobin HR = hazard ratio hs-CRP = high-sensitivity C-reactive protein LDL-C = low-density lipoprotein cholesterol SCH = subclinical hypothyroidism T2DM = type 2 diabetes THRT = thyroid hormone replacement therapy TSH = thyroid-stimulating hormone.
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16
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Zhang J, Liu J, Qin X. Advances in early biomarkers of diabetic nephropathy. ACTA ACUST UNITED AC 2018; 64:85-92. [PMID: 29561946 DOI: 10.1590/1806-9282.64.01.85] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 09/09/2017] [Indexed: 01/06/2023]
Abstract
Diabetic nephropathy is the main cause of chronic kidney disease, and represents the most common and serious complication of diabetes. The exact pathogenesis is complex and not elucidated. Several factors and mechanisms contribute to the development and outcome of diabetic nephropathy. An early diagnosis and intervention may slow down disease progression. A variety of biological markers associated with diabetic nephropathy were found in recent years, which was important for predicting the occurrence and development of the disease. Therefore, this article provides an overview of early biomarkers that are associated with diabetic nephropathy.
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Affiliation(s)
- Jin Zhang
- Masters Student, Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jianhua Liu
- MD, PhD. Associate Professor of Laboratory Medicine, Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiaosong Qin
- MD, PhD. Professor of Laboratory Medicine, Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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17
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Evidence for the link between defective autophagy and inflammation in peripheral blood mononuclear cells of type 2 diabetic patients. J Physiol Biochem 2018; 74:369-379. [DOI: 10.1007/s13105-018-0624-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Accepted: 03/22/2018] [Indexed: 01/23/2023]
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18
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Li L, Jia D, Graf R, Yang J. Elevated serum level of pancreatic stone protein/regenerating protein (PSP/reg) is observed in diabetic kidney disease. Oncotarget 2018; 8:38145-38151. [PMID: 28418911 PMCID: PMC5503521 DOI: 10.18632/oncotarget.16369] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 02/27/2017] [Indexed: 12/16/2022] Open
Abstract
Diabetic kidney disease (DKD) is a major complication of diabetes, and serves as an important cause of end-stage renal disease (ESRD). The role of chronic inflammation in DKD is becoming widely accepted. Pancreatic stone protein/regenerating protein (PSP/reg) is a secretory protein, which is elevated in blood during infected conditions and organ failure. The aim of this study was to investigate the relationship between serum PSP/reg and DKD in patients with type 2 diabetes (T2DM). A total of 120 subjects which includes newly diagnosed T2DM patients, diabetes patients without DKD, DKD patients, as well as healthy controls were enrolled in this study. Serum PSP/reg levels were significantly higher in DKD subjects compared with those of healthy controls (p < 0.001), newly diagnosed T2DM (p < 0.001) and diabetes patients without DKD (p < 0.001). PSP/reg levels correlated positively with glycated hemoglobin (HbA1c) (p < 0.001) and serum creatinine (p < 0.001). Meanwhile, serum PSP level was negatively correlated with estimated glomerular filtration rate (eGFR) (p < 0.001). The area under the curve (AUC) for presence of DKD was 0.854. In conclusion: PSP/reg levels are significantly up-regulated in DKD patients and might be related to renal injury. A follow-up study with a large cohort is needed.
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Affiliation(s)
- Ling Li
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Dingjiaqiao, Nanjing, PR China
| | - Dongyu Jia
- Women's Cancer Program, Cedars-Sinai Medical Center, Beverly Boulevard, Los Angeles, CA, USA
| | - Rolf Graf
- Department of Visceral and Transplantation Surgery, University Hospital of Zurich, Rämistrasse, Zurich, Switzerland
| | - Jiayue Yang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Dingjiaqiao, Nanjing, PR China.,Department of Internal Medicine, Division of Diabetes, Metabolism and Endocrinology, Nanjing Medical University Affiliated Wuxi People's Hospital, Wuxi, PR China
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19
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Increased levels of circulating (TNF-α) is associated with (-308G/A) promoter polymorphism of TNF-α gene in Diabetic Nephropathy. Int J Biol Macromol 2018; 107:2113-2121. [DOI: 10.1016/j.ijbiomac.2017.10.078] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Revised: 10/06/2017] [Accepted: 10/13/2017] [Indexed: 12/21/2022]
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20
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Slieker RC, van der Heijden AAWA, van Leeuwen N, Mei H, Nijpels G, Beulens JWJ, 't Hart LM. HbA 1c is associated with altered expression in blood of cell cycle- and immune response-related genes. Diabetologia 2018; 61:138-146. [PMID: 29159468 PMCID: PMC6448931 DOI: 10.1007/s00125-017-4467-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 09/01/2017] [Indexed: 12/22/2022]
Abstract
AIMS/HYPOTHESIS Individuals with type 2 diabetes are heterogeneous in their glycaemic control as tracked by blood HbA1c levels. Here, we investigated the extent to which gene expression levels in blood reflect current and future HbA1c levels. METHODS HbA1c levels at baseline and 1 and 2 year follow-up were compared with gene expression levels in 391 individuals with type 2 diabetes from the Hoorn Diabetes Care System Cohort (15,564 genes, RNA sequencing). The functions of associated baseline genes were investigated further using pathway enrichment analysis. Using publicly available data, we investigated whether the genes identified are also associated with HbA1c in the target tissues, muscle and pancreas. RESULTS At baseline, 220 genes (1.4%) were associated with baseline HbA1c. Identified genes were enriched for cell cycle and complement system activation pathways. The association of 15 genes extended to the target tissues, muscle (n = 113) and pancreatic islets (n = 115). At follow-up, expression of 25 genes (0.16%) associated with 1 year HbA1c and nine genes (0.06%) with 2 year HbA1c. Five genes overlapped across all time points, and 18 additional genes between baseline and 1 year follow-up. After adjustment for baseline HbA1c, the number of significant genes at 1 and 2 years markedly decreased, suggesting that gene expression levels in whole blood reflect the current glycaemic state and but not necessarily the future glycaemic state. CONCLUSIONS/INTERPRETATION HbA1c levels in individuals with type 2 diabetes are associated with expression levels of genes that link to the cell cycle and complement system activation.
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Affiliation(s)
- Roderick C Slieker
- Department of Molecular Cell Biology, Leiden University Medical Center, Postal Box 9600, 2300 RC, Leiden, the Netherlands
- Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, the Netherlands
| | - Amber A W A van der Heijden
- Department of General Practice and Elderly Care Medicine, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, the Netherlands
| | - Nienke van Leeuwen
- Department of Molecular Cell Biology, Leiden University Medical Center, Postal Box 9600, 2300 RC, Leiden, the Netherlands
| | - Hailiang Mei
- Sequencing Analysis Support Core, Leiden University Medical Center, Leiden, the Netherlands
| | - Giel Nijpels
- Department of General Practice and Elderly Care Medicine, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, the Netherlands
| | - Joline W J Beulens
- Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, the Netherlands
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Leen M 't Hart
- Department of Molecular Cell Biology, Leiden University Medical Center, Postal Box 9600, 2300 RC, Leiden, the Netherlands.
- Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, the Netherlands.
- Molecular Epidemiology Section, Leiden University Medical Center, Leiden, the Netherlands.
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21
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Fernández-Juárez G, Villacorta Perez J, Luño Fernández JL, Martinez-Martinez E, Cachofeiro V, Barrio Lucia V, Tato Ribera AM, Mendez Abreu A, Cordon A, Oliva Dominguez JA, Praga Terente M. High levels of circulating TNFR1 increase the risk of all-cause mortality and progression of renal disease in type 2 diabetic nephropathy. Nephrology (Carlton) 2017; 22:354-360. [PMID: 27003829 DOI: 10.1111/nep.12781] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Revised: 02/25/2016] [Accepted: 03/15/2016] [Indexed: 11/28/2022]
Abstract
BACKGROUND Several studies have demonstrated that levels of circulating inflammatory markers such as tumour necrosis factorα (TNFα), are associated with early progression of diabetic nephropathy (DN). The aim of this study was to investigate whether there is an association between circulating TNFα receptor and disease progression in patients with advanced type 2 DN and severe proteinuria. METHODS Between 2006 and 2011, we measured levels of circulating soluble TNFα receptor 1 (TNFR1) and soluble TNFα receptor 2 (TNFR2) at baseline and 4 and 12 months in 101 patients included in a multicenter randomized controlled trial to compare the effect of optimal doses of renin-angiotensin system blockers in monotherapy or in combination (dual blockade) to slow progression of established type 2 DN. The primary composite endpoint was a >50% increase in baseline serum creatinine, end-stage renal disease, or death. RESULTS The median follow-up was 32 months (IQR, 18-48), during which time 28 patients (22.7%) achieved the primary endpoint. The TNFR1 level, but not the TNFR2 level, was correlated with other inflammatory markers. Cox regression analysis showed that the highest TNFR1 levels (HR, 2.60; 95%CI, 1.11-86.34) and baseline proteinuria (HR 1.32; 95%CI 1.15-1.52) were associated with the primary endpoint. The mixed model analysis revealed that TNFR1 and the TNFR2 levels did not change after starting treatment with renin-angiotensin system blockers. CONCLUSIONS Our results show that the highest levels of TNFR1 are independently associated with progression of renal disease and death in type 2 DN. The renin angiotensin blockers have no effect on these inflammatory markers.
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Papadopoulou-Marketou N, Kanaka-Gantenbein C, Marketos N, Chrousos GP, Papassotiriou I. Biomarkers of diabetic nephropathy: A 2017 update. Crit Rev Clin Lab Sci 2017; 54:326-342. [DOI: 10.1080/10408363.2017.1377682] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Nektaria Papadopoulou-Marketou
- Diabetes Centre of the Division of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, National and Kapodistrian University of Athens, “Aghia Sophia” Children’s Hospital, Athens, Greece
- Department of Endocrinology, Department of Medical and Health Sciences, Linkoping University, Linkoping, Sweden
| | - Christina Kanaka-Gantenbein
- Diabetes Centre of the Division of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, National and Kapodistrian University of Athens, “Aghia Sophia” Children’s Hospital, Athens, Greece
| | | | - George P. Chrousos
- Diabetes Centre of the Division of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, National and Kapodistrian University of Athens, “Aghia Sophia” Children’s Hospital, Athens, Greece
| | - Ioannis Papassotiriou
- Department of Clinical Biochemistry, “Aghia Sophia” Children’s Hospital, Athens, Greece
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Chen YL, Qiao YC, Xu Y, Ling W, Pan YH, Huang YC, Geng LJ, Zhao HL, Zhang XX. Serum TNF-α concentrations in type 2 diabetes mellitus patients and diabetic nephropathy patients: A systematic review and meta-analysis. Immunol Lett 2017; 186:52-58. [PMID: 28414180 DOI: 10.1016/j.imlet.2017.04.003] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 03/25/2017] [Accepted: 04/10/2017] [Indexed: 11/24/2022]
Abstract
OBJECTIVES The aim of this study was to investigate whether the concentrations of serum tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine, increased in type 2 diabetes mellitus (T2DM) and type 2 diabetic nephropathy (T2DN) patients. METHODS The four databases (PubMed, CNKI, WanFang and Chinese-Cqvip) were searched from Jan 1, 1999 to October 1, 2016 for all clinical case-control studies about the serum TNF-α concentrations in T2DM and T2DN patients. All relevant data were extracted from published reports. The meta-analysis was performed to compare the changes of serum TNF-α concentrations of T2DN and T2DM patients in Eastern and Western with healthy controls. We further evaluated concentrations of serum TNF-α in T2DN patients with mincroalbuminuria or macroalbuminuria. Random-effects models were adopted to assess the pooling data among various variations. RESULTS In total of 6 studies (744 patients and 277 healthy controls) were included in this study. Compared with healthy controls (both p<0.01), the groups of different albuminuria levels and ethnicities both showed that the serum TNF-α levels were significantly elevated in T2DN patients as well as in eastern T2DN patients (p=0.001), but not significant changed in western T2DN patients (p=0.081). The results were stable through sensitivity analysis and no significant publications bias existed in this meta-analysis. CONCLUSIONS Serum TNF-α concentrations are obviously increased in T2DN and T2DM patients, but higher in T2DN patients, suggesting an elevated inflammatory burden in T2DN patients.
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Affiliation(s)
- Yin-Ling Chen
- Center of Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin 541004, China; Department of Immunology, Faculty of Basic Medicine, Guilin Medical University, Guilin 541004, China
| | - Yong-Chao Qiao
- Department of Immunology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, China
| | - Yan Xu
- Department of Immunology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, China
| | - Wei Ling
- Center of Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin 541004, China
| | - Yan-Hong Pan
- Center of Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin 541004, China; Department of Immunology, Faculty of Basic Medicine, Guilin Medical University, Guilin 541004, China
| | - Yong-Cheng Huang
- Center of Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin 541004, China
| | - Li-Jun Geng
- Center of Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin 541004, China; Department of Immunology, Faculty of Basic Medicine, Guilin Medical University, Guilin 541004, China
| | - Hai-Lu Zhao
- Center of Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin 541004, China; Department of Immunology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, China; Department of Immunology, Faculty of Basic Medicine, Guilin Medical University, Guilin 541004, China
| | - Xiao-Xi Zhang
- Center of Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin 541004, China; Department of Immunology, Faculty of Basic Medicine, Guilin Medical University, Guilin 541004, China.
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Griffin TP, Martin WP, Islam N, O'Brien T, Griffin MD. The Promise of Mesenchymal Stem Cell Therapy for Diabetic Kidney Disease. Curr Diab Rep 2016; 16:42. [PMID: 27007719 DOI: 10.1007/s11892-016-0734-6] [Citation(s) in RCA: 43] [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] [Indexed: 12/21/2022]
Abstract
Diabetes mellitus (DM) commonly leads to progressive chronic kidney disease despite current best medical practice. The pathogenesis of diabetic kidney disease (DKD) involves a complex network of primary and secondary mechanisms with both intra-renal and systemic components. Apart from inhibition of the renin angiotensin aldosterone system, targeting individual pathogenic mediators with drug therapy has not, thus far, been proven to have high clinical value. Stem or progenitor cell therapies offer an alternative strategy for modulating complex disease processes through suppressing multiple pathogenic pathways and promoting pro-regenerative mechanisms. Mesenchymal stem cells (MSCs) have shown particular promise based on their accessibility from adult tissues and their diverse mechanisms of action including secretion of paracrine anti-inflammatory and cyto-protective factors. In this review, the progress toward clinical translation of MSC therapy for DKD is critically evaluated. Results from animal models suggest distinct potential for systemic MSC infusion to favourably modulate DKD progression. However, only a few early phase clinical trials have been initiated and efficacy in humans remains to be proven. Key knowledge gaps and research opportunities exist in this field. These include the need to gain greater understanding of in vivo mechanism of action, to identify quantifiable biomarkers of response to therapy and to define the optimal source, dose and timing of MSC administration. Given the rising prevalence of DM and DKD worldwide, continued progress toward harnessing the inherent regenerative functions of MSCs and other progenitor cells for even a subset of those affected has potential for profound societal benefits.
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Affiliation(s)
- Tomás P Griffin
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland
- Centre for Diabetes, Endocrinology and Metabolism, Galway University Hospitals, Saolta University Health Group, Galway, Ireland
| | - William Patrick Martin
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland
- Centre for Diabetes, Endocrinology and Metabolism, Galway University Hospitals, Saolta University Health Group, Galway, Ireland
| | - Nahidul Islam
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland
| | - Timothy O'Brien
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland
- Centre for Diabetes, Endocrinology and Metabolism, Galway University Hospitals, Saolta University Health Group, Galway, Ireland
| | - Matthew D Griffin
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland.
- Nephrology Services, Galway University Hospitals, Saolta University Health Group, Galway, Ireland.
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25
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Li Y, Wang Y, Ding X, Duan B, Li L, Wang X. Serum Levels of TNF-α and IL-6 Are Associated With Pregnancy-Induced Hypertension. Reprod Sci 2016; 23:1402-8. [DOI: 10.1177/1933719116641760] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Yuan Li
- Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
- Zibo Central Hospital, Zibo, Shandong, China
| | - Yanyun Wang
- Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | | | - Bide Duan
- Zibo Central Hospital, Zibo, Shandong, China
| | - Lei Li
- Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Xietong Wang
- Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
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Gluhovschi C, Gluhovschi G, Petrica L, Timar R, Velciov S, Ionita I, Kaycsa A, Timar B. Urinary Biomarkers in the Assessment of Early Diabetic Nephropathy. J Diabetes Res 2016; 2016:4626125. [PMID: 27413755 PMCID: PMC4927990 DOI: 10.1155/2016/4626125] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 05/12/2016] [Indexed: 12/12/2022] Open
Abstract
Diabetic nephropathy (DN) is a frequent and severe complication of diabetes mellitus (DM). Its diagnosis in incipient stages may allow prompt interventions and an improved prognosis. Towards this aim, biomarkers for detecting early DN can be used. Microalbuminuria has been proven a remarkably useful biomarker, being used for diagnosis of DN, for assessing its associated condition-mainly cardiovascular ones-and for monitoring its progression. New researches are pointing that some of these biomarkers (i.e., glomerular, tubular, inflammation markers, and biomarkers of oxidative stress) precede albuminuria in some patients. However, their usefulness is widely debated in the literature and has not yet led to the validation of a new "gold standard" biomarker for the early diagnosis of DN. Currently, microalbuminuria is an important biomarker for both glomerular and tubular injury. Other glomerular biomarkers (transferrin and ceruloplasmin) are under evaluation. Tubular biomarkers in DN seem to be of a paramount importance in the early diagnosis of DN since tubular lesions occur early. Additionally, biomarkers of inflammation, oxidative stress, podocyte biomarkers, and vascular biomarkers have been employed for assessing early DN. The purpose of this review is to provide an overview of the current biomarkers used for the diagnosis of early DN.
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Affiliation(s)
- Cristina Gluhovschi
- Division of Nephrology, University of Medicine and Pharmacy “V. Babes”, 300041 Timisoara, Romania
- *Cristina Gluhovschi:
| | | | - Ligia Petrica
- Division of Nephrology, University of Medicine and Pharmacy “V. Babes”, 300041 Timisoara, Romania
| | - Romulus Timar
- Department of Diabetes and Metabolic Diseases, University of Medicine and Pharmacy “V. Babes”, 300041 Timisoara, Romania
| | - Silvia Velciov
- Division of Nephrology, University of Medicine and Pharmacy “V. Babes”, 300041 Timisoara, Romania
| | - Ioana Ionita
- Division of Hematology, University of Medicine and Pharmacy “V. Babes”, 300041 Timisoara, Romania
| | - Adriana Kaycsa
- Department of Biochemistry, University of Medicine and Pharmacy “V. Babes”, 300041 Timisoara, Romania
| | - Bogdan Timar
- Department of Diabetes and Metabolic Diseases, University of Medicine and Pharmacy “V. Babes”, 300041 Timisoara, Romania
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27
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Montero RM, Covic A, Gnudi L, Goldsmith D. Diabetic nephropathy: What does the future hold? Int Urol Nephrol 2015; 48:99-113. [PMID: 26438328 PMCID: PMC4705119 DOI: 10.1007/s11255-015-1121-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 09/19/2015] [Indexed: 12/24/2022]
Abstract
The consensus management of diabetic nephropathy (DN) in 2015 involves good control of glycaemia, dyslipidaemia and blood pressure (BP). Blockade of the renin-angiotensin-aldosterone system using angiotensin-converting enzyme inhibitors, angiotensin-2 receptor blockers or mineralocorticoid inhibitors are key therapeutic approaches, shown to be beneficial once overt nephropathy is manifest, as either, or both, of albuminuria and loss of glomerular filtration rate. Some significant additional clinical benefits in slowing the progression of DN was reported from the Remission clinic experience, where simultaneous intensive control of BP, tight glycaemic control, weight loss, exercise and smoking cessation were prioritised in the management of DN. This has not proved possible to translate to more conventional clinical settings. This review briefly looks over the history and limitations of current therapy from landmark papers and expert reviews, and following an extensive PubMed search identifies the most promising clinical biomarkers (both established and proposed). Many challenges need to be addressed urgently as in order to obtain novel therapies in the clinic; we also need to examine what we mean by remission, stability and progression of DN in the modern era.
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Affiliation(s)
- R M Montero
- Renal, Dialysis and Transplantation Unit, Guy's and St Thomas' Hospital, London, UK.
| | - A Covic
- Hospital "C.I.Parhon" and University of Medicine "Grigore T Popa", Iasi, Romania
| | - L Gnudi
- Cardiovascular Division, Department of Diabetes and Endocrinology, Guy's and St Thomas' Hospital, School of Medicine and Life Science, King's College London, London, UK
| | - D Goldsmith
- Renal, Dialysis and Transplantation Unit, Guy's and St Thomas' Hospital, London, UK
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28
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Lee SY, Choi ME. Urinary biomarkers for early diabetic nephropathy: beyond albuminuria. Pediatr Nephrol 2015; 30:1063-75. [PMID: 25060761 PMCID: PMC4305495 DOI: 10.1007/s00467-014-2888-2] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 06/11/2014] [Accepted: 06/12/2014] [Indexed: 12/27/2022]
Abstract
Diabetic nephropathy (DN) is the most common cause of end-stage kidney disease in the USA and accounts for a significant increase in morbidity and mortality in patients with diabetes. Early detection is critical in improving clinical management. Although microalbuminuria is regarded as the gold standard for diagnosing the onset of DN, its predictive powers are limited. Consequently, great efforts have been made in recent years to identify better strategies for the detection of early stages of DN and progressive kidney function decline in diabetic patients. Here, we review the various urinary biomarkers that have emerged from these studies which hold promise as more sensitive diagnostic tools for the earlier detection of diabetic kidney disease and the prediction of progression to end-stage kidney disease. A number of key biomarkers present in the urine have been identified that reflect kidney injury at specific sites along the nephron, including glomerular/podocyte damage and tubular damage, oxidative stress, inflammation and activation of the intrarenal renin-angiotensin system. We also describe newer approaches, including urinary microRNAs, which are short noncoding mRNAs that regulate gene expression, and urine proteomics, that can be used to identify potential novel biomarkers in the development and progression of diabetic kidney disease.
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Affiliation(s)
- So-Young Lee
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115,Department of Internal Medicine, Bundang CHA Medical Center, CHA University, Seongnam, South Korea
| | - Mary E. Choi
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115,Division of Nephrology & Hypertension, Department of Medicine, Weill Cornell Medical College, New York, New York 10065, U.S.A.,Address correspondence to: Mary E. Choi, Fax: 212-746-7933; , Weill Cornell Medical College, Division of Nephrology & Hypertension, 525 East 68 Street, Box 3, New York, NY 10065
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29
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El-Samahy MH, Adly AAM, Ismail EA, Salah NY. Regulatory T cells with CD62L or TNFR2 expression in young type 1 diabetic patients: relation to inflammation, glycemic control and micro-vascular complications. J Diabetes Complications 2015; 29:120-6. [PMID: 25113439 DOI: 10.1016/j.jdiacomp.2014.07.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2014] [Revised: 06/19/2014] [Accepted: 07/09/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND Alteration of regulatory T cells (Tregs) may contribute to ineffective suppression of proinflammatory cytokines in type 1 diabetes. AIM We determined the percentage of Tregs expressing CD62L or tumor necrosis factor receptor type 2 (TNFR2) in 70 young type 1 diabetic patients compared with 30 controls and assessed their relation to inflammation, glycemic control and micro-vascular complications. METHODS High-sensitivity C-reactive protein (hs-CRP), hemoglobin A1c (HbA1c), tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) were assessed with flow cytometric analysis of Tregs, Tregs expressing CD62L or TNFR2. RESULTS The percentage of CD4(+)CD25(high) T cells and CD4(+)CD25(high)CD62L(high) cells were significantly decreased while CD4(+)CD25(high)TNFR2(+) T cells were elevated in patients with micro-vascular complications than those without and controls (p<0.001). ROC curve revealed that the cutoff values of Tregs, Tregs expressing CD62L and Tregs expressing TNFR2 (7.46%, 24.2% and 91.9%, respectively) could detect micro-vascular complications. Significant negative correlations were observed between Tregs expressing CD62L and disease duration, FBG, HbA1c, urinary albumin excretion and hs-CRP, whereas, positive correlations were found between Tregs expressing TNFR2 and these variables (p<0.05). TNF-α was significantly increased while IL-10 was decreased among patients with micro-vascular complications than those without (p<0.05). CONCLUSIONS Alteration in the frequency of Tregs and Tregs expressing CD62L or TNFR2 in type 1 diabetes is associated with increased inflammation, poor glycemic control and risk of micro-vascular complications.
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Affiliation(s)
- Mona H El-Samahy
- Pediatrics Department, Faculty of Medicine, Ain Shams University
| | - Amira A M Adly
- Pediatrics Department, Faculty of Medicine, Ain Shams University
| | - Eman A Ismail
- Clinical Pathology Department, Faculty of Medicine, Ain Shams University.
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Yang M, Liu J, Xu J, Sun T, Sheng L, Chen Z, Wang F, Huang X, Wu Y, Mao J, Zhang R. Elevated Systemic Neutrophil Count Is Associated with Diabetic Macroalbuminuria among Elderly Chinese. Int J Endocrinol 2015; 2015:348757. [PMID: 26843862 PMCID: PMC4710918 DOI: 10.1155/2015/348757] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Revised: 10/19/2015] [Accepted: 11/08/2015] [Indexed: 11/17/2022] Open
Abstract
Background. This study investigated an association between systemic absolute neutrophil count (ANC) and albuminuria in elderly Chinese people. Methods. A cross-sectional study was conducted on 2265 participants attending a routine medical examination in Minhang District as part of a Platform of Chronic Disease program. Their drug history, waist circumference, height, blood pressure, fasting blood glucose, ANC, and urine albumin levels were recorded. This study conformed to the requirements of the STROBE statement. Results. Of the 2265 subjects, 1254 (55.4%) were diabetic and 641 (28.3%) had albuminuria. The mean ANC of patients with diabetes comorbid with macroalbuminuria was significantly higher than that of both the nondiabetic patients and patients with diabetes with lower levels of albuminuria; the latter 2 groups had statistically similar ANC. ANC significantly and positively correlated with levels of urine albumin. Based on multivariate analysis, with each 10(9)/L increase in ANC, the increase in rates of macroalbuminuria was significant but not in rates of albuminuria positivity. Based on areas under the receiver operating characteristic curve, ANC was the strongest factor predicting macroalbuminuria. Conclusions. Elevated ANC was associated with macroalbuminuria in diabetes, indicating that neutrophil-mediated inflammation may be involved in the exacerbation of albuminuria.
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Affiliation(s)
- Min Yang
- Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China
| | - Jun Liu
- Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China
- *Jun Liu:
| | - Jiong Xu
- Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China
| | - Tiange Sun
- Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China
| | - Li Sheng
- Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China
| | - Zaoping Chen
- Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China
| | - Fang Wang
- Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China
| | - Xinmei Huang
- Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China
| | - Yueyue Wu
- Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China
| | - Jianfeng Mao
- Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China
| | - Rui Zhang
- Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China
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Currie G, McKay G, Delles C. Biomarkers in diabetic nephropathy: Present and future. World J Diabetes 2014; 5:763-776. [PMID: 25512779 PMCID: PMC4265863 DOI: 10.4239/wjd.v5.i6.763] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Revised: 10/03/2014] [Accepted: 10/27/2014] [Indexed: 02/05/2023] Open
Abstract
Diabetic nephropathy (DN) is the leading cause of end stage renal disease in the Western world. Microalbuminuria (MA) is the earliest and most commonly used clinical index of DN and is independently associated with cardiovascular risk in diabetic patients. Although MA remains an essential tool for risk stratification and monitoring disease progression in DN, a number of factors have called into question its predictive power. Originally thought to be predictive of future overt DN in 80% of patients, we now know that only around 30% of microalbuminuric patients progress to overt nephropathy after 10 years of follow up. In addition, advanced structural alterations in the glomerular basement membrane may already have occurred by the time MA is clinically detectable.Evidence in recent years suggests that a significant proportion of patients with MA can revert to normoalbuminuria and the concept of nonalbuminuric DN is well-documented, reflecting the fact that patients with diabetes can demonstrate a reduction in glomerular filtration rate without progressing from normo-to MA. There is an unmet clinical need to identify biomarkers with potential for earlier diagnosis and risk stratification in DN and recent developments in this field will be the focus of this review article.
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Tesch G, Sourris KC, Summers SA, McCarthy D, Ward MS, Borg DJ, Gallo LA, Fotheringham AK, Pettit AR, Yap FYT, Harcourt BE, Tan ALY, Kausman JY, Nikolic-Paterson D, Kitching AR, Forbes JM. Deletion of bone-marrow-derived receptor for AGEs (RAGE) improves renal function in an experimental mouse model of diabetes. Diabetologia 2014; 57:1977-85. [PMID: 24957662 DOI: 10.1007/s00125-014-3291-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Accepted: 05/09/2014] [Indexed: 01/11/2023]
Abstract
AIMS/HYPOTHESIS The AGEs and the receptor for AGEs (RAGE) are known contributors to diabetic complications. RAGE also has a physiological role in innate and adaptive immunity and is expressed on immune cells. The aim of this study was to determine whether deletion of RAGE from bone-marrow-derived cells influences the pathogenesis of experimental diabetic nephropathy. METHODS Groups (n = 8/group) of lethally irradiated 8 week old wild-type (WT) mice were reconstituted with bone marrow from WT (WT → WT) or RAGE-deficient (RG) mice (RG → WT). Diabetes was induced using multiple low doses of streptozotocin after 8 weeks of bone marrow reconstitution and mice were followed for a further 24 weeks. RESULTS Compared with diabetic WT mice reconstituted with WT bone marrow, diabetic WT mice reconstituted with RG bone marrow had lower urinary albumin excretion and podocyte loss, more normal creatinine clearance and less tubulo-interstitial injury and fibrosis. However, glomerular collagen IV deposition, glomerulosclerosis and cortical levels of TGF-β were not different among diabetic mouse groups. The renal tubulo-interstitium of diabetic RG → WT mice also contained fewer infiltrating CD68(+) macrophages that were activated. Diabetic RG → WT mice had lower renal cortical concentrations of CC chemokine ligand 2 (CCL2), macrophage inhibitory factor (MIF) and IL-6 than diabetic WT → WT mice. Renal cortical RAGE ligands S100 calgranulin (S100A)8/9 and AGEs, but not high mobility box protein B-1 (HMGB-1) were also decreased in diabetic RG → WT compared with diabetic WT → WT mice. In vitro, bone-marrow-derived macrophages from WT but not RG mice stimulated collagen IV production in cultured proximal tubule cells. CONCLUSIONS/INTERPRETATION These studies suggest that RAGE expression on haemopoietically derived immune cells contributes to the functional changes seen in diabetic nephropathy by promoting macrophage infiltration and renal tubulo-interstitial damage.
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Affiliation(s)
- Greg Tesch
- Department of Nephrology, Monash Medical Centre, Monash Health, Clayton, Melbourne, VIC, Australia
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Jha JC, Jandeleit-Dahm KA, Cooper ME. New insights into the use of biomarkers of diabetic nephropathy. Adv Chronic Kidney Dis 2014; 21:318-26. [PMID: 24780461 DOI: 10.1053/j.ackd.2014.03.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2013] [Revised: 03/05/2014] [Accepted: 03/10/2014] [Indexed: 12/21/2022]
Abstract
Diabetic nephropathy (DN) is a major microvascular complication of diabetes characterized by increasing albuminuria and progressive loss of kidney function. Increased excretion of albumin into the urine is a key feature of DN, and its assessment is considered to be an early marker predicting the onset and progression of DN. However, albuminuria has certain limitations; therefore, the quest for more reliable renal biomarkers with higher sensitivity and specificity are needed for early prediction of the onset and monitoring of the progression of DN. Furthermore, such biomarkers may also provide a better insight into identifying the complex pathophysiological processes responsible for DN. This article aims to provide a comprehensive and critical review of the current literature on relevant biomarkers of kidney injury, including markers of renal fibrosis, inflammation, and oxidative stress, as well as addressing contemporary proteomic approaches.
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Kurashina T, Nagasaka S, Watanabe N, Yabe D, Sugi N, Nin K, Hosokawa M, Nomura Y, Fukushima M, Nakai Y, Nishimura F, Taniguchi A. Circulating TNF receptor 2 is closely associated with the kidney function in non-diabetic Japanese subjects. J Atheroscler Thromb 2014; 21:730-8. [PMID: 24717758 DOI: 10.5551/jat.21055] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
AIM Chronic kidney disease (CKD) is associated with cardiovascular events. Tumor necrosis factor (TNF) and/or its receptors have been postulated to be involved in renal pathophysiology. It is unclear whether an increased TNF system activity is present before the development of apparent CKD. METHODS Four hundred and twenty non-diabetic Japanese subjects with an estimated GFR (eGFR) greater than 60 ml/min/1.73 m(2) were recruited for measurement of the HbA1c, insulin, TNF system activity (TNF-α, soluble TNF receptor 1 (sTNF-R1) and sTNF-R2) levels and various parameters, including the lipid, high-sensitivity C-reactive protein (hsCRP), high-molecular-weight (HMW) adiponectin and leptin levels. The subjects were stratified according to the eGFR: the G1 level (eGFR ≧90 ml/min/1.73 m(2)) and the G2 level (90 ＞eGFR ≧60 ml/min/1.73 m(2)). RESULTS Whereas no significant differences were observed in gender, body mass index (BMI), blood pressure, insulin, TNF-α, hsCRP, HMW adiponectin or leptin between the two groups, the values for age, HbA1c, triglycerides, sTNF-R1 and sTNF-R2 were significantly higher in the subjects with a G2 level of eGFR than in those with a G1 level. In contrast, the HDL cholesterol levels were significantly lower in the subjects with a G2 level than in those with a G1 level. Linear negative correlations were also observed between eGFR and age, BMI, HbA1c, triglycerides, sTNF-R1 and sTNFR2, respectively. A multiple logistic regression analysis revealed that only sTNF-R2 was associated with the presence of a G2 level of eGFR (Odds ratio 1.092, 95% CI 1.013-1.177, P=0.021). CONCLUSIONS The circulating sTNF-R2 level is closely associated with the kidney function in non-diabetic Japanese subjects.
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Tang LQ, Liu S, Zhang ST, Zhu LN, Wang FL. Berberine regulates the expression of E-prostanoid receptors in diabetic rats with nephropathy. Mol Biol Rep 2014; 41:3339-47. [DOI: 10.1007/s11033-014-3196-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2013] [Accepted: 01/23/2014] [Indexed: 10/25/2022]
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Lampropoulou IT, Stangou M, Papagianni A, Didangelos T, Iliadis F, Efstratiadis G. TNF-α and microalbuminuria in patients with type 2 diabetes mellitus. J Diabetes Res 2014; 2014:394206. [PMID: 25587544 PMCID: PMC4284977 DOI: 10.1155/2014/394206] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2014] [Revised: 09/11/2014] [Accepted: 09/19/2014] [Indexed: 01/15/2023] Open
Abstract
AIM Recent evidence suggests that chronic subclinical inflammation plays a key role in the pathogenesis and progression of diabetic nephropathy. Aim of the present study was to investigate possible correlation between the presence and degree of microalbuminuria and markers of inflammation in patients with type 2 diabetes mellitus (DM). PATIENTS-METHODS Eighty patients were enrolled and clinical and laboratory data were recorded. Albumin-creatinine ratio (ACR) was calculated in first-morning urine samples. Serum and urinary tumor necrosis factor-α (TNF-α) levels were determined by ELISA. RESULTS Forty-five patients had normoalbuminuria, 33 microalbuminuria, and 2 macroalbuminuria. Patients with microalbuminuria were older, with higher glycosylated hemoglobin levels (HbA1c) and they more frequently had diabetic retinopathy, neuropathy, and cardiovascular disease and were on treatment with angiotensin converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARBs). ACR was significantly correlated with the presence of cardiovascular disease, hypertension, and HbA1c levels and the administration of clopidogrel and ACEi or ARBs. ACR was not correlated with C-reactive protein, fibrinogen, or serum TNF-α levels but had a strong correlation with urinary TNF-α levels. CONCLUSIONS In patients with type 2 DM, urinary, but not serum, TNF-α levels are associated with the presence and severity of microalbuminuria.
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Affiliation(s)
- I.-Th. Lampropoulou
- Department of Nephrology, “Hippokratio” General Hospital, Aristotle University of Thessaloniki, 49 Konstantinoupoleos Street, 546 42 Thessaloniki, Greece
| | - M. Stangou
- Department of Nephrology, “Hippokratio” General Hospital, Aristotle University of Thessaloniki, 49 Konstantinoupoleos Street, 546 42 Thessaloniki, Greece
| | - A. Papagianni
- Department of Nephrology, “Hippokratio” General Hospital, Aristotle University of Thessaloniki, 49 Konstantinoupoleos Street, 546 42 Thessaloniki, Greece
- *A. Papagianni:
| | - T. Didangelos
- 1st Propedeutic Department of Internal Medicine, Diabetes Center, “AHEPA” General Hospital, Aristotle University of Thessaloniki, 546 36 Thessaloniki, Greece
| | - F. Iliadis
- 1st Propedeutic Department of Internal Medicine, Diabetes Center, “AHEPA” General Hospital, Aristotle University of Thessaloniki, 546 36 Thessaloniki, Greece
| | - G. Efstratiadis
- Department of Nephrology, “Hippokratio” General Hospital, Aristotle University of Thessaloniki, 49 Konstantinoupoleos Street, 546 42 Thessaloniki, Greece
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Tomé-Carneiro J, Larrosa M, Yáñez-Gascón MJ, Dávalos A, Gil-Zamorano J, Gonzálvez M, García-Almagro FJ, Ruiz Ros JA, Tomás-Barberán FA, Espín JC, García-Conesa MT. One-year supplementation with a grape extract containing resveratrol modulates inflammatory-related microRNAs and cytokines expression in peripheral blood mononuclear cells of type 2 diabetes and hypertensive patients with coronary artery disease. Pharmacol Res 2013; 72:69-82. [DOI: 10.1016/j.phrs.2013.03.011] [Citation(s) in RCA: 272] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Revised: 03/25/2013] [Accepted: 03/25/2013] [Indexed: 12/11/2022]
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Moresco RN, Sangoi MB, De Carvalho JAM, Tatsch E, Bochi GV. Diabetic nephropathy: traditional to proteomic markers. Clin Chim Acta 2013; 421:17-30. [PMID: 23485645 DOI: 10.1016/j.cca.2013.02.019] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Revised: 02/06/2013] [Accepted: 02/09/2013] [Indexed: 01/11/2023]
Abstract
Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes and it is defined as a rise in the urinary albumin excretion (UAE) rate and abnormal renal function. Currently, changes in albuminuria are considered a hallmark of onset or progression of DN. However, some patients with diabetes have advanced renal pathological changes and progressive kidney function decline even if urinary albumin levels are in the normal range, indicating that albuminuria is not the perfect marker for the early detection of DN. The present article provides an overview of the literature reporting some relevant biomarkers that have been found to be associated with DN and that potentially may be used to predict the onset and/or monitor the progression of nephropathy. In particular, biomarkers of renal damage, inflammation, and oxidative stress may be useful tools for detection at an early stage or prediction of DN. Proteomic-based biomarker discovery represents a novel strategy to improve diagnosis, prognosis and treatment of DN; however, proteomics-based approaches are not yet available in most of the clinical chemistry laboratories. The use of a panel with a combination of biomarkers instead of urinary albumin alone seems to be an interesting approach for early detection of DN, including markers of glomerular damage (e.g., albumin), tubular damage (e.g., NAG and KIM-1), inflammation (e.g., TNF-α) and oxidative stress (e.g., 8-OHdG) because these mechanisms contribute to the development and outcomes of this disease.
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Affiliation(s)
- Rafael N Moresco
- Laboratório de Pesquisa em Bioquímica Clínica, Departamento de Análises Clínicas e Toxicológicas, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil.
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Izumi Y, Yabe D, Taniguchi A, Fukushima M, Nakai Y, Hosokawa M, Okumura T, Nin K, Matsumoto K, Nishimura F, Nagasaka S, Seino Y. Circulating TNF receptor 2 is associated with the development of chronic kidney disease in non-obese Japanese patients with type 2 diabetes. Diabetes Res Clin Pract 2013; 99:145-50. [PMID: 23375231 DOI: 10.1016/j.diabres.2012.11.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Revised: 10/26/2012] [Accepted: 11/07/2012] [Indexed: 12/14/2022]
Abstract
AIMS Chronic low-grade inflammation and/or obesity are suggested to induce chronic kidney disease (CKD) in patients with type 2 diabetes. This cross-sectional study was performed to investigate the relationship between inflammatory biomarkers and CKD in non-obese patients with type 2 diabetes. METHODS 106 non-obese Japanese patients with type 2 diabetes were recruited for the measurement of GFR, TNF, HMW adiponectin, leptin, hsCRP and some variables including urinary albumin. BMI, serum creatinine, and urinary albumin levels were 22.2 ± 0.2 kg/m(2) (17.1-24.9 kg/m(2)), 0.76 ± 0.02 mg/dl (0.39-1.38 mg/dl), 40.4 ± 4.3mg/gCr (1.6-195.0mg/gCr), respectively. They were stratified into two groups based on the value of eGFR: low eGFR (eGFR<60 ml/min/1.73 m(2)) and normal eGFR (eGFR>60 ml/min/1.73 m(2)). Logistic regression analysis was used for statistical analysis. RESULTS Whereas univariate logistic regression analysis showed that gender, diabetes duration, triglyceride, HDL cholesterol, uric acid, urinary albumin, and soluble TNF receptors (sTNF-R1, sTNF-R2) are associated with the development of stage 3 CKD, multivariate logistic regression analysis revealed that sTNF-R2 (Odds ratio 1.003, 95% confidence interval 1.000 to 1.005, P=0.030) showed significant associations with the development of stage 3 CKD. CONCLUSIONS Circulating TNF receptor 2 is an independent risk factor for CKD in non-obese Japanese patients with type 2 diabetes.
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Affiliation(s)
- Yoshio Izumi
- Department of Internal Medicine, Osaka North Postal Services Agency Hospital, Osaka, Japan
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Fallahzadeh MK, Dormanesh B, Sagheb MM, Roozbeh J, Vessal G, Pakfetrat M, Daneshbod Y, Kamali-Sarvestani E, Lankarani KB. Effect of Addition of Silymarin to Renin-Angiotensin System Inhibitors on Proteinuria in Type 2 Diabetic Patients With Overt Nephropathy: A Randomized, Double-Blind, Placebo-Controlled Trial. Am J Kidney Dis 2012; 60:896-903. [PMID: 22770926 DOI: 10.1053/j.ajkd.2012.06.005] [Citation(s) in RCA: 97] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2012] [Accepted: 06/11/2012] [Indexed: 02/08/2023]
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Dayan A, Narin B, Biteker M, Aksoy S, Fotbolcu H, Duman D. Coronary calcium score, albuminuria and inflammatory markers in type 2 diabetic patients: associations and prognostic implications. Diabetes Res Clin Pract 2012; 98:98-103. [PMID: 22595190 DOI: 10.1016/j.diabres.2012.04.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2012] [Revised: 04/09/2012] [Accepted: 04/16/2012] [Indexed: 01/04/2023]
Abstract
AIMS To investigate the relationship of coronary artery calcium (CAC) scores with common carotid artery intima media thickness (CCA-IMT), albuminuria and inflammatory factors in type 2 diabetes. METHODS AND RESULTS 128 asymptomatic type 2 diabetic patients, with at least one cardiovascular risk factor in addition to diabetes, were included in the study. CAC scores, carotid arteries plaque formation and CCA-IMT were assessed. The patients were followed for a mean period of 36.6 ± 3.3 months. Linear regression analysis identified the logarithmically transformed (Ln) albuminuria (β=0.32, P=0.007), age (β=0.04, P=0.001) and the uric acid (β=0.13, P=0.04) as independent determinants of the CAC score. During follow-up period, cardiovascular events occurred in 18 out of 46 patients with CAC score ≥100 compared with 5 out of 82 patients with CAC score <100 (log rank, P<0.0001). Multivariate Cox proportional hazards analysis identified LnCAC score (P<0.0001), LnAlbuminuria (P=0.01) and uric acid (P=0.03) as independent predictors for cardiovascular events. CONCLUSIONS There was a significant relationship between CAC score, albuminuria and inflammation in patients with type 2 diabetes. LnCAC score together with LnAlbuminuria and uric acid were identified as independent predictors of cardiovascular events in these patients.
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Affiliation(s)
- Akın Dayan
- Haydarpaşa Numune Education and Research Hospital, Department of Internal Medicine, Istanbul, Turkey
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Triñanes J, Salido E, Fernández J, Rufino M, González-Posada JM, Torres A, Hernández D. Type 1 diabetes increases the expression of proinflammatory cytokines and adhesion molecules in the artery wall of candidate patients for kidney transplantation. Diabetes Care 2012; 35:427-33. [PMID: 22210567 PMCID: PMC3263898 DOI: 10.2337/dc11-1665] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Diabetes may accelerate atheromatosis in uremic patients. Our aim was to assess the influence of type 1 diabetes on the atheromatosis-related inflammation in patients with chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS We analyzed the expression of proinflammatory cytokines and adhesion molecules in the inferior epigastric artery walls of type 1 diabetic patients with CKD (n = 22) and compared it with nondiabetic uremic patients (n = 92) at the time of kidney transplantation. We evaluated the expression of interleukin (IL)-6, monocyte chemotractant protein (MCP)-1, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule-1, and the activation of nuclear factor-κβ p65 (NFkB-p65). Common carotid intima-media thickness (c-IMT) was determined by conventional echography. RESULTS IL-6, MCP-1, and VCAM-1 proteins were elevated in type 1 diabetic patients compared with nondiabetic subjects (P < 0.05). The nuclear localization of NFkB-p65 was higher in type 1 diabetic patients (P < 0.01) and correlated with the levels of MCP-1 in this group (r = 0.726, P < 0.001). Arterial fibrosis correlated with IL-6 and MCP-1 levels (r = 0.411, P < 0.001 and r = 0.378, P = 0.001). A significant correlation was observed between VCAM-1 levels and both the degree of arterial narrowing and c-IMT. CONCLUSIONS Type 1 diabetes produces a proinflammatory state in the arteries of end-stage CKD patients, with increased levels of IL-6, MCP-1, and VCAM-1, as well as a greater degree of p65 activation, which are associated with more severe vascular lesions and higher c-IMT. Although causality is not demonstrated, these findings support the major role of inflammation in type 1 diabetic patients with CKD.
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Affiliation(s)
- Javier Triñanes
- Research Unit, University Hospital of the Canary Islands, Tenerife, Spain
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Taslıpınar A, Yaman H, Yılmaz MI, Demırbas S, Saglam M, Taslıpınar MY, Agıllı M, Kurt YG, Sonmez A, Azal O, Bolu E, Yenıcesu M, Kutlu M. The relationship between inflammation, endothelial dysfunction and proteinuria in patients with diabetic nephropathy. Scandinavian Journal of Clinical and Laboratory Investigation 2011; 71:606-12. [DOI: 10.3109/00365513.2011.598944] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic proinflammatory cytokine that has been implicated as playing a causative role in many disease states, including sepsis, pneumonia, diabetes, rheumatoid arthritis, inflammatory bowel disease, psoriasis and cancer. To inhibit the enzymatic and biologic activities of MIF, we and others have developed small-molecule MIF inhibitors. Most MIF inhibitors bind within the hydrophobic pocket that contains highly conserved amino acids known to be essential for MIF's proinflammatory activity. The best characterized of these small-molecule MIF inhibitors, (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) has been validated in scores of laboratories worldwide. Like neutralizing anti-MIF antibodies, ISO-1 significantly improves survival and reduces disease progression and/or severity in multiple murine models where MIF is implicated. This MIF inhibitor, its derivatives and other MIF-targeted compounds show great promise for future testing in disease states where increased MIF activity has been discovered.
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Lu J, Randell E, Han Y, Adeli K, Krahn J, Meng QH. Increased plasma methylglyoxal level, inflammation, and vascular endothelial dysfunction in diabetic nephropathy. Clin Biochem 2011; 44:307-11. [DOI: 10.1016/j.clinbiochem.2010.11.004] [Citation(s) in RCA: 98] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2010] [Revised: 11/11/2010] [Accepted: 11/15/2010] [Indexed: 12/31/2022]
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Idasiak-Piechocka I, Oko A, Pawliczak E, Kaczmarek E, Czekalski S. Urinary excretion of soluble tumour necrosis factor receptor 1 as a marker of increased risk of progressive kidney function deterioration in patients with primary chronic glomerulonephritis. Nephrol Dial Transplant 2010; 25:3948-56. [PMID: 20525973 DOI: 10.1093/ndt/gfq310] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND The effects of tumor necrosis factor α (TNF α), a potent proinflammatory cytokine, in the kidneys are mediated by two membrane receptors (TNFR), TNFR1 and TNFR2. The expression of both TNF and TNFRs increases in several kidney diseases and is associated with the shedding of the receptors out of the cell membranes. In an experimental model of glomerulonephritis (GN), elevated concentrations of TNFRs in serum and TNFRs excretion in urine were demonstrated. The aim of this study was evaluation of urinary excretion of TNFR1 and its relationship with the clinical markers of kidney injury in patients with GN. The value of basal urinary TNFR1 excretion as a prognostic indicator of the progression of kidney function impairment was also assessed. MATERIAL AND METHODS Fifty-five patients with newly diagnosed, biopsy-proven primary GN were included in the study. In all patients, and in 20 healthy subjects, UTNFR1 was measured using an ELISA . In the patients, risk factors of the progression of impairment of kidney function (reduced eCcr, nephrotic syndrome, hypertension and intensity of morphological lesions in the kidneys) were evaluated. The appropriate treatment was then introduced and the patients were in follow-up for 4 years. The progression of kidney function impairment was defined as a reduction of eCcr > 5 mL/min/1.73 m2 /year during follow-up. The association of basal TNFR1 excretion with the progression was evaluated. RESULTS Urinary excretion of TNFR1 in the patients with GN (4039.2 ± 3801.5 pg/mgCr) was greater than in the healthy subjects (1358.9 ± 927.8 pg/mgCr, P < 0,00002). A significant negative correlation between TNFR1 excretion and eCcr (Sr=0.464, P < 0.01) and a positive correlation between TNFR1 excretion and proteinuria (Sr = 0,463, P < 0.01) were found. In 13 patients, a marked reduction of eCcr was observed during follow-up. Logistic regression analysis revealed that TNFR1 excretion > 3863.3 pg/mgCr predicts progression of renal function impairment along with advanced interstitial fibrosis in the kidney biopsy specimens at presentation. CONCLUSION Markedly elevated urinary TNFR1 excretion may be considered as a good marker of an activated TNFα-pathway in patients with newly diagnosed GN and as a potentially modifiable risk factor of progressive kidney function impairment.
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Affiliation(s)
- Ilona Idasiak-Piechocka
- Department of Nephrology, Transplantology and Internal Medicine, Poznań University of Medical Sciences, Poznań, Poland.
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Kajitani N, Shikata K, Nakamura A, Nakatou T, Hiramatsu M, Makino H. Microinflammation is a common risk factor for progression of nephropathy and atherosclerosis in Japanese patients with type 2 diabetes. Diabetes Res Clin Pract 2010; 88:171-6. [PMID: 20138680 DOI: 10.1016/j.diabres.2010.01.012] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2009] [Revised: 01/06/2010] [Accepted: 01/11/2010] [Indexed: 12/27/2022]
Abstract
AIM This study aimed to evaluate the change of serum levels of proinflammatory molecules in patients with type 2 diabetes and clarify the involvement of these molecules in diabetic nephropathy and atherosclerosis. METHODS Sixty-six Japanese type 2 diabetic patients (T2DM) and 39 healthy control subjects were enrolled. We assessed clinical parameters, urinary albumin excretion rate (AER), brachial-ankle pulse wave velocity (baPWV), intima media thickness (IMT) and serum levels of proinflammatory molecules. RESULTS Serum levels of IL-6, IP-10 and MCP-1 were significantly higher in T2DM than in control subjects. In T2DM, serum levels of high-sensitivity (hs) CRP, IP-10, hsTNF-alpha, VCAM-1 and E-selectin were positively correlated with AER. Serum levels of IP-10, hsTNF-alpha and VCAM-1 were positively correlated with baPWV. Serum levels of hsCRP, IL-6, IP-10 and hsTNF-alpha were positively correlated with IMT. Multiple linear regression analysis revealed that serum levels of hsTNF-alpha were independently associated with AER (beta=0.235, P=0.038) and serum levels of IP-10 were independently associated with baPWV (beta=0.209, P=0.047) and IMT (beta=0.303, P=0.032). CONCLUSION Our results suggest that low-grade inflammation, microinflammation, may be a common risk factor for diabetic nephropathy and atherosclerosis in Japanese type 2 diabetic patients.
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Affiliation(s)
- Nobuo Kajitani
- Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama 700-8558, Japan
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Matheson A, Willcox MDP, Flanagan J, Walsh BJ. Urinary biomarkers involved in type 2 diabetes: a review. Diabetes Metab Res Rev 2010; 26:150-71. [PMID: 20222150 DOI: 10.1002/dmrr.1068] [Citation(s) in RCA: 109] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Diabetes mellitus is one of the most challenging health concerns of the 21st century. With at least 30% of the diabetic population remaining undiagnosed, effective and early diagnosis is of critical concern. Development of a diagnostic test, more convenient and reliable than those currently used, would therefore be highly beneficial. Urine as a diagnostic medium allows for non-invasive detection of biomarkers, including some associated with type 2 diabetes and its complications. This review provides a synopsis of those urinary biomarkers that potentially may provide a basis for the development of improved diagnostic tests. Three main pathways for the sourcing of potential makers are identified: kidney damage, oxidative stress and low-grade inflammation including atherosclerosis/vascular damage. This review briefly presents each pathway and some of the most relevant urinary biomarkers that may be used to monitor the development or progression of diabetes and its complications. In particular, biomarkers of renal dysfunction such as transferrin, type IV collagen and N-acetyl-beta-D-glucosaminidase might prove to be more sensitive than urinary albumin, the current gold standard, in the detection of incipient nephropathy and risk assessment of cardiovascular disease. Inflammatory markers including orosomucoid, tumour necrosis factor-alpha, transforming growth factor-beta, vascular endothelial growth factor and monocyte chemoattractant protein-1, as well as oxidative stress markers such as 8-hydroxy-2'deoxyguanosine may also be useful biomarkers for diagnosis or monitoring of diabetic complications, particularly kidney disease. However, the sensitivity of these markers compared with albumin requires further investigation.
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Affiliation(s)
- Agnès Matheson
- Minomic Pty Ltd, Frenchs Forest, New South Wales, Australia.
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Kalaitzidis R, Bakris G. Pathogenesis and treatment of microalbuminuria in patients with diabetes: the road ahead. J Clin Hypertens (Greenwich) 2010; 11:636-43. [PMID: 19878372 DOI: 10.1111/j.1751-7176.2009.00184.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The incidence of type 2 diabetes is increasing in the United States, which is expected to result in an increased prevalence of microalbuminuria and higher cardiovascular risk. Microalbuminuria is an indication that a low-level inflammatory process is ongoing. In patients with hypertension, with or without diabetes, increasing urinary albumin excretion (UAE) is associated with elevated levels of inflammatory markers, endothelial dysfunction, and platelet activation. Microalbuminuria is associated with an increased incidence of cardiovascular disease (CVD) morbidity and mortality in patients with hypertension and in those with diabetes with or without hypertension. Antihypertensive agents that modulate the renin-angiotensin-aldosterone system (RAAS) can delay the onset and reduce progression of microalbuminuria and decrease CVD morbidity and mortality in patients with diabetes. Clinical trials provide a spectrum of results regarding the protective effects of RAAS-blocking agents. Consideration of baseline blood pressure (BP), UAE and CVD risk, and the extent of BP lowering with treatment is necessary when interpreting clinical trial results in patients with microalbuminuria. It remains to be determined whether targeting the underlying inflammatory process can retard or prevent microalbuminuria progression or whether treatment of microalbuminuria can prevent end-stage renal disease or death.
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Nakano D, Ichihara A. Anti-inflammatory effects of prorenin/(pro)renin receptor blockade: potential mechanisms of action. Clin Exp Pharmacol Physiol 2009; 37:275-6. [PMID: 19930421 DOI: 10.1111/j.1440-1681.2009.05340.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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