|
1
|
Swaminathan SM, Rao IR, Shenoy SV, Prabhu AR, Mohan PB, Rangaswamy D, Bhojaraja MV, Nagri SK, Nagaraju SP. Novel biomarkers for prognosticating diabetic kidney disease progression. Int Urol Nephrol 2023; 55:913-928. [PMID: 36271990 PMCID: PMC10030535 DOI: 10.1007/s11255-022-03354-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 08/21/2022] [Indexed: 10/24/2022]
Abstract
The global burden of diabetic kidney disease (DKD) is escalating, and it remains as a predominant cause of the end-stage renal disease (ESRD). DKD is associated with increased cardiovascular disease and morbidity in all types of diabetes. Prediction of progression with albuminuria and eGFR is challenging in DKD, especially in non-proteinuric DKD patients. The pathogenesis of DKD is multifactorial characterized by injury to all components of the nephron, whereas albuminuria is an indicator of only glomerular injury. The limits in the diagnostic and prognostic value of urine albumin demonstrate the need for alternative and clinically significant early biomarkers, allowing more targeted and effective diabetic treatment, to reduce the burden of DKD and ESRD. Identification of biomarkers, based on multifactorial pathogenesis of DKD can be the crucial paradigm in the treatment algorithm of DKD patients. This review focuses on the potential biomarkers linked to DKD pathogenesis, particularly with the hope of broadening the diagnostic window to identify patients with different stages of DKD progression.
Collapse
Affiliation(s)
- Shilna Muttickal Swaminathan
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Indu Ramachandra Rao
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Srinivas Vinayak Shenoy
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Attur Ravindra Prabhu
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Pooja Basthi Mohan
- Department of Gastroenterology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Dharshan Rangaswamy
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Mohan V Bhojaraja
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Shivashankara Kaniyoor Nagri
- Department of Medicine, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Shankar Prasad Nagaraju
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India.
| |
Collapse
|
|
2
|
Garbicz D, Pilžys T, Wiśniowski I, Grzesiuk M, Cylke R, Kosieradzki M, Grzesiuk E, Piwowarski J, Marcinkowski M, Lisik W. Replacing centrifugation with mixing in urine analysis enriches protein pool in the urine samples. Anal Biochem 2021; 628:114284. [PMID: 34111418 DOI: 10.1016/j.ab.2021.114284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/25/2021] [Accepted: 06/02/2021] [Indexed: 11/30/2022]
Abstract
Urine is the basic diagnostic material, easy to collect, not requiring invasive approach. During standard procedure the urine samples are centrifuged and the supernatant analysed physically, biochemically, and microscopically. The centrifugation step removes proteins including those forming aggregates especially in the state of illness and after transplantation. Here, we analysed the effect of urine centrifuging on specific protein content in urine samples obtained from cardiovascular patients (CVD) and after kidney or liver transplantation. We tested homogeneous whole urine samples, standardly centrifuge one, and the pellet after centrifuging. Protein content was examined using Western blot analysis and mass spectrometry (MS) of samples from CVD patients or the one after transplantation. The average of 21% proteins from non-centrifuged samples were found in the pellet removed after standard centrifugation. MS analysis confirmed that diagnostically important proteins were located there in. In 90% of cases whole urine samples contained more proteins than standard supernatant, among them e.g. proteins involved in immunological response like immunoglobulins and complement compounds secreted by leucocytes. Replacing centrifuging with intensive mixing of urine samples provides a method of enriching the samples with proteins removed during standard procedure, thus increasing possibility of finding new biomarkers for diseases undiagnosable with classic urine analysis.
Collapse
Affiliation(s)
- Damian Garbicz
- Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland
| | - Tomaš Pilžys
- Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland
| | - Iga Wiśniowski
- Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland
| | - Małgorzata Grzesiuk
- Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland; Department of Biochemistry and Microbiology, Institute of Biology, Warsaw University of Life Sciences (SGGW), Poland
| | - Radosław Cylke
- Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Maciej Kosieradzki
- Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Elżbieta Grzesiuk
- Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland
| | - Jan Piwowarski
- Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland
| | - Michał Marcinkowski
- Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland.
| | - Wojciech Lisik
- Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland
| |
Collapse
|
|
3
|
Uwaezuoke SN. The role of novel biomarkers in predicting diabetic nephropathy: a review. Int J Nephrol Renovasc Dis 2017; 10:221-231. [PMID: 28860837 PMCID: PMC5566367 DOI: 10.2147/ijnrd.s143186] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Diabetic nephropathy (DN) is one of the microvascular complications of the kidney arising commonly from type 1 diabetes mellitus (T1DM), and occasionally from type 2 diabetes mellitus (T2DM). Microalbuminuria serves as an early indicator of DN risk and a predictor of its progression as well as cardiovascular disease risk in both T1DM and T2DM. Although microalbuminuria remains the gold standard for early detection of DN, it is not a sufficiently accurate predictor of DN risk due to some limitations. Thus, there is a paradigm shift to novel biomarkers which would help to predict DN risk early enough and possibly prevent the occurrence of end-stage kidney disease. These new biomarkers have been broadly classified into glomerular biomarkers, tubular biomarkers, biomarkers of inflammation, biomarkers of oxidative stress, and miscellaneous biomarkers which also include podocyte biomarkers, some of which are also considered as tubular and glomerular biomarkers. Although they are potentially useful for the evaluation of DN, current data still preclude the routine clinical use of majority of them. However, their validation using high-quality and large longitudinal studies is of paramount importance, as well as the subsequent development of a biomarker panel which can reliably predict and evaluate this renal microvascular disease. This paper aims to review the predictive role of these biomarkers in the evaluation of DN.
Collapse
Affiliation(s)
- Samuel N Uwaezuoke
- Pediatric Nephrology Firm, Department of Pediatrics, University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu, Nigeria
| |
Collapse
|
|
4
|
Currie G, McKay G, Delles C. Biomarkers in diabetic nephropathy: Present and future. World J Diabetes 2014; 5:763-776. [PMID: 25512779 PMCID: PMC4265863 DOI: 10.4239/wjd.v5.i6.763] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Revised: 10/03/2014] [Accepted: 10/27/2014] [Indexed: 02/05/2023] Open
Abstract
Diabetic nephropathy (DN) is the leading cause of end stage renal disease in the Western world. Microalbuminuria (MA) is the earliest and most commonly used clinical index of DN and is independently associated with cardiovascular risk in diabetic patients. Although MA remains an essential tool for risk stratification and monitoring disease progression in DN, a number of factors have called into question its predictive power. Originally thought to be predictive of future overt DN in 80% of patients, we now know that only around 30% of microalbuminuric patients progress to overt nephropathy after 10 years of follow up. In addition, advanced structural alterations in the glomerular basement membrane may already have occurred by the time MA is clinically detectable.Evidence in recent years suggests that a significant proportion of patients with MA can revert to normoalbuminuria and the concept of nonalbuminuric DN is well-documented, reflecting the fact that patients with diabetes can demonstrate a reduction in glomerular filtration rate without progressing from normo-to MA. There is an unmet clinical need to identify biomarkers with potential for earlier diagnosis and risk stratification in DN and recent developments in this field will be the focus of this review article.
Collapse
|
|
5
|
Aoki A, Murata M, Asano T, Ikoma A, Sasaki M, Saito T, Otani T, Jinbo S, Ikeda N, Kawakami M, Ishikawa SE. Association of serum osteoprotegerin with vascular calcification in patients with type 2 diabetes. Cardiovasc Diabetol 2013; 12:11. [PMID: 23302066 PMCID: PMC3558393 DOI: 10.1186/1475-2840-12-11] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2012] [Accepted: 10/31/2012] [Indexed: 01/22/2023] Open
Abstract
Background Osteoprotegerin is a member of the tumor necrosis factor-related family and inhibits RANK stimulation of osteoclast formation as a soluble decoy receptor. The goal of this study was to determine the relationship of serum osteoprotegerin with vascular calcification in patients with type 2 diabetes. Methods The subjects were 124 patients with type 2 diabetes mellitus, including 88 males and 36 females with a mean (± SD) age of 65.6 ± 8.2 years old. Serum levels of osteoprotegerin, osteocalcin, fibroblast growth factor 23 (FGF23), 25-hydroxyvitamin D3 and adiponectin were measured by ELISA. Vascular calcification in the cervical artery was examined by ultrasound sonography. The subjects were divided into 4 quartiles depending on serum osteoprotegerin levels. Results Vascular calcification was significantly higher in the 4th quartile and significantly lower in the 1st quartile of serum osteoprotegerin levels, compared to other quartiles. There were no differences in serum osteoprotegerin and vascular calcification among patients with different stages of diabetic nephropathy, but serum FGF23 levels were elevated in those with stage 4 diabetic nephropathy. Simple regression analysis showed that serum osteoprotegerin levels had significant positive correlations with age, systolic blood pressure and serum adiponectin levels, and significant negative correlations with BMI and serum 25-hydroxyvitamin D3. Conclusions These findings suggest that elevated serum osteoprotegerin may be involved in vascular calcification independently of progression of diabetic nephropathy in patients with type 2 diabetes.
Collapse
Affiliation(s)
- Atsushi Aoki
- Department of Medicine, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
6
|
Urinary markers of glomerular injury in diabetic nephropathy. Int J Nephrol 2012; 2012:146987. [PMID: 22645683 PMCID: PMC3356892 DOI: 10.1155/2012/146987] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2012] [Accepted: 02/20/2012] [Indexed: 12/15/2022] Open
Abstract
Diabetic nephropathy, the leading cause of renal failure worldwide, affects approximately one-third of all people with diabetes. Microalbuminuria is considered the first sign and the best predictor of progression to renal failure and cardiovascular events. However, albuminuria has several limitations. Therefore, earlier, more sensitive and specific biomarkers with greater predictability are needed. The aim of this paper is to discuss the current literature on biomarkers of glomerular injury that have been implicated in diabetic kidney disease.
Collapse
|
|
7
|
Matheson A, Willcox MDP, Flanagan J, Walsh BJ. Urinary biomarkers involved in type 2 diabetes: a review. Diabetes Metab Res Rev 2010; 26:150-71. [PMID: 20222150 DOI: 10.1002/dmrr.1068] [Citation(s) in RCA: 109] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Diabetes mellitus is one of the most challenging health concerns of the 21st century. With at least 30% of the diabetic population remaining undiagnosed, effective and early diagnosis is of critical concern. Development of a diagnostic test, more convenient and reliable than those currently used, would therefore be highly beneficial. Urine as a diagnostic medium allows for non-invasive detection of biomarkers, including some associated with type 2 diabetes and its complications. This review provides a synopsis of those urinary biomarkers that potentially may provide a basis for the development of improved diagnostic tests. Three main pathways for the sourcing of potential makers are identified: kidney damage, oxidative stress and low-grade inflammation including atherosclerosis/vascular damage. This review briefly presents each pathway and some of the most relevant urinary biomarkers that may be used to monitor the development or progression of diabetes and its complications. In particular, biomarkers of renal dysfunction such as transferrin, type IV collagen and N-acetyl-beta-D-glucosaminidase might prove to be more sensitive than urinary albumin, the current gold standard, in the detection of incipient nephropathy and risk assessment of cardiovascular disease. Inflammatory markers including orosomucoid, tumour necrosis factor-alpha, transforming growth factor-beta, vascular endothelial growth factor and monocyte chemoattractant protein-1, as well as oxidative stress markers such as 8-hydroxy-2'deoxyguanosine may also be useful biomarkers for diagnosis or monitoring of diabetic complications, particularly kidney disease. However, the sensitivity of these markers compared with albumin requires further investigation.
Collapse
Affiliation(s)
- Agnès Matheson
- Minomic Pty Ltd, Frenchs Forest, New South Wales, Australia.
| | | | | | | |
Collapse
|