|
1
|
Lantzaki V, Fulton EA, McLaughlin M, Bennet ED, Conway EA, Ridyard AE. Urine Neutrophil Gelatinase-Associated Lipocalin in Non-Associative Immune Mediated Hemolytic Anemia: A Prospective Controlled Study in 22 Dogs. J Vet Intern Med 2025; 39:e70002. [PMID: 39871050 PMCID: PMC11772105 DOI: 10.1111/jvim.70002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 01/08/2025] [Accepted: 01/08/2025] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND Urine neutrophil gelatinase-associated lipocalin (uNGAL) is a biomarker for the early diagnosis of AKI. OBJECTIVES To evaluate uNGAL in dogs with non-associative immune mediated hemolytic anemia (IMHA) and to evaluate whether uNGAL correlates with disease severity markers, negative prognostic indicators and outcome. ANIMALS Twenty-two dogs with non-associative IMHA and 14 healthy dogs. METHODS Prospective case-control study. uNGAL was measured by a commercially available ELISA-kit and corrected to urine creatinine (uNGAL to creatinine ratio [UNCR]). uNGAL and UNCR of IMHA cases were compared to that of healthy dogs and the correlation with other clinicopathological markers was evaluated. uNGAL and UNCR were also compared between dogs with a CHAOS or ASA score < 3 and ≥ 3. RESULTS uNGAL and UNCR were significantly higher in dogs with IMHA when compared to healthy controls (uNGAL median 114.58 and 0.43 ng/mL, respectively, p < 0.001; UNCR median 174.87 and 0.13 ng/mg, respectively, p < 0.001). uNGAL and UNCR were moderately positively correlated with urea (p = 0.005, r = 0.58, 0.20-0.81 95% CI and p = 0.001, r = 0.64, 0.29-0.84 95% CI, respectively) and total bilirubin (p = 0.003, r = 0.60, 0.22-0.82 95% CI and p = 0.002, r = 0.62, 0.25-0.83 95% CI, respectively). These were also significantly higher in dogs with hemoglobinuria compared to those without (uNGAL: median 269 and 30.99 ng/mL, respectively, p < 0.001; UNCR: median 585.3 and 352 37.47 ng/mg, respectively, p < 0.001). There was no statistically significant difference in uNGAL or UNCR when assessing survival to discharge (p = 0.24 and p = 0.16, respectively, 95% CI). CONCLUSIONS This study suggests that renal injury might be underappreciated in dogs with IMHA.
Collapse
|
|
2
|
Nadendla RR, Khairunnisa K, Aziz N, Pyne C, Panigrahy UP, Wal P, Kulkarni MH, Rasheed A. An Updated Review on Diabetic Nephropathy: Potential Mechanisms, Biomarkers, Therapeutic Targets and Interventional Therapies. Curr Diabetes Rev 2025; 21:e240624231266. [PMID: 38919001 DOI: 10.2174/0115733998291920240611063402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 04/19/2024] [Accepted: 05/03/2024] [Indexed: 06/27/2024]
Abstract
BACKGROUND Diabetic nephropathy (DN), the primary risk factor for end-stage kidney disease (ESKD) that requires dialysis or renal transplantation, affects up to 50% of individuals with diabetes. OBJECTIVE In this article, potential mechanisms, biomarkers, and possible therapeutic targets will be discussed, as well as their interventional therapies. METHODS A literature review was done from databases like Google Scholar, PUBMEDMEDLINE, and Scopus using standard keywords "Diabetic Nephropathy," "Biomarkers," "Pathophysiology," "Cellular Mechanism," "Cell Therapy," "Treatment Therapies" from 2010- 2023. It has been studied that metabolic as well as hemodynamic pathways resulting from hyperglycemia act as mediators for renal disease. RESULTS We identified 270 articles, of which 210 were reviewed in full-text and 90 met the inclusion criteria. Every therapy regimen for the prevention and treatment of DN must include the blocking of ANG-II action. By reducing inflammatory and fibrotic markers brought on by hyperglycemia, an innovative approach to halting the progression of diabetic mellitus (DN) involves combining sodium-glucose cotransporter-2 inhibitors with renin-angiotensin-aldosterone system blockers. When compared to taking either medicine alone, this method works better. AGEs, protein kinase C (PKC), and the renin-angiotensin aldosterone system (RAAS) are among the components that are inhibited in DN management strategies. CONCLUSION Thus, it can be concluded that the multifactorial condition of DN needs to be treated at an early stage. Novel therapies with a combination of cell therapies and diet management are proven to be effective in the management of DN.
Collapse
Affiliation(s)
- Rama Rao Nadendla
- Chalapathi Institute of Pharmaceutical Sciences, Guntur, Andhra Pradesh, India
| | | | - Namra Aziz
- PSIT-Pranveer Singh Institute of Technology (Pharmacy), NH-19, Kanpur-209305, UP, India
| | - Chandana Pyne
- PSIT-Pranveer Singh Institute of Technology (Pharmacy), NH-19, Kanpur-209305, UP, India
| | - Uttam Prasad Panigrahy
- Faculty of Pharmaceutical Science, Assam Downtown University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India
| | - Pranay Wal
- PSIT-Pranveer Singh Institute of Technology (Pharmacy), NH-19, Kanpur-209305, UP, India
| | | | - Azhar Rasheed
- PSIT-Pranveer Singh Institute of Technology (Pharmacy), NH-19, Kanpur-209305, UP, India
| |
Collapse
|
|
3
|
Varatharajan S, Jain V, Pyati AK, Neeradi C, Reddy KS, Pallavali JR, Pandiyaraj IP, Gaur A. Neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and periostin: Novel urinary biomarkers in diabetic nephropathy. World J Nephrol 2024; 13:98880. [PMID: 39723350 PMCID: PMC11572651 DOI: 10.5527/wjn.v13.i4.98880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 09/25/2024] [Accepted: 10/20/2024] [Indexed: 11/07/2024] Open
Abstract
BACKGROUND Globally, diabetic nephropathy (DN) is the primary cause of chronic kidney disease. Currently, renal function is monitored indirectly using measures of serum creatinine, estimated glomerular filtration rate (eGFR), and proteinuria. Novel urinary biomarkers utilized in the early stages of DN have been described; these indicators can be used in the early identification of the disease, which is important for initiating treatment to halt or impediment the advance of diabetic nephropathy. AIM To estimate neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and periostin (POSTN) levels as novel urinary biomarkers in DN. METHODS In this hospital based cross-sectional study, a total of 160 patients of both genders aged 18 years or more; 40 healthy participants and 120 patients with diabetes mellitus (DM) were included. Patients with DM were divided into normoalbuminuria (n = 40), microalbuminuria (n = 40), and macroalbuminuria (n = 40) groups as per urine albumin creatinine ratio (uACR). Blood urea, serum creatinine, uACR were measured. Urine NGAL, KIM-1, and POSTN were measured by enzyme linked immunosorbent assay. The eGFR was calculated and compared with urinary markers. RESULTS NGAL, KIM-1, and POSTN levels increased significantly in normo, micro, and macroalbuminuria with the highest in the macroalbuminuria group. Albumin creatinine ratio (ACR) showed a positive correlation with NGAL, KIM-1, and POSTN levels. The eGFR showed a weak negative correlation with ACR, NGAL, KIM-1, and POSTN. NGAL was significantly lower in stage 1 compared to stage 2, 3, and 4 kidney disease. KIM-1 was significantly decreased in stage 1 compared to stage 4 kidney disease. POSTN was significantly decreased in stage 1 compared to stage 3 and 4 kidney disease. The receiver operator curve analysis of ACR, NGAL, KIM-1, and POSTN showed good sensitivity of 80%, 75.8%, 63.3%, and 80 % respectively with a cut-off of 12.5 mg/g, 4.5 μg/L, 1.5 ng/mL, and 37.5 ng/mL. CONCLUSION Urinary NGAL and POSTN are independent markers of DN.
Collapse
Affiliation(s)
- Sakthivadivel Varatharajan
- Department of General Medicine, All India Institute of Medical Sciences-Bibinagar, Hyderabad 508126, Telangana, India
| | - Vishakha Jain
- Department of General Medicine, All India Institute of Medical Sciences-Bibinagar, Hyderabad 508126, Telangana, India
| | - Anand K Pyati
- Department of Biochemistry, All India Institute of Medical Sciences-Bibinagar, Hyderabad 508126, Telangana, India
| | - Charan Neeradi
- Department of General Medicine, All India Institute of Medical Sciences-Bibinagar, Hyderabad 508126, Telangana, India
| | - Kotha Sugunakar Reddy
- Department of General Medicine, Neelima Institute of Medical Sciences, Hyderabad 500088, Telangana, India
| | - Janardhana Reddy Pallavali
- Department of General Medicine, All India Institute of Medical Sciences-Bibinagar, Hyderabad 508126, Telangana, India
| | - Ilakkiya Priya Pandiyaraj
- Department of General Medicine, All India Institute of Medical Sciences-Bibinagar, Hyderabad 508126, Telangana, India
| | - Archana Gaur
- Department of Physiology, All India Institute of Medical Sciences-Bibinagar, Hyderabad 508126, Telangana, India
| |
Collapse
|
|
4
|
Li Q, Xie Y, Zuo M, Li F. A comprehensive review of biomarker research in diabetic nephropathy from a global bibliometric and visualization perspective. Medicine (Baltimore) 2024; 103:e40729. [PMID: 39612398 PMCID: PMC11608688 DOI: 10.1097/md.0000000000040729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 11/08/2024] [Indexed: 12/01/2024] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is a common complication of diabetes, which is prone to develop into end-stage renal disease, and early diagnosis and treatment is the key to effective management of DN. Biomarkers have important clinical significance in the diagnosis and treatment of DN and have attracted extensive attention from researchers in recent years. The aim of this study was to visualize the field of biomarker research in DN through bibliometric analysis, to summarize the current status and predict future trends of this field, with a view to providing valuable insights for scholars and policy makers. METHODS Literature search and data collection from Web of Science Core Collection. Calculations and visualizations were performed using Microsoft Excel, VOSviewer, Bibliometrix R-package, and CiteSpace. RESULTS We identified 1274 publications about biomarker research in DN from 1995 to November 01, 2023, with a steady increase in annual publications. China, Steno Diabetes Center in Denmark, and Frontiers in Endocrinology were the most productive country, institution, and journal, respectively; Mischak, Harald was both the most productive and highly cited author, and Kidney International was the most cited journal. The high frequency keywords were "albuminuria," "chronic kidney disease" and "expression." In addition, "macrophage," "fibrosis" and "omics" are potentially promising topics. CONCLUSION Our study comprehensively and visually summarized the important findings of global biomarker research in DN and revealed the structure, hotspots, and evolutionary trends in this field. It would inspire subsequent studies from a macroscopic perspective and provide a basis for rational allocation of resources and identification of collaborations among researchers.
Collapse
Affiliation(s)
- Qin Li
- Hunan University of Medicine, Huaihua, China
| | - Yafei Xie
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Meiying Zuo
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Fang Li
- Hunan University of Medicine, Huaihua, China
| |
Collapse
|
|
5
|
Sachan N, Dabas A, Mantan M, Dabla PK. Urinary biomarkers NG AL and beta-2 microglobulin in children with type 1 diabetes mellitus. J Pediatr Endocrinol Metab 2024; 37:764-772. [PMID: 39166792 DOI: 10.1515/jpem-2024-0172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 07/14/2024] [Indexed: 08/23/2024]
Abstract
OBJECTIVES To study the urinary neutrophil gelatinase-associated lipocalin (NGAL) and beta-2-microglobulin (β2M) levels as markers of tubular damage in children with type 1 diabetes (T1DM). METHODS Forty T1DM children and 40 age-matched controls were enrolled. Subjects with coexisting kidney disorder, intake of oral glucose lowering drugs and syndromic diabetes mellitus were excluded. Fasting plasma glucose, glycated hemoglobin (HbA1c), kidney function, urinary albumin-creatinine ratio (UACR), NGAL and β2M were measured and compared in cases and controls. RESULTS The median (IQR) age of cases and controls was 10.6 (8, 14.2) and 10.7 (8.4, 13.7) years, respectively. Cases had disease duration of 4 (3, 6.8) years and HbA1c 10.9 (9, 13.1) %. Microalbuminuria was seen in 14 (35 %). Median (IQR) levels of UACR were higher in cases than controls [19.38 (10.27, 35.26) and 6.49 (3.10, 11.65) µg/mg; p<0.001], similarly NGAL/creatinine [352.21 (191.49, 572.45) and 190.54 (125.91, 322.83) ng/mg; p=0.006], unlike β2M/creatinine [1.7 (0.43, 6.02) and 2.12 (1.05, 4.47) µg/mg; p=0.637]. Children with higher HbA1c (≥10 %) had higher urinary ACR and tubular biomarkers than HbA1c<10 % (p>0.05). Urinary ACR showed positive correlation with NGAL/creatinine (r=0.38, p=0.019) and β2M/creatinine (r=0.42, p=0.009). CONCLUSIONS Urinary biomarkers NGAL and β2M were elevated in the presence of normal urinary microalbumin levels suggestive of early tubular damage in T1DM.
Collapse
Affiliation(s)
- Nimisha Sachan
- Department of Pediatrics, 28862 Maulana Azad Medical College and Lok Nayak Hospital , New Delhi, India
| | - Aashima Dabas
- Department of Pediatrics, 28862 Maulana Azad Medical College and Lok Nayak Hospital , New Delhi, India
| | - Mukta Mantan
- Department of Pediatrics, 28862 Maulana Azad Medical College and Lok Nayak Hospital , New Delhi, India
| | - Pradeep K Dabla
- Department of Biochemistry, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi, India
| |
Collapse
|
|
6
|
Dai Q, Huang S, Fang Y, Ding X. Identifying the Potential Diagnostic Gene Biomarkers and Forecasting the Potential Therapeutic Agents for Advanced Diabetic Nephropathy Based on Pyroptosis and Ferroptosis. J Inflamm Res 2024; 17:5763-5779. [PMID: 39224660 PMCID: PMC11368145 DOI: 10.2147/jir.s467388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024] Open
Abstract
Background Diabetic nephropathy (DN) is a prevalent complication of diabetes, often leading to end-stage kidney disease (ESKD). Advanced DN progresses to ESKD rapidly, yet effective diagnostic indicators and treatments are lacking. Methods Two DN-related datasets were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using the R packages. Pyroptosis-related genes (PRGs) and ferroptosis-related genes (FRGs) were collected from their respective database. Pyroptosis- and ferroptosis-related differentially expressed genes (PFRDEGs) were identified by overlapping DEGs, PRGs, and FRGs for further analysis, including functional enrichment and immune infiltration. Hub genes were identified using a PPI network via MCODE-plugin in Cytoscape. GeneMANIA was utilized to explore intermolecular interactions among hub genes. Based on these hub genes, a diagnostic model was constructed using the receiver operating characteristic curve and potential therapeutic agents were retrieved. Correlation analysis between hub genes and estimated glomerular filtration rate was performed using Nephroseq v5 database, and expression of hub genes was validated in external GEO database, Nephroseq v5 database and DN mice in vivo. Results Four hub genes (CYBB, LCN2, JUN and ADIPOQ) were identified, and three of the four hub genes (CYBB, LCN2 and ADIPOQ) were found to be potential biomarkers for advanced DN. On this basis, three potential therapeutic agents were screened. More importantly, a series of biological experiments confirmed that CYBB and LCN2 were significantly up-regulated in DN mice. Conclusion This study identifies three hub genes as diagnostic biomarkers and mines three potential therapeutic agents for advanced DN, providing new insights into the role of pyroptosis and ferroptosis in advanced DN and laying the foundation for future research.
Collapse
Affiliation(s)
- Qin Dai
- Department of Nephrology, Xuhui District Central Hospital, Shanghai, People’s Republic of China
- Department of Nephrology, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Siyi Huang
- Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China
| | - Yi Fang
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Xiaoqiang Ding
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| |
Collapse
|
|
7
|
Juin SK, Pushpakumar S, Sen U. Nimbidiol protects from renal injury by alleviating redox imbalance in diabetic mice. Front Pharmacol 2024; 15:1369408. [PMID: 38835661 PMCID: PMC11148448 DOI: 10.3389/fphar.2024.1369408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 04/17/2024] [Indexed: 06/06/2024] Open
Abstract
Introduction Chronic hyperglycemia-induced oxidative stress plays a crucial role in the development of diabetic nephropathy (DN). Moreover, adverse extracellular matrix (ECM) accumulation elevates renal resistive index leading to progressive worsening of the pathology in DN. Nimbidiol is an alpha-glucosidase inhibitor, isolated from the medicinal plant, 'neem' (Azadirachta indica) and reported as a promising anti-diabetic compound. Previously, a myriad of studies demonstrated an anti-oxidative property of a broad-spectrum neem-extracts in various diseases including diabetes. Our recent study has shown that Nimbidiol protects diabetic mice from fibrotic renal dysfunction in part by mitigating adverse ECM accumulation. However, the precise mechanism remains poorly understood. Methods The present study aimed to investigate whether Nimbidiol ameliorates renal injury by reducing oxidative stress in type-1 diabetes. To test the hypothesis, wild-type (C57BL/6J) and diabetic Akita (C57BL/6-Ins2Akita/J) mice aged 10-14 weeks were used to treat with saline or Nimbidiol (400 μg kg-1 day-1) for 8 weeks. Results Diabetic mice showed elevated blood pressure, increased renal resistive index, and decreased renal vasculature compared to wild-type control. In diabetic kidney, reactive oxygen species and the expression levels of 4HNE, p22phox, Nox4, and ROMO1 were increased while GSH: GSSG, and the expression levels of SOD-1, SOD-2, and catalase were decreased. Further, eNOS, ACE2, Sirt1 and IL-10 were found to be downregulated while iNOS and IL-17 were upregulated in diabetic kidney. The changes were accompanied by elevated expression of the renal injury markers viz., lipocalin-2 and KIM-1 in diabetic kidney. Moreover, an upregulation of p-NF-κB and a downregulation of IkBα were observed in diabetic kidney compared to the control. Nimbidiol ameliorated these pathological changes in diabetic mice. Conclusion Altogether, the data of our study suggest that oxidative stress largely contributes to the diabetic renal injury, and Nimbidiol mitigates redox imbalance and thereby protects kidney in part by inhibiting NF-κB signaling pathway in type-1 diabetes.
Collapse
Affiliation(s)
- Subir Kumar Juin
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY, United States
- Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, United States
| | - Sathnur Pushpakumar
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY, United States
| | - Utpal Sen
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY, United States
| |
Collapse
|
|
8
|
Natale P, Palmer SC, Navaneethan SD, Craig JC, Strippoli GF. Angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers for preventing the progression of diabetic kidney disease. Cochrane Database Syst Rev 2024; 4:CD006257. [PMID: 38682786 PMCID: PMC11057222 DOI: 10.1002/14651858.cd006257.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/01/2024]
Abstract
BACKGROUND Guidelines suggest that adults with diabetes and kidney disease receive treatment with angiotensin-converting-enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). This is an update of a Cochrane review published in 2006. OBJECTIVES We compared the efficacy and safety of ACEi and ARB therapy (either as monotherapy or in combination) on cardiovascular and kidney outcomes in adults with diabetes and kidney disease. SEARCH METHODS We searched the Cochrane Kidney and Transplants Register of Studies to 17 March 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA We included studies evaluating ACEi or ARB alone or in combination, compared to each other, placebo or no treatment in people with diabetes and kidney disease. DATA COLLECTION AND ANALYSIS Two authors independently assessed the risk of bias and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) or standardised mean difference (SMD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS One hundred and nine studies (28,341 randomised participants) were eligible for inclusion. Overall, the risk of bias was high. Compared to placebo or no treatment, ACEi may make little or no difference to all-cause death (24 studies, 7413 participants: RR 0.91, 95% CI 0.73 to 1.15; I2 = 23%; low certainty) and with similar withdrawals from treatment (7 studies, 5306 participants: RR 1.03, 95% CI 0.90 to 1.19; I2 = 0%; low certainty). ACEi may prevent kidney failure (8 studies, 6643 participants: RR 0.61, 95% CI 0.39 to 0.94; I2 = 0%; low certainty). Compared to placebo or no treatment, ARB may make little or no difference to all-cause death (11 studies, 4260 participants: RR 0.99, 95% CI 0.85 to 1.16; I2 = 0%; low certainty). ARB have uncertain effects on withdrawal from treatment (3 studies, 721 participants: RR 0.85, 95% CI 0.58 to 1.26; I2 = 2%; low certainty) and cardiovascular death (6 studies, 878 participants: RR 3.36, 95% CI 0.93 to 12.07; low certainty). ARB may prevent kidney failure (3 studies, 3227 participants: RR 0.82, 95% CI 0.72 to 0.94; I2 = 0%; low certainty), doubling of serum creatinine (SCr) (4 studies, 3280 participants: RR 0.84, 95% CI 0.72 to 0.97; I2 = 32%; low certainty), and the progression from microalbuminuria to macroalbuminuria (5 studies, 815 participants: RR 0.44, 95% CI 0.23 to 0.85; I2 = 74%; low certainty). Compared to ACEi, ARB had uncertain effects on all-cause death (15 studies, 1739 participants: RR 1.13, 95% CI 0.68 to 1.88; I2 = 0%; low certainty), withdrawal from treatment (6 studies, 612 participants: RR 0.91, 95% CI 0.65 to 1.28; I2 = 0%; low certainty), cardiovascular death (13 studies, 1606 participants: RR 1.15, 95% CI 0.45 to 2.98; I2 = 0%; low certainty), kidney failure (3 studies, 837 participants: RR 0.56, 95% CI 0.29 to 1.07; I2 = 0%; low certainty), and doubling of SCr (2 studies, 767 participants: RR 0.88, 95% CI 0.52 to 1.48; I2 = 0%; low certainty). Compared to ACEi plus ARB, ACEi alone has uncertain effects on all-cause death (6 studies, 1166 participants: RR 1.08, 95% CI 0.49 to 2.40; I2 = 20%; low certainty), withdrawal from treatment (2 studies, 172 participants: RR 0.78, 95% CI 0.33 to 1.86; I2 = 0%; low certainty), cardiovascular death (4 studies, 994 participants: RR 3.02, 95% CI 0.61 to 14.85; low certainty), kidney failure (3 studies, 880 participants: RR 1.36, 95% CI 0.79 to 2.32; I2 = 0%; low certainty), and doubling of SCr (2 studies, 813 participants: RR 1.14, 95% CI 0.70 to 1.85; I2 = 0%; low certainty). Compared to ACEi plus ARB, ARB alone has uncertain effects on all-cause death (7 studies, 2607 participants: RR 1.02, 95% CI 0.76 to 1.37; I2 = 0%; low certainty), withdrawn from treatment (3 studies, 1615 participants: RR 0.81, 95% CI 0.53 to 1.24; I2 = 0%; low certainty), cardiovascular death (4 studies, 992 participants: RR 3.03, 95% CI 0.62 to 14.93; low certainty), kidney failure (4 studies, 2321 participants: RR 1.15, 95% CI 0.67 to 1.95; I2 = 29%; low certainty), and doubling of SCr (3 studies, 2252 participants: RR 1.18, 95% CI 0.85 to 1.64; I2 = 0%; low certainty). Comparative effects of different ACEi or ARB and low-dose versus high-dose ARB were rarely evaluated. No study compared different doses of ACEi. Adverse events of ACEi and ARB were rarely reported. AUTHORS' CONCLUSIONS ACEi or ARB may make little or no difference to all-cause and cardiovascular death compared to placebo or no treatment in people with diabetes and kidney disease but may prevent kidney failure. ARB may prevent the doubling of SCr and the progression from microalbuminuria to macroalbuminuria compared with a placebo or no treatment. Despite the international guidelines suggesting not combining ACEi and ARB treatment, the effects of ACEi or ARB monotherapy compared to dual therapy have not been adequately assessed. The limited data availability and the low quality of the included studies prevented the assessment of the benefits and harms of ACEi or ARB in people with diabetes and kidney disease. Low and very low certainty evidence indicates that it is possible that further studies might provide different results.
Collapse
Affiliation(s)
- Patrizia Natale
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
- Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari Aldo Moro, Bari, Italy
| | - Suetonia C Palmer
- Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand
| | | | - Jonathan C Craig
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
- College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Giovanni Fm Strippoli
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari Aldo Moro, Bari, Italy
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
| |
Collapse
|
|
9
|
Chen J, Zhang Q, Guo J, Gu D, Liu J, Luo P, Bai Y, Chen J, Zhang X, Nie S, Chen C, Feng Y, Wang J. Single-cell transcriptomics reveals the ameliorative effect of rosmarinic acid on diabetic nephropathy-induced kidney injury by modulating oxidative stress and inflammation. Acta Pharm Sin B 2024; 14:1661-1676. [PMID: 38572101 PMCID: PMC10985035 DOI: 10.1016/j.apsb.2024.01.003] [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: 10/16/2023] [Revised: 12/11/2023] [Accepted: 01/04/2024] [Indexed: 04/05/2024] Open
Abstract
Diabetic nephropathy (DN) is a severe complication of diabetes, characterized by changes in kidney structure and function. The natural product rosmarinic acid (RA) has demonstrated therapeutic effects, including anti-inflammation and anti-oxidative-stress, in renal damage or dysfunction. In this study, we characterized the heterogeneity of the cellular response in kidneys to DN-induced injury and RA treatment at single cell levels. Our results demonstrated that RA significantly alleviated renal tubular epithelial injury, particularly in the proximal tubular S1 segment and on glomerular epithelial cells known as podocytes, while attenuating the inflammatory response of macrophages, oxidative stress, and cytotoxicity of natural killer cells. These findings provide a comprehensive understanding of the mechanisms by which RA alleviates kidney damage, oxidative stress, and inflammation, offering valuable guidance for the clinical application of RA in the treatment of DN.
Collapse
Affiliation(s)
- Junhui Chen
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herbal Medicine, Jiangxi University of Chinese Medicine, Nanchang 330006, China
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen 518020, China
| | - Qian Zhang
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen 518020, China
- School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Jinan Guo
- Department of Urology, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, the First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020, China
| | - Di Gu
- Department of Urology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510230, China
| | - Jing Liu
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen 518020, China
| | - Piao Luo
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen 518020, China
- School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yunmeng Bai
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen 518020, China
| | - Jiayun Chen
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen 518020, China
- School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Xinzhou Zhang
- Department of Nephrology, Shenzhen Key Laboratory of Kidney Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, the First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020, China
| | - Sheng Nie
- Department of Nephrology, Nanfang Hospital, the First Affiliated Hospital of Southern Medical University, Guangzhou 510515, China
| | - Chunbo Chen
- Department of Critical Care Medicine, Shenzhen People's Hospital (the Second Clinical Medical College, Jinan University, the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, China
| | - Yulin Feng
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herbal Medicine, Jiangxi University of Chinese Medicine, Nanchang 330006, China
| | - Jigang Wang
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herbal Medicine, Jiangxi University of Chinese Medicine, Nanchang 330006, China
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen 518020, China
- School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
- State Key Laboratory for Quality Esurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| |
Collapse
|
|
10
|
Kandeil M, Shaarawy MA, Mourad HA, Mahmoud MO. Renoprotective Potency of Sitagliptin versus Pioglitazone in Type 2 Diabetic Patients: Impact on LncMIAT. ACS OMEGA 2023; 8:43218-43226. [PMID: 38024775 PMCID: PMC10652733 DOI: 10.1021/acsomega.3c07008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/14/2023] [Accepted: 10/17/2023] [Indexed: 12/01/2023]
Abstract
Background: Diabetes mellitus (DM) represents one of the most important reasons for chronic kidney diseases due to the high level of blood glucose that destructs blood vessels. Objective: The present study focused on investigating the protective impact of sitagliptin on kidney complication in type 2 diabetes mellitus (T2DM) patients in comparison to pioglitazone to examine which has the superior effect against the nephritic complication of DM. Methods: Eighty adult subjects were classified into four groups: control group, pioglitazone-treated T2DM patients (P group), sitagliptin-treated T2DM patients for less than one year (SL group), and sitagliptin-treated T2DM patients for more than one year (SM group). Blood samples were withdrawn from all subjects for analysis of neutrophil gelatinase-associated lipocalin (NGAL), vanin-1, kidney injury molecule-1 (KIM-1), glyoxalase-1 (Glo-1), methylglyoxal (MG), cystatin-C, and interleukin-18 (IL-18) using competitive ELISA kits. Also, long noncoding myocardial infarction associated transcript (lncMIAT) was measured in whole blood using qRT-PCR. Results: The present study revealed that the lncMIAT expression level was significantly higher in the P group as compared to the SL group, SM group, or healthy control group. Additionally, serum NGAL, vanin-1, KIM-1, Glo-1, MG, and cystatin-C were significantly higher in the P group and SL group as compared to the SM group and healthy control group. Conclusion: Sitagliptin protected the kidney through downregulation of lncMIAT besides amelioration of kidney injury marker levels, which was more preferable than in pioglitazone therapy.
Collapse
Affiliation(s)
- Mohamed
A. Kandeil
- Biochemistry
Department, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef 62511, Egypt
| | - Mohamed A. Shaarawy
- Internal
Medicine and Nephrology Department, Faculty
of Medicine, El-Minia University, El-Minia 61519, Egypt
| | - Hamdy A. Mourad
- Biochemistry
Department, Faculty of Pharmacy, Beni-Suef
University, Beni-Suef 62514, Egypt
| | - Mohamed O. Mahmoud
- Biochemistry
Department, Faculty of Pharmacy, Beni-Suef
University, Beni-Suef 62514, Egypt
| |
Collapse
|
|
11
|
Jiang S, Su H. Cellular crosstalk of mesangial cells and tubular epithelial cells in diabetic kidney disease. Cell Commun Signal 2023; 21:288. [PMID: 37845726 PMCID: PMC10577991 DOI: 10.1186/s12964-023-01323-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 09/17/2023] [Indexed: 10/18/2023] Open
Abstract
Diabetic kidney disease (DKD) is a major cause of end-stage renal disease and imposes a heavy global economic burden; however, little is known about its complicated pathophysiology. Investigating the cellular crosstalk involved in DKD is a promising avenue for gaining a better understanding of its pathogenesis. Nonetheless, the cellular crosstalk of podocytes and endothelial cells in DKD is better understood than that of mesangial cells (MCs) and renal tubular epithelial cells (TECs). As the significance of MCs and TECs in DKD pathophysiology has recently become more apparent, we reviewed the existing literature on the cellular crosstalk of MCs and TECs in the context of DKD to acquire a comprehensive understanding of their cellular communication. Insights into the complicated mechanisms underlying the pathophysiology of DKD would improve its early detection, care, and prognosis. Video Abstract.
Collapse
Affiliation(s)
- Shan Jiang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Hua Su
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| |
Collapse
|
|
12
|
Sachan N, Dabas A, Mantan M, Dabla PK. Urinary Biomarkers NGAL and Beta-2 Microglobulin for Detection of Diabetic Nephropathy in Type 1 Diabetes Mellitus.. [DOI: 10.21203/rs.3.rs-3417003/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/27/2024]
Abstract
Abstract
Objectives: Urinary neutrophil gelatinase-associated lipocalin (NGAL) and beta-2 microglobulin(β2M) have been evaluated as markers of tubular damage in type 2 diabetes mellitus. There is limited data on their performance to screen nephropathy in type 1 diabetes mellitus (T1DM).
Methods: This case-control study enrolled 40 children with T1DM and 40 age-matched controls age 2-18 years. Subjects with coexisting renal disorder and syndromic diabetes mellitus were excluded. Fasting plasma glucose, glycated hemoglobin (HbA1c), and renal function were measured. Urinary levels of urine albumin-creatinine ratio (ACR), neutrophil gelatinase-associated lipocalin (NGAL) and beta-2 microglobulin (β2M) were measured for an associated with disease duration, glycemic control and microalbuminuria. Correlation (r) was measured for statistical association between biochemical markers and area-under-curve (AUC) calculated to predict nephropathy.
Results: The median (IQR) age of cases and controls was 10.6(8,14.2) and 10.7 (8.4,13.7) years, respectively, disease duration 4 (3,6.8) years and HbA1c 10.9(9.,13.1)% in cases. Microalbuminuria was seen in 14(35%) but none had macroalbuminuria.The urinary ACR and NGAL were significantly higher in cases than controls [19.38 (10.27,35.26) and 6.49 (3.10,11.65) µg/mg; p<0.001] and [352.21(191.49,572.45) and 190.54 (125.91,322.83) ng/mg; p=0.006], respectively, unlike β2M [1.7 (0.43,6.02) and 2.12 (1.05,4.47) µg/mg; p=0.637]. Children with higher HbA1C (>10%) had higher urinary ACR, NGAL and β2M levels than those with HbA1C<10%. Urinary ACR showed positive correlation with NGAL/creatinine (r= 0.38, p value=0.019) and β2M/ creatinine (r=0.48, p value= 0.004) in cases. The AUC was 0.57 (95% CI 0.36,0.78); p value= 0.48 for NGAL/creatinine, and 0.62 (95%CI 0.43,0.81); p value=0.21 for β2M /creatinine to predict microalbuminuria (ACR >30mg/g).
Conclusion: Urinary biomarkers NGAL and β2M showed a good correlation with ACR suggesting their role in screening of diabetic tubulopathy before overt glomerular damage in T1DM.
Collapse
Affiliation(s)
| | | | | | - Pradeep Kumar Dabla
- Govind Ballabh Pant Institute of Postgraduate Medical Education and Research: Govind Ballabh Pant Hospital
| |
Collapse
|
|
13
|
Xu C, Ha X, Yang S, Tian X, Jiang H. Advances in understanding and treating diabetic kidney disease: focus on tubulointerstitial inflammation mechanisms. Front Endocrinol (Lausanne) 2023; 14:1232790. [PMID: 37859992 PMCID: PMC10583558 DOI: 10.3389/fendo.2023.1232790] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 09/19/2023] [Indexed: 10/21/2023] Open
Abstract
Diabetic kidney disease (DKD) is a serious complication of diabetes that can lead to end-stage kidney disease. Despite its significant impact, most research has concentrated on the glomerulus, with little attention paid to the tubulointerstitial region, which accounts for the majority of the kidney volume. DKD's tubulointerstitial lesions are characterized by inflammation, fibrosis, and loss of kidney function, and recent studies indicate that these lesions may occur earlier than glomerular lesions. Evidence has shown that inflammatory mechanisms in the tubulointerstitium play a critical role in the development and progression of these lesions. Apart from the renin-angiotensin-aldosterone blockade, Sodium-Glucose Linked Transporter-2(SGLT-2) inhibitors and new types of mineralocorticoid receptor antagonists have emerged as effective ways to treat DKD. Moreover, researchers have proposed potential targeted therapies, such as inhibiting pro-inflammatory cytokines and modulating T cells and macrophages, among others. These therapies have demonstrated promising results in preclinical studies and clinical trials, suggesting their potential to treat DKD-induced tubulointerstitial lesions effectively. Understanding the immune-inflammatory mechanisms underlying DKD-induced tubulointerstitial lesions and developing targeted therapies could significantly improve the treatment and management of DKD. This review summarizes the latest advances in this field, highlighting the importance of focusing on tubulointerstitial inflammation mechanisms to improve DKD outcomes.
Collapse
Affiliation(s)
- Chengren Xu
- Division of Nephrology, Department of Internal Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Xiaowen Ha
- Division of Nephrology, Department of Internal Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Shufen Yang
- Division of Nephrology, Department of Internal Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Xuefei Tian
- Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States
| | - Hong Jiang
- Division of Nephrology, Department of Internal Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| |
Collapse
|
|
14
|
Dahiya K, Prashant P, Dhankhar R, Dhankhar K, Kumar S, Vashist S. Lipocalin-2 as a biomarker for diabetic nephropathy. World J Meta-Anal 2023; 11:92-101. [DOI: 10.13105/wjma.v11.i4.92] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 03/11/2023] [Accepted: 03/29/2023] [Indexed: 04/14/2023] Open
Abstract
Diabetes is a major global public health issue. The prevalence of type 1 diabetes is comparatively static, as hereditary and genetic causes are involved, while type 2 diabetes (T2D) prevalence is increasing day by day. T2D is associated with chronic complications, including diabetic neuropathy (DN), nephropathy, retinopathy, and other complications like diabetic foot. DN is the main complication of both types of diabetes. DN can be diagnosed by routine laboratory tests, microalbuminuria > 300 mg/24 h, and a gradual decrease in glomerular filtration rate. As the appearance of microalbuminuria is a late manifestation, an early marker for renal damage is needed. Lipocalin-2, also known as neutrophil gelatinase-associated lipocalin (NGAL), is a small protein purified from neutrophil granules and a good marker for kidney disease. NGAL is a transporter protein responsible for many physiological processes, such as inflammation, generation of the immune response, and metabolic homeostasis. NGAL has been reported to depict the early changes in renal damage when urine microalbumin is still undetecable. Therefore, elucidating the role of NGAL in detecting DN and understanding its mechanism can help establish it as a potential early marker for DN.
Collapse
Affiliation(s)
- Kiran Dahiya
- Department of Biochemistry, Pt BD Sharma Post Graduate Institute of Medical Sciences, Rohtak 124001, Haryana, India
| | - Praveen Prashant
- Department of Biochemistry, Pt BD Sharma Post Graduate Institute of Medical Sciences, Rohtak 124001, Haryana, India
| | - Rakesh Dhankhar
- Department of Radiation Oncology, Pt BD Sharma Post Graduate Institute of Medical Sciences, Rohtak 124001, India
| | - Kumud Dhankhar
- Phase III, JSS Medical College, Mysuru 570015, Karnataka, India
| | | | - Sonia Vashist
- Department of Dermatology, Dr Sonia’s Dermatology Clinic, Rewari 123401, Haryana, India
| |
Collapse
|
|
15
|
Ishak SI, Aguizy FE, Elsebaie EH, Youssef MRL, Ismail MM, Abdelraouf FH, Ghaffar HAA, Riad NM. Role of urinary NGAL and microalbuminuria in the detection of subclinical acute kidney injury in pediatric intensive care unit and diabetic children. LA PEDIATRIA MEDICA E CHIRURGICA 2022; 44. [DOI: 10.4081/pmc.2022.285] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 06/20/2022] [Indexed: 11/22/2022] Open
Abstract
Subclinical Acute Kidney Injury (AKI) describes patients who did not fulfill the classical criteria for AKI diagnosis but showed elevated levels of new biomarkers reflecting tubular injury. One of these biomarkers is Neutrophil Gelatinase-Associated Lipocalin (NGAL). The aim of this study is to investigate the role of urinary NGAL and microalbuminuria as non-invasive biomarkers in the detection of subclinical AKI. Analysis of urinary NGAL and microalbuminuria in 91 subjects [30 pediatric intensive care unit (PICU) patients, 31 diabetic patients and 30 healthy controls] recruited from Cairo University Pediatric Hospital was done. Our study revealed that urinary NGAL was significantly higher in the PICU group followed by the diabetic group and lowest in the controls group (p=0.022). A positive correlation was found between urinary NGAL and microalbuminuria in the PICU group (Rvalue= 0.585, p-value=0.001). In diabetic group, a positive correlation was found between urinary NGAL and fasting blood glucose, 2 hours post prandial and HbA1C (R-value=0.421; pvalue= 0.021; R-value=0.426; p-value=0.019; R-value=0.438; pvalue= 0.018 respectively). Urinary NGAL may be a potential biomarker to detect subclinical AKI before actual functional renal damage leading to early intervention and reduction of mortality.
Collapse
|
|
16
|
Gonzalez J, Jatem E, Roig J, Valtierra N, Ostos E, Abo A, Santacana M, Garcia A, Segarra A. Usefulness of urinary biomarkers to estimate the interstitial fibrosis surface in diabetic nephropathy with normal kidney function. Nephrol Dial Transplant 2022; 37:2102-2110. [PMID: 35583251 DOI: 10.1093/ndt/gfac185] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Kidney biopsies of patients with diabetic nephropathy (DN) and normal kidney function may exhibit interstitial fibrosis (IF) without reduction of glomerular filtration rate because of hyperfiltration. The aim of our study was to analyze the performance of a set of biomarkers of tubular injury to estimate the extent of IF in patients with DN and normal kidney function. PATIENTS AND METHODS This cross-sectional study included 118 adults with DN diagnosed by kidney biopsy and GFR ≥ 90 mL/min/1.73 m2 and a control group of healthy subjects. We measured the urinary excretion of MCP-1, NGAL, KIM-1, L-FABP, β2-microglobulin and DKK-3 at the time of kidney biopsy. GFR was measured by Cr-EDTA (mGFR). IF was quantified using a quantitative morphometric procedure. Predictive multivariate models were developed to estimate the IF surface. RESULTS patients with DN showed significantly higher levels of DKK-3, MCP-1 and L-FABP and significantly lower levels of EGF than healthy controls. There were no significant between-group differences in the levels of β2-microglobulin, KIM-1 or NGAL. IF was negatively associated with EGF and a positively with age, proteinuria, MCP-1, DKK-3 and L-FABP but no with β2-microglobulin, KIM-1, NGAL or GFR. The best model to predict IF surface accounted for 59% of its variability and included age, proteinuria, EGF, DKK-3 and MCP-1. CONCLUSIONS our study provides a model to estimate the IF in DN that can be useful to assess the progression of IF in patients with normal kidney function.
Collapse
Affiliation(s)
- Jorge Gonzalez
- Servicio de Nefrologia Hospital Arnau de Vilanova, Lleida
| | - Elias Jatem
- Servicio de Nefrologia Hospital Arnau de Vilanova, Lleida
| | - Jordi Roig
- Servicio de Nefrologia Hospital Arnau de Vilanova, Lleida
| | | | - Elena Ostos
- Vall d'Hebrón Institut de Recerca, Barcelona
| | - Anabel Abo
- Servicio de Anatomia Patológica, Hospital Arnau de Vilanova, Lleida
| | - Maria Santacana
- Servicio de Anatomia Patológica, Hospital Arnau de Vilanova, Lleida.,Institut de Recerca Biomèdica August Pi i Sunyer, Lleida
| | - Alicia Garcia
- Institut de Recerca Biomèdica August Pi i Sunyer, Lleida
| | - Alfons Segarra
- Servicio de Nefrologia Hospital Arnau de Vilanova, Lleida.,Vall d'Hebrón Institut de Recerca, Barcelona.,Institut de Recerca Biomèdica August Pi i Sunyer, Lleida.,Servicio de Nefrologia Hospital Vall d'Hebrón, Barcelona, Spain
| |
Collapse
|
|
17
|
Trutin I, Bajic Z, Turudic D, Cvitkovic-Roic A, Milosevic D. Cystatin C, renal resistance index, and kidney injury molecule-1 are potential early predictors of diabetic kidney disease in children with type 1 diabetes. Front Pediatr 2022; 10:962048. [PMID: 35967553 PMCID: PMC9372344 DOI: 10.3389/fped.2022.962048] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 07/13/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Diabetic kidney disease (DKD) is the main cause of end-stage renal disease in patients with diabetes mellitus type I (DM-T1). Microalbuminuria and estimated glomerular filtration rate (eGFR) are standard predictors of DKD. However, these predictors have serious weaknesses. Our study aimed to analyze cystatin C, renal resistance index, and urinary kidney injury molecule-1 (KIM-1) as predictors of DKD. METHODS We conducted a cross-sectional study in 2019 on a consecutive sample of children and adolescents (10-18 years) diagnosed with DM-T1. The outcome was a risk for DKD estimated using standard predictors: age, urinary albumin, eGFR, serum creatinine, DM-T1 duration, HbA1c, blood pressure, and body mass index (BMI). We conducted the analysis using structural equation modeling. RESULTS We enrolled 75 children, 36 girls and 39 boys with the median interquartile range (IQR) age of 14 (11-16) years and a median (IQR) duration of DM-T1 of 6 (4-9) years. The three focal predictors (cystatin C, resistance index, and urinary KIM-1) were significantly associated with the estimated risk for DKD. Raw path coefficients for cystatin C were 3.16 [95% CI 0.78; 5.53; p = 0.009, false discovery rate (FDR) < 5%], for renal resistance index were -8.14 (95% CI -15.36; -0.92; p = 0.027; FDR < 5%), and for urinary KIM-1 were 0.47 (95% CI 0.02; 0.93; p = 0.040; FDR < 5%). CONCLUSION Cystatin C, renal resistance index, and KIM-1 may be associated with the risk for DKD in children and adolescents diagnosed with DM-T1. We encourage further prospective cohort studies to test our results.
Collapse
Affiliation(s)
- Ivana Trutin
- Department of Pediatrics, University Hospital Center Sestre Milosrdnice, Zagreb, Croatia
| | - Zarko Bajic
- Research Unit "Dr. Mirko Grmek", University Psychiatric Hospital "Sveti Ivan", Zagreb, Croatia
| | - Daniel Turudic
- Department of Pediatrics, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Andrea Cvitkovic-Roic
- Helena Clinic for Pediatric Medicine, Zagreb, Croatia.,Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Danko Milosevic
- School of Medicine, University of Zagreb, Zagreb, Croatia.,Department of Pediatrics, General Hospital Zabok and Hospital of Croatian Veterans, Bracak, Croatia
| |
Collapse
|
|
18
|
Padmini PJ, Ashok V. Urine neutrophil gelatinase-associated lipocalin as an early biochemical marker of microalbuminuria in predicting early kidney damage in patients with type 2 diabetes mellitus. UKRAINIAN BIOCHEMICAL JOURNAL 2021. [DOI: 10.15407/ubj93.06.055] [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] Open
|
|
19
|
Xu Y, Shan X, Wang H. A nomogram for predicting the risk of new-onset albuminuria based on baseline urinary ACR, orosomucoid, and HbA1c in patients with type 2 diabetes. J Diabetes Complications 2021; 35:108058. [PMID: 34635404 DOI: 10.1016/j.jdiacomp.2021.108058] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/28/2021] [Accepted: 09/29/2021] [Indexed: 12/18/2022]
Abstract
OBJECTIVES Numerous biomarkers have been shown to be associated with albuminuria. However, few of them are valuable separate predictors of albuminuria development. This study aimed to develop a model for predicting the short-term risk of new-onset albuminuria in normoalbuminuric patients with type 2 diabetes (T2D). METHODS 213 patients with T2D who were normoalbuminuric at the baseline were enrolled in this study. Basal levels of clinical characteristics and renal biomarkers including urinary orosomucoid (alpha-1-acid-glycoprotein, UORM), neutrophil gelatinase-associated lipocalin, retinol-binding protein, alpha-1-microglobulin, transferrin, and albumin-to-creatinine ratio (ACR) were utilized to analyze the association with the short-term risk of new-onset albuminuria. RESULTS 19.72% of normoalbuminuric subjects at baseline progressed to albuminuria over the 2-year follow-up period. Except for NGAL, the basal levels of the other five renal biomarkers were significantly associated with new-onset albuminuria risk in the univariate analysis. In the multivariate logistic regression analysis using Forward: LR method, a model incorporating UORM/Cr, ACR, and HbA1c was established. Comparatively, this model had a higher potential to predict new-onset albuminuria risk compared with the single use of renal markers. In the validation of this model performed by 5-fold cross-validation method, the accuracy of this model was 0.818 ± 0.008 in the training sets, 0.827 ± 0.062 in the test sets, indicating a good capability for assessing albuminuria risk. Finally, a nomogram based on this model was constructed to facilitate its use in clinical practice. CONCLUSION The combined analysis of UORM/Cr, ACR and HbA1c may be of potential value for predicting the short-term risk of new-onset albuminuria in such patients.
Collapse
Affiliation(s)
- Yina Xu
- Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua city, Zhejiang Province, China
| | - Xiaoyun Shan
- Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua city, Zhejiang Province, China
| | - Huabin Wang
- Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua city, Zhejiang Province, China; Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua city, Zhejiang Province, China.
| |
Collapse
|
|
20
|
Involvement of Tricarboxylic Acid Cycle Metabolites in Kidney Diseases. Biomolecules 2021; 11:biom11091259. [PMID: 34572472 PMCID: PMC8465464 DOI: 10.3390/biom11091259] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/17/2021] [Accepted: 08/23/2021] [Indexed: 02/08/2023] Open
Abstract
Mitochondria are complex organelles that orchestrate several functions in the cell. The primary function recognized is energy production; however, other functions involve the communication with the rest of the cell through reactive oxygen species (ROS), calcium influx, mitochondrial DNA (mtDNA), adenosine triphosphate (ATP) levels, cytochrome c release, and also through tricarboxylic acid (TCA) metabolites. Kidney function highly depends on mitochondria; hence mitochondrial dysfunction is associated with kidney diseases. In addition to oxidative phosphorylation impairment, other mitochondrial abnormalities have been described in kidney diseases, such as induction of mitophagy, intrinsic pathway of apoptosis, and releasing molecules to communicate to the rest of the cell. The TCA cycle is a metabolic pathway whose primary function is to generate electrons to feed the electron transport system (ETS) to drives energy production. However, TCA cycle metabolites can also release from mitochondria or produced in the cytosol to exert different functions and modify cell behavior. Here we review the involvement of some of the functions of TCA metabolites in kidney diseases.
Collapse
|
|
21
|
Assessment of renal function in obese and overweight children with NGAL and KIM-1 biomarkers. NUTR HOSP 2021; 34:436-442. [PMID: 32207310 DOI: 10.20960/nh.02651] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
Introduction Aim and background: the incidence of obesity has increased among children, and obesity has been considered an independent risk factor for chronic kidney disease. We aimed to determine the degree of kidney function impairment by evaluating urine neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) levels. Materials and methods: in total, 15 obese, 26 overweight, and 26 control adolescents aged 10 to 16 years were enrolled into the study. Urine samples were evaluated for NGAL and KIM-1 levels using enzyme-linked immunosorbent assay kits. We investigated the association between obesity and related comorbidities with urinary NGAL and KIM-1 excretion. Results: no significant differences were noted between the obese, overweight, and control groups in urinary NGAL and KIM-1 excretion (p = 0.327 and p = 0.917, respectively). In the obese and overweight groups urinary NGAL levels were 50.39 [30.88-74.22] in females and 26.67 [23.24-45.59] in males (p = 0.013). Also, urinary NGAL levels were increased in obese and overweight adolescents with LDL dyslipidemia at 64.12 [30.98-114.32] as compared to those without LDL dyslipidemia: 39.51 [25.59.56.37] (p = 0.024). Furthermore, a correlation was observed between insulin and homeostasis model assessment of insulin resistance levels with the NGAL/creatinine ratio in the overweight group (r = 0.515; p = 0.008, and r = 0.483; p = 0.014, respectively). Such correlation was not found in the obese group. Conclusion: the effect of obesity on renal function could not be determined in children. A longer exposure may be required for obesity-induced disruption of renal function in children. Renal function may be disrupted by dyslipidemia in obese adolescents. Furthermore, obesity impaired renal function in female adolescents. The normalization of these urinary markers as related to urine creatinine should be discussed.
Collapse
|
|
22
|
Diabetic nephropathy: A twisted thread to unravel. Life Sci 2021; 278:119635. [PMID: 34015285 DOI: 10.1016/j.lfs.2021.119635] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/04/2021] [Accepted: 05/12/2021] [Indexed: 12/18/2022]
Abstract
Diabetic nephropathy (DN), a persistent microvascular problem of diabetes mellitus is described as an elevated level of albumin excretion in urine and impaired renal activity. The morbidity and mortality of type-1 diabetics and type-2 diabetics due to end stage renal disease is also a result of the increased prevalence of DN. DN typically occurs as a consequence of an association among metabolic and hemodynamic variables, activating specific pathways leading to renal injury. According to current interventions, intensive glucose regulation decreases the threat of DN incidence and growth, and also suppressing the renin-angiotensin system (RAS) is a significant goal for hemodynamic and metabolism-related deformities in DN. However, the pathogenesis of DN is multifactorial so novel approaches other than glucose and blood pressure control are required for treatment. This review briefly summarizes the reported pathogenesis of DN, current interventions for its treatment, and possible novel interventions to unweave the thread of DN.
Collapse
|
|
23
|
Fox J, Macaluso F, Moore C, Mesenbring E, Johnson RJ, Hamman RF, James KA. Urine tungsten and chronic kidney disease in rural Colorado. ENVIRONMENTAL RESEARCH 2021; 195:110710. [PMID: 33460634 PMCID: PMC7987874 DOI: 10.1016/j.envres.2021.110710] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 12/23/2020] [Accepted: 12/31/2020] [Indexed: 06/12/2023]
Abstract
BACKGROUND Chronic kidney disease (CKD) is a cause of global morbidity and mortality in agricultural communities. The San Luis Valley (SLV) is a rural agricultural community in southern Colorado with geographic and sociodemographic risk factors for CKD, including a water supply contaminated by heavy metals. METHODS We obtained pre-existing sociodemographic, clinical, and urine trace metal data for 1659 subjects from the San Luis Valley Diabetes Study, a prospective cohort study. We assessed prospective associations between urine tungsten (W) and time-to-CKD using accelerated failure time models (n = 1659). Additionally, logistic models were used to assess relationships between urine W and renal injury markers (NGAL, KIM1) using Tobit regression (n = 816), as well as epidemiologically-defined CKD of unknown origin (CKDu) using multiple logistic regression (n = 620). RESULTS Elevated urine W was strongly associated with decreased time-to-CKD, even after controlling for hypertension and diabetes. Depending on how CKD was defined, a doubling of urine W was associated with a 27% (95% CI 11%, 46%) to 31% (14%, 51%) higher odds of developing CKD within 5 years. The relationship between urine W and select renal injury markers was not significant, although urine NGAL was modified by diabetes status. Elevated (>95%ile) urinary W was significantly associated with CKDu (OR 5.93, 1.83, 19.21) while adjusting for known CKD risk factors. CONCLUSIONS Our data suggest that increased exposure to W is associated with decreased time-to-CKD and may be associated with CKDu. Given persistence of associations after controlling for diabetes and hypertension, W may exert a primary effect on the kidney, although this needs to be evaluated further in future studies.
Collapse
Affiliation(s)
- Jacob Fox
- Colorado School of Public Health, Departments of Environmental & Occupational Health and Epidemiology, University of Colorado Anschutz Medical Campus, Fitzsimons Building, 3rd Floor, 13001 E. 17th Place, B119, Aurora, CO, 80045, USA.
| | - Francesca Macaluso
- Colorado School of Public Health, Departments of Environmental & Occupational Health and Epidemiology, University of Colorado Anschutz Medical Campus, Fitzsimons Building, 3rd Floor, 13001 E. 17th Place, B119, Aurora, CO, 80045, USA.
| | - Camille Moore
- Colorado School of Public Health, Departments of Environmental & Occupational Health and Epidemiology, University of Colorado Anschutz Medical Campus, Fitzsimons Building, 3rd Floor, 13001 E. 17th Place, B119, Aurora, CO, 80045, USA; Center for Genes, Environment and Health, National Jewish Health, Smith Building; A647, 1400 Jackson Street, Denver, CO, 80206, USA.
| | - Elise Mesenbring
- Colorado School of Public Health, Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Fitzsimons Building, 3rd Floor, 13001 E. 17th Place, B119, Aurora, CO, 80045, USA.
| | - Richard J Johnson
- School of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Fitzsimons Building, 3rd Floor 13001 E. 17th Place, B119, Aurora, CO, 80045, USA.
| | - Richard F Hamman
- Colorado School of Public Health, Departments of Environmental & Occupational Health and Epidemiology, University of Colorado Anschutz Medical Campus, Fitzsimons Building, 3rd Floor, 13001 E. 17th Place, B119, Aurora, CO, 80045, USA.
| | - Katherine A James
- Colorado School of Public Health, Departments of Environmental & Occupational Health and Epidemiology, University of Colorado Anschutz Medical Campus, Fitzsimons Building, 3rd Floor, 13001 E. 17th Place, B119, Aurora, CO, 80045, USA.
| |
Collapse
|
|
24
|
Chen G, Shan X, Wang H. Significant association of urinary alpha‐1‐microglobulin compared to urinary neutrophil gelatinase‐associated lipocalin with renal insufficiency in patients with type 2 diabetes. Nephrology (Carlton) 2021; 26:400-407. [PMID: 33484208 DOI: 10.1111/nep.13851] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 12/30/2020] [Accepted: 01/17/2021] [Indexed: 12/11/2022]
Affiliation(s)
- Guangming Chen
- Department of General Practice, Affiliated Jinhua Hospital Zhejiang University School of Medicine Jinhua China
| | - Xiaoyun Shan
- Department of Clinical Laboratory, Affiliated Jinhua Hospital Zhejiang University School of Medicine Jinhua China
| | - Huabin Wang
- Department of Clinical Laboratory, Affiliated Jinhua Hospital Zhejiang University School of Medicine Jinhua China
- Central Laboratory, Affiliated Jinhua Hospital Zhejiang University School of Medicine Jinhua China
| |
Collapse
|
|
25
|
Karaman S, Sabancıoğulları E, Karaman E, Başaranoğlu M, Çetin M, Karaman K. Indicator of early kidney injury in adolescents with polycystic ovary syndrome: Can urine NGAL level be? Gynecol Endocrinol 2021; 37:117-120. [PMID: 32608277 DOI: 10.1080/09513590.2020.1787377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
INTRODUCTION AND PURPOSE The Urinary Neutrophil-gelatinase associated lipocalin (NGAL) levels which are a biomarker for early diagnosis of kidney damage that may develop in patients with Polycystic Ovary Syndrome (PCOS) were investigated in the study. MATERIAL AND METHODS The 30 patients diagnosed with Polycystic Ovarian Syndrome between the ages of 13 and 18 who applied to the Yuzuncu Yil University General Children's Outpatient Clinic were included in the PCOS group and 30 healthy adolescents without any known acute or chronic illness and drug use were included in the control group. FINDINGS Urine NGAL value was 842.204 ± 21.561 in PCOS group and 775.379 ± 23.98 in control group. NGAL level in PCOS group was statistically significantly higher than control group (p: .045). When we examine the relationship between dyslipidemia and PCOS; While dyslipidemia was positive in 10 (33.7%) patients in the PCOS group, it was negative in 20 (66.7%) patients. While 1 patient had dyslipidemia, 29 patients did not have dyslipidemia in the control group. A significant relationship was found between dyslipidemia and PCOS (p: .005). CONCLUSION We found that subclinical kidney dysfunction started in early stage patients in PCOS in our study. The urine NGAL level was thought to increase in response to increased oxidative stress in PCOS. We found no relationship between, insulin resistance and urea, BUN, creatinine and NGAL levels. However, we found a negative correlation between NGAL level and LDL. In addition, dyslipidemia, insulin resistance and ALT elevation were detected in the PCOS group.
Collapse
Affiliation(s)
- Serap Karaman
- Department of Pediatric, Yuzuncu Yil University, Van, Turkey
| | | | - Erbil Karaman
- Medical Faculty, Obstetric and Gynecology, Yuzuncu Yil University, Van, Turkey
| | | | - Mecnun Çetin
- Medical Faculty, Department of Pediatric Cardiology, Yuzuncu Yil University, Van, Turkey
| | - Kamuran Karaman
- Medical Faculty, Department of Pediatric Hematology, Yuzuncu Yil University, Van, Turkey
| |
Collapse
|
|
26
|
Ugarte F, Santapau D, Gallardo V, Garfias C, Yizmeyián A, Villanueva S, Sepúlveda C, Rocco J, Pasten C, Urquidi C, Cavada G, San Martin P, Cano F, Irarrázabal CE. Urinary Extracellular Vesicles as a Source of NGAL for Diabetic Kidney Disease Evaluation in Children and Adolescents With Type 1 Diabetes Mellitus. Front Endocrinol (Lausanne) 2021; 12:654269. [PMID: 35046888 PMCID: PMC8762324 DOI: 10.3389/fendo.2021.654269] [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] [Received: 01/15/2021] [Accepted: 11/15/2021] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Tubular damage has a role in Diabetic Kidney Disease (DKD). We evaluated the early tubulointerstitial damage biomarkers in type-1 Diabetes Mellitus (T1DM) pediatric participants and studied the correlation with classical DKD parameters. METHODS Thirty-four T1DM and fifteen healthy participants were enrolled. Clinical and biochemical parameters [Glomerular filtration Rate (GFR), microalbuminuria (MAU), albumin/creatinine ratio (ACR), and glycated hemoglobin A1c (HbA1c)] were evaluated. Neutrophil gelatinase-associated lipocalin (NGAL), Hypoxia-inducible Factor-1α (HIF-1α), and Nuclear Factor of Activated T-cells-5 (NFAT5) levels were studied in the supernatant (S) and the exosome-like extracellular vesicles (E) fraction from urine samples. RESULTS In the T1DM, 12% had MAU >20 mg/L, 6% ACR >30 mg/g, and 88% had eGFR >140 ml/min/1.72 m2. NGAL in the S (NGAL-S) or E (NGAL-E) fraction was not detectable in the control. The NGAL-E was more frequent (p = 0.040) and higher (p = 0.002) than NGAL-S in T1DM. The T1DM participants with positive NGAL had higher age (p = 0.03), T1DM evolution (p = 0.03), and serum creatinine (p = 0.003) than negative NGAL. The NGAL-E correlated positively with tanner stage (p = 0.0036), the median levels of HbA1c before enrollment (p = 0.045) and was independent of ACR, MAU, and HbA1c at the enrollment. NFAT5 and HIF-1α levels were not detectable in T1DM or control. CONCLUSION Urinary exosome-like extracellular vesicles could be a new source of early detection of tubular injury biomarkers of DKD in T1DM patients.
Collapse
Affiliation(s)
- Francisca Ugarte
- Pediatric Endocrinology Unit, Pediatric Service, Clinica Universidad de los Andes, Santiago, Chile
- Departament of Pediatrics, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
- Pediatric Endocrinology and Diabetes Unit, Hospital Dr. Exequiel González Cortés, Santiago, Chile
| | - Daniela Santapau
- Centro de Medicina Regenerativa, Facultad de Medicina, Clinica Alemana-Universidad del Desarrollo, Santiago, Chile
| | - Vivian Gallardo
- Pediatric Endocrinology and Diabetes Unit, Hospital Dr. Exequiel González Cortés, Santiago, Chile
| | - Carolina Garfias
- Pediatric Endocrinology Unit, Pediatric Service, Clinica Universidad de los Andes, Santiago, Chile
| | - Anahí Yizmeyián
- Pediatric Endocrinology and Diabetes Unit, Hospital Dr. Exequiel González Cortés, Santiago, Chile
| | - Soledad Villanueva
- Pediatric Endocrinology and Diabetes Unit, Hospital Dr. Exequiel González Cortés, Santiago, Chile
| | - Carolina Sepúlveda
- Pediatric Endocrinology and Diabetes Unit, Hospital Dr. Exequiel González Cortés, Santiago, Chile
| | - Jocelyn Rocco
- Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Centro de Investigación e Innovación Biomédica (CIIB), Universidad de los Andes, Santiago, Chile
| | - Consuelo Pasten
- Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Centro de Investigación e Innovación Biomédica (CIIB), Universidad de los Andes, Santiago, Chile
- School of Medicine, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Cinthya Urquidi
- Department of Epidemiology and Health Studies, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Gabriel Cavada
- Department of Public Health, School of Public Health, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Pamela San Martin
- School of Medicine, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Francisco Cano
- Pediatric Nephrology Unit, Pediatric Service, Hospital Luis Calvo Mackennna, Santiago, Chile
| | - Carlos E. Irarrázabal
- Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Centro de Investigación e Innovación Biomédica (CIIB), Universidad de los Andes, Santiago, Chile
- School of Medicine, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
- *Correspondence: Carlos E. Irarrázabal,
| |
Collapse
|
|
27
|
Kheiripour N, Alipoor B, Ranjbar A, Pourfarjam Y, Kazemi Najafabadi F, Dehkhodaei N, Farhadiannezhad M, Ghasemi H. The effects of synthetic orally administrated insulin nanoparticles in comparison to injectable insulin on the renal function markers of type 1- diabetic rats. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2020; 23:810-818. [PMID: 32695298 PMCID: PMC7351444 DOI: 10.22038/ijbms.2020.42292.9985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 01/31/2020] [Indexed: 11/23/2022]
Abstract
OBJECTIVES Injectable insulin is the most widely used therapy in patients with type 1 diabetes which has several disadvantages. The present study was aimed to evaluate the efficacy of injectable insulin on diabetes mellitus-related complications in comparison to orally encapsulated insulin nanoparticles. MATERIALS AND METHODS This study involved 42 Wistar rats separated into 5 groups, including control (C), diabetic control (D), diabetic receiving regular insulin (INS), diabetic receiving encapsulated insulin nanoparticle (INP), and diabetic receiving chitosan for two months. Biochemical parameters in serum and urine were measured using spectrophotometric or ELISA methods. mRNA levels of kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) were evaluated using quantitative PCR. RESULTS There were no significant differences between the two forms of insulin in controlling the glycemic condition (P-value>0.05), but oral INP was more effective in correcting diabetic dyslipidemia in comparison to injectable insulin (P-value<0.05). Urine volume and creatinine excretion were significantly modulated by insulin and oral INP in diabetic groups (P-value<0.05), although the effects of INP on the modulation of execration of urea, acid uric, and albumin was more dramatic. Oral INP caused a significant decrease in urine concentration of KIM-1 and NGAL as well as expression of KIM-1 in renal tissue (P-value<0.05). CONCLUSION Our results suggested that oral INP is more effective than injectable insulin in modulation of urine and serum diabetic-related parameters.
Collapse
Affiliation(s)
- Nejat Kheiripour
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Behnam Alipoor
- Department of Laboratory Sciences, Faculty of Paramedicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Akram Ranjbar
- Toxicology and Pharmacology Department, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Yasin Pourfarjam
- Department of Chemistry, University of Cincinnati, Cincinnati, OH, United States of America
| | - Farzaneh Kazemi Najafabadi
- Toxicology and Pharmacology Department, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Narges Dehkhodaei
- Toxicology and Pharmacology Department, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | | | - Hassan Ghasemi
- Department of Clinical Biochemistry, Abadan Faculty of Medical Sciences, Abadan, Iran
| |
Collapse
|
|
28
|
Kamianowska M, Szczepański M, Sawicka E, Bebko B, Wasilewska A. The tubular damage markers: neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in newborns with exposure to maternal diabetes during pregnancy. Arch Med Sci 2020; 20:762-768. [PMID: 39050156 PMCID: PMC11264081 DOI: 10.5114/aoms.2020.95424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 04/15/2020] [Indexed: 07/27/2024] Open
Abstract
Introduction Chronic kidney disease and end-stage renal disease have been found to be caused by diabetes. More recently, the renal tubulointerstitium has been increasingly assumed to play a role in the pathogenesis of diabetic nephropathy with prolonged exposure to a variety of metabolic and haemodynamic injuring factors associated with sustained hyperglycaemia as contributing factors. This study aimed to investigate whether maternal diabetes could be the factor affecting kidney function in a newborn with the use of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) - biomarkers of renal injury. Material and methods The study included 138 full-term newborns: 50 newborns from diabetic pregnancies and 88 healthy newborns. The concentrations of NGAL and KIM-1 were determined in urine in the first or the second day of life with a commercially available ELISA kit. Results Considerably higher urine level of NGAL (25.7 (11.8-40.8)) and NGAL/cr. (29.1 (19.1-47.4)) in babies from diabetic pregnancies has been found when compared to the reference group (16.74 (9.9-27.5)) and (21.9 (14.6-29.8)) (p = 0.01, p < 0.01) respectively. We also found a significantly higher urine level of NGAL (27.8 (13.6-44.2)), NGAL/cr. (31.9 (17.6-57.4)), and KIM-1/cr. (2.6 (1.6-5.5)) in babies of diabetic mothers treated with insulin when compared to the reference group (16.7 (9.9-27.5)), (21.9 (14.6-29.8)), (1.9 (0.8-3.2)), (p = 0.01, p = 0.02, p = 0.02), respectively. Conclusions Based on the results of this study, we indicate for the first time that maternal diabetes mellitus during pregnancy may be considered as the cause of tubular kidney damage in newborns.
Collapse
Affiliation(s)
- Monika Kamianowska
- Department of Neonatology and Neonatal Intensive Care, Medical University of Bialystok, Bialystok, Poland
| | - Marek Szczepański
- Department of Neonatology and Neonatal Intensive Care, Medical University of Bialystok, Bialystok, Poland
| | - Ewa Sawicka
- Department of Neonatology and Neonatal Intensive Care, Medical University of Bialystok, Bialystok, Poland
| | - Barbara Bebko
- Department of Neonatology and Neonatal Intensive Care, Medical University of Bialystok, Bialystok, Poland
| | - Anna Wasilewska
- Department of Paediatrics and Nephrology, Medical University of Bialystok, Bialystok, Poland
| |
Collapse
|
|
29
|
Defauw P, Schoeman JP, Leisewitz AL, Goddard A, Duchateau L, Aresu L, Meyer E, Daminet S. Evaluation of acute kidney injury in dogs with complicated or uncomplicated Babesia rossi infection. Ticks Tick Borne Dis 2020; 11:101406. [PMID: 32107174 DOI: 10.1016/j.ttbdis.2020.101406] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 01/25/2020] [Accepted: 02/03/2020] [Indexed: 11/26/2022]
Abstract
Dogs with babesiosis can present with multiple complications, including acute kidney injury (AKI). The objective of this study was to characterize AKI in dogs with babesiosis caused by Babesia rossi at presentation and after treatment. Thirty-five client-owned dogs with B. rossi infection and 10 control dogs were included in this prospective observational study. Blood and urine were collected in Babesia-infected dogs at presentation (T0, n = 35), after 24 h (T24h, n = 11), and after 1 month (T1m, n = 9). The following urinary kidney injury biomarkers were assessed: urinary protein to creatinine ratio (UPC), urinary glomerular injury biomarkers (immunoglobulin G (uIgG) and C-reactive protein (uCRP)), and urinary tubular injury biomarkers (retinol-binding protein (uRBP) and neutrophil gelatinase-associated lipocalin (uNGAL)). Serum functional renal biomarkers were creatinine (sCr) and symmetric dimethylarginine (sSDMA). Post-mortem kidney biopsies were analyzed by light and transmission electron microscopy. At T0, all kidney injury biomarkers were significantly higher in Babesia-infected dogs compared to healthy controls (P < 0.001), while functional renal biomarkers were not significantly different (P > 0.05). At T24h, all urinary tubular injury biomarkers and UPC decreased significantly (P < 0.01), while glomerular injury biomarkers did not (P = 0.084). At T1m, all urinary kidney injury biomarkers decreased to values not significantly different from healthy controls (P > 0.5). Significant changes in functional renal biomarkers were not seen after treatment (P > 0.05). Dogs with complicated babesiosis had significantly higher glomerular injury biomarkers, UPC, and sSDMA compared to uncomplicated cases (P < 0.05), while all tubular injury biomarkers and sCr were not significantly different (P > 0.1). Dogs with babesiosis caused by B. rossi showed transient kidney injury, which was detected by all kidney injury biomarkers, but remained undetected by functional biomarkers. All infected dogs, irrespective of disease severity, suffered comparable kidney injury based on tubular injury biomarker concentrations, while loss of function was seen more often in dogs with complicated babesiosis based on sSDMA results.
Collapse
Affiliation(s)
- P Defauw
- Small Animal Department, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium.
| | - J P Schoeman
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, Pretoria, Onderstepoort 0110, South Africa.
| | - A L Leisewitz
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, Pretoria, Onderstepoort 0110, South Africa.
| | - A Goddard
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, Pretoria, Onderstepoort 0110, South Africa.
| | - L Duchateau
- Biometrics Research Group, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium.
| | - L Aresu
- Department of Veterinary Science, University of Turin, Largo Braccini 2, 10095 Grugliasco, Torino, Italy.
| | - E Meyer
- Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
| | - S Daminet
- Small Animal Department, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium.
| |
Collapse
|
|
30
|
Yang DH, Lee SY. Diabetic kidney disease: seven questions. JOURNAL OF THE KOREAN MEDICAL ASSOCIATION 2020. [DOI: 10.5124/jkma.2020.63.1.6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Affiliation(s)
- Dong Ho Yang
- Division of Nephrology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - So-Young Lee
- Division of Nephrology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| |
Collapse
|
|
31
|
Association of neutrophil-gelatinase-associated lipocalin with microvascular complications in patients with type 2 diabetes: a cross-sectional study. Cardiovasc Endocrinol Metab 2019; 8:82-87. [PMID: 31646302 DOI: 10.1097/xce.0000000000000180] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 08/12/2019] [Indexed: 11/25/2022]
Abstract
Diabetic nephropathy and diabetic retinopathy are serious microvascular complications of diabetes mellitus. Recent studies have demonstrated that neutrophil-gelatinase-associated lipocalin (NGAL) may be accompanied by these complications during and before the appearance of microalbuminuria. In this study, we set out to research the role of NGAL in patients with diabetic nephropathy and diabetic retinopathy. Material and methods Eighty-two patients with type 2 diabetes were enrolled in our study. Urinary microalbumine and NGAL levels were measured in urine samples over 24 hours. We also studied NGAL levels in serum. All patients went through an ophthalmologic examination. The results were evaluated based on the presence of microalbuminuria and retinopathy. Results There were no significant differences in serum and urine NGAL levels between normoalbuminuric (n = 66) and microalbuminuric (n = 16) patients. We also did not find any significant difference in patients with retinopathy (n = 16) or without retinopathy (n = 66). Conclusion There are controversial findings about the role of NGAL in diabetic patients in medical literature. Standard values of urine and serum NGAL levels have yet to be determined. Our study suggests that NGAL is not a useful marker to differentiate microalbuminuric patients from normoalbuminuric subjects. We also did not find a relationship between NGAL levels and the presence of retinopathy. Additional studies with larger sample sizes will be required to confirm or refute these findings.
Collapse
|
|
32
|
The Predictive Role of the Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced Nephrotoxicity. Int J Mol Sci 2019; 20:ijms20205238. [PMID: 31652595 PMCID: PMC6834366 DOI: 10.3390/ijms20205238] [Citation(s) in RCA: 116] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/09/2019] [Accepted: 10/17/2019] [Indexed: 12/14/2022] Open
Abstract
Acute kidney injury (AKI) following platinum-based chemotherapeutics is a frequently reported serious side-effect. However, there are no approved biomarkers that can properly identify proximal tubular injury while routine assessments such as serum creatinine lack sensitivity. Kidney-injury-molecule 1 (KIM-1) is showing promise in identifying cisplatin-induced renal injury both in vitro and in vivo studies. In this review, we focus on describing the mechanisms of renal tubular cells cisplatin-induced apoptosis, the associated inflammatory response and oxidative stress and the role of KIM-1 as a possible biomarker used to predict cisplatin associated AKI.
Collapse
|
|
33
|
Shufang H, Kui C, Li Y, Yu Z. Diagnostic Values of Urinary Biomarkers in Early Diagnosis of Diabetic Nephropathy. INT J PHARMACOL 2019. [DOI: 10.3923/ijp.2019.851.856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
|
|
34
|
Khan FA, Fatima SS, Khan GM, Shahid S. Evaluation of kidney injury molecule-1 as a disease progression biomarker in diabetic nephropathy. Pak J Med Sci 2019; 35:992-996. [PMID: 31372130 PMCID: PMC6659046 DOI: 10.12669/pjms.35.4.154] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background & Objective: Kidney Injury Molecule-1 (KIM-1) is a peptide whose release into circulation is specific to tubular injury. This study aimed to estimate levels of kidney injury molecule-1 in diabetic patients with and without kidney disease. And evaluate the role of KIM-1 as an early screening marker of progressive kidney injury. Methods: This follow-up study included n=85 subjects from the diabetic clinic of Jinnah Post Graduate Medical Center (JPMC) in collaboration with Aga Khan University from November 2016 till September 2017. They were divided as: i) Group A1 (n=30) participants with diabetes for <5 years without microalbuminuria ii) Group A2 (n= 30) subjects with diabetes for 6-10 years with microalbuminuria; iii) Group B (n=25) subjects as healthy control group. All study participants were followed for 6 months and their blood glucose, urea, creatinine, electrolytes, albuminuria and serum KIM-1 were assayed. Results: High KIM-1 at baseline was present in group A2 patients as compared to controls and group A1 (p<0.001). Higher levels were seen after six months in group A1 along with the presence of micro albuminuria (p<0.001) suggesting kidney damage. Moderate positive association were seen for KIM1 with creatinine levels (r=0.530; p<0.001), and HbA1c (r=0.576; p<0.001) in all patients. While a strong positive association was seen for blood urea nitrogen as a marker for kidney function both at baseline (r= 0.728; p=0.000) and follow up (r=0.747; p=0.001). Multiple logistic regression controlling for age showed that KIM1 was independently associated with BUN (r=0.727; p<0.001), creatinine (r=0.510; p<0.001) and HbA1c (r=0.401; p=0.008) in all groups. Conclusion: Rising KIM-1 levels with progressive kidney damage with or without derangement of kidney function is reported in this study. This finding may pave a way towards identifying KIM1 as a prognostic marker for kidney injury.
Collapse
Affiliation(s)
- Fatima Abid Khan
- Fatima Abid Khan, Department of Physiology, Jinnah Sindh Medical University, Karachi Pakistan
| | - Syeda Sadia Fatima
- Syeda Sadia Fatima, Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan
| | - Ghulam Mustafa Khan
- Ghulam Mustafa Khan, Department of Physiology, Basic Medical Sciences Institute, Jinnah Post Graduate Medical Centre, Karachi, Pakistan
| | - Sana Shahid
- Sana Shahid, Department of Physiology, Sir Syed College of Medicine for Girls, Karachi, Pakistan
| |
Collapse
|
|
35
|
Brunner HI, Gulati G, Klein-Gitelman MS, Rouster-Stevens KA, Tucker L, Ardoin SP, Onel KB, Mainville R, Turnier J, Aydin POA, Witte D, Huang B, Bennett MR, Devarajan P. Urine biomarkers of chronic kidney damage and renal functional decline in childhood-onset systemic lupus erythematosus. Pediatr Nephrol 2019; 34:117-128. [PMID: 30159624 PMCID: PMC6294330 DOI: 10.1007/s00467-018-4049-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Revised: 07/20/2018] [Accepted: 08/07/2018] [Indexed: 12/20/2022]
Abstract
OBJECTIVES To delineate urine biomarkers that reflect kidney structural damage and predict renal functional decline in pediatric lupus nephritis (LN). METHODS In this prospective study, we evaluated kidney biopsies and urine samples of 89 patients with pediatric LN. Urinary levels of 10 biomarkers [adiponectin, ceruloplasmin, kidney injury molecule-1, monocyte chemotactic protein-1, neutrophil gelatinase-associated lipocalin, osteopontin, transforming growth factor-ß (TGFß), vitamin-D binding protein, liver fatty acid binding protein (LFABP), and transferrin] were measured. Regression analysis was used to identify individual and combinations of biomarkers that determine LN damage status [NIH-chronicity index (NIH-CI) score ≤ 1 vs. ≥ 2] both individually and in combination, and biomarker levels were compared for patients with vs. without renal functional decline, i.e., a 20% reduction of the glomerular filtration rate (GFR) within 12 months of a kidney biopsy. RESULTS Adiponectin, LFABP, and osteopontin levels differed significantly with select histological damage features considered in the NIH-CI. The GFR was associated with NIH-CI scores [Pearson correlation coefficient (r) = - 0.49; p < 0.0001] but not proteinuria (r = 0.20; p > 0.05). Similar to the GFR [area under the ROC curve (AUC) = 0.72; p < 0.01], combinations of osteopontin and adiponectin levels showed moderate accuracy [AUC = 0.75; p = 0.003] in discriminating patients by LN damage status. Renal functional decline occurred more commonly with continuously higher levels of the biomarkers, especially of TGFß, transferrin, and LFABP. CONCLUSION In combination, urinary levels of adiponectin and osteopontin predict chronic LN damage with similar accuracy as the GFR. Ongoing LN activity as reflected by high levels of LN activity biomarkers heralds renal functional decline. KEY MESSAGES • Levels of osteopontin and adiponectin measured at the time of kidney biopsy are good predictors of histological damage with lupus nephritis. • Only about 20% of children with substantial kidney damage from lupus nephritis will have an abnormally low urine creatinine clearance. • Continuously high levels of biomarkers reflecting lupus nephritis activity are risk factors of declining renal function.
Collapse
Affiliation(s)
- Hermine I. Brunner
- Division of Rheumatology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, MC 4010, Cincinnati, OH 45229, USA
| | - Gaurav Gulati
- Division of Allergy and Rheumatology, Department of Medicine, University of Cincinnati, Cincinnati, USA
| | - Marisa S. Klein-Gitelman
- Department of Pediatrics, Division of Rheumatology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, USA
| | - Kelly A. Rouster-Stevens
- Division of Rheumatology, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, GA, USA
| | - Lori Tucker
- Division of Rheumatology, Department of Pediatrics, British Columbia Children’s Hospital, Vancouver, Canada
| | - Stacey P. Ardoin
- Division of Rheumatology, Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, USA
| | - Karen B. Onel
- Division of Pediatric Rheumatology, Hospital for Special Surgery, Weill Cornell Medicine, New York, NY, USA
| | - Rylie Mainville
- Division of Nephrology and Hypertension, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Jessica Turnier
- Division of Rheumatology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, MC 4010, Cincinnati, OH 45229, USA
| | - Pinar Ozge Avar Aydin
- Division of Rheumatology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, MC 4010, Cincinnati, OH 45229, USA
| | - David Witte
- Division of Pathology, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, USA
| | - Bin Huang
- Division of Biostatistics and Epidemiology, Department of Pediatrics, Cincinnati Children’s Hospital and Medical Center, University of Cincinnati, Cincinnati, OH, USA
| | - Michael R. Bennett
- Division of Rheumatology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, MC 4010, Cincinnati, OH 45229, USA,Division of Nephrology and Hypertension, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Prasad Devarajan
- Division of Rheumatology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, MC 4010, Cincinnati, OH 45229, USA,Division of Nephrology and Hypertension, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| |
Collapse
|
|
36
|
Gaipov A, Taubaldiyeva Z, Askarov M, Turebekov Z, Kozina L, Myngbay A, Ulyanova O, Tuganbekova S. Infusion of autologous bone marrow derived mononuclear stem cells potentially reduces urinary markers in diabetic nephropathy. J Nephrol 2018; 32:65-73. [PMID: 30406605 DOI: 10.1007/s40620-018-0548-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 10/11/2018] [Indexed: 12/21/2022]
Abstract
BACKGROUND Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Previous studies demonstrated safety and efficacy of autologous bone marrow-derived mononuclear cells (ABM-MNCs) in induced type-1 diabetes mellitus (T1DM) rats. However, the effect of ABM-MNCs on urinary markers of DN in humans is not well studied. We evaluated the therapeutic effect of ABM-MNCs on the urinary markers microalbuminuria (MAU), urinary type-IV collagen and urinary neutrophil gelatinase-associated lipocalin (uNGAL) in T1DM patients with and without nephropathy. METHODS This prospective open-label pilot study included 15 patients with T1DM, who had completed 2 visits within 6 months. Patients were divided into two groups according to the presence (DN, n = 7) and absence of nephropathy (T1DM, n = 8). ABM-MNCs were injected at each visit as per study protocol. Routine laboratory data, diabetes tests (fasting serum C-peptide and insulin, glycated hemoglobin, fasting and postprandial glucose), 24-h MAU and urinary type-IV collagen were measured at each visit. uNGAL levels were studied before and after 3 days of ABM-MNCs infusion at each visit. RESULTS Mean age of patients was 29.2 ± 10.4 years, 33% were male, and 27% of the overall group had hypertension. MAU was significantly reduced in the overall group (- 26.0%, p = 0.037), including in DN (- 83.2%, p = 0.021). A short-term significant reduction of uNGAL levels was observed 3 days after ABM-MNCs administration during the both the 1st visit (median 13.4 vs. 9.5 ng/ml, p = 0.027) and 2nd visit (median 8.8 vs. 6.4 ng/ml, p = 0.042) in both groups. However this reduction did not remain significant at the 6-month follow-up. Urinary type-IV collagen did not respond significantly to ABM-MNCs infusion. CONCLUSION Infusion of autologous bone marrow-derived mononuclear cells significantly reduced levels of MAU in DN patients. Further studies with larger sample size are needed to confirm these observations.
Collapse
Affiliation(s)
- Abduzhappar Gaipov
- Department of Extracorporeal Hemocorrection, JSC National Scientific Medical Research Center, Avenue Abylai-Khan #42, Astana, Kazakhstan, 010009.
| | - Zhannat Taubaldiyeva
- Department of Endocrinology, JSC National Scientific Medical Research Center, Avenue Abylai-Khan #42, Astana, Kazakhstan, 010009
| | - Manarbek Askarov
- Department of Stem Cell Technology, JSC National Scientific Medical Research Center, Avenue Abylai-Khan #42, Astana, Kazakhstan, 010009
| | - Zaiyrkhan Turebekov
- Department of Internal Medicine, JSC National Scientific Medical Research Center, Avenue Abylai-Khan #42, Astana, Kazakhstan, 010009
| | - Larisa Kozina
- Department of Biochemistry, JSC National Scientific Medical Research Center, Avenue Abylai-Khan #42, Astana, Kazakhstan, 010009
| | - Askhat Myngbay
- Private Institution "National Laboratory Astana", Nazarbayev University, Astana, Kazakhstan
| | - Olga Ulyanova
- Department of Endocrinology, JSC National Scientific Medical Research Center, Avenue Abylai-Khan #42, Astana, Kazakhstan, 010009
| | - Saltanat Tuganbekova
- Department of Internal Medicine, JSC National Scientific Medical Research Center, Avenue Abylai-Khan #42, Astana, Kazakhstan, 010009
| |
Collapse
|
|
37
|
Hosny SS, Bekhet MM, Hebah HA, Mohamed NR. Urinary neutrophil gelatinase-associated lipocalin in type 2 diabetes: Relation to nephropathy and retinopathy. Diabetes Metab Syndr 2018; 12:1019-1024. [PMID: 29960862 DOI: 10.1016/j.dsx.2018.06.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 06/20/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Diabetes mellitus is the leading cause of end stage renal disease worldwide. Early identification of diabetic nephropathy even before appearance of microalbuminuria is a challenge for early prevention of occurrence and progression of this complication. Neutrophil gelatinase-associated lipocalin is a small protein that belongs to the lipocalin protein. Urinary neutrophil gelatinase-associated lipocalin is a promising early marker in different renal problems. AIM OF THE WORK To measure urinary neutrophil gelatinase-associated lipocalin in type 2 diabetic patients and to assess its role as an early marker for diagnosis of diabetic nephropathy and diabetic retinopathy. PATIENT AND METHODS The current study included 60 subjects with type 2 diabetes and 20 healthy control subjects. Diabetic subjects were divided into 3 groups according to urinary albumin creatinine ratio; 20 normoalbuminuric patients, 20 micro-albuminuric patients and 20 macroalbuminuric patients. They were subjected to history taking, full clinical examination, fundus examination, anthropometric measurement, urinary neutrophil gelatinase-associated lipocalin and urinary albumin creatinine ratio. RESULTS Urinary neutrophil gelatinase-associated lipocalin was higher in all diabetic groups than in the control group, with no difference in between diabetic groups. The difference was of great value when comparing normoalbuminuric group with control as albumin creatinine ratio was not different while the urinary neutrophil gelatinase-associated lipocalin was statistically significant (5.94 ± 1.85 ng/dl vs 1.96 ± 0.65, p < 0.001). No correlation was found with retinopathy. CONCLUSION Urinary neutrophil gelatinase-associated lipocalin is a sensitive marker for early detection of diabetic nephropathy even in normoalbuminuric patients denoting early tubular damage before microalbuminuria. It is not correlated with retinopathy.
Collapse
Affiliation(s)
- Salwa S Hosny
- Department of Internal Medicine and Endocrinology, Faculty of Medicine - Ain Shams University, Cairo, Egypt
| | - Meram M Bekhet
- Department of Internal Medicine and Endocrinology, Faculty of Medicine - Ain Shams University, Cairo, Egypt.
| | - Hayam A Hebah
- Department of Internal Medicine and Nephrology, Faculty of Medicine - Ain Shams University, Cairo, Egypt
| | - Nagwa R Mohamed
- Department of Internal Medicine and Endocrinology, Faculty of Medicine - Ain Shams University, Cairo, Egypt
| |
Collapse
|
|
38
|
Kim SY, Jeong TD, Lee W, Chun S, Sunwoo S, Kim SB, Min WK. Plasma Neutrophil Gelatinase-Associated Lipocalin as a Marker of Tubular Damage in Diabetic Nephropathy. Ann Lab Med 2018; 38:524-529. [PMID: 30027695 PMCID: PMC6056390 DOI: 10.3343/alm.2018.38.6.524] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 01/04/2018] [Accepted: 05/25/2018] [Indexed: 12/31/2022] Open
Abstract
Background An increase in neutrophil gelatinase-associated lipocalin (NGAL) indicates tubular injury. Diabetic nephropathy causes typical changes in the kidney, characterized by glomerulosclerosis and eventual tubular damage. We validated the usefulness of plasma NGAL (pNGAL) as a biomarker of tubular damage in patients with diabetic nephropathy. Methods We included 376 patients with diabetes mellitus (260 patients with chronic renal insufficiency who had not received hemodialysis and 116 hemodialyzed due to diabetic nephropathy) and 24 healthy controls. Patients with chronic renal insufficiency were divided into three groups according to urinary albumin excretion (UAE) levels. pNGAL levels were measured using the Triage NGAL test (Alere, San Diego, CA, USA) and were compared between groups. We also examined whether pNGAL level was related to the degree of albuminuria and cystatin C-based glomerular filtration rate (GFR). Results Mean pNGAL levels of the healthy controls, chronic renal insufficiency patients with diabetes mellitus, and hemodialyzed patients were 61.9±5.3 ng/mL, 93.4±71.8 ng/mL, and 1,536.9±554.9 ng/mL, respectively. pNGAL level increased significantly in patients with severe albuminuria (P<0.001) and had a moderate correlation with the degree of albuminuria (r=0.467; P<0.001) and GFR (r=0.519; P<0.001). Multivariate regression analysis showed that the pNGAL level was associated with tubular damage independent of patient age, sex, and GFR. Conclusions pNGAL level independently reflects the degree of tubular damage in patients with diabetic nephropathy. Measurement of pNGAL, combined with UAE, would enable simultaneous, highly reliable assessments of tubular damage for such patients.
Collapse
Affiliation(s)
- So Young Kim
- Department of Laboratory Medicine, LabGenomics Clinical Laboratory, Seongnam, Korea
| | - Tae Dong Jeong
- Department of Laboratory Medicine, College of Medicine, Ewha Womans University, Seoul, Korea
| | - Woochang Lee
- Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea
| | - Sail Chun
- Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea.
| | - Sung Sunwoo
- Department of Family Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea
| | - Soon Bae Kim
- Department of Internal Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea
| | - Won Ki Min
- Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea
| |
Collapse
|
|
39
|
Bjornstad P, Pyle L, Cherney DZI, Johnson RJ, Sippl R, Wong R, Rewers M, Snell-Bergeon JK. Plasma biomarkers improve prediction of diabetic kidney disease in adults with type 1 diabetes over a 12-year follow-up: CACTI study. Nephrol Dial Transplant 2018; 33:1189-1196. [PMID: 28992280 PMCID: PMC6030887 DOI: 10.1093/ndt/gfx255] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2017] [Accepted: 07/11/2017] [Indexed: 01/15/2023] Open
Abstract
Background The objective of the study was to determine whether plasma biomarkers of kidney injury improve the prediction of diabetic kidney disease (DKD) in adults with type 1 diabetes (T1D) over a period of 12 years. Methods Participants (n = 527, 53% females) in the Coronary Artery Calcification in T1D (CACTI) Study were examined during 2002-04, at a mean (± standard deviation) age of 39.6 ± 9.0 years with 24.8 years as the median duration of diabetes. Urine albumin-to-creatinine (ACR) and estimated glomerular filtration rate (eGFR) by CKD-EPI (chronic kidney disease epidemiology collaboration) creatinine were measured at the baseline and after mean follow-up of 12.1 ± 1.5 years. Albuminuria was defined as ACR ≥30 mg/g and impaired GFR as eGFR <60 mL/min/1.73 m2. Kidney injury biomarkers (Meso Scale Diagnostics) were measured on stored baseline plasma samples. A principal component analysis (PCA) identified two components: (i) kidney injury molecule-1, calbindin, osteoactivin, trefoil factor 3 and vascular endothelial growth factor; and (ii) β-2 microglobulin, cystatin C, neutrophil gelatinase-associated lipocalin and osteopontin that were used in the multivariable regression analyses. Results Component 2 of the PCA was associated with increase in log modulus ACR [β ± standard error (SE): 0.16 ± 0.07, P = 0.02] and eGFR (β ± SE: -2.56 ± 0.97, P = 0.009) over a period of 12 years after adjusting for traditional risk factors (age, sex, HbA1c, low-density lipoprotein cholesterol and systolic blood pressure and baseline eGFR/baseline ACR). Only Component 2 of the PCA was associated with incident-impaired GFR (odds ratio 2.08, 95% confidence interval 1.18-3.67, P = 0.01), adjusting for traditional risk factors. The addition of Component 2 to traditional risk factors significantly improved C-statistics and net-reclassification improvement for incident-impaired GFR (ΔAUC: 0.02 ± 0.01, P = 0.049, and 29% non-events correctly reclassified, P < 0.0001). Conclusions Plasma kidney injury biomarkers can help predict development of DKD in T1D.
Collapse
Affiliation(s)
- Petter Bjornstad
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA
- Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, CO, USA
| | - Laura Pyle
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, and Department of Physiology, University of Toronto, ON, Canada
| | - Richard J Johnson
- Department of Nephrology, University of Colorado Denver, Aurora, CO, USA
| | - Rachel Sippl
- Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, CO, USA
| | - Randy Wong
- Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, CO, USA
| | - Marian Rewers
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA
- Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, CO, USA
| | - Janet K Snell-Bergeon
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA
- Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, CO, USA
| |
Collapse
|
|
40
|
Undiagnosed Kidney Injury in Uninsured and Underinsured Diabetic African American Men and Putative Role of Meprin Metalloproteases in Diabetic Nephropathy. Int J Nephrol 2018; 2018:6753489. [PMID: 29854459 PMCID: PMC5949186 DOI: 10.1155/2018/6753489] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Revised: 02/23/2018] [Accepted: 03/05/2018] [Indexed: 11/18/2022] Open
Abstract
Diabetes is the leading cause of chronic kidney disease. African Americans are disproportionately burdened by diabetic kidney disease (DKD) and end stage renal disease (ESRD). Disparities in DKD have genetic and socioeconomic components, yet its prevalence in African Americans is not adequately studied. The current study used multiple biomarkers of DKD to evaluate undiagnosed DKD in uninsured and underinsured African American men in Greensboro, North Carolina. Participants consisted of three groups: nondiabetic controls, diabetic patients without known kidney disease, and diabetic patients with diagnosed DKD. Our data reveal undiagnosed kidney injury in a significant proportion of the diabetic patients, based on levels of both plasma and urinary biomarkers of kidney injury, namely, urinary albumin to creatinine ratio, kidney injury molecule-1, cystatin C, and neutrophil gelatinase-associated lipocalin. We also found that the urinary levels of meprin A, meprin B, and two kidney meprin targets (nidogen-1 and monocytes chemoattractant protein-1) increased with severity of kidney injury, suggesting a potential role for meprin metalloproteases in the pathophysiology of DKD in this subpopulation. The study also demonstrates a need for more aggressive tests to assess kidney injury in uninsured diabetic patients to facilitate early diagnosis and targeted interventions that could slow progression to ESRD.
Collapse
|
|
41
|
Motawi TK, Shehata NI, ElNokeety MM, El-Emady YF. Potential serum biomarkers for early detection of diabetic nephropathy. Diabetes Res Clin Pract 2018; 136:150-158. [PMID: 29253627 DOI: 10.1016/j.diabres.2017.12.007] [Citation(s) in RCA: 21] [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: 07/09/2017] [Revised: 10/28/2017] [Accepted: 12/12/2017] [Indexed: 12/09/2022]
Abstract
AIM Diabetic nephropathy (DN) is considered as one of the diabetic complications affecting up to 40% of patients with type 1 or type 2 diabetes. In clinical practice, the frequently used markers of renal disease and progression are serum creatinine, estimated glomerular filtration rate (eGFR) and albuminuria. The aim of this study is to determine new biomarkers in human serum which are promising for early detection of DN. METHODS This study included 50 patients with type 2 diabetes mellitus (T2DM) and 25 clinically healthy individuals. The patients were divided into two groups; group I included 25 T2DM patients with normoalbuminuria, and group II consisted of 25 T2DM patients with microalbuminuria. In all groups, neutrophil gelatinase-associated lipocalin (NGAL), β-trace protein (βTP) and microRNA- 130b (miR-130b) were estimated. RESULTS The serum levels of NGAL and βTP were significantly elevated in T2DM patients with microalbuminuria (group II) compared with T2DM patients with normoalbuminuria (group I) and control subjects but there was no significant difference between group I and control subjects. Serum miR-130b level was significantly decreased in patients with T2DM (groups I and II) compared with healthy control subjects, with a higher decrease in their levels in group II compared with group I. CONCLUSION Our results suggest that serum NGAL and βTP as tubular and glomerular markers respectively, together with serum miR-130b may be independent and reliable biomarkers for early detection of DN in patients with T2DM.
Collapse
Affiliation(s)
- Tarek Kamal Motawi
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Kasr Al Ainy, St. Cairo 11562, Egypt
| | - Nagwa Ibrahim Shehata
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Kasr Al Ainy, St. Cairo 11562, Egypt
| | - Mahmoud Mohamed ElNokeety
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Kasr Al Ainy, St. Cairo 11562, Egypt
| | - Yasmin Farid El-Emady
- The Holding Company for Biological Products & Vaccines (VACSERA), 51 Wezaret ElZeraa St., Agouza, Giza 12622, Egypt.
| |
Collapse
|
|
42
|
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: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [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.
Collapse
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
| |
Collapse
|
|
43
|
Hwang S, Park J, Kim J, Jang HR, Kwon GY, Huh W, Kim YG, Kim DJ, Oh HY, Lee JE. Tissue expression of tubular injury markers is associated with renal function decline in diabetic nephropathy. J Diabetes Complications 2017; 31:1704-1709. [PMID: 29037450 DOI: 10.1016/j.jdiacomp.2017.08.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 07/28/2017] [Accepted: 08/20/2017] [Indexed: 12/17/2022]
Abstract
AIMS The pathogenesis of diabetic kidney disease (DKD) is complex and multifactorial; increasing evidence suggests that tubular injury and inflammatory process are involved in disease progression. We investigated the potential association of renal expression of tubular injury markers, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and inflammatory markers, tumor necrosis factor receptor (TNFR) 1 and 2 with renal progression in pathologically proven diabetic nephropathy (DN). METHODS We identified 122 patients with confirmed DN. After excluding patients with other coexisting renal disease or estimated glomerular filtration rate (eGFR) <30mL/min/1.73m2, 35 patients were included. Annual decline of (GFR decline slope) was calculated using linear regression analysis. Tissue tubular and glomerular expressions of NGAL, KIM-1, TNFR1, and TNFR2 were assessed using immunohistochemistry. RESULTS Median baseline urinary protein to creatinine ratio (uPCR) was 6.76 (2.18-7.61) mg/mg Cr, median baseline eGFR was 50 (43-66) mL/min per 1.73m2, and median GFR decline slope was 15.6 (4.4-35.1) mL/min per 1.73m2 per year. Positive correlations were observed between tubular expressions of NGAL and KIM-1, and GFR decline slopes (r=0.601, p<0.001; r=0.516, p=0.001, respectively), and between tubular expressions of KIM-1 and uPCR (r=0.596, p<0.001), and between NGAL and interstitial fibrosis and tubular atrophy (IFTA) score (r=0.391, p=0.024). No correlations were found between glomerular or tubular expressions of TNFRs, and clinical parameters including GFR decline slopes. On multivariate analysis, the association between tubular expressions of KIM-1 and GFR decline slopes was dependent on uPCR. Tubular expressions of NGAL were independently associated with GFR decline slopes, with an adjusted coefficient factor of 0.290 (95% confidence interval, 0.009-0.202, p=0.038). CONCLUSIONS These findings suggest that tubular injury plays a key role in the pathogenesis of DKD in high-risk patients. Further studies are warranted to determine whether tubular injury could be a therapeutic target in DKD.
Collapse
Affiliation(s)
- Subin Hwang
- Nephrology Division, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jeeeun Park
- Nephrology Division, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jinhae Kim
- Nephrology Division, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hye Ryoun Jang
- Nephrology Division, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Ghee Young Kwon
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Wooseong Huh
- Nephrology Division, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yoon-Goo Kim
- Nephrology Division, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dae Joong Kim
- Nephrology Division, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Ha Young Oh
- Nephrology Division, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jung Eun Lee
- Nephrology Division, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
| |
Collapse
|
|
44
|
El-Ashmawy NE, Khedr EG, El-Bahrawy HA, El-Berashy SA. Effect of human umbilical cord blood-derived mononuclear cells on diabetic nephropathy in rats. Biomed Pharmacother 2017; 97:1040-1045. [PMID: 29136782 DOI: 10.1016/j.biopha.2017.10.151] [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] [Received: 07/26/2017] [Revised: 10/25/2017] [Accepted: 10/25/2017] [Indexed: 02/02/2023] Open
Abstract
Diabetic nephropathy (DN) is damage to the kidney which can lead to chronic renal failure, eventually requiring dialysis. Diabetes mellitus is the most common cause of adult kidney failure worldwide in the developed world. The current work was designed to elucidate the effect of mononuclear cells (MNCs) injection on reverse DN in rats exposed to streptozotocin (STZ) injection compared to metformin as a known hypoglycemic drug, 40 Male rats were divided equally into 4 groups; normal control group, diabetic control group, MNCs group were diabetic rats treated with MNCs (30×106 MNCs/rat once iv dose) in the tail vein of the rat, and metformin group were diabetic rats treated with metformin (100mg/kg orally daily dose) for four weeks. The results indicated an improvement effect of MNCs and metformin on STZ-induced DN in rats, which was evidenced by significant decrease in urinary albumin/creatinine ratio, N-acetyl-β-d-glucosaminidase (NAG), urinary kidney injury molecule-1 (KIM-1), serum urea, serum creatinine and fasting blood glucose and significant increase in C- peptide level, compared to diabetic control group. Additionally MNCs treated group exhibited pronounced effects in all previous parameters compared to metformin treated group. It is proved that MNCs treatment was superior to metformin in controlling hyperglycemia, and improving renal function in diabetic rats.
Collapse
Affiliation(s)
- Nahla E El-Ashmawy
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Eman G Khedr
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Hoda A El-Bahrawy
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Shimaa A El-Berashy
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt.
| |
Collapse
|
|
45
|
Futrakul N, Futrakul P. Biomarker for early renal microvascular and diabetic kidney diseases. Ren Fail 2017; 39:505-511. [PMID: 28494191 PMCID: PMC6014362 DOI: 10.1080/0886022x.2017.1323647] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 02/20/2017] [Accepted: 04/23/2017] [Indexed: 12/20/2022] Open
Abstract
Recognition of early stage of diabetic kidney disease, under common practice using biomarkers, namely microalbuminuria, serum creatinine level above 1 mg/dL and accepted definition of diabetic kidney disease associated with creatinine clearance value below 60 mL/min/1.73 m2, is unlikely. This would lead to delay treatment associated with therapeutic resistance to vasodilator due to a defective vascular homoeostasis. Other alternative biomarkers related to the state of microalbuminuria is not sensitive to screen for early diabetic kidney disease (stages I, II). In this regard, a better diagnostic markers to serve for this purpose are creatinine clearance, fractional excretion of magnesium (FE Mg), cystatin C. Recently, renal microvascular disease and renal ischemia have been demonstrated to correlate indirectly with the development of diabetic kidney disease and its function. Among these are angiogenic and anti-angiogenic factors, namely VEGF, VEGF receptors, angiopoietins and endostatin. With respect to therapeutic prevention, implementation of treatment at early stage of diabetic and nondiabetic kidney disease is able to restore renal perfusion and function.
Collapse
Affiliation(s)
- Narisa Futrakul
- Department of Physiology, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand
| | - Prasit Futrakul
- Academy of Science, The Royal Institute of Thailand and Bhumirajanagarindra Kidney Institute, Bangkok, Thailand
| |
Collapse
|
|
46
|
Gala-Błądzińska A, Dumnicka P, Kuśnierz-Cabala B, Rybak K, Drożdż R, Żyłka A, Kuźniewski M. Urinary Neutrophil Gelatinase-Associated Lipocalin Is Complementary to Albuminuria in Diagnosis of Early-Stage Diabetic Kidney Disease in Type 2 Diabetes. BIOMED RESEARCH INTERNATIONAL 2017; 2017:4691389. [PMID: 28845433 PMCID: PMC5563398 DOI: 10.1155/2017/4691389] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 03/19/2017] [Accepted: 07/06/2017] [Indexed: 12/31/2022]
Abstract
BACKGROUND Two clinical phenotypes of diabetic kidney disease (DKD) have been reported, that is, with or without increased albuminuria. The aim of study was to assess the usefulness of urinary neutrophil gelatinase-associated lipocalin (uNGAL) for the early diagnosis of DKD in the type 2 diabetes mellitus (T2DM). METHODS The study group consisted of 123 patients with T2DM (mean age 62 ± 14 years), with urine albumin/creatinine ratio (uACR) < 300 mg/g and eGFR ≥ 60 ml/min/1.73 m2. The control group included 22 nondiabetic patients with comparable age, sex, and comorbidities. uNGAL, albumin, and creatinine were measured in the first morning urine samples. uACR and uNGAL/creatinine ratios (uNCR) were calculated. RESULTS In the control group, maximum uNCR was 39.64 µg/g. In T2DM group, 24 patients (20%) had higher results, with the maximum value of 378.6 µg/g. Among patients with uNCR > 39.64 µg/g, 13 (54%) did not have markedly increased albuminuria. Women with T2DM had higher uNCR than men (p < 0.001), without difference in uACR (p = 0.09). uNCR in T2DM patients correlated significantly with HbA1c. Sex, total cholesterol, and uACR were independent predictors of uNCR above 39.64 µg/g. CONCLUSIONS Increased uNGAL and uNCR may indicate early tubular damage, associated with dyslipidemia and worse diabetes control, especially in females with T2DM.
Collapse
Affiliation(s)
- Agnieszka Gala-Błądzińska
- Department of Dialysis and Nephrology, St. Queen Jadwiga Clinical District Hospital No. 2 in Rzeszów, Lwowska 60 Street, 35-301 Rzeszów, Poland
| | - Paulina Dumnicka
- Department of Medical Diagnostics, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland
| | - Beata Kuśnierz-Cabala
- Department of Diagnostics, Chair of Clinical Biochemistry, Jagiellonian University Medical College, 15A Kopernika Street, 31-501 Krakow, Poland
| | - Katarzyna Rybak
- Department of Internal Medicine, Nephrology & Endocrinology, St. Queen Jadwiga Clinical District Hospital No. 2 in Rzeszów, Lwowska 60 Street, 35-301 Rzeszów, Poland
| | - Ryszard Drożdż
- Department of Medical Diagnostics, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland
| | - Agnieszka Żyłka
- St. Queen Jadwiga Clinical District Hospital No. 2 in Rzeszów, Lwowska 60 Street, 35-301 Rzeszów, Poland
| | - Marek Kuźniewski
- Department of Nephrology, Jagiellonian University Medical College, 15 Kopernika Street, 31-501 Krakow, Poland
| |
Collapse
|
|
47
|
Chen C, Wang C, Hu C, Han Y, Zhao L, Zhu X, Xiao L, Sun L. Normoalbuminuric diabetic kidney disease. Front Med 2017; 11:310-318. [PMID: 28721497 DOI: 10.1007/s11684-017-0542-7] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 04/26/2017] [Indexed: 12/20/2022]
Abstract
Diabetic kidney disease (DKD) is one of the primary causes of end-stage renal disease (ESRD). Early diagnosis is very important in preventing the development of DKD. Urinary albumin excretion rate (UAER) and glomerular filtration rate (GFR) are widely accepted as criteria for the diagnosis and clinical grading of DKD, and microalbuminuria has been recommended as the first clinical sign of DKD. The natural history of DKD has been divided into three stages: normoalbuminuria, microalbuminuria, and macroalbuminuria. However, this clinical paradigm has been questioned recently, as studies have shown that a portion of diabetes mellitus (DM) patients with normoalbuminuria have progressive renal insufficiency, referred to as normoalbuminuric diabetic kidney disease (NADKD) or nonalbuminuric diabetic nephropathy. Epidemiologic research has demonstrated that normoalbuminuric diabetic kidney disease is common, and the large number of NADKD patients suggests that the traditional paradigm needs to be shifted. Currently, the pathogenesis of NADKD remains unclear, but many clinical studies have identified some clinical and pathological features of NADKD. In addition, the long-term outcomes of NADKD patients remain controversial. In this article, we reviewed the latest studies addressing the pathogenesis, pathology, treatment and prevention of NADKD.
Collapse
Affiliation(s)
- Chao Chen
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Chang Wang
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Chun Hu
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Yachun Han
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Li Zhao
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Xuejing Zhu
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Li Xiao
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Lin Sun
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, 410011, China.
| |
Collapse
|
|
48
|
Comparison between the effects of hydrochlorothiazide and indapamide on the kidney in hypertensive patients inadequately controlled with losartan. J Hum Hypertens 2017; 31:848-854. [PMID: 28703124 DOI: 10.1038/jhh.2017.51] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 04/25/2017] [Accepted: 06/02/2017] [Indexed: 02/05/2023]
Abstract
The aim of the study is to compare the effects of hydrochlorothiazide and indapamide on the kidney in patients with hypertension inadequately controlled with losartan. A total of 140 patients who met the criteria and inadequately controlled with losartan 50 mg per day for 2 weeks were randomized in two groups and administered either hydrochlorothiazide 12.5 mg per day (n=70) or indapamide (sustained release) 1.5 mg per day (n=70) in combination with losartan 50 mg per day. Office blood pressure (BP) were collected at baseline and upon each follow-up visit. Creatinine, urine albumin-creatinine ratio (ACR), urine neutrophil gelatinase-associated lipocalin (NGAL) and renal resistive index (RRI) were also collected at baseline and at the 24-week follow-up. None of the baseline characteristics was statistically significantly different between the two groups. After excluding those patients with office BP uncontrolled, 46 patients in the hydrochlorothiazide group (45.7% males, 58.8±10.8 years) and 44 patients in the indapamide group (38.4% males, 61.5±10.9 years) were analysed. There were insignificant changes in creatinine and significant decreases in ACR, NGAL and RRI compared to baseline levels in the two groups. The decrease in ACR (3.8 (0, 28.7) vs 4.2 (0.4, 64.8) mg g-1, P=0.485) was not significantly different between the two groups, while the decrease in NGAL (16.07±7.07 vs 28.77±7.64 ng ml-1, P<0.001) and RRI (0.04±0.02 vs 0.07±0.04, P<0.001) was more significant in the indapamide group than in the hydrochlorothiazide group. In conclusion, indapamide is superior to hydrochlorothiazide to improve renal tubular injury and renal haemodynamics in combination with losartan in hypertensive patients with controlled BP.
Collapse
|
|
49
|
Siddiqi Z, Karoli R, Kaul A, Fatima J, Varshney S, Beg MS. Evaluation of neutrophil gelatinase-associated lipocalin and cystatin C as early markers of diabetic nephropathy. Ann Afr Med 2017; 16:101-106. [PMID: 28671149 PMCID: PMC5579892 DOI: 10.4103/aam.aam_12_17] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Diabetes mellitus (DM) is a major cause of concern because of its increasing prevalence rate and related microvascular as well as macrovascular complications, including kidney disease. Microalbuminuria has been accepted as the earliest marker for diabetic nephropathy; however, a large proportion of renal impairment occurs in nonalbuminuric state. We planned to investigate the serum and urinary levels of the tubular damage markers (neutrophil gelatinase-associated lipocalin [NGAL] and cystatin C [Cys C]) in patients of type 2 diabetes to detect early kidney injury. MATERIALS AND METHODS This cross-sectional hospital-based study included 180 patients with type 2 DM according to the American Diabetes Association criteria. Serum NGAL (S.NGAL) and urine NGAL (U.NGAL) and Cys C were measured in all study participants and investigated for correlation with microalbuminuria. RESULTS Our results showed that U.NGAL and S.NGAL levels were significantly high in patients with microalbuminuria as compared to normoalbuminuric controls. Serum Cys C was also higher in microalbuminuric patients than who had normoalbuminuria. A positive correlation of urinary albumin excretion with S.NGAL and U.NGAL was noted. U.NGAL also showed positive correlation with duration of diabetes, glycated hemoglobin, and dyslipidemia. Receiver operating characteristic curve analysis showed that the area under the curve for U.NGAL and S.NGAL were 1 and 0.8, respectively, which indicates that they are sensitive markers for early renal damage. CONCLUSION Urinary biomarkers were significantly elevated in normoalbuminuric type 2 diabetic patients compared with nondiabetic controls and could be used as markers of nephropathy at a very early stage even before the development of microalbuminuria, the current gold standard for early diagnosis. Despite the promise of these new biomarkers, further large, multicenter prospective studies are still needed.
Collapse
Affiliation(s)
- Zeba Siddiqi
- Department of Medicine, Era's Lucknow Medical College, Lucknow, Uttar Pradesh, India
| | - Ritu Karoli
- Department of Medicine, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Anupama Kaul
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Jalees Fatima
- Department of Medicine, Era's Lucknow Medical College, Lucknow, Uttar Pradesh, India
| | - Shishir Varshney
- Department of Medicine, Era's Lucknow Medical College, Lucknow, Uttar Pradesh, India
| | - Mohd. Sameer Beg
- Department of Medicine, Era's Lucknow Medical College, Lucknow, Uttar Pradesh, India
| |
Collapse
|
|
50
|
Yuan Y, Sun H, Sun Z. Advanced glycation end products (AGEs) increase renal lipid accumulation: a pathogenic factor of diabetic nephropathy (DN). Lipids Health Dis 2017; 16:126. [PMID: 28659153 PMCID: PMC5490221 DOI: 10.1186/s12944-017-0522-6] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 06/16/2017] [Indexed: 12/26/2022] Open
Abstract
Background Advanced glycation end products (AGEs) are pathogenic factors of diabetic nephropathy (DN), causing renal damage in various ways. The aim of this study is to investigate the ectopic lipid accumulation caused by AGEs in human renal tubular epithelial cell line (HK-2) cells and the kidney of type 2 diabetic rats. Methods In vivo study, diabetes was induced in male Sprague–Dawley rats through intraperitoneal injection of high-fat/high-sucrose diet and low-dose streptozocin (STZ). Two weeks after STZ injection, the diabetic rats were randomly divided into two groups, namely, untreated diabetic and Aminoguanidine Hydrochloride (AG, an AGEs formation inhibitor)-treated (100 mg/Kg/day, i.g., for 8 weeks) group. In vitro study, according to the different treatments, HK-2 were divided into 6 groups. Intracellular cholesterol content was assessed by Oil Red O staining and cholesterol enzymatic assay. Expression of mRNA and protein of molecules controlling cholesterol homeostasis in the treated cells was examined by real-time quantitative PCR and western blotting, respectively. SREBP cleavage-activating protein (SCAP) translocation was detected by confocal microscopy. Results Here we found Nε-(carboxymethyl) lysine (CML, a member of the AGEs family) increased Oil Red O staining and intracellular cholesterol ester (CE) in HK-2 cells; Anti-RAGE (AGEs receptor) reduced lipid droplets and the CE level. A strong staining of Oil Red O was also found in the renal tubules of the diabetic rats, which could be alleviated by AG. CML upregulated both mRNA and protein expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR), LDL receptor (LDLr), sterol regulatory element binding protein-2 (SREBP-2) and SCAP, which were inhibited by anti-RAGE. The upregulation of these molecules in the kidney of the diabetic rats was also ameliorated by AG. Furthermore, AG reduced serum and renal CML deposition, and improved urine protein and u-NGAL in type 2 diabetic rats. Conclusions Overall, these results suggest that CML caused DN might be via disturbing the intracellular feedback regulation of cholesterol. Inhibition of CML-induced lipid accumulation might be a potential renoprotective role in the progression of DN.
Collapse
Affiliation(s)
- Yang Yuan
- Department of Endocrinology, Affiliated Zhongda Hospital of Southeast University, No. 87 DingJiaQiao Road, Nanjing, 210009, People's Republic of China
| | - Hong Sun
- Department of Endocrinology, Affiliated Zhongda Hospital of Southeast University, No. 87 DingJiaQiao Road, Nanjing, 210009, People's Republic of China.,Department of Endocrinology and Metabolism, The first Affiliated Hospital of Soochow University, 188 shizi street, suzhou, 215006, jiangsu, China
| | - Zilin Sun
- Department of Endocrinology, Affiliated Zhongda Hospital of Southeast University, No. 87 DingJiaQiao Road, Nanjing, 210009, People's Republic of China.
| |
Collapse
|