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Mokgonyana PJ, Mokwatsi GG, Gwini SM, Gafane-Matemane LF. The relationship between kidney function and the soluble (pro)renin receptor in young adults: the African-PREDICT study. BMC Nephrol 2025; 26:172. [PMID: 40181300 PMCID: PMC11966904 DOI: 10.1186/s12882-025-04038-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 02/21/2025] [Indexed: 04/05/2025] Open
Abstract
High renin angiotensin-aldosterone system (RAAS) activity is associated with target organ damage. Soluble (pro)renin receptor [s(P)RR] forms part of the RAAS cascade and is associated with kidney damage through both angiotensin II-dependent and -independent pathways. Additionally, s(P)RR levels are higher in hypertension and chronic kidney disease (CKD) patients. However, little is known regarding ethnic and sex differences in s(P)RR levels and its potential associations with kidney function in young healthy adults. Identifying these associations in young populations is essential for identification of areas of intervention to prevent CKD. This study aimed to compare levels of s(P)RR across ethnic and sex groups and determine s(P)RR associations with markers of kidney function, including estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (uACR) and alpha 1-microglobulin (uA1M). The study included 1156 young healthy Black and White South Africans aged 20-30 years (Men, N = 555; Women, N = 601). We measured uA1M, albumin and creatinine in urine to calculate uACR. s(P)RR, cystatin C and creatinine were measured in serum and eGFR was calculated. Independent t-tests and multiple regression analyses were carried out to compare groups and explore associations. s(P)RR levels were higher in White participants, and higher in White men than in women (all p < 0.001). eGFR was higher in both Black men and women than in White men and women (both p ≤ 0.001). Both uA1M and uACR were higher in Black men than in White men (both p ≤ 0.003). We observed an independent negative association between eGFR and s(P)RR in Black women only (Adj.R2 = 0.309; Std. β=-0.141; p = 0.026), while uA1M associated positively with s(P)RR in the White group only (Adj.R2 = 0.063; Std. β = 0.115; p = 0.018). No associations were evident between uACR and s(P)RR in any of the groups. The positive association between uA1M and s(P)RR suggest that s(P)RR may contribute to kidney damage in young White participants through pathways associated with inflammation and fibrosis. A better understanding of mechanisms linking s(P)RR to kidney damage may lead to discovery of areas of therapeutic interventions for the prevention and treatment of CKD in different population groups. Trial registration ClinicalTrials.gov NCT03292094. Registration date 2017-09-12.
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Affiliation(s)
- Phuti J Mokgonyana
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom Campus, Private Bag X6001, Potchefstroom, 2520, South Africa
| | - Gontse G Mokwatsi
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom Campus, Private Bag X6001, Potchefstroom, 2520, South Africa
- MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom Campus, Private Bag X6001, Potchefstroom, 2520, South Africa
| | - Stella M Gwini
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Lebo F Gafane-Matemane
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom Campus, Private Bag X6001, Potchefstroom, 2520, South Africa.
- MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom Campus, Private Bag X6001, Potchefstroom, 2520, South Africa.
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Li X, Zhang X, Wang S, Li Y, Meng C, Wang J, Chang B, Yang J. Simultaneous detection of multiple urinary biomarkers in patients with early-stage diabetic kidney disease using Luminex liquid suspension chip technology. Front Endocrinol (Lausanne) 2024; 15:1443573. [PMID: 39229378 PMCID: PMC11369644 DOI: 10.3389/fendo.2024.1443573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 07/30/2024] [Indexed: 09/05/2024] Open
Abstract
Background Several urinary biomarkers have good diagnostic value for diabetic kidney disease (DKD); however, the predictive value is limited with the use of single biomarkers. We investigated the clinical value of Luminex liquid suspension chip detection of several urinary biomarkers simultaneously. Methods The study included 737 patients: 585 with diabetes mellitus (DM) and 152 with DKD. Propensity score matching (PSM) of demographic and medical characteristics identified a subset of 78 patients (DM = 39, DKD = 39). Two Luminex liquid suspension chips were used to detect 11 urinary biomarkers according to their molecular weight and concentration. The biomarkers, including cystatin C (CysC), nephrin, epidermal growth factor (EGF), kidney injury molecule-1 (KIM-1), retinol-binding protein4 (RBP4), α1-microglobulin (α1-MG), β2-microglobulin (β2-MG), vitamin D binding protein (VDBP), tissue inhibitor of metalloproteinases-1 (TIMP-1), tumor necrosis factor receptor-1 (TNFR-1), and tumor necrosis factor receptor-2 (TNFR-2) were compared in the DM and DKD groups. The diagnostic values of single biomarkers and various biomarker combinations for early diagnosis of DKD were assessed using receiver operating characteristic (ROC) curve analysis. Results Urinary levels of VDBP, RBP4, and KIM-1 were markedly higher in the DKD group than in the DM group (p < 0.05), whereas the TIMP-1, TNFR-1, TNFR-2, α1-MG, β2-MG, CysC, nephrin, and EGF levels were not significantly different between the groups. RBP4, KIM-1, TNFR-2, and VDBP reached p < 0.01 in univariate analysis and were entered into the final analysis. VDBP had the highest AUC (0.780, p < 0.01), followed by RBP4 (0.711, p < 0.01), KIM-1 (0.640, p = 0.044), and TNFR-2 (0.615, p = 0.081). However, a combination of these four urinary biomarkers had the highest AUC (0.812), with a sensitivity of 0.742 and a specificity of 0.760. Conclusions The urinary levels of VDBP, RBP4, KIM-1, and TNFR-2 can be detected simultaneously using Luminex liquid suspension chip technology. The combination of these biomarkers, which reflect different mechanisms of kidney damage, had the highest diagnostic value for DKD. However, this finding should be explored further to understand the synergistic effects of these biomarkers.
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Affiliation(s)
- Xinran Li
- National Health Commission (NHC) Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Xinxin Zhang
- National Health Commission (NHC) Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Shenglan Wang
- National Health Commission (NHC) Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Yuan Li
- National Health Commission (NHC) Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Cheng Meng
- National Health Commission (NHC) Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Jingyu Wang
- National Health Commission (NHC) Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Baocheng Chang
- National Health Commission (NHC) Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Juhong Yang
- National Health Commission (NHC) Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- Department of Endocrinology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
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Soltani-Fard E, Taghvimi S, Karimi F, Vahedi F, Khatami SH, Behrooj H, Deylami Hayati M, Movahedpour A, Ghasemi H. Urinary biomarkers in diabetic nephropathy. Clin Chim Acta 2024; 561:119762. [PMID: 38844018 DOI: 10.1016/j.cca.2024.119762] [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: 04/18/2024] [Revised: 06/01/2024] [Accepted: 06/03/2024] [Indexed: 06/10/2024]
Abstract
Diabetic nephropathy (DN), a significant consequence of diabetes, is associated with adverse cardiovascular and renal disease as well as mortality. Although microalbuminuria is considered the best non-invasive marker for DN, better predictive markers are needed of sufficient sensitivity and specificity to detect disease in general and in early disease specifically. Even prior to appearance of microalbuminuria, urinary biomarkers increase in diabetics and can serve as accurate nephropathy biomarkers even in normoalbuminuria. In this review, a number of novel urine biomarkers including those reflecting kidney damage caused by glomerular/podocyte damage, tubular damage, oxidative stress, inflammation, and intrarenal renin-angiotensin system activation are discussed. Our review also includes emerging biomarkers such as urinary microRNAs. These short noncoding miRNAs regulate gene expression and could be utilized to identify potential novel biomarkers in DN development and progression. .
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Affiliation(s)
- Elahe Soltani-Fard
- Student Research Committee, Shahrekord University of Medical Sciences, Shahrekord, Iran; Department of Molecular Medicine, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Sina Taghvimi
- Department of Biology, Faculty of Sciences, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | | | - Farzaneh Vahedi
- Biomedical and Microbial Advanced Technologies Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Seyyed Hossein Khatami
- Student Research Committee, Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | | | | | - Hassan Ghasemi
- Research Center for Environmental Contaminants (RCEC), Abadan University of Medical Sciences, Abadan, Iran.
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Altman J, Bai S, Purohit S, White J, Steed D, Liu S, Hopkins D, She JX, Sharma A, Zhi W. A candidate panel of eight urinary proteins shows potential of early diagnosis and risk assessment for diabetic kidney disease in type 1 diabetes. J Proteomics 2024; 300:105167. [PMID: 38574989 DOI: 10.1016/j.jprot.2024.105167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 03/22/2024] [Accepted: 04/01/2024] [Indexed: 04/06/2024]
Abstract
Diabetic kidney disease (DKD) poses a significant health challenge for individuals with diabetes. At its initial stages, DKD often presents asymptomatically, and the standard for non-invasive diagnosis, the albumin-creatinine ratio (ACR), employs discrete categorizations (normal, microalbuminuria, macroalbuminuria) with limitations in sensitivity and specificity across diverse population cohorts. Single biomarker reliance further restricts the predictive value in clinical settings. Given the escalating prevalence of diabetes, our study uses proteomic technologies to identify novel urinary proteins as supplementary DKD biomarkers. A total of 158 T1D subjects provided urine samples, with 28 (15 DKD; 13 non-DKD) used in the discovery stage and 131 (45 DKD; 40 pDKD; 46 non-DKD) used in the confirmation. We identified eight proteins (A1BG, AMBP, AZGP1, BTD, RBP4, ORM2, GM2A, and PGCP), all of which demonstrated excellent area-under-the-curve (AUC) values (0.959 to 0.995) in distinguishing DKD from non-DKD. Furthermore, this multi-marker panel successfully segregated the most ambiguous group (microalbuminuria) into three distinct clusters, with 80% of subjects aligning either as DKD or non-DKD. The remaining 20% exhibited continued uncertainty. Overall, the use of these candidate urinary proteins allowed for the better classification of DKD and offered potential for significant improvements in the early identification of DKD in T1D populations.
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Affiliation(s)
- Jeremy Altman
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA 30912, USA.
| | - Shan Bai
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA 30912, USA.
| | - Sharad Purohit
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA 30912, USA; Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
| | - John White
- Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
| | - Dennis Steed
- Southeastern Endocrine and Diabetes, Atlanta, GA 30076, USA
| | - Su Liu
- Department of Endocrinology, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu Province
| | - Diane Hopkins
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA 30912, USA; Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
| | - Jin-Xiong She
- Jinfiniti Precision Medicine, Augusta, GA 30901, USA.
| | - Ashok Sharma
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA 30912, USA; Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Population Health Sciences, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
| | - Wenbo Zhi
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA 30912, USA; Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
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Jha R, Lopez-Trevino S, Kankanamalage HR, Jha JC. Diabetes and Renal Complications: An Overview on Pathophysiology, Biomarkers and Therapeutic Interventions. Biomedicines 2024; 12:1098. [PMID: 38791060 PMCID: PMC11118045 DOI: 10.3390/biomedicines12051098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 05/09/2024] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
Diabetic kidney disease (DKD) is a major microvascular complication of both type 1 and type 2 diabetes. DKD is characterised by injury to both glomerular and tubular compartments, leading to kidney dysfunction over time. It is one of the most common causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Persistent high blood glucose levels can damage the small blood vessels in the kidneys, impairing their ability to filter waste and fluids from the blood effectively. Other factors like high blood pressure (hypertension), genetics, and lifestyle habits can also contribute to the development and progression of DKD. The key features of renal complications of diabetes include morphological and functional alterations to renal glomeruli and tubules leading to mesangial expansion, glomerulosclerosis, homogenous thickening of the glomerular basement membrane (GBM), albuminuria, tubulointerstitial fibrosis and progressive decline in renal function. In advanced stages, DKD may require treatments such as dialysis or kidney transplant to sustain life. Therefore, early detection and proactive management of diabetes and its complications are crucial in preventing DKD and preserving kidney function.
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Affiliation(s)
- Rajesh Jha
- Kansas College of Osteopathic Medicine, Wichita, KS 67202, USA;
| | - Sara Lopez-Trevino
- Department of Diabetes, School of Translational Medicine, Monash University, Melbourne, VIC 3004, Australia
| | - Haritha R. Kankanamalage
- Department of Diabetes, School of Translational Medicine, Monash University, Melbourne, VIC 3004, Australia
| | - Jay C. Jha
- Department of Diabetes, School of Translational Medicine, Monash University, Melbourne, VIC 3004, Australia
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Liang Q, Jing J, He H, Huang X, Liu J, Wang M, Qi Z, Zhang L, Huang Z, Yan Y, Liu S, Gao M, Zou Y. Manganese induces podocyte injury through regulating MTDH/ALKBH5/NLRP10 axis: Combined analysis at epidemiology and molecular biology levels. ENVIRONMENT INTERNATIONAL 2024; 187:108672. [PMID: 38648691 DOI: 10.1016/j.envint.2024.108672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 03/01/2024] [Accepted: 04/16/2024] [Indexed: 04/25/2024]
Abstract
Manganese (Mn) is an essential micronutrient required for various biological processes but excess exposure to Mn can cause neurotoxicity. However, there are few reports regarding the toxicity effect of Mn on the kidney as well as the underlying molecule mechanism. Herein, in vivo experiments were adopted to assess the toxicity effects associated with Mn, and found that chronic Mn treatment induced the injury of glomerular podocytes but not renal tubule in rats. Genome-wide CRISPR/Cas9 knockout screen was then employed to explore the biotargets of the toxic effect of Mn on podocytes. Through functional analyses of the enriched candidate genes, NLRP10 was found to be significantly up-regulated and mediated Mn-induced podocyte apoptosis. Further mechanism investigation revealed that NLRP10 expression was regulated by demethylase AlkB homolog 5 (ALKBH5) in an m6A-dependent fashion upon Mn treatment. Moreover, Mn could directly bind to Metadherin (MTDH) and promoted its combination with ALKBH5 to promote NLRP10 expression and cell apoptosis. Finally, logistic regressions, restricted cubic spline regressions and uniform cubic B-spline were used to investigate the association between Mn exposure and the risk of chronic kidney disease (CKD). A U-shaped nonlinear relationship between CKD risk and plasma Mn level, and a positive linear relationship between CKD risk and urinary Mn levels was found in our case-control study. To sum up, our findings illustrated that m6A-dependent NLRP10 regulation is indispensable for podocyte apoptosis and nephrotoxicity induced by Mn, providing fresh insight into understanding the health risk of Mn and a novel target for preventing renal injury in Mn-intoxicated patients.
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Affiliation(s)
- Qiuju Liang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Jiajun Jing
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; School of Public Health, Guangxi Medical University, Nanning 530021, China
| | - Huiming He
- School of Public Health, Guangxi Medical University, Nanning 530021, China; Institute of Parasitic Disease Control and Prevention, Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning 530021, China
| | - Xiaofeng Huang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100085, China
| | - Jianing Liu
- School of Public Health, Guangxi Medical University, Nanning 530021, China
| | - Mingjun Wang
- Department of Nephrology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Zijuan Qi
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan 250014, Shandong, China
| | - Li'e Zhang
- School of Public Health, Guangxi Medical University, Nanning 530021, China
| | - Ziang Huang
- Department of Mathematics, University of California at Davis, CA 95616, USA
| | - Yuanliang Yan
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Sijin Liu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100085, China
| | - Ming Gao
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100085, China.
| | - Yunfeng Zou
- School of Public Health, Guangxi Medical University, Nanning 530021, China.
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Semnani-Azad Z, Wang WZN, Cole DEC, Johnston LW, Wong BYL, Fu L, Retnakaran R, Harris SB, Hanley AJ. Urinary Vitamin D Binding Protein: A Marker of Kidney Tubular Dysfunction in Patients at Risk for Type 2 Diabetes. J Endocr Soc 2024; 8:bvae014. [PMID: 38352963 PMCID: PMC10862653 DOI: 10.1210/jendso/bvae014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Indexed: 02/16/2024] Open
Abstract
Context Recent studies have reported elevated urinary vitamin D binding protein (uVDBP) concentrations in patients with diabetic kidney disease, although the utility of uVDBP to predict deterioration of kidney function over time has not been examined. Objective Our objective was to assess the association of uVDBP with longitudinal changes in kidney function. Methods Adults at-risk for type 2 diabetes from the Prospective Metabolism and Islet Cell Evaluation (PROMISE) study had 3 assessments over 6 years (n = 727). Urinary albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were used as measures of kidney function. Measurements of uVDBP were performed with enzyme-linked immunosorbent assay and normalized to urine creatinine (uVDBP:cr). Generalized estimating equations (GEEs) evaluated longitudinal associations of uVDBP and uVDBP:cr with measures of kidney function, adjusting for covariates. Results Renal uVDBP loss increased with ACR severity at baseline. Individuals with normoalbuminuria, microalbuminuria, and macroalbuminuria had median log uVDBP:cr concentrations of 1.62 μg/mmol, 2.63 μg/mmol, and 2.48 μg/mmol, respectively, and ACR positively correlated with uVDBP concentrations (r = 0.37; P < .001). There was no significant association between uVDBP and eGFR at baseline. Adjusted longitudinal GEE models indicated that each SD increase both in baseline and longitudinal uVDBP:cr was significantly associated with higher ACR over 6 years (β = 30.67 and β = 32.91, respectively). Conversely, neither baseline nor longitudinal uVDBP:cr measures showed a significant association with changes in eGFR over time. These results suggest that loss of uVDBP:cr over time may be a useful marker for predicting renal tubular damage in individuals at risk for diabetes.
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Affiliation(s)
- Zhila Semnani-Azad
- Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA
- Department of Nutritional Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Windy Z N Wang
- Department of Nutritional Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - David E C Cole
- Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Pediatrics (Genetics), University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Luke W Johnston
- Department of Public Health, Aarhus University, Aarhus 8000, Denmark
| | - Betty Y L Wong
- Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
| | - Lei Fu
- Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Ravi Retnakaran
- Division of Endocrinology and Metabolism, University of Toronto, Toronto, ON M5S 1A8, Canada
- Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
| | - Stewart B Harris
- Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada
| | - Anthony J Hanley
- Department of Nutritional Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada
- Division of Endocrinology and Metabolism, University of Toronto, Toronto, ON M5S 1A8, Canada
- Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
- Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5S 1A8, Canada
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Sinha SK, Nicholas SB. Pathomechanisms of Diabetic Kidney Disease. J Clin Med 2023; 12:7349. [PMID: 38068400 PMCID: PMC10707303 DOI: 10.3390/jcm12237349] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 11/15/2023] [Accepted: 11/22/2023] [Indexed: 03/15/2024] Open
Abstract
The worldwide occurrence of diabetic kidney disease (DKD) is swiftly rising, primarily attributed to the growing population of individuals affected by type 2 diabetes. This surge has been transformed into a substantial global concern, placing additional strain on healthcare systems already grappling with significant demands. The pathogenesis of DKD is intricate, originating with hyperglycemia, which triggers various mechanisms and pathways: metabolic, hemodynamic, inflammatory, and fibrotic which ultimately lead to renal damage. Within each pathway, several mediators contribute to the development of renal structural and functional changes. Some of these mediators, such as inflammatory cytokines, reactive oxygen species, and transforming growth factor β are shared among the different pathways, leading to significant overlap and interaction between them. While current treatment options for DKD have shown advancement over previous strategies, their effectiveness remains somewhat constrained as patients still experience residual risk of disease progression. Therefore, a comprehensive grasp of the molecular mechanisms underlying the onset and progression of DKD is imperative for the continued creation of novel and groundbreaking therapies for this condition. In this review, we discuss the current achievements in fundamental research, with a particular emphasis on individual factors and recent developments in DKD treatment.
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Affiliation(s)
- Satyesh K. Sinha
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
- College of Medicine, Charles R Drew University of Medicine and Science, Los Angeles, CA 90059, USA
| | - Susanne B. Nicholas
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
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Zhao Z, Yan Q, Fang L, Li G, Liu Y, Li J, Pan S, Zhou S, Duan J, Liu D, Liu Z. Identification of urinary extracellular vesicles differentially expressed RNAs in diabetic nephropathy via whole-transcriptome integrated analysis. Comput Biol Med 2023; 166:107480. [PMID: 37738894 DOI: 10.1016/j.compbiomed.2023.107480] [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: 02/15/2023] [Revised: 08/30/2023] [Accepted: 09/15/2023] [Indexed: 09/24/2023]
Abstract
BACKGROUND Diabetic nephropathy (DN) is a common systemic microvascular complication of diabetes and a leading cause of chronic kidney disease worldwide. Urinary extracellular vesicles (uEVs), which are natural nanoscale vesicles that protect RNA from degradation, have the potential to serve as an invasive diagnostic biomarker for DN. METHODS We enrolled 24 participants, including twelve with renal biopsy-proven T2DN and twelve with T2DM, and isolated uEVs using ultracentrifugation. We performed microarrays for mRNAs, lncRNAs, and circRNAs in parallel, and Next-Generation Sequencing for miRNAs. Differentially expressed RNAs (DE-RNAs) were subjected to CIBERSORTx, ssGSEA analysis, GO enrichment, PPI network analysis, and construction of the lncRNA/circRNA-miRNA-mRNA regulatory network. Candidate genes and potential biomarker RNAs were validated using databases and machine learning models. RESULTS A total of 1684 mRNAs, 126 lncRNAs, 123 circRNAs and 66 miRNAs were found in uEVs in T2DN samples compared with T2DM. CIBERSORTx revealed the involvement of uEVs in immune activity and ssGSEA explored possible cell or tissue sources of uEVs. A ceRNA co-expression and regulation relationship network was constructed. Candidate genes MYO1C and SP100 mRNA were confirmed to be expressed in the kidney using Nephroseq database, scRNA-seq dataset, and Human Protein Atlas database. We further selected 2 circRNAs, 2 miRNAs, and 2 lncRNAs from WGCNAs and ceRNAs and demonstrated their efficacy as potential diagnostic biomarkers for T2DN using machine learning algorithms. CONCLUSIONS This study reported, for the first time, the whole-transcriptome genetic resources found in urine extracellular vesicles of T2DN patients. The results provide additional support for the possible interactions, and regulators between RNAs from uEVs themselves and as potential biomarkers in DN.
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Affiliation(s)
- Zihao Zhao
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China; Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China; Academy of Medical Science, Zhengzhou University, Zhengzhou, 450052, PR China
| | - Qianqian Yan
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China; Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China; Academy of Medical Science, Zhengzhou University, Zhengzhou, 450052, PR China
| | - Li Fang
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China; Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China; Academy of Medical Science, Zhengzhou University, Zhengzhou, 450052, PR China
| | - Guangpu Li
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China; Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China; Academy of Medical Science, Zhengzhou University, Zhengzhou, 450052, PR China
| | - Yong Liu
- Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China
| | - Jia Li
- Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China
| | - Shaokang Pan
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China; Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China
| | - Sijie Zhou
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China
| | - Jiayu Duan
- Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China
| | - Dongwei Liu
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China; Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China.
| | - Zhangsuo Liu
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China; Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China.
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10
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Zhou Y, Zhang Y, Chen J, Wang T, Li H, Wu F, Shang J, Zhao Z. Diagnostic value of α1-MG and URBP in early diabetic renal impairment. Front Physiol 2023; 14:1173982. [PMID: 37929213 PMCID: PMC10621041 DOI: 10.3389/fphys.2023.1173982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 10/09/2023] [Indexed: 11/07/2023] Open
Abstract
Aims/Introduction: Diabetic kidney disease (DKD) is defined as diabetes with impaired renal function, elevated urinary albumin excretion, or both. DKD is one of the most common microvascular complications of diabetes and plays an important role in the cause of end-stage renal disease (ESRD). About 5% of people with type 2 diabetes (T2DM) already have kidney damage at the time they are diagnosed, but other triggers of renal insufficiency, such as obesity, hyperlipidemia, glomerular atherosclerosis are often present, making it difficult to define "diabetic kidney disease" or "diabetic nephropathy" precisely in epidemiology or clinical practice. Therefore, the aim of this study is to identify diabetic patients with CKD at an early stage, and evaluate the value of tubular injury markers including α1-microglobulin (α1-MG), β2-microglobulin (β2-MG), N-acetyl-beta-D-glucosaminidase (NAG) and Urinary retinol binding protein (URBP) in the development of diabetes to DKD. Materials and methods: We recruited a total of 182 hospitalized patients with T2DM in the First Affiliated Hospital of Zhengzhou University from February 2018 to April 2023. We collected basic clinical characteristics and laboratory biochemical parameters of the patients. Based on their levels of urinary albumin creatinine ratio (UACR) and glomerular filtration rate (GFR), patients were divided into DM group (UACR≤30 mg/g and eGFR≥90 mL/min/1.73 m2, n = 63) and DKD group (UACR>30 mg/g or eGFR<90 mL/min/1.73 m2, n = 119) excluding other causes of chronic kidney disease. We further developed diagnostic models to improve the ability to predict the risk of developing DKD by screening potential risk factors using univariate and multivariate logistic regression analysis. Calibration plots and curve analysis were used to validate the model and clinical usefulness. Next, we screened patients with relatively normal estimated glomerular filtration rate (eGFR) (≥90 mL/min/1.73 m2) to investigate whether tubular injury markers could accurately predict the risk of DKD in patients with normal renal function. We defined the rate of GFR decline as a prognostic indicator of renal function in patients and collected the information of the re-hospitalized DKD patients to determine whether the relevant indicators had an impact on the renal prognosis. Results: The patients with DKD had higher levels of tubular injury markers than patients with DM. URBP, α1-MG, eGFR were statistically different in both univariate and multivariate logistic regression analyses and displayed great predictive power after modeling with an area under curve of 0.987. The calibration curve showed medium agreement. Decision curve showed it would add more net benefits for clinical decision. After adjusting eGFR and serum creatinine (Scr), URBP was demonstrated to be associated with early renal function impairment. Conclusion: Tubular injury markers play an important role in early diabetic renal function impairment.
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Affiliation(s)
- Yukun Zhou
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Yiding Zhang
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Jiaojiao Chen
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Ting Wang
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Huangmin Li
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Feng Wu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Jin Shang
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
- Laboratory of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Laboratory Animal Platform of Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Zhanzheng Zhao
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
- Laboratory of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Laboratory Animal Platform of Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
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11
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Dahiya K, Prashant P, Dhankhar R, Dhankhar K, Kumar S, Vashist S. Lipocalin-2 as a biomarker for diabetic nephropathy. World J Meta-Anal 2023; 11:92-101. [DOI: 10.13105/wjma.v11.i4.92] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 03/11/2023] [Accepted: 03/29/2023] [Indexed: 04/14/2023] Open
Abstract
Diabetes is a major global public health issue. The prevalence of type 1 diabetes is comparatively static, as hereditary and genetic causes are involved, while type 2 diabetes (T2D) prevalence is increasing day by day. T2D is associated with chronic complications, including diabetic neuropathy (DN), nephropathy, retinopathy, and other complications like diabetic foot. DN is the main complication of both types of diabetes. DN can be diagnosed by routine laboratory tests, microalbuminuria > 300 mg/24 h, and a gradual decrease in glomerular filtration rate. As the appearance of microalbuminuria is a late manifestation, an early marker for renal damage is needed. Lipocalin-2, also known as neutrophil gelatinase-associated lipocalin (NGAL), is a small protein purified from neutrophil granules and a good marker for kidney disease. NGAL is a transporter protein responsible for many physiological processes, such as inflammation, generation of the immune response, and metabolic homeostasis. NGAL has been reported to depict the early changes in renal damage when urine microalbumin is still undetecable. Therefore, elucidating the role of NGAL in detecting DN and understanding its mechanism can help establish it as a potential early marker for DN.
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Affiliation(s)
- Kiran Dahiya
- Department of Biochemistry, Pt BD Sharma Post Graduate Institute of Medical Sciences, Rohtak 124001, Haryana, India
| | - Praveen Prashant
- Department of Biochemistry, Pt BD Sharma Post Graduate Institute of Medical Sciences, Rohtak 124001, Haryana, India
| | - Rakesh Dhankhar
- Department of Radiation Oncology, Pt BD Sharma Post Graduate Institute of Medical Sciences, Rohtak 124001, India
| | - Kumud Dhankhar
- Phase III, JSS Medical College, Mysuru 570015, Karnataka, India
| | | | - Sonia Vashist
- Department of Dermatology, Dr Sonia’s Dermatology Clinic, Rewari 123401, Haryana, India
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12
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Gholaminejad A, Moein S, Roointan A, Mortazavi M, Nouri R, Mansourian M, Gheisari Y. Circulating β2 and α1 microglobulins predict progression of nephropathy in diabetic patients: a meta-analysis of prospective cohort studies. Acta Diabetol 2022; 59:1417-1427. [PMID: 35939238 DOI: 10.1007/s00592-022-01940-w] [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: 03/12/2022] [Accepted: 07/04/2022] [Indexed: 11/26/2022]
Abstract
AIMS To study the association of circulating β2 (B2M) and α1 microglobulins (A1M) with diabetic nephropathy (DN) progression, a meta-analysis was performed on the prospective cohort studies. METHODS Up to October 2021, a comprehensive search of the PubMed, EMBASE, Scopus, Web of Science, and Cochrane Library databases was performed. The primary outcome (progression of DN) was defined as a decrease in eGFR or the occurrence of end stage renal disease or DN-related mortality. Eligible studies were included in a pooled analysis that used either fixed-effect or random-effect models to compensate for variation in measurement standards between studies. The funnel plot and Egger's test were used to assess publication bias. RESULTS The meta-analysis included 4398 people from 9 prospective trials (8 cohorts) for B2M and 3110 people from 4 prospective trials (3 cohorts) for A1M. Diabetic individuals with higher B2M levels had an increased risk for DN (relative risk [RR]: 1.81, 95% confidence interval [CI]: 1.56-2.09). Likewise, higher A1M was associated with augmented probability of DN (RR: 1.96, 95% CI: 1.46-2.62). The funnel plot and Egger's tests indicated no publication bias for A1M. Additionally, to compensate for putative publication bias for B2M, using trim and fill analysis, four studies were filled for this marker and the results remained significant (RR: 1.62, 95% CI: 1.37-1.92). CONCLUSIONS The elevated serum levels of B2M and A1M could be considered as potential predictors of DN progression in diabetic patients. PROTOCOL REGISTRATION PROSPERO CRD42021278300.
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Affiliation(s)
- Alieh Gholaminejad
- Regenerative Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran
| | - Shiva Moein
- Regenerative Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran
| | - Amir Roointan
- Regenerative Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran
| | - Mojgan Mortazavi
- Isfahan Kidney Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Rasool Nouri
- Department of Medical Library and Information Sciences, School of Management and Medical Information Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Marjan Mansourian
- Department of Epidemiology and Biostatistics, School of Health, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Yousof Gheisari
- Regenerative Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran.
- Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran.
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13
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Prediction of the Short-Term Risk of New-Onset Renal Dysfunction in Patients with Type 2 Diabetes: A Longitudinal Observational Study. J Immunol Res 2022; 2022:6289261. [PMID: 35497878 PMCID: PMC9045969 DOI: 10.1155/2022/6289261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 04/04/2022] [Indexed: 11/17/2022] Open
Abstract
Background Studies in the past decade have reported many novel biomarkers for predicting the new-onset or progression risk of renal dysfunction in patients with type 2 diabetes (T2D) based on the genomic, metabolomic, and proteomic technologies. These novel predictive markers, however, are difficult to be widely used in clinical practice over the short term due to their high technology content, instability, and high cost. This study was aimed at evaluating the associations of clinical features and six traditional renal markers with the short-term risk of new-onset renal dysfunction in patients with T2D. Methods This study involved 213 participants with T2D and normal renal function at baseline. The baseline levels of the albumin-to-creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), alpha-1-microglobulin-to-creatinine ratio (A1MCR), neutrophil gelatinase-associated lipocalin-to-creatinine ratio, transferrin-to-creatinine ratio (UTRF/Cr), and retinol-binding protein-to-creatinine ratio (URBP/Cr) were analyzed. Multivariate logistic models were established and validated. Results During the two-year follow-up period, 23.01% participants progressed to renal dysfunction. The basal levels of ACR, A1MCR, UTRF/Cr, and URBP/Cr were the independent risk factors of new-onset renal dysfunction (P < 0.05). Several logistic models incorporating clinical characteristics and these renal markers were constructed for predicting the short-term risk of new-onset renal dysfunction. Comparatively, the model including age, glycated hemoglobin (HbA1c), hypertension, ACR, A1MCR, UTRF/Cr, and URBP/Cr levels at baseline had the highest potential (C − index = 0.785, P < 0.001). This model was validated using the K-fold cross-validation method; the accuracy was 0.815 ± 0.013 in training sets and 0.784 ± 0.019 in validation sets, indicating a good consistency for predicting the new-onset renal dysfunction risk. Finally, a nomogram based on this model was constructed to provide a quantitative tool to assess the individualized risk of short-term new-onset renal dysfunction. Conclusion The model incorporating these markers and clinical features may have a high potential to predict the short-term risk of new-onset renal dysfunction.
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14
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Craig A, Gafane-Matemane L, Smith W, Mels C, Uys L, Breet Y, Brits S, Mokwatsi G, Hanssen H, Kruger R. Elevated blood pressure positively associates with alpha-1 microglobulin in prepubescent children: the ExAMIN Youth SA study. J Hypertens 2022; 40:136-142. [PMID: 34857706 DOI: 10.1097/hjh.0000000000002989] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
OBJECTIVES AND METHODS Hypertension is a growing health concern in childhood populations and individuals of African descent. As the kidneys play a significant role in blood pressure regulation, we compared alpha-1 microglobulin (A1M) as a marker of proximal tubular function between young healthy black and white children (n = 957; aged: 5-9 years) and explored its association with blood pressure. RESULTS The black children had higher levels of A1M (P < 0.001) and higher DBP (P < 0.001) when compared with their white counterparts. In multiple regression analysis, SBP (adj. R2 = 0.173, β = 0.151; P < 0.001) and DBP (adj. R2 = 0.110, β = 0.179; P < 0.001) associated positively with A1M in the black children. In binary logistic regression, each standard deviation increase in A1M increased the odds of having elevated blood pressure by 28% (P = 0.002) in the black group, independent of age, sex, BMI z-score and body height. No significance was reached in the white children. CONCLUSION Our findings highlight the importance of a marker of proximal tubular function, especially in children of black ethnicity, in the setting of elevated blood pressure. Early childhood screening for elevated blood pressure remains essential in order to promote primary prevention of hypertension and early onset kidney damage in children.
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Affiliation(s)
| | - Lebo Gafane-Matemane
- Hypertension in Africa Research Team (HART)
- MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, South Africa
| | - Wayne Smith
- Hypertension in Africa Research Team (HART)
- MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, South Africa
| | - Carina Mels
- Hypertension in Africa Research Team (HART)
- MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, South Africa
| | - Lisa Uys
- Hypertension in Africa Research Team (HART)
- MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, South Africa
| | - Yolandi Breet
- Hypertension in Africa Research Team (HART)
- MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, South Africa
| | | | - Gonste Mokwatsi
- Hypertension in Africa Research Team (HART)
- MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, South Africa
| | - Henner Hanssen
- Department of Sport, Exercise and Health, University of Basel, Basel, Switzerland
| | - Ruan Kruger
- Hypertension in Africa Research Team (HART)
- MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, South Africa
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15
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Diabetic nephropathy: A twisted thread to unravel. Life Sci 2021; 278:119635. [PMID: 34015285 DOI: 10.1016/j.lfs.2021.119635] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/04/2021] [Accepted: 05/12/2021] [Indexed: 12/18/2022]
Abstract
Diabetic nephropathy (DN), a persistent microvascular problem of diabetes mellitus is described as an elevated level of albumin excretion in urine and impaired renal activity. The morbidity and mortality of type-1 diabetics and type-2 diabetics due to end stage renal disease is also a result of the increased prevalence of DN. DN typically occurs as a consequence of an association among metabolic and hemodynamic variables, activating specific pathways leading to renal injury. According to current interventions, intensive glucose regulation decreases the threat of DN incidence and growth, and also suppressing the renin-angiotensin system (RAS) is a significant goal for hemodynamic and metabolism-related deformities in DN. However, the pathogenesis of DN is multifactorial so novel approaches other than glucose and blood pressure control are required for treatment. This review briefly summarizes the reported pathogenesis of DN, current interventions for its treatment, and possible novel interventions to unweave the thread of DN.
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16
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Bae J, Won YJ, Lee BW. Non-Albumin Proteinuria (NAP) as a Complementary Marker for Diabetic Kidney Disease (DKD). Life (Basel) 2021; 11:life11030224. [PMID: 33802211 PMCID: PMC7998887 DOI: 10.3390/life11030224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/06/2021] [Accepted: 03/06/2021] [Indexed: 11/16/2022] Open
Abstract
Diabetic kidney disease (DKD) is one of the most common forms of chronic kidney disease. Its pathogenic mechanism is complex, and it can affect entire structures of the kidney. However, conventional approaches to early stage DKD have focused on changes to the glomerulus. Current standard screening tools for DKD, albuminuria, and estimated glomerular filtration rate are insufficient to reflect early tubular injury. Therefore, many tubular biomarkers have been suggested. Non-albumin proteinuria (NAP) contains a wide range of tubular biomarkers and is convenient to measure. We reviewed the clinical meanings of NAP and its significance as a marker for early stage DKD.
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Affiliation(s)
- Jaehyun Bae
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Catholic Kwandong University College of Medicine, International St. Mary’s Hospital, Incheon KS006, Korea; (J.B.); (Y.J.W.)
| | - Young Jun Won
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Catholic Kwandong University College of Medicine, International St. Mary’s Hospital, Incheon KS006, Korea; (J.B.); (Y.J.W.)
| | - Byung-Wan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul KS013, Korea
- Correspondence:
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17
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Ma Y, Wang H, Shan X, Zhu F, Wang W. High risk of tubular damage in normoalbuminuric adults with type 2 diabetes for over 14 years. J Diabetes 2021; 13:261-264. [PMID: 33150688 DOI: 10.1111/1753-0407.13131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 10/06/2020] [Accepted: 11/01/2020] [Indexed: 12/21/2022] Open
Abstract
Highlights The level of urinary α1 -microglobulin to creatinine ratio (A1MCR) increases with longer diabetes duration. Patients with a diabetes duration >14 years have a higher tubular damage rate. Being male and a diabetes duration >14 years have an interaction effect on increased A1MCR.
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Affiliation(s)
- Yongjun Ma
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Huabin Wang
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Xiaoyun Shan
- Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Fang Zhu
- Department of Pathology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Weiyuan Wang
- Department of Clinical Laboratory, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
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18
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Chen G, Shan X, Wang H. Significant association of urinary alpha‐1‐microglobulin compared to urinary neutrophil gelatinase‐associated lipocalin with renal insufficiency in patients with type 2 diabetes. Nephrology (Carlton) 2021; 26:400-407. [PMID: 33484208 DOI: 10.1111/nep.13851] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 12/30/2020] [Accepted: 01/17/2021] [Indexed: 12/11/2022]
Affiliation(s)
- Guangming Chen
- Department of General Practice, Affiliated Jinhua Hospital Zhejiang University School of Medicine Jinhua China
| | - Xiaoyun Shan
- Department of Clinical Laboratory, Affiliated Jinhua Hospital Zhejiang University School of Medicine Jinhua China
| | - Huabin Wang
- Department of Clinical Laboratory, Affiliated Jinhua Hospital Zhejiang University School of Medicine Jinhua China
- Central Laboratory, Affiliated Jinhua Hospital Zhejiang University School of Medicine Jinhua China
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Insights into predicting diabetic nephropathy using urinary biomarkers. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2020; 1868:140475. [DOI: 10.1016/j.bbapap.2020.140475] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 05/27/2020] [Accepted: 06/14/2020] [Indexed: 12/20/2022]
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20
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Wang H, Xu W, Huang C, Liu Y, Wang L, Wang J, Zhang F, Xu H. High ACR level is a strong risk factor for renal tubular impairment in patients with type 2 diabetes: A longitudinal observational study. Diabetes Res Clin Pract 2020; 165:108272. [PMID: 32561454 DOI: 10.1016/j.diabres.2020.108272] [Citation(s) in RCA: 5] [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: 01/23/2020] [Revised: 05/03/2020] [Accepted: 06/11/2020] [Indexed: 01/06/2023]
Abstract
BACKGROUND Several studies have indicated that high albuminuria is associated with renal function decline. However, the relationship between the urinary albumin-to-creatinine ratio (ACR) and risk of developing tubular injury remains unclear. Our aim was to investigate the association of ACR with the risk of developing tubular impairment in patients with type 2 diabetes. METHODS This longitudinal observational study compared baseline with follow-up data in 183 patients with type 2 diabetes. ACR, urinary alpha-1-microglobulin-to-creatinine ratio (A1MCR) and estimated glomerular filtration rate (eGFR) were used to evaluate albuminuira, tubular injury and glomerular filtration function, respectively. RESULTS Levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and A1MCR were significantly different at the two-year follow-up compared with baseline levels. Among patients both with baseline ACR above and below 30 mg/g, the percentage with A1MCR > 15 mg/g clearly increased after follow-up (P < 0.05). The risk of A1MCR rising from normal ranges to >15 mg/g over the follow-up increased with increasing baseline ACR values lower baseline eGFR. Among the patients with baseline ACR > 63.10 mg/g, all showed increased A1MCR values at follow-up compared with baseline. In the multivariate regression analysis, the patients with baseline ACR > 63.10 mg/g had a strong risk of A1MCR rising from normal to >15 mg/g (odds ratio (OR) = 11.12, P = 0.001) over the follow-up, while the males had a 2.89-fold risk of A1MCR increasing from normal to >15 mg/g compared with females. CONCLUSION Baseline ACR level is related to increased risk of developing renal tubular injury; in particular, this association is much stronger in patients with type 2 diabetes and baseline ACR > 63.10 mg/g.
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Affiliation(s)
- Huabin Wang
- Central Laboratory, Jinhua Municipal Central Hospital, People's Republic of China
| | - Wenxia Xu
- Central Laboratory, Jinhua Municipal Central Hospital, People's Republic of China
| | - Caiqun Huang
- Central Laboratory, Jinhua Municipal Central Hospital, People's Republic of China
| | - Ying Liu
- Central Laboratory, Jinhua Municipal Central Hospital, People's Republic of China
| | - Lude Wang
- Central Laboratory, Jinhua Municipal Central Hospital, People's Republic of China
| | - Jing Wang
- Central Laboratory, Jinhua Municipal Central Hospital, People's Republic of China
| | - Feng Zhang
- Central Laboratory, Jinhua Municipal Central Hospital, People's Republic of China
| | - Huimin Xu
- Department of Grass-roots Guidance, Jinhua Municipal Central Hospital, People's Republic of China.
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21
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Sun ZJ, Wang JW, Chang DY, Chen SH, Zhang HF, Wu SL, He K, Zhang LX, Chen M, Zhao MH. Unstably controlled systolic blood pressure trajectories are associated with markers for kidney damage in prediabetic population: results from the INDEED cohort study. J Transl Med 2020; 18:194. [PMID: 32398098 PMCID: PMC7216344 DOI: 10.1186/s12967-020-02361-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Accepted: 05/02/2020] [Indexed: 12/27/2022] Open
Abstract
Background The association between blood pressure change and kidney damage in patients with abnormal blood glucose remains unclear. The current study aimed to identify systolic blood pressure (SBP) trajectories among the prediabetic population and to determine their association with kidney damage after a long-term follow-up. Methods The incidence, development, and prognosis of diabetic kidney disease (INDEED) study is nested in the Kailuan cohort study with a focus on population with diabetes and prediabetes. We screened out people with prediabetes in 2006 and with more than three SBP records from 2006 to 2014 biennially. We used the latent mixture modeling to fit five groups of trajectories of SBP. In 2016, estimated glomerular filtration rate (eGFR), urinary albumin creatinine ratio (uACR), and urinary α1-microglobulin (α1MG), transferrin and α1-acid glycoprotein were measured, and the association between SBP trajectories and these markers was analyzed by linear regression and logistic regression models. Results Totally, 1451 participants with prediabetes and without kidney damage were identified in 2006. Five heterogeneous SBP trajectories were detected based on the longitudinal data from 2006 to 2014, as low-stable group (n = 323), moderate-stable group (n = 726), moderate-increasing group (n = 176), moderate-decreasing group (n = 181), and high-stable group (n = 45). Linear regression analysis showed that the moderate and high SBP groups had lower eGFR, higher uACR, higher urinary α1MG, higher transferrin, and higher α1-acid glycoprotein than the low-stable group. Multivariable analysis attenuated the association but did not change the statistical significance. Conclusions Prediabetic patients with persistent high-level SBP trajectory or gradually increased SBP trajectory had severer kidney damage during follow-up.
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Affiliation(s)
- Zi-Jun Sun
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Jin-Wei Wang
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Dong-Yuan Chang
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Shuo-Hua Chen
- Health Care Center of Kailuan Group, Tangshan, 063000, China
| | - Hui-Fen Zhang
- Laboratory Department of Kailuan General Hospital, Tangshan, 063000, China
| | - Shou-Ling Wu
- Department of Cardiology, Kailuan General Hospital Affiliated to North China University of Science and Technology, Tangshan, 063000, China
| | - Kevin He
- Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Lu-Xia Zhang
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Min Chen
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, China.
| | - Ming-Hui Zhao
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, China.,Peking-Tsinghua Center for Life Sciences, Beijing, 100034, China
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22
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Wang H, Bao X, Ma Y, Shan X, Huang C. Urinary orosomucoid 1 protein to creatinine ratio as a potential biomarker for early screening of kidney impairment in type‐2 diabetes patients. Nephrology (Carlton) 2020; 25:667-675. [PMID: 32147922 DOI: 10.1111/nep.13707] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 10/29/2019] [Accepted: 03/02/2020] [Indexed: 12/31/2022]
Affiliation(s)
- Huabin Wang
- Central LaboratoryJinhua Municipal Central Hospital Jinhua China
| | - Xinyu Bao
- Hangzhou Medical College Zhejiang China
| | - Yongjun Ma
- Central LaboratoryJinhua Municipal Central Hospital Jinhua China
| | - Xiaoyun Shan
- Department of Clinical LaboratoryJinhua Municipal Central Hospital Jinhua China
| | - Caiqun Huang
- Central LaboratoryJinhua Municipal Central Hospital Jinhua China
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23
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Yang DH, Lee SY. Diabetic kidney disease: seven questions. JOURNAL OF THE KOREAN MEDICAL ASSOCIATION 2020. [DOI: 10.5124/jkma.2020.63.1.6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Affiliation(s)
- Dong Ho Yang
- Division of Nephrology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - So-Young Lee
- Division of Nephrology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
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24
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Kobayashi S, Amano H, Terawaki H, Ogura M, Kawaguchi Y, Yokoo T. Spot urine protein/creatinine ratio as a reliable estimate of 24-hour proteinuria in patients with immunoglobulin A nephropathy, but not membranous nephropathy. BMC Nephrol 2019; 20:306. [PMID: 31387546 PMCID: PMC6685245 DOI: 10.1186/s12882-019-1486-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 07/23/2019] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Proteinuria is known to be associated with both kidney function deterioration and cardiovascular diseases. While proteinuria estimation from 24-h urine samples has traditionally been considered as the standard method for assessment of the degree of urinary protein excretion, sample collection is associated with several technical problems such as inaccurate collection and the potential spread of drug-resistant pathogens. Therefore, the spot urine protein/creatinine ratio (PCR) assessment is currently recommended as an alternative. While the utility of PCR has been validated, studies on the association between spot urine PCR and 24-h proteinuria (24HP) in patients with chronic glomerular nephritis (CGN) and nephrotic syndrome (NS) are limited. This study aimed to evaluate whether an estimated result from a spot urine PCR could sufficiently approximate the daily urine protein excretion amount from a 24-h urine sample in patients with immunoglobulin A nephropathy (IgAN), minimal change disease (MCD), and membranous nephropathy- nephrotic syndrome (MN-NS). METHODS The study participants included 161 patients with IgAN, MCD, or MGN-NS at the Jikei University Kashiwa Hospital and Kanagawa Prefecture Shiomidai Hospital. The correlation between spot urine PCR and a 24-h urine protein was investigated using linear regression analysis with Spearman's correlation (r) coefficient and intraclass correlation coefficient (ICC). RESULTS While high correlation coefficients (r = 0.86, P < 0.001) and substantial agreement (ICC: 0.806, P < 0.001) were observed in patients with IgAN, similar correlations were not observed in patients with MCD or MN-NS. In the patients with MCD, r was 0.53 (P < 0.001), which signified a slight correlation, and in the patients with MN-NS, r was 0.289 (P = 0.17), which was not statistically significant. CONCLUSIONS This study revealed that spot urine PCR is a reliable estimate of 24HP value in patients with IgAN. In contrast, there is a considerable difference between the daily urine protein excretion amount based on a 24-h urine sample and that which is calculated from spot urine PCR in patients with NS.
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Affiliation(s)
- Seiji Kobayashi
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
- Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan
| | - Hoichi Amano
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
- Graduate School of Public Health, Teikyo University, Tokyo, Japan
| | - Hiroyuki Terawaki
- Department of Internal Medicine, Nephrology Teikyo University School of Medicine Teikyo University Chiba Medical Center, Ichihara, Chiba Japan
| | - Makoto Ogura
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Yoshindo Kawaguchi
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Takashi Yokoo
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
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25
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Wang H, Lou Y, Ma Y, Shan X. Estimating the glomerular filtration rate and tubular dysfunction in an elderly population with normoalbuminuria in China. Clin Chim Acta 2019; 495:377-381. [DOI: 10.1016/j.cca.2019.05.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 05/07/2019] [Accepted: 05/07/2019] [Indexed: 10/26/2022]
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26
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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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Wan X, Zhang L, Gu H, Wang S, Liu X. The Association of Serum hsCRP and Urinary Alpha1-Microglobulin in Patients with Type 2 Diabetes Mellitus. BIOMED RESEARCH INTERNATIONAL 2019; 2019:6364390. [PMID: 31281843 PMCID: PMC6590668 DOI: 10.1155/2019/6364390] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 05/27/2019] [Indexed: 11/17/2022]
Abstract
This study aimed to investigate the association of serum hsCRP and urinary A1MG in patients with T2DM. Numerous investigations have proven that serum hypersensitive C-reactive protein (hsCRP) concentration in patients with type 2 diabetes mellitus (T2DM) is increased. Also, increased urinary alpha-1 microglobulin (A1MG) can be an early sign of renal damage, primarily on the proximal tubules in T2DM. Little information is available with respect to the associations of serum hsCRP levels and urinary A1MG in T2DM. A total of 520 patients with T2DM were recruited to participate in this study. Serum hsCRP and UA1MG (urinary alpha1-microglobulin to creatinine ratio), UACR (urinary microalbumin to creatinine ratio), UIGG (urinary immunoglobulin G to creatinine ratio), and UTRF (urinary transferrin to creatinine ratio) were obtained. The association of serum hsCRP level and each urinary protein parameter was analyzed by using the regression analysis, respectively. LnhsCRP was positively associated with the lnUA1MG in all three linear regression models (adjusted β in model 3=0.122, SE=0.027, P<0.001). Furthermore, the high hsCRP group (hsCRP > 3mg/L) was associated with increasing risk of high UA1MG (adjusted OR in model 3=1.610, 95% CI 1.037-2.499, P=0.034) by logistic regression. This study suggests that serum hsCRP levels independently associate with UA1MG in patients with T2DM. Further research is warranted to elucidate these interactions.
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Affiliation(s)
- Xiaohua Wan
- Department of Clinical Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Lin Zhang
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, 100730, China
- Beijing Diabetes Institute, Beijing, 100730, China
| | - Haitong Gu
- Department of Clinical Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Shenglai Wang
- Department of Clinical Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Xiangyi Liu
- Department of Clinical Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
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28
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Natali P, De Santis E, Patelli G, Cucinelli MR, Varani M, Trenti T. A new suggested approach in screening for Bence Jones protein and potential kidney damage. Clin Chem Lab Med 2019; 57:e54-e56. [DOI: 10.1515/cclm-2018-0600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 07/11/2018] [Indexed: 11/15/2022]
Affiliation(s)
- Patrizia Natali
- Department of Laboratory Medicine , OCSAE, Local Unit Health of Modena , Modena , Italy
| | - Elena De Santis
- Department of Laboratory Medicine , OCSAE, Local Unit Health of Modena , Modena , Italy
| | - Giovanna Patelli
- Department of Laboratory Medicine , OCSAE, Local Unit Health of Modena , Modena , Italy
| | | | - Manuela Varani
- Department of Laboratory Medicine , OCSAE, Local Unit Health of Modena , Modena , Italy
| | - Tommaso Trenti
- Department of Laboratory Medicine , OCSAE, Local Unit Health of Modena , Modena , Italy
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29
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Charkoftaki G, Wang Y, McAndrews M, Bruford EA, Thompson DC, Vasiliou V, Nebert DW. Update on the human and mouse lipocalin (LCN) gene family, including evidence the mouse Mup cluster is result of an "evolutionary bloom". Hum Genomics 2019; 13:11. [PMID: 30782214 PMCID: PMC6381713 DOI: 10.1186/s40246-019-0191-9] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 01/17/2019] [Indexed: 12/12/2022] Open
Abstract
Lipocalins (LCNs) are members of a family of evolutionarily conserved genes present in all kingdoms of life. There are 19 LCN-like genes in the human genome, and 45 Lcn-like genes in the mouse genome, which include 22 major urinary protein (Mup) genes. The Mup genes, plus 29 of 30 Mup-ps pseudogenes, are all located together on chromosome (Chr) 4; evidence points to an “evolutionary bloom” that resulted in this Mup cluster in mouse, syntenic to the human Chr 9q32 locus at which a single MUPP pseudogene is located. LCNs play important roles in physiological processes by binding and transporting small hydrophobic molecules —such as steroid hormones, odorants, retinoids, and lipids—in plasma and other body fluids. LCNs are extensively used in clinical practice as biochemical markers. LCN-like proteins (18–40 kDa) have the characteristic eight β-strands creating a barrel structure that houses the binding-site; LCNs are synthesized in the liver as well as various secretory tissues. In rodents, MUPs are involved in communication of information in urine-derived scent marks, serving as signatures of individual identity, or as kairomones (to elicit fear behavior). MUPs also participate in regulation of glucose and lipid metabolism via a mechanism not well understood. Although much has been learned about LCNs and MUPs in recent years, more research is necessary to allow better understanding of their physiological functions, as well as their involvement in clinical disorders.
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Affiliation(s)
- Georgia Charkoftaki
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, 06520-8034, USA
| | - Yewei Wang
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, 06520-8034, USA
| | - Monica McAndrews
- Mouse Genome Informatics, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA
| | - Elspeth A Bruford
- HUGO Gene Nomenclature Committee, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
| | - David C Thompson
- Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA
| | - Vasilis Vasiliou
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, 06520-8034, USA.
| | - Daniel W Nebert
- Department of Environmental Health and Center for Environmental Genetics; Department of Pediatrics and Molecular and Developmental Biology, Cincinnati Children's Research Center, University Cincinnati Medical Center, Cincinnati, OH, 45267, USA
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30
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Patel DN, Kalia K. Characterization of low molecular weight urinary proteins at varying time intervals in type 2 diabetes mellitus and diabetic nephropathy patients. Diabetol Metab Syndr 2019; 11:39. [PMID: 31131043 PMCID: PMC6525442 DOI: 10.1186/s13098-019-0430-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 04/20/2019] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND To identify low molecular weight urinary proteins capable of detecting diabetic nephropathy patients which may predict renal alterations at early stages and prevent it from worsening further. METHOD Three hundred ninety (390) age-matched subjects were divided into 8 groups depending upon duration of diabetes and the severity of renal damage. Urinary proteome profile of all subjects was determined with the help of microfluidic array. Participants with similar profile were further selected to study proteome map of urinary low molecular weight proteins with the help of 2 dimensional gel electrophoresis. RESULTS Out of 390 total patients 268 patients showed a similar one dimensional proteomic pattern. Further, two-dimensional urinary proteomic pattern of these patients with molecular weight < 50 kDa was studied. Eight proteins with molecular weight 11, 15, 17, 23, 34, 38 and 46 kDa were identified with MALDI-QTOF. These low molecular weight proteins showed gradual increase in urinary excretion along with the duration of diabetes and severity of renal damage. CONCLUSION The study concludes that proteomic analysis might be a useful tool for detecting some novel markers capable of detecting patients susceptible to diabetic nephropathy in the early phase.
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Affiliation(s)
- Dhara N. Patel
- Department of Medical Laboratory Technology, Charotar Institute of Paramedical Sciences, CHARUSAT, CHARUSAT-Campus, Highway 139, Off, Nadiad-Petlad Road, Changa, Gujarat 388421 India
| | - Kiran Kalia
- Present Address: National Institute of Pharmaceutical Education and Research (NIPER-G), Gandhinagar Opposite Air Force Station, Palaj, Gandhinagar, Gujarat 382355 India
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31
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Using magnetic resonance diffusion tensor imaging to evaluate renal function changes in diabetic patients with early-stage chronic kidney disease. Clin Radiol 2018; 74:116-122. [PMID: 30360880 DOI: 10.1016/j.crad.2018.09.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 09/25/2018] [Indexed: 12/15/2022]
Abstract
AIM To investigate the clinical value of diffusion tensor imaging (DTI) in assessing renal function changes in diabetic patients with early-stage chronic kidney disease (CKD), and the relationship of DTI parameters with estimated glomerular filtration rate (eGFR) and urinary biomarkers. MATERIALS AND METHODS Thirty-six patients with diabetes mellitus (DM; 30 CKD stage 1 and 6 CKD stage 2) and 26 healthy control subjects were enrolled. DTI was performed using a clinical 3 T MRI system. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values were calculated from the renal cortex and medulla. The correlation of the DTI parameters with eGFR and urinary biomarkers was evaluated. RESULTS FA values were significantly reduced in the renal cortex and medulla of DM group compared with the control group (cortical FA, Z=-2.834, p=0.005; medullary FA, t=2.768, p=0.007). In the DM group, FA values in the renal cortex and medulla were positively correlated with eGFR, while FA values in the medulla were negatively correlated with the urinary albumin/creatinine ratio, urinary alpha-1 microglobulin/creatinine ratio, and urinary transferring/creatinine ratio. ADC values in the renal cortex and medulla showed a trend towards an increase in the DM group compared with the control group. CONCLUSIONS Renal DTI is a promising method for assessing early renal function changes in DM patients.
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32
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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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33
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Zhang Q, Jiang X, Cui X, Liu R. A study on the biological reference interval of urinary alpha 1-microglobulin in a group of Chinese people. J Clin Lab Anal 2018; 32:e22305. [PMID: 28771883 PMCID: PMC6816998 DOI: 10.1002/jcla.22305] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 07/11/2017] [Indexed: 02/03/2023] Open
Abstract
OBJECTIVE The aim of this study was to explore the possible influences of age and gender on urinary Alpha 1-Microglobulin (α1-MG) concentrations and establish specific reference values of urinary α1-MG in a group of healthy adults. METHODS Two hundred and ninety-nine adults (141 males and 158 females) aged 20-60 were selected and grouped by gender and age. Urinary levels of α1-MG were detected in morning spot-urine samples, and statistical analysis was performed to explore the association between urinary α1-MG and clinical parameters, and the differences between groups were compared. The 95th percentile of distribution was used as the normal upper limit. RESULTS The value of urinary α1-MG was sex-dependent (P<0.001), the 95th percentile of urinary α1-MG of males was 26.4 mg/L, whereas females was 8.6 mg/L. Whereas urinary α1-microglobulin-to-creatinine ratio (α1-MG/Cr) was both gender-and age-dependent (both P<0.001), and age 30 may be the cut-off point in this study. The 95th percentile of males and females aged 20-30 was 16.9 mg/g, of males aged 31-60 was 19.8 mg/g, of females aged 31-60 was 28.5 mg/g. DISCUSSIONS The relationship between urinary α1-MG concentrations and gender, age is different from previous studies. It is recommended that hospitals and laboratories should develop their own α1-MG reference intervals based on their experimental conditions.
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Affiliation(s)
- Qian Zhang
- Graduate School of Tianjin Medical UniversityTianjinChina
- Department of Clinical LaboratoryTianjin Union Medical CenterTianjinChina
| | - Xu Jiang
- Graduate School of Tianjin Medical UniversityTianjinChina
| | - Xiao‐Fan Cui
- Department of Clinical LaboratoryTianjin Union Medical CenterTianjinChina
| | - Rui Liu
- Department of Clinical LaboratoryTianjin Union Medical CenterTianjinChina
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Brosius FC, Ju W. The Promise of Systems Biology for Diabetic Kidney Disease. Adv Chronic Kidney Dis 2018; 25:202-213. [PMID: 29580584 DOI: 10.1053/j.ackd.2017.10.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 10/19/2017] [Accepted: 10/23/2017] [Indexed: 12/21/2022]
Abstract
Diabetic kidney disease (DKD) has a complex and prolonged pathogenesis involving many cell types in the kidney as well as extrarenal factors. It is clinically silent for many years after the onset of diabetes and usually progresses over decades. Given this complexity, a comprehensive and unbiased molecular approach is best suited to help identify the most critical mechanisms responsible for progression of DKD and those most suited for targeted intervention. Systems biological investigations provide such an approach since they examine the entire network of molecular changes that occur in a disease process in a comprehensive way instead of focusing on a single abnormal molecule or pathway. Systems biological studies can also start with analysis of the disease in humans, not in animal or cell culture models that often poorly reproduce the changes in human DKD. Indeed, in the last decade, systems biological approaches have led to the identification of critical molecular abnormalities in DKD and have directly led to development of new biomarkers and potential treatments for DKD.
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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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Petrica L, Vlad M, Vlad A, Gluhovschi G, Gadalean F, Dumitrascu V, Popescu R, Gluhovschi C, Matusz P, Velciov S, Bob F, Ursoniu S, Vlad D. Podocyturia parallels proximal tubule dysfunction in type 2 diabetes mellitus patients independently of albuminuria and renal function decline: A cross-sectional study. J Diabetes Complications 2017; 31:1444-1450. [PMID: 28161386 DOI: 10.1016/j.jdiacomp.2017.01.007] [Citation(s) in RCA: 8] [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: 10/24/2016] [Revised: 12/21/2016] [Accepted: 01/03/2017] [Indexed: 01/01/2023]
Abstract
AIMS Detection of podocytes in the urine of patients with type 2 diabetes may indicate severe injury to the podocytes. In the course of type 2 diabetes the proximal tubule is involved in urinary albumin processing. We studied the significance of podocyturia in relation with proximal tubule dysfunction in type 2 diabetes. METHODS A total of 86 patients with type 2 diabetes (34-normoalbuminuria; 30-microalbuminuria; 22-macroalbuminuria) and 28 healthy subjects were enrolled in the study and assessed concerning urinary podocytes, podocyte-associated molecules, and biomarkers of proximal tubule dysfunction. Urinary podocytes were examined in cell cultures by utilizing monoclonal antibodies against podocalyxin and synaptopodin. RESULTS Podocytes were detected in the urine of 10% of the healthy controls, 24% of the normoalbuminuric, 40% of the microalbuminuric, and 82% of the macroalbuminuric patients. In multivariate logistic regression analysis, urinary podocytes correlated with urinary albumin:creatinine ratio (p=0.006), urinary nephrin/creat (p=0.001), urinary vascular endothelial growth factor/creat (p=0.001), urinary kidney injury molecule-1/creat (p=0.003), cystatin C (p=0.001), urinary advanced glycation end-products (p=0.002), eGFR (p=0.001). CONCLUSIONS In patients with type 2 diabetes podocyturia parallels proximal tubule dysfunction independently of albuminuria and renal function decline. Advanced glycation end-products may impact the podocytes and the proximal tubule.
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Affiliation(s)
- Ligia Petrica
- "Victor Babes" University of Medicine and Pharmacy, Department of Nephrology, P-ta Eftimie Murgu 2A, 300041 Timisoara, Romania
| | - Mihaela Vlad
- "Victor Babes" University of Medicine and Pharmacy, Department of Endocrinology, P-ta Eftimie Murgu 2A, 300041 Timisoara, Romania.
| | - Adrian Vlad
- "Victor Babes" University of Medicine and Pharmacy, Department of Diabetes and Metabolic Diseases, P-ta Eftimie Murgu 2A, 300041 Timisoara, Romania
| | - Gheorghe Gluhovschi
- "Victor Babes" University of Medicine and Pharmacy, Department of Nephrology, P-ta Eftimie Murgu 2A, 300041 Timisoara, Romania
| | - Florica Gadalean
- "Victor Babes" University of Medicine and Pharmacy, Department of Nephrology, P-ta Eftimie Murgu 2A, 300041 Timisoara, Romania
| | - Victor Dumitrascu
- "Victor Babes" University of Medicine and Pharmacy, Department of Pharmacology, P-ta Eftimie Murgu 2A, 300041 Timisoara, Romania
| | - Roxana Popescu
- "Victor Babes" University of Medicine and Pharmacy, Department of Cellular and Molecular Biology, P-ta Eftimie Murgu 2A, 300041 Timisoara, Romania
| | - Cristina Gluhovschi
- "Victor Babes" University of Medicine and Pharmacy, Department of Nephrology, P-ta Eftimie Murgu 2A, 300041 Timisoara, Romania
| | - Petru Matusz
- "Victor Babes" University of Medicine and Pharmacy, Department of Anatomy and Embryology, P-ta Eftimie Murgu 2A, 300041 Timisoara, Romania
| | - Silvia Velciov
- "Victor Babes" University of Medicine and Pharmacy, Department of Nephrology, P-ta Eftimie Murgu 2A, 300041 Timisoara, Romania
| | - Flaviu Bob
- "Victor Babes" University of Medicine and Pharmacy, Department of Nephrology, P-ta Eftimie Murgu 2A, 300041 Timisoara, Romania
| | - Sorin Ursoniu
- "Victor Babes" University of Medicine and Pharmacy, Department of Public Health Medicine, P-ta Eftimie Murgu 2A, 300041 Timisoara, Romania
| | - Daliborca Vlad
- "Victor Babes" University of Medicine and Pharmacy, Department of Pharmacology, P-ta Eftimie Murgu 2A, 300041 Timisoara, Romania
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Uwaezuoke SN. The role of novel biomarkers in predicting diabetic nephropathy: a review. Int J Nephrol Renovasc Dis 2017; 10:221-231. [PMID: 28860837 PMCID: PMC5566367 DOI: 10.2147/ijnrd.s143186] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Diabetic nephropathy (DN) is one of the microvascular complications of the kidney arising commonly from type 1 diabetes mellitus (T1DM), and occasionally from type 2 diabetes mellitus (T2DM). Microalbuminuria serves as an early indicator of DN risk and a predictor of its progression as well as cardiovascular disease risk in both T1DM and T2DM. Although microalbuminuria remains the gold standard for early detection of DN, it is not a sufficiently accurate predictor of DN risk due to some limitations. Thus, there is a paradigm shift to novel biomarkers which would help to predict DN risk early enough and possibly prevent the occurrence of end-stage kidney disease. These new biomarkers have been broadly classified into glomerular biomarkers, tubular biomarkers, biomarkers of inflammation, biomarkers of oxidative stress, and miscellaneous biomarkers which also include podocyte biomarkers, some of which are also considered as tubular and glomerular biomarkers. Although they are potentially useful for the evaluation of DN, current data still preclude the routine clinical use of majority of them. However, their validation using high-quality and large longitudinal studies is of paramount importance, as well as the subsequent development of a biomarker panel which can reliably predict and evaluate this renal microvascular disease. This paper aims to review the predictive role of these biomarkers in the evaluation of DN.
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Affiliation(s)
- Samuel N Uwaezuoke
- Pediatric Nephrology Firm, Department of Pediatrics, University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu, Nigeria
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Aguiar P, Azevedo O, Pinto R, Marino J, Baker R, Cardoso C, Ducla Soares JL, Hughes D. New biomarkers defining a novel early stage of Fabry nephropathy: A diagnostic test study. Mol Genet Metab 2017; 121:162-169. [PMID: 28526293 DOI: 10.1016/j.ymgme.2017.05.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 05/12/2017] [Accepted: 05/12/2017] [Indexed: 11/26/2022]
Abstract
BACKGROUND Renal involvement in Fabry disease is a major determinant of overall disease prognosis and early enzyme replacement therapy seems effective in preventing progression of kidney injury. Gb3 storage, glomerular sclerosis and tubulo-interstitial fibrosis may occur with minimal or no changes on standard renal tests, hence alternative markers of renal dysfunction are crucial. In this study we compared several biomarkers with albuminuria in the identification of incipient Fabry nephropathy and their diagnostic accuracy to identify chronic kidney disease (CKD) stage≥2. METHODS In this multicentre, prospective, cross-sectional and diagnostic test study, a cohort of 78 Fabry patients and 25 healthy controls was consecutively recruited. Patients were grouped by severity of nephropathy: 1) albuminuria<30mg/g; 2) albuminuria 30-299mg/g; 3) albuminuria>300mg/g; 4) glomerular filtration rate (GFR)<60mL/min/1.73m2. Several index tests, namely biomarkers of glomerular (transferrin and type IV collagen) and tubular (α1-microglobulin, N-acetyl-β-glucosaminidase and alanine aminopeptidase) dysfunction were compared with the reference standard (albuminuria). RESULTS Significant increase of all tested biomarkers in Fabry patients, even in the subgroup of patients without evidence of nephropathy. We also found inverse significant correlations between estimated GFR and collagen type IV (ρ=-0.289; p=0.003) or N-acetyl-β-glucosaminidase (ρ=-0.448; p<0.001), which were stronger than with albumin (ρ=-0.274; p=0.019). There was also better diagnostic accuracy of N-acetyl-β-glucosaminidase to predict CKD stage≥2. CONCLUSIONS These results suggest that studied biomarkers may overcome the limitations of albuminuria as sensitive marker of early renal dysfunction and as marker for CKD progression risk. These biomarkers may also define novel early stages of nephropathy characterized by mesangial expansion and/or tubular damage.
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Affiliation(s)
- Patrício Aguiar
- Medicine 1 Department, Centro Hospitalar Lisboa Norte, Lisbon, Portugal.
| | - Olga Azevedo
- Department of Cardiology, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, ICVS/3Bs PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Rui Pinto
- JCS. Dr Joaquim Chaves, Lab Análises Clínicas, Miraflores, Portugal
| | - Jacira Marino
- Lysosomal Storage Disorders Unit, Royal Free London NHS Foundation Trust and University College London, London, United Kingdom
| | - Robert Baker
- Lysosomal Storage Disorders Unit, Royal Free London NHS Foundation Trust and University College London, London, United Kingdom
| | - Carlos Cardoso
- JCS. Dr Joaquim Chaves, Lab Análises Clínicas, Miraflores, Portugal
| | | | - Derralynn Hughes
- Lysosomal Storage Disorders Unit, Royal Free London NHS Foundation Trust and University College London, London, United Kingdom
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Campion CG, Sanchez-Ferras O, Batchu SN. Potential Role of Serum and Urinary Biomarkers in Diagnosis and Prognosis of Diabetic Nephropathy. Can J Kidney Health Dis 2017; 4:2054358117705371. [PMID: 28616250 PMCID: PMC5461910 DOI: 10.1177/2054358117705371] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 02/17/2017] [Indexed: 12/11/2022] Open
Abstract
PURPOSE OF REVIEW Diabetic nephropathy (DN) is a progressive kidney disease caused by alterations in kidney architecture and function, and constitutes one of the leading causes of end-stage renal disease (ESRD). The purpose of this review is to summarize the state of the art of the DN-biomarker field with a focus on the new strategies that enhance the sensitivity of biomarkers to predict patients who will develop DN or are at risk of progressing to ESRD. OBJECTIVE In this review, we provide a description of the pathophysiology of DN and propose a panel of novel putative biomarkers associated with DN pathophysiology that have been increasingly investigated for diagnosis, to predict disease progression or to provide efficient personal treatment. METHODS We performed a review of the literature with PubMed and Google Scholar to collect baseline data about the pathophysiology of DN and biomarkers associated. We focused our research on new and emerging biomarkers of DN. KEY FINDINGS In this review, we summarized the critical signaling pathways and biological processes involved in DN and highlighted the pathogenic mediators of this disease. We next proposed a large review of the major advances that have been made in identifying new biomarkers which are more sensitive and reliable compared with currently used biomarkers. This includes information about emergent biomarkers such as functional noncoding RNAs, microRNAs, long noncoding RNAs, exosomes, and microparticles. LIMITATIONS Despite intensive strategies and constant investigation, no current single treatment has been able to reverse or at least mitigate the progression of DN, or reduce the morbidity and mortality associated with this disease. Major difficulties probably come from the renal disease being heterogeneous among the patients. IMPLICATIONS Expanding the proteomics screening, including oxidative stress and inflammatory markers, along with metabolomics approaches may further improve the prognostic value and help in identifying the patients with diabetes who are at high risk of developing kidney diseases.
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Affiliation(s)
- Carole G. Campion
- Centre de recherche, Centre Hospitalier de l’Université de Montréal (CRCHUM), Québec, Canada
| | - Oraly Sanchez-Ferras
- Department of Biochemistry, Goodman Cancer Research Centre, McGill University, Montreal, Québec, Canada
| | - Sri N. Batchu
- St. Michael’s Hospital, University of Toronto, Ontario, Canada
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Jiang X, Zhang Q, Wang HB, Cui XF, Liu R. Associations of urinary, glomerular, and tubular markers with the development of diabetic kidney disease in type 2 diabetes patients. J Clin Lab Anal 2017; 32. [PMID: 28236320 DOI: 10.1002/jcla.22191] [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: 08/31/2016] [Accepted: 01/26/2017] [Indexed: 01/24/2023] Open
Abstract
OBJECTIVES To evaluate the associations of urinary markers (eg albumin), glomerular (eg transferrin [TRF], immunoglobulin G [IgG]), and tubular (eg α1-microglobulin [α1-MG], β2-microglobulin [β2-MG]) markers with the development of diabetic kidney disease (DKD) in type 2 diabetes patients, as assessed by estimated glomerular filtration rate (eGFR) and albuminuria. MATERIAL AND METHODS A total of 252 type 2 diabetes patients and 50 nondiabetic controls from Tianjin, China, were selected. Diabetic patients were divided into three groups according to eGFR levels, including groups A, B, and C with eGFR ≥90 (n=94), 60-89 (n=94), and 30-59 (n=64) mL/min/1.73 m2 . Urine levels of glomerular and tubular markers were detected in first morning urine samples, and their associations with eGFR and albuminuria analyzed. RESULTS Urinary levels of IgG, TRF, and β2-MG were significantly elevated in diabetic patients with normal eGFR compared with nondiabetic control subjects. Urinary levels of all markers increased per eGFR stratum. All kidney damage markers were significantly associated with eGFR in univariate analysis (standard β between -0.35 and -0.28; all P<.001). After adjusting for known confounders, only the tubular markers α1-MG (standard β=-0.25; P=.013) and β2-MG (standard β=-0.18; P=.039) retained significant associations with eGFR. All kidney damage markers were significantly associated with albuminuria, independent of age, duration of diabetes, and eGFR (standard β between 0.45 and 0.86; all P<.001). CONCLUSION Only the tubular markers α1 -MG and β2 -MG were associated with eGFR independent of albuminuria, suggesting that they may play an important role in the development of DKD.
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Affiliation(s)
- Xu Jiang
- Graduate School of Tianjin Medical University, Tianjin, China.,Department of Clinical Laboratory, Tianjin Union Medical Center, Tianjin, China
| | - Qian Zhang
- Graduate School of Tianjin Medical University, Tianjin, China
| | - Hua-Bin Wang
- Jinhua Municipal Central Hospital, Jinhua, China
| | - Xiao-Fan Cui
- Department of Clinical Laboratory, Tianjin Union Medical Center, Tianjin, China
| | - Rui Liu
- Department of Clinical Laboratory, Tianjin Union Medical Center, Tianjin, China
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Papadopoulou-Marketou N, Chrousos GP, Kanaka-Gantenbein C. Diabetic nephropathy in type 1 diabetes: a review of early natural history, pathogenesis, and diagnosis. Diabetes Metab Res Rev 2017; 33. [PMID: 27457509 DOI: 10.1002/dmrr.2841] [Citation(s) in RCA: 158] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 06/20/2016] [Accepted: 07/15/2016] [Indexed: 12/16/2022]
Abstract
Diabetic nephropathy constitutes a devastating complication in patients with type 1 diabetes mellitus, and its diagnosis is traditionally based on microalbuminuria. The aim of this review is to update through the medical literature the suggested early natural course of diabetic nephropathy, the theories behind the pathways of its pathogenesis, and its diagnosis. Poor glycemic control, dyslipidemia, smoking, advanced glycation end products, and environmental and genetic clues play an important role in the development of diabetic nephropathy. Microalbuminuria has been traditionally considered as a primary early marker of microvascular complication unraveling the risk for progress to the advanced stages of chronic kidney disease, but because of our inability to make an early diagnosis of diabetic nephropathy in young patients as well as nonalbuminuric diabetic nephropathy, recently, other additional markers of renal injury like serum and urinary neutrophil gelatinase-associated lipocalin, chitinase-3-like protein 1, cystatin C, and plasma growth differentiation factor 15 have been proposed to unmask early renal dysfunction, even before microalbuminuria supervenes. Copyright © 2016 John Wiley & Sons, Ltd.
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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
| | - 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
| | - 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
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Saif A, Soliman N. Urinary α 1 -microglobulin and albumin excretion in children and adolescents with type 1 diabetes. J Diabetes 2017; 9:61-64. [PMID: 26847470 DOI: 10.1111/1753-0407.12383] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Revised: 12/01/2015] [Accepted: 01/07/2016] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The present study investigated the correlation between urinary α1 -microglobulin as a marker of tubular dysfunction and albumin excretion in children and adolescents with type 1 diabetes (T1D). METHODS Ninety-two Egyptian patients with T1D were included in the study (mean [± SD] age 14.14 ± 5.13 years). The duration of diabetes in all patients was >5 years (mean [± SD] duration 8.28 ± 2.62 years) and all had normal renal function. Forty healthy subjects were also included as a control group. Urinary albumin excretion was assessed in all patients and urinary α1 -microglobulin was measured in both patients and control in the morning urine specimen. RESULTS Analysis of the results showed that patients had significantly higher levels of urinary α1 -microglobulin than the controls (P < 0.01). Among the patients, there was a strong positive correlation between urinary α1 -microglobulin and urinary albumin excretion (P < 0.01). Positive correlations were also found between urinary α1 -microglobulin and duration of diabetes (P < 0.01), HbA1c (P < 0.05), and fasting and postprandial blood glucose (P < 0.05 for both). CONCLUSION The present study shows that urinary α1 -microglobulin is strongly correlated with urinary albumin excretion in children and adolescents with T1D. In addition, it demonstrates the importance of tubular dysfunction as an early and integral component of diabetic nephropathy syndrome in these patients. The results of the present study emphasize the value of tight glycemic control in slowing the progression of tubular dysfunction, especially in patients with a longer duration of diabetes.
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Affiliation(s)
- Aasem Saif
- Departments of Internal Medicine, Cairo University, Cairo, Egypt
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Urinary Markers of Tubular Injury in Early Diabetic Nephropathy. Int J Nephrol 2016; 2016:4647685. [PMID: 27293888 PMCID: PMC4884862 DOI: 10.1155/2016/4647685] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 04/26/2016] [Indexed: 01/08/2023] Open
Abstract
Diabetic nephropathy (DN) is a common and serious complication of diabetes associated with adverse outcomes of renal failure, cardiovascular disease, and premature mortality. Early and accurate identification of DN is therefore of critical importance to improve patient outcomes. Albuminuria, a marker of glomerular involvement in early renal damage, cannot always detect early DN. Thus, more sensitive and specific markers in addition to albuminuria are needed to predict the early onset and progression of DN. Tubular injury, as shown by the detection of tubular injury markers in the urine, is a critical component of the early course of DN. These urinary tubular markers may increase in diabetic patients, even before diagnosis of microalbuminuria representing early markers of normoalbuminuric DN. In this review we summarized some new and important urinary markers of tubular injury, such as neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (L-FABP), N-acetyl-beta-glucosaminidase (NAG), alpha-1 microglobulin (A1M), beta 2-microglobulin (B2-M), and retinol binding protein (RBP) associated with early DN.
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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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Bjornstad P, Cherney DZ, Maahs DM, Nadeau KJ. Diabetic Kidney Disease in Adolescents With Type 2 Diabetes: New Insights and Potential Therapies. Curr Diab Rep 2016; 16:11. [PMID: 26803647 PMCID: PMC5841446 DOI: 10.1007/s11892-015-0708-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) and dialysis in the Western world. Early DKD, including microalbuminuria and renal hyperfiltration, is common in adolescents with type 2 diabetes (T2D). Furthermore, youth-onset T2D carries a higher risk of progressive DKD than adult-onset T2D of similar diabetes duration. DKD is characterized by a long clinically silent period without signs of disease. Therefore, a major challenge in preventing DKD is the difficulty in identifying high-risk T2D patients at an early stage. The Type 2 Diabetes in Adolescents and Youth (TODAY) study demonstrated a high initial prevalence that increased over time, irrespective of treatment arm. This key observation underscores the importance of discovering new therapeutic targets to supplement conventional management, in order to reduce DKD risk. In this review, we focus on early DKD in T2D and summarize potential novel biomarkers and therapeutic targets.
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Affiliation(s)
- Petter Bjornstad
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA.
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, 13123 East 16th Ave, Box B265, Aurora, CO, 80045, USA.
| | - David Z Cherney
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada
| | - David M Maahs
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, 13123 East 16th Ave, Box B265, Aurora, CO, 80045, USA
- Department of Medicine, Division of Nephrology, University of Colorado, Aurora, CO, USA
| | - Kristen J Nadeau
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, 13123 East 16th Ave, Box B265, Aurora, CO, 80045, USA
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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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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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Bellei E, Monari E, Bergamini S, Cuoghi A, Tomasi A, Guerzoni S, Ciccarese M, Pini LA. Validation of potential candidate biomarkers of drug-induced nephrotoxicity and allodynia in medication-overuse headache. J Headache Pain 2015; 16:559. [PMID: 26272683 PMCID: PMC4536253 DOI: 10.1186/s10194-015-0559-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 07/21/2015] [Indexed: 12/15/2022] Open
Abstract
Background Medication-overuse headache (MOH) is a chronic disorder that results from the overuse of analgesics drugs, triptans or other acute headache compounds. Although the exact mechanisms underlying MOH remain still unknown, several studies suggest that it may be associated with development of “central sensitization”, which may cause cutaneous allodynia (CA). Furthermore, the epidemiology of drug-induced disorders suggests that medication overuse could lead to nephrotoxicity. The aim of this work was to confirm and validate the results obtained from previous proteomics studies, in which we analyzed the urinary proteome of MOH patients in comparison with healthy non-abusers individuals. Methods MOH patients were divided into groups on the basis of the drug abused: triptans, non-steroidal anti-inflammatory drugs (NSAIDs) and mixtures, (mainly containing indomethacin, paracetamol and, in some cases, caffeine). Healthy subjects, with a history of normal renal function, were used as controls. In this study, four proteins that were found differentially expressed in urine, and, on the basis of the literature review, resulted related to kidney diseases, were verified by Western Blot and Enzyme-linked Immunosorbent Assay (ELISA); Prostaglandin-H2 D-synthase (PTGDS), uromodulin (UROM), alpha-1-microglobulin (AMBP) and cystatin-C (CYSC). Results Western blot analysis allowed to validate our previous proteomics data, confirming that all MOH patients groups show a significant over-excretion of urinary PTGDS, UROM, AMBP and CYSC (excluding triptans group for this latter), in comparison with controls. Moreover, the expression of PTGDS was further evaluated by ELISA. Also by this assay, a significant increase of PTGDS was observed in all MOH abusers, according to 2-DE and Western blot results. Conclusions In this study, we confirmed previous findings concerning urinary proteins alterations in MOH patients, identified and demonstrated the over-expression of PTGDS, UROM, AMBP, and CYSC, particularly in NSAIDs and mixtures abusers. Over-expression of these proteins have been related to renal dysfunction and probably, PTGDS, to the development of CA. The detection and confirmation of this proteins pattern represent a promising tool for a better understanding of potential nephrotoxicity induced by drugs overuse and may enhance awareness related to the MOH-associated risks, even in absence of clinical symptoms.
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Affiliation(s)
- Elisa Bellei
- Department of Diagnostic Medicine, Clinic and Public Health, Proteomic Lab, University of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy,
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Tubular proteinuria is the dominant type of proteinuria in an elderly community population in China. Int Urol Nephrol 2015. [PMID: 26216674 DOI: 10.1007/s11255-015-1064-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
PURPOSE To explore the types of proteinuria in the elderly population in China. METHODS Seven hundred and fourteen elderly people (≥ 60 years old) from Tianjin, China, were selected for the study. The albumin-to-creatinine ratio and α1-microglobulin-to-creatinine ratio from morning urine samples were used as indicators of proteinuria. The prevalence of proteinuria was evaluated and the proportion of three different types of proteinuria (mixed, glomerular, and tubular) was assessed in the subjects by analyzing these indicators. RESULTS Of the 714 subjects, 29.13 % had elevated ACR and 46.36 % had elevated MCR. The proportion of subjects with either elevated ACR or MCR was 53.78 %. The correlation between MCR and ACR was moderate (r = 0.58, R (2) = 0.34, P < 0.001). Overall, tubular proteinuria was dominant (45.83 %), followed by mixed glomerular and tubular proteinuria (35.68 %), and significantly higher than glomerular proteinuria. A diet high in salt was the independent risk factor for tubular proteinuria; physical activity was the independent risk factor for glomerular proteinuria. The risk of glomerular proteinuria was lower in males than in females, but the risk of tubular proteinuria was higher in males. CONCLUSIONS The prevalence of tubular proteinuria was higher than that of glomerular proteinuria, and the risk factors are different, in the elderly in China; therefore, tubular damage markers should get more attention in the overall population.
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Fiseha T. Urinary biomarkers for early diabetic nephropathy in type 2 diabetic patients. Biomark Res 2015; 3:16. [PMID: 26146561 PMCID: PMC4491239 DOI: 10.1186/s40364-015-0042-3] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 06/26/2015] [Indexed: 02/06/2023] Open
Abstract
Diabetic nephropathy (DN) is a serious complication of diabetes associated with increased risk of mortality, and cardiovascular and renal outcomes. Diagnostic markers to detect DN at early stage are important as early intervention can slow loss of kidney function and improve patient outcomes. Urinary biomarkers may be elevated in diabetic patients even before the appearance of microalbuminuria, and can be used as useful marker for detecting nephropathy in patients with normoalbuminuria (early DN). We reviewed some new and important urinary biomarkers, such as: Neutrophil gelatinase associated lipocalin (NGAL), N-acetyl-beta-glucosaminidase (NAG), Cystatin C, alpha 1-microglobulin, immunoglobulin G or M, type IV collagen, nephrin, angiotensinogen and liver-type fatty acid–binding protein (L-FABP) associated with early DN in type 2 diabetic patients. Our search identified a total of 42 studies that have been published to date. Urinary levels of these biomarkers were elevated in type 2 diabetic patients compared with non-diabetic controls, including in patients who had no signs indicating nephropathy (without microalbuminuria), and showed positive correlation with albuminuria. Despite the promise of these new urinary biomarkers, further large, multicenter prospective studies are still needed to confirm their clinical utility as a screening tool for early type 2 DN in every day practice.
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Affiliation(s)
- Temesgen Fiseha
- Department of Clinical Laboratory Science, College of Medicine and Health Science, Wollo University, Dessie, Ethiopia
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