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Chauhan S, Bhandari U, Habib A. Insights into the Novel Biomarkers Expressed in Diabetic Nephropathy: Potential Clinical Applications. Curr Pharm Des 2025; 31:619-629. [PMID: 39415582 DOI: 10.2174/0113816128333694240928161703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 08/05/2024] [Accepted: 08/07/2024] [Indexed: 10/19/2024]
Abstract
Diabetic nephropathy (DN) is increasing worldwide in parallel with type 2 diabetes mellitus. Identifying diagnostic biomarkers for DN at an early stage is crucial due to the considerable societal and economic burden associated with diabetes mellitus (DM) and its risk factors. In the past, early indicators of microvascular problems, such as microalbuminuria (MA), have been used to predict the possibility of developing advanced chronic kidney disease (CKD). However, because of the incapacity of MA to appropriately estimate DN, particularly, non-albuminuric DN, additional markers have been suggested for recognizing the early renal abnormalities and structural lesions, even before MA. This study aims to assess the existing and future biomarkers used to diagnose or predict early DN. This review provides comprehensive insight into diagnostic approaches for early detection of CKD, addressing the following areas: (i) markers of glomerular damage, (ii) markers of tubular damage, (iii) oxidative stress biomarkers, (iv) inflammatory biomarkers and (v) futuristic biomarkers such as micro-ribonucleic acids (miRNAs), proteomics, metabolomics and genomics and gut microbiota. Early detection of DN may lead to improvement in clinical management and quality of life, emphasizing the importance of identifying a specific and reliable predictive biomarker. Emerging serum and urinary biomarkers offer promise for early DN diagnosis, potentially reducing prevalence and preventing progression to end-stage renal disease (ESRD). Further advancements in miRNAs, proteomics, metabolomics genomics and gut microbiota offer prospects for even earlier and more precise DN diagnosis.
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Affiliation(s)
- Shalu Chauhan
- Department of Pharmacology, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi 110062, India
| | - Uma Bhandari
- Department of Pharmacology, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi 110062, India
| | - Anwar Habib
- Department of Medicine, Hamdard Institute of Medical Sciences & Research (HIMSR), Jamia Hamdard, New Delhi 110062, India
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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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Makhammajanov Z, Gaipov A, Myngbay A, Bukasov R, Aljofan M, Kanbay M. Tubular toxicity of proteinuria and the progression of chronic kidney disease. Nephrol Dial Transplant 2024; 39:589-599. [PMID: 37791392 DOI: 10.1093/ndt/gfad215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Indexed: 10/05/2023] Open
Abstract
Proteinuria is a well-established biomarker of chronic kidney disease (CKD) and a risk predictor of associated disease outcomes. Proteinuria is also a driver of CKD progression toward end-stage kidney disease. Toxic effects of filtered proteins on proximal tubular epithelial cells enhance tubular atrophy and interstitial fibrosis. The extent of protein toxicity and the underlying molecular mechanisms responsible for tubular injury during proteinuria remain unclear. Nevertheless, albumin elicits its toxic effects when degraded and reabsorbed by proximal tubular epithelial cells. Overall, healthy kidneys excrete over 1000 individual proteins, which may be potentially harmful to proximal tubular epithelial cells when filtered and/or reabsorbed in excess. Proteinuria can cause kidney damage, inflammation and fibrosis by increasing reactive oxygen species, autophagy dysfunction, lysosomal membrane permeabilization, endoplasmic reticulum stress and complement activation. Here we summarize toxic proteins reported in proteinuria and the current understanding of molecular mechanisms of toxicity of proteins on proximal tubular epithelial cells leading to CKD progression.
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Affiliation(s)
| | - Abduzhappar Gaipov
- Department of Medicine, School of Medicine, Nazarbayev University, Astana, Kazakhstan
- Clinical Academic Department of Internal Medicine, CF "University Medical Center", Astana, Kazakhstan
| | - Askhat Myngbay
- Department of Biology, School of Sciences and Humanities, Nazarbayev University, Astana, Kazakhstan
| | - Rostislav Bukasov
- Department of Chemistry, School of Sciences and Humanities, Nazarbayev University, Astana, Kazakhstan
| | - Mohamad Aljofan
- Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana, Kazakhstan
| | - Mehmet Kanbay
- Division of Nephrology, Department of Internal Medicine, Koc University, Istanbul, Turkey
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Novak R, Salai G, Hrkac S, Vojtusek IK, Grgurevic L. Revisiting the Role of NAG across the Continuum of Kidney Disease. Bioengineering (Basel) 2023; 10:bioengineering10040444. [PMID: 37106631 PMCID: PMC10136202 DOI: 10.3390/bioengineering10040444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 03/28/2023] [Accepted: 03/30/2023] [Indexed: 04/07/2023] Open
Abstract
Acute and chronic kidney diseases are an evolving continuum for which reliable biomarkers of early disease are lacking. The potential use of glycosidases, enzymes involved in carbohydrate metabolism, in kidney disease detection has been under investigation since the 1960s. N-acetyl-beta-D-glucosaminidase (NAG) is a glycosidase commonly found in proximal tubule epithelial cells (PTECs). Due to its large molecular weight, plasma-soluble NAG cannot pass the glomerular filtration barrier; thus, increased urinary concentration of NAG (uNAG) may suggest injury to the proximal tubule. As the PTECs are the workhorses of the kidney that perform much of the filtration and reabsorption, they are a common starting point in acute and chronic kidney disease. NAG has previously been researched, and it is widely used as a valuable biomarker in both acute and chronic kidney disease, as well as in patients suffering from diabetes mellitus, heart failure, and other chronic diseases leading to kidney failure. Here, we present an overview of the research pertaining to uNAG’s biomarker potential across the spectrum of kidney disease, with an additional emphasis on environmental nephrotoxic substance exposure. In spite of a large body of evidence strongly suggesting connections between uNAG levels and multiple kidney pathologies, focused clinical validation tests and knowledge on underlining molecular mechanisms are largely lacking.
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Affiliation(s)
- Ruder Novak
- Center for Translational and Clinical Research, Department of Proteomics, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Grgur Salai
- Department of Pulmonology, University Hospital Dubrava, 10000 Zagreb, Croatia
| | - Stela Hrkac
- Department of of Clinical Immunology, Allergology and Rheumatology, University Hospital Dubrava, 10000 Zagreb, Croatia
| | - Ivana Kovacevic Vojtusek
- Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb, 10000 Zagreb, Croatia
| | - Lovorka Grgurevic
- Center for Translational and Clinical Research, Department of Proteomics, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Department of Anatomy, “Drago Perovic”, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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Association between Urinary Advanced Glycation End Products and Subclinical Inflammation in Children and Adolescents: Results from the Italian I.Family Cohort. Nutrients 2022; 14:nu14194135. [PMID: 36235787 PMCID: PMC9571918 DOI: 10.3390/nu14194135] [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: 08/29/2022] [Revised: 09/26/2022] [Accepted: 09/30/2022] [Indexed: 12/02/2022] Open
Abstract
Advanced Glycation End Products (AGEs) have been positively correlated with inflammation in adults, while inconsistent evidence is available in children. We evaluated the association between urinary AGEs, measured by fluorescence spectroscopy, and biomarkers of subclinical inflammation in 676 healthy children/adolescents (age 11.8 ± 1.6 years, M ± SD) from the Italian cohort of the I.Family project. Urinary fluorescent AGEs were used as independent variable and high-sensitivity C-reactive protein (hs-CRP) was the primary outcome, while other biomarkers of inflammation were investigated as secondary outcomes. Participants with urinary AGEs above the median of the study population showed statistically significantly higher hs-CRP levels as compared to those below the median (hs-CRP 0.44 ± 1.1 vs. 0.24 ± 0.6 mg/dL, M ± SD p = 0.002). We found significant positive correlations between urinary AGEs and hs-CRP (p = 0.0001), IL-15 (p = 0.001), IP-10 (p = 0.006), and IL-1Ra (p = 0.001). At multiple regression analysis, urinary AGEs, age, and BMI Z-score were independent variables predicting hs-CRP levels. We demonstrated for the first time, in a large cohort of children and adolescents, that the measurement of fluorescent urinary AGEs may represent a simple, noninvasive, and rapid technique to evaluate the association between AGEs and biomarkers of inflammation. Our data support a role of AGEs as biomarkers of subclinical inflammation in otherwise healthy children and adolescents.
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Pelle MC, Provenzano M, Busutti M, Porcu CV, Zaffina I, Stanga L, Arturi F. Up-Date on Diabetic Nephropathy. Life (Basel) 2022; 12:1202. [PMID: 36013381 PMCID: PMC9409996 DOI: 10.3390/life12081202] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/27/2022] [Accepted: 08/02/2022] [Indexed: 12/11/2022] Open
Abstract
Diabetes is one of the leading causes of kidney disease. Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease (ESKD) worldwide, and it is linked to an increase in cardiovascular (CV) risk. Diabetic nephropathy (DN) increases morbidity and mortality among people living with diabetes. Risk factors for DN are chronic hyperglycemia and high blood pressure; the renin-angiotensin-aldosterone system blockade improves glomerular function and CV risk in these patients. Recently, new antidiabetic drugs, including sodium-glucose transport protein 2 inhibitors and glucagon-like peptide-1 agonists, have demonstrated additional contribution in delaying the progression of kidney disease and enhancing CV outcomes. The therapeutic goal is regression of albuminuria, but an atypical form of non-proteinuric diabetic nephropathy (NP-DN) is also described. In this review, we provide a state-of-the-art evaluation of current treatment strategies and promising emerging treatments.
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Affiliation(s)
- Maria Chiara Pelle
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Michele Provenzano
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy
| | - Marco Busutti
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy
| | - Clara Valentina Porcu
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy
| | - Isabella Zaffina
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Lucia Stanga
- Oncology Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy
| | - Franco Arturi
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
- Research Centre for the Prevention and Treatment of Metabolic Diseases (CR METDIS), University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
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Advanced Glycation End Products (AGEs) and Chronic Kidney Disease: Does the Modern Diet AGE the Kidney? Nutrients 2022; 14:nu14132675. [PMID: 35807857 PMCID: PMC9268915 DOI: 10.3390/nu14132675] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 12/13/2022] Open
Abstract
Since the 1980s, chronic kidney disease (CKD) affecting all ages has increased by almost 25%. This increase may be partially attributable to lifestyle changes and increased global consumption of a “western” diet, which is typically energy dense, low in fruits and vegetables, and high in animal protein and ultra-processed foods. These modern food trends have led to an increase in the consumption of advanced glycation end products (AGEs) in conjunction with increased metabolic dysfunction, obesity and diabetes, which facilitates production of endogenous AGEs within the body. When in excess, AGEs can be pathological via both receptor-mediated and non-receptor-mediated pathways. The kidney, as a major site for AGE clearance, is particularly vulnerable to AGE-mediated damage and increases in circulating AGEs align with risk of CKD and all-cause mortality. Furthermore, individuals with significant loss of renal function show increased AGE burden, particularly with uraemia, and there is some evidence that AGE lowering via diet or pharmacological inhibition may be beneficial for CKD. This review discusses the pathways that drive AGE formation and regulation within the body. This includes AGE receptor interactions and pathways of AGE-mediated pathology with a focus on the contribution of diet on endogenous AGE production and dietary AGE consumption to these processes. We then analyse the contribution of AGEs to kidney disease, the evidence for dietary AGEs and endogenously produced AGEs in driving pathogenesis in diabetic and non-diabetic kidney disease and the potential for AGE targeted therapies in kidney disease.
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Citra C, Limijadi EKS, Rachmawati B. The Differences of N–Acetyl–β–Glucosaminidase and β2 Microglobulin levels in Patients with and without Early Diabetic Nephropathy. INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY 2022; 28:121-126. [DOI: 10.24293/ijcpml.v28i2.1836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/17/2024]
Abstract
Diabetic Nephropathy (DN) is becoming the most serious microvascular complication, which be marked by the presence of persistent albuminuria. N–asetil–β–glucosaminidase is dominant lyzosom enzyme in the renal tubule epitel. β2 microglobulin is low molecular weight protein which produced by major histocompatibility complex class 1 (MHC-1) expressed cell in all nucleated cell. N–asetil–β–glucosaminidase and β2 microglobulin could be new usefull marker for early DN. Analytic observational study with cross sectional approach was conducted in May – July 2019 involving 27 non diabetic patients (K1), 27 diabetic patients without DN (K2) and 27 diabetic patients with early DN (K3) at the Clinical Pathology department of Faculty of Medicine, Diponegoro University and Diabetic Clinic. Data include age, gender, fasting blood glucose, blood preasure and urine albumin creatinine ratio. N–asetil–β–glucosaminidase level between groups were analyzed using Anova, β2 microglobulin level between groups using Kruskal Wallis, p<0.05 were considered significant. There are significant differences in levels of N–asetil–β–glucosaminidase between K1 and K2 (p =0.01), K1 and K3 (p =< 0.01), K2 and K3 (p = 0.03) and β2 microglobulin between K1 and K2 (p = 0.02), K1 and K3 (p =< 0.01), K2 and K3 (p< 0.01). N-acetyl-β-glucosaminidase and β2 microglobulin levels were higher in K2 compared to K1 and increased higher in K3 compared to K1 and K2. N-acetyl-β-glucosaminidase and β2 microglobulin can be used as an alternative marker for early DN.
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Ataga KI, Saraf SL, Derebail VK. The nephropathy of sickle cell trait and sickle cell disease. Nat Rev Nephrol 2022; 18:361-377. [PMID: 35190716 PMCID: PMC9832386 DOI: 10.1038/s41581-022-00540-9] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/19/2022] [Indexed: 01/13/2023]
Abstract
Sickle cell syndromes, including sickle cell disease (SCD) and sickle cell trait, are associated with multiple kidney abnormalities. Young patients with SCD have elevated effective renal plasma flow and glomerular filtration rates, which decrease to normal ranges in young adulthood and subnormal levels with advancing age. The pathophysiology of SCD-related nephropathy is multifactorial - oxidative stress, hyperfiltration and glomerular hypertension are all contributing factors. Albuminuria, which is an early clinical manifestation of glomerular damage, is common in individuals with SCD. Kidney function declines more rapidly in individuals with SCD than in those with sickle cell trait or in healthy individuals. Multiple genetic modifiers, including APOL1, HMOX1, HBA1 and HBA2 variants are also implicated in the development and progression of SCD-related nephropathy. Chronic kidney disease and rapid decline in estimated glomerular filtration rate are associated with increased mortality in adults with SCD. Renin-angiotensin-aldosterone system inhibitors are the standard of care treatment for albuminuria in SCD, despite a lack of controlled studies demonstrating their long-term efficacy. Multiple studies of novel therapeutic agents are ongoing, and patients with SCD and kidney failure should be evaluated for kidney transplantation. Given the high prevalence and severe consequences of kidney disease, additional studies are needed to elucidate the pathophysiology, natural history and treatment of SCD-related nephropathy.
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Affiliation(s)
- Kenneth I Ataga
- Center for Sickle Cell Disease, University of Tennessee Health Scienter Center, Memphis, TN, USA.
| | - Santosh L Saraf
- Division of Hematology/Oncology, University of Illinois, Chicago, IL, USA
| | - Vimal K Derebail
- Division of Nephrology and Hypertension, University of North Carolina, Chapel Hill, NC, USA
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Tanaka SI, Fujioka Y, Tsujino T, Ishida T, Hirata KI. Association between urinary N-acetyl-β-glucosaminidase activity–urinary creatinine concentration ratio and risk of disability and all-cause mortality. PLoS One 2022; 17:e0265637. [PMID: 35333903 PMCID: PMC8956177 DOI: 10.1371/journal.pone.0265637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 03/07/2022] [Indexed: 12/03/2022] Open
Abstract
Background Recent studies have suggested that chronic kidney disease is associated with cardiovascular disease, dementia, and frailty, all of which cause disability and early death. We investigated whether increased activity of urinary N-acetyl-β-glucosaminidase (NAG), a marker of kidney injury, is associated with risk of disability or all-cause mortality in a general population. Methods Follow-up data from the Hidaka Cohort Study, a population-based cohort study of members of a Japanese rural community, were obtained via questionnaires completed by participants or their relatives. Multivariable analyses were used to investigate relations between urinary NAG activity–urinary creatinine concentration ratio and risk of disability or all-cause mortality. Results A total of 1182 participants were followed up for a median of 12.4 years. The endpoints were receipt of support under the public long-term care insurance program, and all-cause mortality. A total of 122 participants (10.3%) were reported to be receiving long-term care and 230 (19.5%) had died. After adjustment for cardiovascular risk factors along with physical activity, and using the quartile 1 results as a reference, the odds ratio (OR) for disability was 2.12 [95% confidence interval (95% confidence interval [CI]), 1.04–4.33; p = 0.038) and the hazard ratio (HR) for all-cause mortality was 1.65 (95% CI, 1.05–2.62; p = 0.031) in participants with urinary NAG/creatinine ratio in quartile 4. Similar results were obtained in participants without proteinuria: OR for disability, 2.46 (95% CI, 1.18–5.16; p = 0.017); and HR for all-cause mortality, 1.62 (95% CI, 1.00–2.63; p = 0.049). Conclusions Increased urinary NAG/creatinine ratio was associated with risk of disability or all-cause mortality in a general population.
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Affiliation(s)
- Shin-ichiro Tanaka
- Department of Internal Medicine, Toyooka Hospital Hidaka Medical Center, Toyooka, Hyogo, Japan
- * E-mail:
| | - Yoshio Fujioka
- Division of Clinical Nutrition, Faculty of Nutrition, Kobe Gakuin University, Kobe, Japan
| | - Takeshi Tsujino
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan
| | - Tatsuro Ishida
- Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Ken-ichi Hirata
- Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
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Yudhana A, Mukhopadhyay S, Prima ODA, Akbar SA, Nuraisyah F, Mufandi I, Fauzi KH, Nasyah NA. Multi sensor application-based for measuring the quality of human urine on first-void urine. SENSING AND BIO-SENSING RESEARCH 2021. [DOI: 10.1016/j.sbsr.2021.100461] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
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Metwalley KA, Farghaly HS, Gabri MF, Abdel-Aziz SM, Ismail AM, Raafat DM, Elnakeeb IF. Midkine: Utility as a Predictor of Early Diabetic Nephropathy in Children with Type 1 Diabetes Mellitus. J Clin Res Pediatr Endocrinol 2021; 13:293-299. [PMID: 33565751 PMCID: PMC8388054 DOI: 10.4274/jcrpe.galenos.2021.2020.0303] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 01/29/2021] [Indexed: 12/25/2022] Open
Abstract
Objective This study aimed to assess the role of serum midkine (MK) as a biomarker for early detection of diabetic nephropathy in children with type 1 diabetes mellitus (T1DM) before microalbuminuria emerges. Methods A total of 120 children with T1DM, comprising 60 microalbuminuric patients (Group 1), 60 normoalbuminuric patients (Group 2), and 60 healthy participants as a control group (Group 3) were included. Detailed medical history, clinical examination, and laboratory assessment of high-sensitivity C-reactive protein (hs-CRP), hemoglobin A1c percentage (HbA1c%), lipid profile, urinary albumin to creatinine ratio (ACR), serum MK and estimated glomerular filtration rate based on serum creatinine were performed in all participants. Results Both Group 1 and Group 2 had significantly higher serum MK compared to controls (p<0.001). Additionally, significantly higher MK concentrations were present in Group 1 compared with Group 2 (p<0.001). Receiver operating characteristic curve analysis revealed that the MK concentration cutoff value of 1512 pg/mL was able to predict microalbuminuria with a sensitivity of 96% and specificity of 92%. Stepwise regression analysis revealed that HbA1c%, hs-CRP, and ACR were independently related to MK levels (p<0.001 for each). Conclusion The results of this study suggest that serum MK is a useful, novel, practical marker for the evaluation of renal involvement in children with T1DM, especially in normoalbuminuric children.
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Affiliation(s)
| | - Hekma Saad Farghaly
- Assiut University Faculty of Medicine, Department of Pediatrics, Assiut, Egypt
| | | | | | | | - Duaa Mohamed Raafat
- Assiut University Faculty of Medicine, Department of Pediatrics, Assiut, Egypt
| | - Islam Fathy Elnakeeb
- Aswan University Faculty of Medicine, Department of Clinical Pathology, Aswan, Egypt
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Będzichowska A, Jobs K, Kloc M, Bujnowska A, Kalicki B. The Assessment of the Usefulness of Selected Markers in the Diagnosis of Chronic Kidney Disease in Children. Biomark Insights 2021; 16:11772719211011173. [PMID: 33958853 PMCID: PMC8060753 DOI: 10.1177/11772719211011173] [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: 11/15/2020] [Accepted: 03/11/2021] [Indexed: 11/15/2022] Open
Abstract
INTRODUCTION The kidney deterioration, which starts in childhood often leads to end-stage renal failure in the future. Therefore, searching for an early, sensitive, and specific biomarkers became a paramount for chronic kidney disease diagnosis. The aim of this study was the assessment of markers: KIM-1, FGF-23, NAG, NGAL, and uromodulin for diagnosis of preclinical phase of the disease in children. PATIENTS AND METHODS 59 children (15 boys, 44 girls from 6 months to 17 years old) with kidney disorders, which had clinical indications for renoscintigraphy, were included in the study. All patients were divided depending on the result of renoscintigraphy (renal scarring vs normal kidney picture) and depending on the level of estimated glomerular filtration rate (glomerular hyperfiltration vs normal filtration rate). The concentration of uromoduline, KIM-1, FGF-23, NAG, and NGAL in serum and of NGAL and uromoduline in urine were measured in all studied groups. RESULTS The children with glomerular hyperfiltration had a statistically significantly higher serum values of FGF-23 and NGAL than the children with normal filtration rate (P < .05). There were no statistically significant differences in serum concentrations of tested markers in children with renal scars in comparison to children with normal renal image. There was no statistically significant difference in the concentration of tested markers in urine. CONCLUSIONS The study confirmed the possible usefulness of FGF-23 and NGAL in detecting the preclinical-stage of renal disease associated with glomerular hyperfiltration in children. The study do not allow to indicate markers, which could be useful in the early diagnosis of kidney damage visible in the scintigraphic examination.
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Affiliation(s)
- Agata Będzichowska
- Department of Pediatrics, Pediatric
Nephrology and Allergology, Military Institute of Medicine, Warsaw, Poland
| | - Katarzyna Jobs
- Department of Pediatrics, Pediatric
Nephrology and Allergology, Military Institute of Medicine, Warsaw, Poland
| | - Małgorzata Kloc
- The Houston Methodist Research
Institute, Houston, TX, USA
- The University of Texas, MD Anderson
Cancer Center, Houston, TX, USA
| | - Anna Bujnowska
- Department of Pediatrics, Pediatric
Nephrology and Allergology, Military Institute of Medicine, Warsaw, Poland
| | - Bolesław Kalicki
- Department of Pediatrics, Pediatric
Nephrology and Allergology, Military Institute of Medicine, Warsaw, Poland
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EVALUATION OF THE FUNCTIONAL STATE OF THE KIDNEYS IN HEALTHY AND PATIENTS WITH TYPE 1 DIABETES WITH DIFFERENT LEVELS OF ALBUMIN IN THE URINE. WORLD OF MEDICINE AND BIOLOGY 2021. [DOI: 10.26724/2079-8334-2021-2-76-64-68] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Sotokawauchi A, Matsui T, Higashimoto Y, Nishino Y, Koga Y, Yagi M, Yamagishi SI. DNA aptamer raised against receptor for advanced glycation end products suppresses renal tubular damage and improves insulin resistance in diabetic mice. Diab Vasc Dis Res 2021; 18:1479164121990533. [PMID: 33535822 PMCID: PMC8482725 DOI: 10.1177/1479164121990533] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE Interaction of advanced glycation end products (AGEs) with the receptor RAGE plays a role in diabetic nephropathy. However, effects of RAGE-aptamer on tubular damage remain unknown. We examined whether RAGE-aptamer inhibited tubular damage in KKAy/Ta mice, obese type 2 diabetic mice with insulin resistance. MATERIALS AND METHODS Male 8-week-old KKAy/Ta mice received continuous intraperitoneal infusion of either control-aptamer or RAGE-aptamer for 8 weeks. Blood biochemistry and blood pressure, and urinary N-acetyl-β-D-glucosaminidase (NAG) activity and albumin excretion levels were monitored. Kidney and adipose tissue samples were obtained for immunohistochemical analyses. RESULTS Although RAGE-aptamer did not affect blood glucose, blood pressure, body weight, or serum creatinine values, it significantly inhibited the increase in urinary NAG activity and HOMA-IR in diabetic mice at 12 and 16 and at 16 weeks old, respectively. Furthermore, compared with control-aptamer-treated mice, renal carboxymethyllysine, RAGE, and NADPH oxidase-driven superoxide generation were significantly decreased in RAGE-aptamer-treated mice at 12 weeks old with subsequent amelioration of histological alterations in glomerular and interstitial area, while adipose tissue adiponectin expression was increased. CONCLUSION Our present results suggest that RAGE-aptamer could inhibit tubular injury in obese type 2 diabetic mice partly by suppressing the AGE-RAGE-oxidative stress axis and improving insulin resistance.
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Affiliation(s)
- Ami Sotokawauchi
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
| | - Takanori Matsui
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
| | | | - Yuri Nishino
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
| | - Yoshinori Koga
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
- Department of Pediatric Surgery, Kurume University School of Medicine, Kurume, Japan
| | - Minoru Yagi
- Department of Pediatric Surgery, Kurume University School of Medicine, Kurume, Japan
| | - Sho-ichi Yamagishi
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan
- Sho-ichi Yamagishi, Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan.
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Yamashita S, Shinozaki T, Murata H, Matsuyama Y, Babazono T. Panel of novel urine biomarkers for incident microalbuminuria in people with type 2 diabetes mellitus. Diabet Med 2020; 37:1910-1918. [PMID: 32096274 DOI: 10.1111/dme.14280] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/22/2020] [Indexed: 12/24/2022]
Abstract
AIM The need to identify novel biomarkers for early diagnosis and treatment of diabetic nephropathy is widely recognized. However, only a few studies have investigated the association between biomarkers and the onset of albuminuria. In this study, we aimed to investigate a panel of biomarkers suitable for predicting microalbuminuria. METHODS Some 346 Japanese people with type 2 diabetes exhibiting normoalbuminuria were studied. The endpoint was defined as the onset of microalbuminuria. Thirty biomarkers were selected from among urinary biomarkers described in previous studies. A panel of biomarkers was selected using least absolute shrinkage and selection operator (LASSO). The prognostic performance of the developed panel was evaluated. RESULTS During a mean follow-up of 6.2 years, 45 people progressed to microalbuminuria. A composite panel of six biomarkers (monocyte chemoattractant protein-1, osteopontin, soluble human tumour necrosis factor receptor-1, tenascin C, vascular endothelial growth factor-A and kidney injury molecule-1) was developed using LASSO. Compared with the basal model comprising estimated GFR and urinary albumin-to-creatinine ratio, addition of these six biomarkers significantly increased the overall C index from 0.773 to 0.824 (P = 0.019). Net reclassification improvement and integrated discrimination improvement were estimated to be 0.412 (P = 0.049) and 0.040 (P = 0.040), respectively. Decision curve analysis also showed that the model with the six novel biomarkers had a better prognostic value for predicting the onset of microalbuminuria. The optimism was moderate or negligible according to measures. CONCLUSIONS The panel consisting of six novel urinary biomarkers effectively predicted incident microalbuminuria in people with type 2 diabetes.
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Affiliation(s)
- S Yamashita
- Department of Medicine, Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - T Shinozaki
- Department of Biostatistics, School of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - H Murata
- Department of Medicine, Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Y Matsuyama
- Department of Biostatistics, School of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - T Babazono
- Department of Medicine, Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
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El-Ebidi AM, Saleem TH, Saadi MGED, Mahmoud HA, Mohamed Z, Sherkawy HS. Cyclophilin A (CyPA) as a Novel Biomarker for Early Detection of Diabetic Nephropathy in an Animal Model. Diabetes Metab Syndr Obes 2020; 13:3807-3819. [PMID: 33116728 PMCID: PMC7585800 DOI: 10.2147/dmso.s260293] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 09/04/2020] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND AND AIM Type 2 diabetes mellitus (DM) is the most common single cause of the end-stage renal disease (ESRD). Cyclophilin A (CyPA) is an 18-kD protein. The connection between diabetic nephropathy (DN) and the secreted form of CyPA (sCyPA) has been elucidated in this study that aims to investigate sCyPA correlation with renal dysfunction. MATERIALS AND METHODS Thirty-four male adult Wistar rats weighing 180-220 g were used. Animals were divided into a study group and a control group, 17 rats in each. Streptozotocin (STZ) and nicotine amide were used to damage some pancreatic cells for induction of type 2 DM. Comparison was made between the study and the control groups. Moreover, a comparison was made between the members of the study group before and after induction of DN. RESULTS The rat model that exhibited a higher concentration of urinary sCyPA was detected early in the eighth week. There was a significantly higher level of 24-h urinary CyPA in the study group compared to the control group (p-value=0.004) and there was a significant elevation in the 24-h urinary Cyp-A in the study group after injection of STZ compared to the values before injection (p-value <0.001). Immunohistochemical analysis of renal tissue revealed that the mean expression of CyPA was higher in the study group than in the control group. For the urinary 24-h CYP-A, using a cutoff of 1.15 ng/mL, the accuracy was 72.4%, sensitivity was (77.8%) and specificity was (67%). CONCLUSION According to this animal study, we proved that CyPA is a valuable marker for DN. It is a more sensitive, noninvasive and rapid biomarker for early detection of any renal affection in human diabetic patients.
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Affiliation(s)
- Abdallah Mahmoud El-Ebidi
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Aswan University, Aswan, Egypt
| | - Tahia H Saleem
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Assuit University, Assuit, Egypt
| | - Mohamed Gamal El-din Saadi
- Department of Internal Medicine and Nephrology, Kasr Al-Aini School of Medicine, Cairo University, Cairo, Egypt
| | | | - Zeinab Mohamed
- Department of Zoology, Faculty of Science, Aswan University, Aswan, Egypt
| | - Hoda S Sherkawy
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Aswan University, Aswan, Egypt
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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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Gao Z, Wang Z, Zhu H, Yuan X, Sun M, Wang J, Zuo M, Cui X, Han Y, Zhang Y, Yang S, Qin Y, Xu J, Yang J, Chang B. Hyperinsulinemia contributes to impaired-glucose-tolerance-induced renal injury via mir-7977/SIRT3 signaling. Ther Adv Chronic Dis 2020; 11:2040622320916008. [PMID: 32523663 PMCID: PMC7236569 DOI: 10.1177/2040622320916008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 03/03/2020] [Indexed: 01/23/2023] Open
Abstract
Background: Increasing evidence indicates that impaired glucose tolerance (IGT) is independently associated with chronic kidney disease, but the characteristics and underlying mechanisms remain largely unknown. Methods: Here, the cross-sectional study was performed to study the characteristics of IGT-induced renal injury (IGT-RI). Furthermore, urine microRNA profile was evaluated and microRNAs involved in tubular injury were determined by in-vitro experiments. Results: It was found that 12.1% of IGT patients had microalbuminuria, which we termed “IGT-RI.” Overall, 100% of patients with IGT-RI exhibited reabsorption dysfunction and 58.3% had structural damage in the renal tubules. Two-hour postprandial insulin, retinol-binding protein, and N-acetyl-β-glucosaminidase were significantly associated with microalbuminuria and they were independent risk factors for IGT-RI. The expression of mir-7977 was altered in IGT-RI patients and may be involved in cellular response to oxidative stress. In proximal tubule epithelial cells in vitro, a high level of insulin increased the expression of mir-7977 and decreased that of sirtuin 3 (SIRT3), leading to oxidative stress. Overexpression of mir-7977 further decreased SIRT3 expression, whereas inhibition of mir-7977 had the opposite effect. Furthermore, mir-7977 can bind to the 3′-untranslated region of SIRT3 mRNA and inhibit its expression. Moreover, inhibition of SIRT3 reduced the expression of cubilin and the endocytosis of albumin. Conclusions: In conclusion, IGT-RI mainly manifests as tubular injury, especially reabsorption dysfunction. Compensatory hyperinsulinemia may be involved. A high level of insulin can activate mir-7977/SIRT3 signaling, resulting in tubular injury by inducing oxidative stress as well as reabsorption dysfunction by inhibiting the expression of cubilin, ultimately contributing to IGT-RI.
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Affiliation(s)
- Zhongai Gao
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Ziyan Wang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Hong Zhu
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Xinxin Yuan
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Mengdi Sun
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Jingyu Wang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Minxia Zuo
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Xiao Cui
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Ying Han
- Department of Endocrinology, Tianjin Haibin People's Hospital, Tianjin, China
| | - Yi Zhang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Shaohua Yang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Yongzhang Qin
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Jie Xu
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Juhong Yang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China
| | - Baocheng Chang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China
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Aragón CC, Tafúr RA, Suárez-Avellaneda A, Martínez MDT, Salas ADL, Tobón GJ. Urinary biomarkers in lupus nephritis. J Transl Autoimmun 2020; 3:100042. [PMID: 32743523 PMCID: PMC7388339 DOI: 10.1016/j.jtauto.2020.100042] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 01/07/2020] [Accepted: 02/06/2020] [Indexed: 02/08/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is the prototypical autoimmune disease that can affect any organ of the body. Multiple mechanisms may contribute to the pathophysiology of systemic lupus, including failure to remove apoptotic bodies, hyperactivity of self-reactive B and T lymphocytes, abnormal exposure to autoantigens, and increased levels of B-cell stimulatory cytokines. The involvement of the kidney, called lupus nephritis (LN), during the course of the disease affects between 30% and 60% of adult SLE patients, and up to 70% of children. LN is an immune-mediated glomerulonephritis that is a common and serious finding in patients with SLE. Nowadays, renal biopsy is considered the gold standard for classifying LN, besides its degree of activity or chronicity. Nevertheless, renal biopsy lacks the ability to predict which patients will respond to immunosuppressive therapy and is a costly and risky procedure that is not practical in the monitoring of LN because serial repetitions would be necessary. Consequently, many serum and urinary biomarkers have been studied in SLE patients for the complementary study of LN, existing conventional biomarkers like proteinuria, protein/creatinine ratio in spot urine, 24 h urine proteinuria, creatinine clearance, among others and non-conventional biomarkers, like Monocyte chemoattractant protein-1 (MCP-1), have been correlated with the histological findings of the different types of LN. In this article, we review the advances in lupus nephritis urinary biomarkers. Such markers ideally should be capable of predicting early sub-clinical flares and could be used to follow response to therapy. In addition, some of these markers have been found to be involved in the pathogenesis of lupus nephritis.
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Affiliation(s)
- Cristian C. Aragón
- GIRAT: Grupo de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Fundación Valle Del Lili and Universidad Icesi, Cali, Colombia
| | - Raúl-Alejandro Tafúr
- GIRAT: Grupo de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Fundación Valle Del Lili and Universidad Icesi, Cali, Colombia
- Universidad Icesi, Medical School, Cali, Colombia
| | - Ana Suárez-Avellaneda
- GIRAT: Grupo de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Fundación Valle Del Lili and Universidad Icesi, Cali, Colombia
| | - MD. Tatiana Martínez
- GIRAT: Grupo de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Fundación Valle Del Lili and Universidad Icesi, Cali, Colombia
- Universidad Icesi, Medical School, Cali, Colombia
| | - Alejandra de las Salas
- GIRAT: Grupo de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Fundación Valle Del Lili and Universidad Icesi, Cali, Colombia
- Universidad Icesi, Medical School, Cali, Colombia
| | - Gabriel J. Tobón
- GIRAT: Grupo de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Fundación Valle Del Lili and Universidad Icesi, Cali, Colombia
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Pérez-López L, Boronat M, Melián C, Brito-Casillas Y, Wägner AM. Animal Models and Renal Biomarkers of Diabetic Nephropathy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1307:521-551. [PMID: 32329028 DOI: 10.1007/5584_2020_527] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Diabetes mellitus (DM) is the first cause of end stage chronic kidney disease (CKD). Animal models of the disease can shed light on the pathogenesis of the diabetic nephropathy (DN) and novel and earlier biomarkers of the condition may help to improve diagnosis and prognosis. This review summarizes the most important features of animal models used in the study of DN and updates the most recent progress in biomarker research.
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Affiliation(s)
- Laura Pérez-López
- Institute of Biomedical and Health Research (IUIBS), University of Las Palmas de Gran Canaria (ULPGC), Las Palmas de Gran Canaria, Spain
| | - Mauro Boronat
- Institute of Biomedical and Health Research (IUIBS), University of Las Palmas de Gran Canaria (ULPGC), Las Palmas de Gran Canaria, Spain
- Department of Endocrinology and Nutrition, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain
| | - Carlos Melián
- Institute of Biomedical and Health Research (IUIBS), University of Las Palmas de Gran Canaria (ULPGC), Las Palmas de Gran Canaria, Spain
- Department of Animal Pathology, Veterinary Faculty, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Arucas, Las Palmas, Spain
| | - Yeray Brito-Casillas
- Institute of Biomedical and Health Research (IUIBS), University of Las Palmas de Gran Canaria (ULPGC), Las Palmas de Gran Canaria, Spain
| | - Ana M Wägner
- Institute of Biomedical and Health Research (IUIBS), University of Las Palmas de Gran Canaria (ULPGC), Las Palmas de Gran Canaria, Spain.
- Department of Endocrinology and Nutrition, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain.
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Maksoud AAA, Sharara SM, Nanda A, Khouzam RN. The renal resistive index as a new complementary tool to predict microvascular diabetic complications in children and adolescents: a groundbreaking finding. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:422. [PMID: 31660321 PMCID: PMC6787385 DOI: 10.21037/atm.2019.08.65] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 08/12/2019] [Indexed: 11/06/2022]
Abstract
The increasing prevalence of type 1 diabetes mellitus (DM) has made it necessary to have new markers for early detection of diabetic nephropathy. Renal resistive index (RI) by using renal Doppler can be a helpful tool in detecting functional alterations in renal hemodynamics. This study was conducted on 100 children and adolescents with type 1 DM. They were further subdivided into two equal subgroups: group 1 with type 1 DM and normo-albuminuria [urinary albumin excretion (UAE) <30 mg/24 hours], and group 2 with type 1 DM and hyper-albuminuria (increased UAE >30 mg/24 hours). There were 37 males (37%) and 63 females (63%); their mean ages were 13.6±2.53 (range, 10-19) years and mean disease duration was 8.867±2.260 (range, 5-13) years. Progressive increase in RI was significantly associated with increased disease duration more than 10 years, elevated serum HbA1c more than 7.5% and early pubertal stages. While not significantly related to sex, weight, height, blood pressure or serum lipid profile, diabetic micro-vascular complications (nephropathy and sensory neuropathy) were more prevalent among patients with RI more than 0.58. Renal RI could be a useful complementary test for the evaluation of functional alterations in renal hemodynamics in the early stages of diabetic nephropathy.
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Affiliation(s)
| | | | - Amit Nanda
- Department of Medicine, Division of Cardiovascular Diseases, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Rami N. Khouzam
- Department of Medicine, Division of Cardiovascular Diseases, University of Tennessee Health Science Center, Memphis, TN, USA
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Serum levels of miR-126 and miR-223 and outcomes in chronic kidney disease patients. Sci Rep 2019; 9:4477. [PMID: 30872798 PMCID: PMC6418179 DOI: 10.1038/s41598-019-41101-8] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 02/28/2019] [Indexed: 01/11/2023] Open
Abstract
Several microRNAs (miRNAs) have been linked to chronic kidney disease (CKD) mortality, cardiovascular (CV) complications and kidney disease progression. However, their association with clinical outcomes remains poorly evaluated. We used real-time qPCR to measure serum levels of miR-126 and miR-223 in a large cohort of 601 CKD patients (CKD stage G1 to G5 patients or on renal replacement therapy – CKD G5D) from Ghent University Hospital and 31 healthy controls. All-cause mortality and cardiovascular and renal events were registered as endpoints over a 6 year follow-up period. miR-126 levels were significantly lower from CKD stage G2 on, compared to controls. The serum levels of miR-223 were significantly lower from CKD stage G3B on. When considering overall mortality, patients with levels of either miR-126 or miR-223 below the median had a lower survival rate. Similar results were observed for CV and renal events. The observed link between the two miRNAs’ seric levels and mortality, cardiovascular events or renal events in CKD appears to depend on eGFR. However, this does not preclude their potential role in the pathophysiology of CKD. In conclusion, CKD is associated with a decrease in circulating miR-223 and miR-126 levels.
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Qin Y, Zhang S, Shen X, Zhang S, Wang J, Zuo M, Cui X, Gao Z, Yang J, Zhu H, Chang B. Evaluation of urinary biomarkers for prediction of diabetic kidney disease: a propensity score matching analysis. Ther Adv Endocrinol Metab 2019; 10:2042018819891110. [PMID: 31832131 PMCID: PMC6887810 DOI: 10.1177/2042018819891110] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Accepted: 11/04/2019] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The aim of this study was to evaluate the diagnostic value of six urinary biomarkers for prediction of diabetic kidney disease (DKD). METHODS The cross-sectional study recruited 1053 hospitalized patients with type 2 diabetes mellitus (T2DM), who were categorized into the diabetes mellitus (DM) with normoalbuminuria (NA) group (n = 753) and DKD group (n = 300) according to 24-h urinary albumin excretion rate (24-h UAE). Data on the levels of six studied urinary biomarkers [transferrin (TF), immunoglobulin G (IgG), retinol-binding protein (RBP), β-galactosidase (GAL), N-acetyl-beta-glucosaminidase (NAG), and β2-microglobulin (β2MG)] were obtained. The propensity score matching (PSM) method was applied to eliminate the influences of confounding variables. RESULTS Patients with DKD had higher levels of all six urinary biomarkers. All indicators demonstrated significantly increased risk of DKD, except for GAL and β2MG. Single RBP yielded the greatest area under the curve (AUC) value of 0.920 compared with the other five markers, followed by TF (0.867) and IgG (0.867). However, GAL, NAG, and β2MG were shown to have a weak prognostic ability. The diagnostic values of the different combinations were not superior to the single RBP. CONCLUSIONS RBP, TF, and IgG could be used as reliable or good predictors of DKD. The combined use of these biomarkers did not improve DKD detection.
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Affiliation(s)
- Yongzhang Qin
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
- Department of Endocrinology, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Shuang Zhang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
- Tianjin Women’s and Children’s Health Center, Tianjin, China
| | - Xiaofang Shen
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Shunming Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Jingyu Wang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Minxia Zuo
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Xiao Cui
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Zhongai Gao
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Juhong Yang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Hong Zhu
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
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Lee M, Hong N, Lee YH, Kang ES, Cha BS, Lee BW. Elevated N-acetyl-β-d-glucosaminidase, a urinary tubular damage marker, is a significant predictor of carotid artery atherosclerosis in type 1 diabetes, independent of albuminuria: A cross-sectional study. J Diabetes Complications 2018; 32:777-783. [PMID: 29980431 DOI: 10.1016/j.jdiacomp.2018.05.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 05/03/2018] [Accepted: 05/27/2018] [Indexed: 01/07/2023]
Abstract
AIMS Recent evidence has shown that renal tubulointerstitial injuries play an important role in diabetic nephropathy. In this study, we evaluated the association between urinary N-acetyl-β-d-glucosaminidase (uNAG), an early renal tubular damage marker, and carotid artery atherosclerosis in patients with type 1 diabetes (T1D). METHODS This was a cross-sectional study of 88 patients with T1D. Demographic and laboratory data; urinary indices, including urinary NAG-to-creatinine ratio (uNCR), and albumin-to-creatinine ratio (uACR); and carotid ultrasonography were investigated. RESULTS Eighty-eight subjects were divided into three groups based on uNCR tertiles. Subjects belonging to the highest tertile of uNCR had the highest average mean and maximum carotid intima-media thickness (IMT). An elevated uNCR was also significantly correlated with increased average mean and maximum carotid IMT, whereas an elevated uACR was not. Even after adjusting for confounding factors, uNCR continued to be a meaningful predictive marker for increased average mean and maximum IMT. Conversely, the uACR could not predict carotid IMT after adjustment for confounding factors. CONCLUSIONS Elevated levels of uNAG are significantly associated with carotid artery atherosclerosis in patients with T1D independently of albuminuria, a marker of glomerular damage.
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Affiliation(s)
- Minyoung Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea.
| | - Namki Hong
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea.
| | - Yong-Ho Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea.
| | - Eun Seok Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea.
| | - Bong Soo Cha
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea.
| | - Byung-Wan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea.
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Pan W, Peng W, Ning F, Zhang Y, Zhang Y, Wang Y, Xie W, Zhang J, Xin H, Li C, Zhang X. Non-invasive detection of the early phase of kidney injury by photoacoustic/computed tomography imaging. NANOTECHNOLOGY 2018; 29:265101. [PMID: 29718825 DOI: 10.1088/1361-6528/aabcee] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
The early diagnosis of kidney diseases, which can remarkably impair the quality of life and are costly, has encountered great difficulties. Therefore, the development of methods for early diagnosis has great clinical significance. In this study, we used an emerging technique of photoacoustic (PA) imaging, which has relatively high spatial resolution and good imaging depth. Two kinds of PA gold nanoparticle (GNP)-based bioprobes were developed based on their superior photo detectability, size controllability and biocompatibility. The kidney injury mouse model was developed by unilateral ureteral obstruction for 96 h and the release of obstruction model). Giving 3.5 and 5.5 nm bioprobes by tail vein injection, we found that the 5.5 nm probe could be detected in the bladder in the model group, but not in the control group. These results were confirmed by computed tomography imaging. Furthermore, the model group did not show changes in the blood biochemical indices (BUN and Scr) and histologic examination. The 5.5 nm GNPs were found to be the critical point for early diagnosis of kidney injury. This new method was faster and more sensitive and accurate for the detection of renal injury, compared with conventional methods, and can be used for the development of a PA GNP-based bioprobe for diagnosing renal injury.
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Affiliation(s)
- Wanma Pan
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China
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Elevated urinary N-acetyl-β-D-glucosaminidase is associated with high glycoalbumin-to-hemoglobin A1c ratio in type 1 diabetes patients with early diabetic kidney disease. Sci Rep 2018; 8:6710. [PMID: 29712934 PMCID: PMC5928247 DOI: 10.1038/s41598-018-25023-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 04/12/2018] [Indexed: 01/23/2023] Open
Abstract
Urinary N-acetyl-β-D-glucosaminidase (uNAG) predicted the progression of diabetic kidney disease (DKD) prior to development of albuminuria in diabetes patients. We sought whether uNAG level is associated with glycoalbumin-to-hemoglobin A1c ratio (G/A ratio), a marker of postprandial hyperglycemia and glycemic excursion, independent of albuminuria and kidney function. The association between uNAG excretion and G/A ratio was assessed in 204 consecutive subjects with type 1 diabetes (T1D) (mean age 43.9 years; 49.0% men). uNAG excretion level increased along with older age, hyperglycemia, and degree of albuminuria, but was not correlated with body mass index or estimated glomerular filtration rate (eGFR). Elevated uNAG showed robust association with higher G/A ratio (adjusted β = 0.103, P = 0.020) after adjustment for age, sex, body mass index, duration of diabetes, uACR, angiotensin blockers use, fasting plasma glucose, and hemoglobin level. uNAG showed better discriminatory performance for individuals with high G/A ratio than albuminuria (AUC 0.613 vs. 0.518, P = 0.038). Measurement of uNAG improved AUC for high G/A ratio from 0.699 to 0.748 (P = 0.043) when added to conventional risk factors (cutoff 5.24 U/g creatinine; sensitivity 62.5% and specificity 58.0%). In conclusion, Elevated uNAG was found to be associated with high G/A ratio in patients with T1D with early stage DKD, independent of age and albuminuria.
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28
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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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29
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Kaul A, Behera MR, Rai MK, Mishra P, Bhaduaria DS, Yadav S, Agarwal V, Karoli R, Prasad N, Gupta A, Sharma RK. Neutrophil Gelatinase-associated Lipocalin: As a Predictor of Early Diabetic Nephropathy in Type 2 Diabetes Mellitus. Indian J Nephrol 2018; 28:53-60. [PMID: 29515302 PMCID: PMC5830810 DOI: 10.4103/ijn.ijn_96_17] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
This study was carried out to look for diagnostic and prognostic role of neutrophil gelatinase-associated lipocalin (NGAL) in early diabetic nephropathy (DN) in type 2 diabetes individuals. NGAL was measured in both urinary and serum sample of 144 type 2 diabetes individuals stratified into three categories based on urinary albumin-creatinine ratio and 54 control populations with estimated glomerular filtration rate >60 mL/min/1.73 m2 and serum creatinine <1.2 mg/dl. The serum NGAL (sNGAL), urine NGAL (uNGAL), and uNGAL/urine creatinine were significantly higher in diabetic individuals than in the control populations with significant difference in between the groups (P < 0.05). Difference of above values between control value and normoalbuminuria was also statistically significant (P < 0.05). Again, sNGAL and uNGAL correlate positively with albuminuria (P < 0.05). Tubular injury may precede glomerular injury in diabetic individuals, and NGAL can be used as a biomarker to diagnose DN even earlier to incipient nephropathy. Both sNGAL and uNGAL can predict albuminuria and be used as a noninvasive tool for diagnosis, staging, and progression of DN.
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Affiliation(s)
- A. Kaul
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - M. R. Behera
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - M. K. Rai
- Department of Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - P. Mishra
- Department of Biostatistics and Health Informatics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - D. S. Bhaduaria
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - S. Yadav
- Department of Medicine, ERA Medical College, Lucknow, Uttar Pradesh, India
| | - V. Agarwal
- Department of Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - R. Karoli
- Department of Endocrinology, ERA Medical College, Lucknow, Uttar Pradesh, India
| | - N. Prasad
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - A. Gupta
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - R. K. Sharma
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
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30
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Milas O, Gadalean F, Vlad A, Dumitrascu V, Gluhovschi C, Gluhovschi G, Velciov S, Popescu R, Bob F, Matusz P, Pusztai AM, Cretu OM, Secara A, Simulescu A, Ursoniu S, Vlad D, Petrica L. Deregulated profiles of urinary microRNAs may explain podocyte injury and proximal tubule dysfunction in normoalbuminuric patients with type 2 diabetes mellitus. J Investig Med 2017; 66:747-754. [PMID: 29279420 DOI: 10.1136/jim-2017-000556] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/18/2017] [Indexed: 12/14/2022]
Abstract
MicroRNAs (miRNAs) are short non-coding RNA species that are important post-transcriptional regulators of gene expression. The aim of the study was to establish a potential explanation of podocyte damage and proximal tubule (PT) dysfunction induced by deregulated miRNAs expression in the course of type 2 diabetes mellitus (DM). A total of 68 patients with type 2 DM and 11 healthy subjects were enrolled in a cross-sectional study and assessed concerning urinary albumin:creatinine ratio (UACR), urinary N-acetyl-β-D-glucosamininidase (NAG), urinary kidney injury molecule-1, urinary nephrin, podocalyxin, synaptopodin, estimated glomerular filtration rate (eGFR), urinary miRNA21, miRNA124, and miRNA192. In univariable regression analysis, miRNA21, miRNA124, and miRNA192 correlated with urinary nephrin, synaptopodin, podocalyxin, NAG, KIM-1, UACR, and eGFR. Multivariable regression analysis yielded models in which miRNA192 correlated with synaptopodin, uNAG, and eGFR (R2=0.902; P<0.0001), miRNA124 correlated with synaptopodin, uNAG, UACR, and eGFR (R2=0.881; P<0.0001), whereas miRNA21 correlated with podocalyxin, uNAG, UACR, and eGFR (R2=0.882; P<0.0001). Urinary miRNA192 expression was downregulated, while urinary miRNA21 and miRNA124 expressions were upregulated. In patients with type 2 DM, there is an association between podocyte injury and PT dysfunction, and miRNA excretion, even in the normoalbuminuria stage. This observation documents a potential role of the urinary profiles of miRNA21, miRNA124, and miRNA192 in early DN. Despite their variability across the segments of the nephron, urinary miRNAs may be considered as a reliable tool for the identification of novel biomarkers in order to characterize the genetic pattern of podocyte damage and PT dysfunction in early DN of type 2 DM.
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Affiliation(s)
- Oana Milas
- Department of Nephrology, County Emergency Hospital Timisoara, Timisoara, Romania.,'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania
| | - Florica Gadalean
- Department of Nephrology, County Emergency Hospital Timisoara, Timisoara, Romania.,'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania
| | - Adrian Vlad
- 'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania.,Department of Diabetes and Metabolic Diseases, County Emergency Hospital Timisoara, Timisoara, Romania
| | - Victor Dumitrascu
- 'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania.,Department of Pharmacology, Timisoara, Romania
| | - Cristina Gluhovschi
- Department of Nephrology, County Emergency Hospital Timisoara, Timisoara, Romania.,'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania
| | - Gheorghe Gluhovschi
- Department of Nephrology, County Emergency Hospital Timisoara, Timisoara, Romania.,'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania
| | - Silvia Velciov
- Department of Nephrology, County Emergency Hospital Timisoara, Timisoara, Romania.,'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania
| | - Roxana Popescu
- 'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania.,Department of Cellular and Molecular Biology, Timisoara, Romania
| | - Flaviu Bob
- Department of Nephrology, County Emergency Hospital Timisoara, Timisoara, Romania.,'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania
| | - Petru Matusz
- 'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania.,Department of Anatomy and Embryology, Timisoara, Romania
| | - Agneta-Maria Pusztai
- 'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania.,Department of Anatomy and Embryology, Timisoara, Romania
| | - Octavian M Cretu
- 'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania.,Department of Surgery I, Timisoara, Romania
| | - Alina Secara
- Department of Nephrology, County Emergency Hospital Timisoara, Timisoara, Romania.,'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania
| | - Anca Simulescu
- Department of Nephrology, County Emergency Hospital Timisoara, Timisoara, Romania.,'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania
| | - Sorin Ursoniu
- 'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania.,Department of Public Health Medicine, Timisoara, Romania.,Centre of Translational Research and Systems Medicine, Timisoara, Romania
| | - Daliborca Vlad
- 'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania.,Department of Pharmacology, Timisoara, Romania
| | - Ligia Petrica
- Department of Nephrology, County Emergency Hospital Timisoara, Timisoara, Romania.,'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania.,Centre of Translational Research and Systems Medicine, Timisoara, Romania
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31
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Zeni L, Norden AGW, Cancarini G, Unwin RJ. A more tubulocentric view of diabetic kidney disease. J Nephrol 2017; 30:701-717. [PMID: 28840540 PMCID: PMC5698396 DOI: 10.1007/s40620-017-0423-9] [Citation(s) in RCA: 154] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 07/22/2017] [Indexed: 12/14/2022]
Abstract
Diabetic nephropathy (DN) is a common complication of Diabetes Mellitus (DM) Types 1 and 2, and prevention of end stage renal disease (ESRD) remains a major challenge. Despite its high prevalence, the pathogenesis of DN is still controversial. Initial glomerular disease manifested by hyperfiltration and loss of glomerular size and charge permselectivity may initiate a cascade of injuries, including tubulo-interstitial disease. Clinically, 'microalbuminuria' is still accepted as an early biomarker of glomerular damage, despite mounting evidence that its predictive value for DN is questionable, and findings that suggest the proximal tubule is an important link in the development of DN. The concept of 'diabetic tubulopathy' has emerged from recent studies, and its causative role in DN is supported by clinical and experimental evidence, as well as plausible pathogenetic mechanisms. This review explores the 'tubulocentric' view of DN. The recent finding that inhibition of proximal tubule (PT) glucose transport (via SGLT2) is nephro-protective in diabetic patients is discussed in relation to the tubule's potential role in DN. Studies with a tubulocentric view of DN have stimulated alternative clinical approaches to the early detection of diabetic kidney disease. There are tubular biomarkers considered as direct indicators of injury of the proximal tubule (PT), such as N-acetyl-β-D-glucosaminidase, Neutrophil Gelatinase-Associated Lipocalin and Kidney Injury Molecule-1, and other functional PT biomarkers, such as Urine free Retinol-Binding Protein 4 and Cystatin C, which reflect impaired reabsorption of filtered proteins. The clinical application of these measurements to diabetic patients will be reviewed in the context of the need for better biomarkers for early DN.
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Affiliation(s)
- Letizia Zeni
- Department of Medical and Surgical Specialities, Radiological Sciences and Public Health, University of Brescia, Piazza del Mercato 15, 25121, Brescia, Italy.
- UCL Centre for Nephrology, UCL Medical School, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK.
- Operative Unit of Nephrology, ASST Spedali Civili, Piazzale Spedali Civili 1, Brescia, Italy.
| | - Anthony G W Norden
- UCL Centre for Nephrology, UCL Medical School, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK
| | - Giovanni Cancarini
- Department of Medical and Surgical Specialities, Radiological Sciences and Public Health, University of Brescia, Piazza del Mercato 15, 25121, Brescia, Italy
- Operative Unit of Nephrology, ASST Spedali Civili, Piazzale Spedali Civili 1, Brescia, Italy
| | - Robert J Unwin
- UCL Centre for Nephrology, UCL Medical School, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK
- Cardiovascular and Metabolic Diseases iMED ECD, AstraZeneca Gothenburg, Mölndal, Sweden
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Lobato GR, Lobato MR, Thomé FS, Veronese FV. Performance of urinary kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and N-acetyl-β-D-glucosaminidase to predict chronic kidney disease progression and adverse outcomes. ACTA ACUST UNITED AC 2017; 50:e6106. [PMID: 28380198 PMCID: PMC5423741 DOI: 10.1590/1414-431x20176106] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Accepted: 02/10/2017] [Indexed: 12/02/2022]
Abstract
Urinary biomarkers can predict the progression of chronic kidney disease (CKD). In this study, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and N-acetyl-β-D-glucosaminidase (NAG) were correlated with the stages of CKD, and the association of these biomarkers with CKD progression and adverse outcomes was determined. A total of 250 patients, including 111 on hemodialysis, were studied. Urinary KIM-1, NGAL, and NAG were measured at baseline. Patients not on dialysis at baseline who progressed to a worse CKD stage were compared with those who did not progress. The association of each biomarker and selected covariates with progression to more advanced stages of CKD, end-stage kidney disease, or death was evaluated by Poisson regression. NGAL was moderately correlated (rs=0.467, P<0.001) with the five stages of CKD; KIM-1 and NAG were also correlated, but weakly. Sixty-four patients (46%) progressed to a more advanced stage of CKD. Compared to non-progressors, those patients exhibited a trend to higher levels of KIM-1 (P=0.064) and NGAL (P=0.065). In patients not on dialysis at baseline, NGAL was independently associated with progression of CKD, ESKD, or death (RR=1.022 for 300 ng/mL intervals; CI=1.007-1.037, P=0.004). In patients on dialysis, for each 300-ng/mL increase in urinary NGAL, there was a 1.3% increase in the risk of death (P=0.039). In conclusion, urinary NGAL was associated with adverse renal outcomes and increased risk of death in this cohort. If baseline urinary KIM-1 and NGAL predict progression to worse stages of CKD is something yet to be explored.
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Affiliation(s)
- G R Lobato
- Programa de Pós Graduação em Medicina: Ciências Médicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil.,Serviço de Nefrologia, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil
| | - M R Lobato
- Serviço de Nefrologia, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil
| | - F S Thomé
- Serviço de Nefrologia, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil
| | - F V Veronese
- Programa de Pós Graduação em Medicina: Ciências Médicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil.,Serviço de Nefrologia, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil
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Kim SR, Lee YH, Lee SG, Kang ES, Cha BS, Lee BW. The renal tubular damage marker urinary N-acetyl-β-D-glucosaminidase may be more closely associated with early detection of atherosclerosis than the glomerular damage marker albuminuria in patients with type 2 diabetes. Cardiovasc Diabetol 2017; 16:16. [PMID: 28122570 PMCID: PMC5267389 DOI: 10.1186/s12933-017-0497-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 01/13/2017] [Indexed: 01/17/2023] Open
Abstract
Background To determine the association between urinary N-acetyl-β-d-glucosaminidase (NAG), a marker of renal tubulopathy, and carotid intima-media thickness (IMT) and plaques in patients with type 2 diabetes mellitus (T2D) and to compare the predictive value of NAG versus albuminuria, a marker of renal glomerulopathy. Methods A total of 343 participants were enrolled in this retrospective cross-sectional study. We recruited participants with T2D who were tested for blood glucose parameters, urinary NAG, and urinary albumin-to-creatinine ratio (ACR) and had been checked for carotid ultrasonography. Results We classified participants into a below-median urinary NAG group (Group I; n = 172) or an above-median group (Group II; n = 171). Mean, maximum, and mean of maximum carotid IMT and the proportion of patients with carotid plaques were significantly higher in Group II compared with Group I. In multiple linear regression analyses, high urinary NAG (Group II) was significantly associated with carotid IMT, independently of urinary ACR and other confounding factors. In terms of carotid plaques, both urinary NAG and ACR were significantly higher in participants with carotid plaques than in those without carotid plaques. After adjustment for confounding factors, both urinary NAG and ACR were significantly associated with the presence of carotid plaques. Conclusions Elevated urinary NAG, a marker of renal tubular damage, was related to increased carotid IMT and the presence of carotid plaques in patients with T2D. Urinary NAG may be a more sensitive biomarker than urinary albumin for early detection of atherosclerosis. Electronic supplementary material The online version of this article (doi:10.1186/s12933-017-0497-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- So Ra Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.,Severance Hospital, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea
| | - Yong-Ho Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.,Severance Hospital, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea
| | - Sang-Guk Lee
- Department of Laboratory Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea
| | - Eun Seok Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.,Severance Hospital, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea
| | - Bong-Soo Cha
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.,Severance Hospital, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea
| | - Byung-Wan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea. .,Severance Hospital, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.
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Samuelsson M, Dereke J, Svensson MK, Landin-Olsson M, Hillman M, on the behalf of the DISS Study group. Soluble plasma proteins ST2 and CD163 as early biomarkers of nephropathy in Swedish patients with diabetes, 15-34 years of age: a prospective cohort study. Diabetol Metab Syndr 2017; 9:41. [PMID: 28559931 PMCID: PMC5445394 DOI: 10.1186/s13098-017-0240-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 05/17/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The aim of this study was to investigate plasma levels of sST2 and sCD163 to determine whether they at an early stage could predict development of diabetic nephropathy and/or diabetic retinopathy in patients at clinical onset. METHODS Patients diagnosed with diabetes mellitus at age 15-34 years between 1987 and 1988 (n = 220) were included. Data such as BMI, smoking, HbA1c and islet cell antibodies were collected at time of diagnosis. Within the 10 year follow-up period, 112 patients (51%) developed following diabetes related complications; retinopathy (n = 91), nephropathy (n = 12) or both (n = 9). Plasma concentrations of sST2 and sCD163 were measured at time of diagnosis and levels compared between different complication groups. RESULTS Plasma levels of sST2 were significantly higher in patients who later developed nephropathy (n = 21; 1012 [773-1493] pg/ml) compared to those who did not (n = 199; 723 [449-1084] pg/ml; p = 0.006). A tendency for higher plasma levels of sCD163 was observed but not statistically significant (p = 0.058). CONCLUSIONS sST2 and sCD163 show promise as potential biomarkers for the development of nephropathy already at clinical onset. sST2 and/or sCD163 could possibly be part of a biomarker panel aimed to find patients at high risk of developing nephropathy. Both markers need to be investigated in a larger prospective study.
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Affiliation(s)
- My Samuelsson
- Department of Clinical Sciences, Diabetes Research Laboratory, Lund University, BMC, B11, 221 84 Lund, Sweden
| | - Jonatan Dereke
- Department of Clinical Sciences, Diabetes Research Laboratory, Lund University, BMC, B11, 221 84 Lund, Sweden
| | | | - Mona Landin-Olsson
- Department of Clinical Sciences, Diabetes Research Laboratory, Lund University, BMC, B11, 221 84 Lund, Sweden
- Department of Endocrinology, Skåne University Hospital Lund, Lund, Sweden
| | - Magnus Hillman
- Department of Clinical Sciences, Diabetes Research Laboratory, Lund University, BMC, B11, 221 84 Lund, Sweden
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Ishibashi Y, Matsui T, Yamagishi SI. Tofogliflozin, a selective inhibitor of sodium-glucose cotransporter 2, suppresses renal damage in KKAy/Ta mice, obese and type 2 diabetic animals. Diab Vasc Dis Res 2016; 13:438-441. [PMID: 27407083 DOI: 10.1177/1479164116657304] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVE Inhibitors of sodium-glucose cotransporter 2 ameliorate hyperglycaemia in diabetes by increasing urinary glucose excretion. However, the effects of sodium-glucose cotransporter 2 inhibitors on tubulointerstitial damage in diabetic nephropathy are not fully elucidated. We examined whether tofogliflozin, an inhibitor of sodium-glucose cotransporter 2, suppressed renal damage in KKAy/Ta mice, obese and type 2 diabetic animals. MATERIALS AND METHODS Male 8-week-old KKAy/Ta mice or control C57BL/6J mice were kept on a standard diet with or without 0.015% tofogliflozin for 5 weeks. Blood glucose and blood pressure, body and kidney weight, urinary N-acetyl-β-d-glucosaminidase activity and albumin excretion levels were monitored. RESULTS Although tofogliflozin treatment did not affect blood pressure, body weight or serum creatinine values, it improved hyperglycaemia and blocked the elevation of urinary N-acetyl-β-d-glucosaminidase activity in KKAy/Ta diabetic mice at 9, 11 and 13 weeks. Furthermore, compared with control mice, urinary albumin excretion levels and kidney weight were increased in 13-week-old KKAy/Ta mice, both of which were suppressed by the treatment with tofogliflozin. CONCLUSION Our present results demonstrated that tofogliflozin could suppress albuminuria and tubulointerstitial injury in obese and type 2 diabetic mice. Inhibition of glucose entry into tubular cells by tofogliflozin may exert renoprotective properties in diabetes.
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Affiliation(s)
- Yuji Ishibashi
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
| | - Takanori Matsui
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
| | - Sho-Ichi Yamagishi
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
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Lin CH, Chang YC, Chuang LM. Early detection of diabetic kidney disease: Present limitations and future perspectives. World J Diabetes 2016; 7:290-301. [PMID: 27525056 PMCID: PMC4958689 DOI: 10.4239/wjd.v7.i14.290] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 05/29/2016] [Accepted: 06/29/2016] [Indexed: 02/05/2023] Open
Abstract
Diabetic kidney disease (DKD) is one of the most common diabetic complications, as well as the leading cause of chronic kidney disease and end-stage renal disease around the world. To prevent the dreadful consequence, development of new assays for diagnostic of DKD has always been the priority in the research field of diabetic complications. At present, urinary albumin-to-creatinine ratio and estimated glomerular filtration rate (eGFR) are the standard methods for assessing glomerular damage and renal function changes in clinical practice. However, due to diverse tissue involvement in different individuals, the so-called “non-albuminuric renal impairment” is not uncommon, especially in patients with type 2 diabetes. On the other hand, the precision of creatinine-based GFR estimates is limited in hyperfiltration status. These facts make albuminuria and eGFR less reliable indicators for early-stage DKD. In recent years, considerable progress has been made in the understanding of the pathogenesis of DKD, along with the elucidation of its genetic profiles and phenotypic expression of different molecules. With the help of ever-evolving technologies, it has gradually become plausible to apply the thriving information in clinical practice. The strength and weakness of several novel biomarkers, genomic, proteomic and metabolomic signatures in assisting the early diagnosis of DKD will be discussed in this article.
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Kim SR, Lee YH, Lee SG, Kang ES, Cha BS, Kim JH, Lee BW. Urinary N-acetyl-β-D-glucosaminidase, an early marker of diabetic kidney disease, might reflect glucose excursion in patients with type 2 diabetes. Medicine (Baltimore) 2016; 95:e4114. [PMID: 27399115 PMCID: PMC5058844 DOI: 10.1097/md.0000000000004114] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Revised: 05/30/2016] [Accepted: 06/10/2016] [Indexed: 12/17/2022] Open
Abstract
Recently, several renal tubular damage markers have gained considerable attention because of their clinical implications as sensitive and specific biomarkers for early stage diabetic kidney disease. However, little is known about the demographic and glucometabolic factors affecting levels of urinary N-acetyl-β-D-glucosaminidase (NAG), a marker of proximal tubular damage, in type 2 diabetes mellitus (T2DM).The aim of this study was to investigate the clinical relevance of urinary NAG with regard to demographic and glucometabolic parameters, as well as nephropathic parameters, by comparing the glomerulopathic marker of albuminuria.In this retrospective cross-sectional study, we enrolled a total of 592 patients with either prediabetes (N = 29) or T2DM (N = 563). Glucometabolic parameters (glucose, hemoglobin A1c, glycated albumin [GA], insulin, C-peptide, homeostasis model assessment [HOMA] of insulin resistance, HOMA-β, postprandial C-peptide-to-glucose ratio [PCGR], and urinary glucose-to-creatinine ratio) and nephropathic parameters (urinary NAG, albumin-to-creatinine ratio [ACR], and estimated glomerular filtration rate) were measured.The levels of urinary NAG showed moderate positive correlation with the levels of urinary ACR in T2DM (r = 0.46). In correlation analysis, urinary NAG was more strongly correlated with body mass index (BMI) (r = -0.22; P < 0.001 vs. r = -0.02; P = 0.74), plasma stimulated glucose (r = 0.25; P < 0.001 vs. r = 0.08; P = 0.10), GA (r = 0.20; P < 0.001 vs. r = 0.13; P = 0.01), PCGR (r = -0.17; P = 0.001 vs. r = -0.09; P = 0.11), and HOMA-β (r = -0.10; P = 0.05 vs. r = -0.02; P = 0.79) than urinary ACR. In multiple regression analysis, age, lower BMI, stimulated glucose, GA, and urinary ACR predicted increased urinary NAG.In conclusion, increase in urinary NAG may be related to glycemic parameters reflecting glucose fluctuation and decreased insulin secretory capacity in patients with T2DM. Further longitudinal, prospective studies are needed to investigate a causal relationship between glucose fluctuations, renal tubular damage, and other vascular complications of diabetes.
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Affiliation(s)
- So Ra Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Graduate School, Yonsei University College of Medicine
- Severance Hospital
| | - Yong-ho Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Graduate School, Yonsei University College of Medicine
- Severance Hospital
| | - Sang-Guk Lee
- Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eun Seok Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Graduate School, Yonsei University College of Medicine
- Severance Hospital
| | - Bong-Soo Cha
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Graduate School, Yonsei University College of Medicine
- Severance Hospital
| | - Jeong-Ho Kim
- Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Byung-Wan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Graduate School, Yonsei University College of Medicine
- Severance Hospital
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Marynissen SJJ, Smets PMY, Ghys LFE, Paepe D, Delanghe J, Galac S, Meyer E, Lefebvre HP, Daminet S. Long-term follow-up of renal function assessing serum cystatin C in dogs with diabetes mellitus or hyperadrenocorticism. Vet Clin Pathol 2016; 45:320-9. [DOI: 10.1111/vcp.12365] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Sofie J. J. Marynissen
- Department of Small Animal Medicine and Clinical Biology; Faculty of Veterinary Medicine; Ghent University; Merelbeke Belgium
| | - Pascale M. Y. Smets
- Department of Small Animal Medicine and Clinical Biology; Faculty of Veterinary Medicine; Ghent University; Merelbeke Belgium
| | - Liesbeth F. E. Ghys
- Department of Small Animal Medicine and Clinical Biology; Faculty of Veterinary Medicine; Ghent University; Merelbeke Belgium
| | - Dominique Paepe
- Department of Small Animal Medicine and Clinical Biology; Faculty of Veterinary Medicine; Ghent University; Merelbeke Belgium
| | - Joris Delanghe
- Department of Clinical Chemistry, Microbiology and Immunology; Faculty of Medicine and Health Sciences; Ghent University; Ghent Belgium
| | - Sara Galac
- Department of Clinical Sciences of Companion Animals; Faculty of Veterinary Medicine; Utrecht University; Utrecht The Netherlands
| | - Evelyne Meyer
- Department of Pharmacology, Toxicology and Biochemistry; Faculty of Veterinary Medicine; Ghent University; Merelbeke Belgium
| | - Hervé P. Lefebvre
- Department of Clinical Sciences and Clinical Research Unit; INRA; École Nationale Vétérinaire de Toulouse (ENVT); Toulouse France
| | - Sylvie Daminet
- Department of Small Animal Medicine and Clinical Biology; Faculty of Veterinary Medicine; Ghent University; Merelbeke Belgium
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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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Ambika S, Saravanan R. Effect of Bergenin on the Kidney of C57BL/6J Mice with High Fat-Diet Induced Oxidative Stress. INTERNATIONAL LETTERS OF NATURAL SCIENCES 2016. [DOI: 10.56431/p-5795v3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The present study evaluated the protective effect of bergenin on high fat diet (HFD) induced diabetic mice. C57BL/6J mice were segregated in two groups, one fed standard diet (NC) and the other fed HFD for 16 weeks. Mice were fed continuously with high fat diet for 16 weeks and subjected to intragastric administration of bergenin (10, 20 and 40 mg/kg body weight (BW)), metformin (25 mg/kg BW) 9 to 16 weeks. At the end of the treatment nephritic markers, lipid peroxidation product, antioxidant and histopathological examination were carried out to assess the efficacy of the treatment. HFD fed mice showed increased plasma glucose, insulin, altered nephritic markers, antioxidant and histopathological abnormalities. Oral Treatment with bergenin (40 mg/kg BW) showed near normalized levels of plasma glucose, lipid peroxidation product, antioxidants, improved insulin and reduced kidney damage. The effects of bergenin were comparable with standard drug, metformin. These data suggest that bergenin protect kidney from deleterious effect of glucose.
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Ambika S, Saravanan R. Effect of Bergenin on the Kidney of C57BL/6J Mice with High Fat-Diet Induced Oxidative Stress. INTERNATIONAL LETTERS OF NATURAL SCIENCES 2016. [DOI: 10.18052/www.scipress.com/ilns.54.58] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The present study evaluated the protective effect of bergenin on high fat diet (HFD) induced diabetic mice. C57BL/6J mice were segregated in two groups, one fed standard diet (NC) and the other fed HFD for 16 weeks. Mice were fed continuously with high fat diet for 16 weeks and subjected to intragastric administration of bergenin (10, 20 and 40 mg/kg body weight (BW)), metformin (25 mg/kg BW) 9 to 16 weeks. At the end of the treatment nephritic markers, lipid peroxidation product, antioxidant and histopathological examination were carried out to assess the efficacy of the treatment. HFD fed mice showed increased plasma glucose, insulin, altered nephritic markers, antioxidant and histopathological abnormalities. Oral Treatment with bergenin (40 mg/kg BW) showed near normalized levels of plasma glucose, lipid peroxidation product, antioxidants, improved insulin and reduced kidney damage. The effects of bergenin were comparable with standard drug, metformin. These data suggest that bergenin protect kidney from deleterious effect of glucose.
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Schutte E, Gansevoort RT, Benner J, Lutgers HL, Lambers Heerspink HJ. Will the future lie in multitude? A critical appraisal of biomarker panel studies on prediction of diabetic kidney disease progression. Nephrol Dial Transplant 2016. [PMID: 26209744 DOI: 10.1093/ndt/gfv119] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Diabetic kidney disease is diagnosed and staged by albuminuria and estimated glomerular filtration rate. Although albuminuria has strong predictive power for renal function decline, there is still variability in the rate of renal disease progression across individuals that are not fully captured by the level of albuminuria. Therefore, research focuses on discovering and validating additional biomarkers that improve risk stratification for future renal function decline and end-stage renal disease in patients with diabetes, on top of established biomarkers. Most studies address the value of single biomarkers to predict progressive renal disease and aim to understand the mechanisms that underlie accelerated renal function decline. Since diabetic kidney disease is a disease encompassing several pathophysiological processes, a combination of biomarkers may be more likely to improve risk prediction than a single biomarker. In this review, we provide an overview of studies on the use of multiple biomarkers and biomarker panels, appraise their study design, discuss methodological pitfalls and make recommendations for future biomarker panel studies.
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Affiliation(s)
- Elise Schutte
- Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Ron T Gansevoort
- Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | | | - Helen L Lutgers
- Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Hiddo J Lambers Heerspink
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Mise K, Hoshino J, Ueno T, Hazue R, Hasegawa J, Sekine A, Sumida K, Hiramatsu R, Hasegawa E, Yamanouchi M, Hayami N, Suwabe T, Sawa N, Fujii T, Hara S, Ohashi K, Takaichi K, Ubara Y. Prognostic Value of Tubulointerstitial Lesions, Urinary N-Acetyl-β-d-Glucosaminidase, and Urinary β2-Microglobulin in Patients with Type 2 Diabetes and Biopsy-Proven Diabetic Nephropathy. Clin J Am Soc Nephrol 2016; 11:593-601. [PMID: 26801478 DOI: 10.2215/cjn.04980515] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 12/16/2015] [Indexed: 01/29/2023]
Abstract
BACKGROUND AND OBJECTIVES Some biomarkers of renal tubular injury are reported to be useful for predicting renal prognosis in the early stage of diabetic nephropathy (DN). Our study compared predictions of the renal prognosis by such biomarkers and by histologic tubulointerstitial damage. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Among 210 patients with type 2 diabetes and biopsy-proven DN managed from 1985 to 2011, 149 patients with urinary N-acetyl-β-d-glucosaminidase (NAG) and urinary β2-microglobulin (β2-MG) data at the time of renal biopsy were enrolled. The primary outcome was a decline in eGFR of ≥50% from baseline or commencement of dialysis for ESRD. RESULTS The median follow-up period was 2.3 years (interquartile range, 1.1-5.3), and the primary outcome was noted in 94 patients. Mean eGFR was 46.3±23.2 ml/min per 1.73 m(2), and 132 patients (89%) had overt proteinuria at baseline. Cox proportional hazards analysis revealed that the association of urinary NAG and β2-MG with the outcome was attenuated after adjustment for known promoters of progression (+1 SD for log NAG: hazard ratio [HR], 1.14; 95% confidence interval [95% CI], 0.84 to 1.55; +1 SD for log β2-MG: HR, 1.23; 95% CI, 0.94 to 1.62). In contrast, the interstitial fibrosis and tubular atrophy (IFTA) score was still significantly correlated with the outcome after adjustment for the same covariates (+1 for IFTA score: HR, 2.31; 95% CI, 1.56 to 3.43). Moreover, adding the IFTA score to a model containing known progression indicators improved prediction of the outcome (increase of concordance index by 0.02; 95% CI, 0.00 to 0.05; category-free net reclassification improvement by 0.54; 95% CI, 0.03 to 1.05; and relative integrated discrimination improvement by 0.07; 95% CI, -0.08 to 0.22). CONCLUSIONS Adding urinary NAG and β2-MG excretion to known promoters of progression did not improve prognostication, whereas adding the IFTA score did. The IFTA score may be superior to these tubulointerstitial markers for predicting the renal prognosis in advanced DN.
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Affiliation(s)
- Koki Mise
- Nephrology Center, Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan; Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences; and
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Shigeko Hara
- Nephrology Center, Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Kenichi Ohashi
- Department of Pathology, and Department of Pathology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
| | - Kenmei Takaichi
- Nephrology Center, Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Yoshifumi Ubara
- Nephrology Center, Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
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Fu CP, Sheu WHH, Lee IT, Lee WJ, Wang JS, Liang KW, Lee WL, Lin SY. Weight loss reduces serum monocyte chemoattractant protein-1 concentrations in association with improvements in renal injury in obese men with metabolic syndrome. Clin Chem Lab Med 2015; 53:623-9. [PMID: 25301674 DOI: 10.1515/cclm-2014-0468] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Accepted: 08/24/2014] [Indexed: 11/15/2022]
Abstract
BACKGROUND Monocyte chemoattractant protein-1 (MCP-1) is involved in obesity-related renal injury. The aim of the present study was to examine the effects of weight loss on changes in MCP-1 and markers of renal injury, specifically serum cystatin C (S-CysC) and urinary N-acetyl glucosaminidase (UNAG), in obese people. METHODS In this prospective study, 40 obese men with metabolic syndrome (MetS) participated in a 3-month dietary and exercise intervention. Twenty-eight subjects completed the study with a ≥5% weight loss. Circulating MCP-1, S-CysC and UNAG to creatinine ratio (UNCR) were determined before and after the weight loss program. RESULTS Obesity-associated components of MetS demonstrated significant improvements after the weight loss program. In addition, at baseline, circulating MCP-1 concentrations were positively correlated with UNCR and S-CysC levels. After weight loss, blood MCP-1 and UNCR levels were significantly decreased, but S-CysC was not affected. Using multiple linear regression analysis, there was a significant relationship between changes in UNCR and MCP-1 after adjusting for other potential confounding factors. CONCLUSIONS Weight loss may improve renal tubular injury by ameliorating obesity-related inflammation in obese men with MetS.
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Baldan-Martin M, de la Cuesta F, Alvarez-Llamas G, Gonzalez-Calero L, Ruiz-Hurtado G, Moreno-Luna R, Mourino-Alvarez L, Sastre-Oliva T, Segura J, Padial LR, Vivanco F, Ruilope LM, Barderas MG. Prediction of development and maintenance of high albuminuria during chronic renin–angiotensin suppression by plasma proteomics. Int J Cardiol 2015; 196:170-7. [DOI: 10.1016/j.ijcard.2015.05.148] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 04/29/2015] [Accepted: 05/26/2015] [Indexed: 10/23/2022]
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Tziomalos K, Athyros VG. Diabetic Nephropathy: New Risk Factors and Improvements in Diagnosis. Rev Diabet Stud 2015; 12:110-118. [PMID: 26676664 PMCID: PMC5397986 DOI: 10.1900/rds.2015.12.110] [Citation(s) in RCA: 167] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 04/30/2015] [Accepted: 04/30/2015] [Indexed: 12/23/2022] Open
Abstract
Diabetic nephropathy is the leading cause of end-stage renal disease. Patients with diabetic nephropathy have a high cardiovascular risk, comparable to patients with coronary heart disease. Accordingly, identification and management of risk factors for diabetic nephropathy as well as timely diagnosis and prompt management of the condition are of paramount importance for effective treatment. A variety of risk factors promotes the development and progression of diabetic nephropathy, including elevated glucose levels, long duration of diabetes, high blood pressure, obesity, and dyslipidemia. Most of these risk factors are modifiable by antidiabetic, antihypertensive, or lipid-lowering treatment and lifestyle changes. Others such as genetic factors or advanced age cannot be modified. Therefore, the rigorous management of the modifiable risk factors is essential for preventing and delaying the decline in renal function. Early diagnosis of diabetic nephropathy is another essential component in the management of diabetes and its complications such as nephropathy. New markers may allow earlier diagnosis of this common and serious complication, but further studies are needed to clarify their additive predictive value, and to define their cost-benefit ratio. This article reviews the most important risk factors in the development and progression of diabetic nephropathy and summarizes recent developments in the diagnosis of this disease.
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Affiliation(s)
- Konstantinos Tziomalos
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
| | - Vasilios G. Athyros
- Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
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Solbu MD, Toft I, Løchen ML, Mathiesen EB, Eriksen BO, Melsom T, Njølstad I, Wilsgaard T, Jenssen TG. N-Acetyl-β-D-Glucosaminidase Does Not Enhance Prediction of Cardiovascular or All-Cause Mortality by Albuminuria in a Low-Risk Population. J Am Soc Nephrol 2015; 27:533-42. [PMID: 26047791 DOI: 10.1681/asn.2014100960] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Accepted: 04/10/2015] [Indexed: 12/31/2022] Open
Abstract
Albuminuria is a well known risk factor for cardiovascular disease and mortality, but focus on renal tubular dysfunction as a potential risk factor is growing also. The association between the urinary activity of N-acetyl-β-D-glucosaminidase (NAG) and cardiovascular risk has been assessed mostly in cross-sectional studies. We studied the cross-sectional associations between urinary NAG and cardiovascular risk factors and the longitudinal associations between NAG, cardiovascular disease, and all-cause mortality in a general population. Urinary NAG/creatinine ratio (NAG ratio) and albumin/creatinine ratio (ACR) were measured in 6834 participants of the Tromsø Study in 1994-1995. During the median 17.5 years of follow-up, 958 myocardial infarctions, 726 ischemic strokes, and 2358 deaths were registered. In multivariable analyses adjusted for albuminuria and cardiovascular risk factors, a baseline NAG ratio in the highest quartile was associated with an increased risk of myocardial infarction (hazard ratio [HR], 1.43; 95% confidence interval [95% CI], 1.16 to 1.76), ischemic stroke (HR, 1.41; 95% CI, 1.10 to 1.80), and all-cause mortality (HR, 1.60; 95% CI, 1.39 to 1.84). Combined, ACR and NAG ratio above median associated with a 48%-80% increased risk for the three end points. However, the NAG ratio did not add significantly to the baseline risk-prediction models when assessed by area under the receiver operating characteristics curve or net reclassification improvement. In conclusion, the nonsignificant improvement of risk prediction does not support the clinical use of NAG ratio in cardiovascular risk assessment in a low-risk group.
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Affiliation(s)
- Marit D Solbu
- Section of Nephrology, University Hospital of North Norway, Tromsø, Norway;
| | - Ingrid Toft
- Section of Nephrology, University Hospital of North Norway, Tromsø, Norway; Departments of Clinical Medicine and
| | - Maja-Lisa Løchen
- Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway
| | - Ellisiv B Mathiesen
- Departments of Clinical Medicine and Department of Neurology, University Hospital of North Norway, Tromsø, Norway; and
| | - Bjørn O Eriksen
- Section of Nephrology, University Hospital of North Norway, Tromsø, Norway; Departments of Clinical Medicine and
| | - Toralf Melsom
- Section of Nephrology, University Hospital of North Norway, Tromsø, Norway; Departments of Clinical Medicine and
| | - Inger Njølstad
- Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway
| | - Tom Wilsgaard
- Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway
| | - Trond G Jenssen
- Departments of Clinical Medicine and Oslo University Hospital, Oslo, Norway
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Panduru NM, Sandholm N, Forsblom C, Saraheimo M, Dahlström EH, Thorn LM, Gordin D, Tolonen N, Wadén J, Harjutsalo V, Bierhaus A, Humpert PM, Groop PH. Kidney injury molecule-1 and the loss of kidney function in diabetic nephropathy: a likely causal link in patients with type 1 diabetes. Diabetes Care 2015; 38:1130-7. [PMID: 25784666 DOI: 10.2337/dc14-2330] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Accepted: 02/23/2015] [Indexed: 02/03/2023]
Abstract
OBJECTIVE We evaluated the predictive value and clinical benefit of urinary kidney injury molecule (KIM)-1 for progression of diabetic nephropathy (DN) in type 1 diabetes. We also investigated its causal role for the decrease of estimated glomerular filtration rate (eGFR) by a Mendelian randomization (MR) approach. RESEARCH DESIGN AND METHODS We followed 1,573 patients with type 1 diabetes for 6 years. KIM-1 was measured at baseline and normalized with urinary creatinine. KIM-1 predictive value was evaluated by Cox regression, while its added predictive benefit was evaluated using a panel of statistical indexes. The causality for the loss of renal function was evaluated with MR, utilizing the top signal from our genome-wide association study (GWAS) as the instrumental variable. RESULTS KIM-1 was not an independent predictor of progression of DN when adjusted for albumin excretion rate (AER) and added no prognostic benefit to AER or eGFR. In multiple regressions, KIM-1 was associated with lower eGFR independently of diabetes duration (β = -4.066; P < 0.0001) but not of AER. In our GWAS, rs2036402 in the KIM1 gene was strongly associated with KIM-1 (β = -0.51; P = 6.5 × 10(-38)). In the MR, KIM-1 was associated with lower eGFR, independently of diabetes duration and AER (β = -5.044; P = 0.040), suggesting a causal relationship. CONCLUSIONS KIM-1 did not predict progression to end-stage renal disease independently of AER and added no prognostic benefit to current biomarkers. Nevertheless, the MR showed that the inverse association of increased KIM-1 levels with lower eGFR is likely to represent a causal link.
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Affiliation(s)
- Nicolae M Panduru
- 2nd Clinical Department, Diabetes Nutrition and Metabolic Diseases Chair, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - Niina Sandholm
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - Carol Forsblom
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - Markku Saraheimo
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - Emma H Dahlström
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - Lena M Thorn
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - Daniel Gordin
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - Nina Tolonen
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - Johan Wadén
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - Valma Harjutsalo
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland
| | - Angelika Bierhaus
- Department of Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany
| | | | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
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49
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Hojs R, Ekart R, Bevc S, Hojs N. Biomarkers of Renal Disease and Progression in Patients with Diabetes. J Clin Med 2015; 4:1010-1024. [PMID: 26239462 PMCID: PMC4470213 DOI: 10.3390/jcm4051010] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2015] [Revised: 04/24/2015] [Accepted: 05/06/2015] [Indexed: 12/28/2022] Open
Abstract
Diabetes prevalence is increasing worldwide, mainly due to the increase in type 2 diabetes. Diabetic nephropathy occurs in up to 40% of people with type 1 or type 2 diabetes. It is important to identify patients at risk of diabetic nephropathy and those who will progress to end stage renal disease. In clinical practice, most commonly used markers of renal disease and progression are serum creatinine, estimated glomerular filtration rate and proteinuria or albuminuria. Unfortunately, they are all insensitive. This review summarizes the evidence regarding the prognostic value and benefits of targeting some novel risk markers for development of diabetic nephropathy and its progression. It is focused mainly on tubular biomarkers (neutrophil-gelatinase associated lipocalin, kidney injury molecule 1, liver-fatty acid-binding protein, N-acetyl-beta-d-glucosaminidase), markers of inflammation (pro-inflammatory cytokines, tumour necrosis factor-α and tumour necrosis factor-α receptors, adhesion molecules, chemokines) and markers of oxidative stress. Despite the promise of some of these new biomarkers, further large, multicenter prospective studies are still needed before they can be used in everyday clinical practice.
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Affiliation(s)
- Radovan Hojs
- Department of Nephrology, Clinic for Internal Medicine, University Clinical Centre Maribor, Ljubljanska 5, Maribor 2000, Slovenia.
- Faculty of Medicine, University of Maribor, Taborska ul. 8, Maribor 2000, Slovenia.
| | - Robert Ekart
- Department of Dialysis, Clinic for Internal Medicine, University Clinical Centre Maribor, Ljubljanska 5, Maribor 2000, Slovenia.
- Faculty of Medicine, University of Maribor, Taborska ul. 8, Maribor 2000, Slovenia.
| | - Sebastjan Bevc
- Department of Nephrology, Clinic for Internal Medicine, University Clinical Centre Maribor, Ljubljanska 5, Maribor 2000, Slovenia.
- Faculty of Medicine, University of Maribor, Taborska ul. 8, Maribor 2000, Slovenia.
| | - Nina Hojs
- Department of Nephrology, Clinic for Internal Medicine, University Clinical Centre Maribor, Ljubljanska 5, Maribor 2000, Slovenia.
- Faculty of Medicine, University of Maribor, Taborska ul. 8, Maribor 2000, Slovenia.
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50
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Jin YP, Su XF, Yin GP, Xu XH, Lou JZ, Chen JJ, Zhou Y, Lan J, Jiang B, Li Z, Lee KO, Ye L, Ma JH. Blood glucose fluctuations in hemodialysis patients with end stage diabetic nephropathy. J Diabetes Complications 2015; 29:395-399. [PMID: 25681043 DOI: 10.1016/j.jdiacomp.2014.12.015] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Revised: 12/24/2014] [Accepted: 12/24/2014] [Indexed: 11/17/2022]
Abstract
OBJECTIVE To characterize blood glucose fluctuation during hemodialysis in patients with end stage diabetic nephropathy (ESDN) by a continuous glucose monitoring system (CGMS), and aim to improve blood glucose control in this patient population. METHODS Forty-six patients with or without type 2 diabetes mellitus (T2DM), receiving hemodialysis, were recruited in this study. Thirty-six patients had end stage diabetic nephropathy (ESDN group), the other ten patients had end stage renal disease without diabetes (ESRD group). A continuous glucose monitoring system (CGMS) was employed to monitor glycemic fluctuation for 72 hours. Blood samples were collected and analyzed. RESULTS Mean, standard deviation (SD), maximum, and mean amplitude glycemic excursion (MAGE) of blood glucose and the ratio of blood glucose readings that was greater than 13.9 mmol/L of ESDN group, were significantly greater than those of ESRD group (p<0.01 for all) during 72 hours of observation. The mean blood glucose was significantly lower, while SD and MAGE were significantly higher in ESDN group on hemodialysis day than on days off hemodialysis (p<0.05), while these were not been observed in ESRD group. Though mean, SD, and MAGE of blood glucose during hemodialysis were significantly lower than those of peri-hemodialysis in both groups (p<0.01 or p<0.05, respectively), they were significantly higher in ESDN group than that in ESRD group (p<0.05). The mean blood glucose value calculated from HbA1c did not reflect the actual mean blood glucose measured by CGM in both groups, and gave an inaccurate impression of a significantly lower mean glucose. CONCLUSIONS ESDN patients had larger glycemic fluctuations as compared with ESRD patients. Hemodialysis caused reduction in mean, SD, and MAGE, which in turn caused bigger glycemic fluctuations on hemodialysis day. The HbA1c in ESDN patients gave an inaccurate value, which did not truly reflect blood glucose status for a prolonged period.
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Affiliation(s)
- Yue-ping Jin
- Department of Endocrinology, Nanjing Medical University Affiliated Nanjing Hospital, Nanjing, China
| | - Xiao-fei Su
- Department of Endocrinology, Nanjing Medical University Affiliated Nanjing Hospital, Nanjing, China
| | - Guo-ping Yin
- Department of Endocrinology, Nanjing Medical University Affiliated Nanjing Hospital, Nanjing, China
| | - Xiao-hua Xu
- Department of Endocrinology, Nanjing Medical University Affiliated Nanjing Hospital, Nanjing, China
| | - Ji-zhuang Lou
- Hemodialysis Center, Nanjing Medical University Affiliated Nanjing Hospital, Nanjing, China
| | - Jian-jun Chen
- Hemodialysis Center, Nanjing Medical University Affiliated Nanjing Hospital, Nanjing, China
| | - Yue Zhou
- Hemodialysis Center, Nanjing Medical University Affiliated Nanjing Hospital, Nanjing, China
| | - Jie Lan
- Department of Endocrinology, Nanjing Medical University Affiliated Nanjing Hospital, Nanjing, China
| | - Bing Jiang
- Department of Endocrinology, Nanjing Medical University Affiliated Nanjing Hospital, Nanjing, China
| | - Zheng Li
- Department of Endocrinology, Nanjing Medical University Affiliated Nanjing Hospital, Nanjing, China
| | - Kok-Onn Lee
- Department of Medicine, National University of Singapore, Singapore
| | - Lei Ye
- National Heart Research Institute Singapore, National Heart Centre, Singapore
| | - Jian-hua Ma
- Department of Endocrinology, Nanjing Medical University Affiliated Nanjing Hospital, Nanjing, China.
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