A Comprehensive review on Biomarkers for assessing Diabetic Kidney Disease


Pavithra D1, Praveen D1, Vijey Aanandhi M2*

1Department of Pharmacy Practice, School of Pharmaceutical Sciences, Vels University (VISTAS), Chennai,  India

2Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Vels University (VISTAS), Chennai, India

*Corresponding Author E-mail: hodpchemistry@velsuniv.ac.in




Diabetic nephropathy affects the body’s ability to grab the energy  found in food . Futher it leads to major complications, where Diabetic nephropathy is seen as one of the major , and dangerous complication of this disorder. Effective and early diagnosis is of critically helpful .Diagnostic tests must be developed which must be more convenient and reliable than those currently used, would be highly beneficial. Urine is used as  diagnostic medium  for easy and  non-invasive detection of biomarkers. This review briefly explains  few of  most relevant urinary biomarkers that are used to monitor the development and progression of Diabetes with its complications. The mortality and morbidity ratio are increasing in greater proportion, the consequences are expected to be at higher risk in near future. In particular, biomarkers of renal dysfunction such as transferrin, type IV collagen and N-acetyl-β-D-glucosamide  are  more sensitive than urinary albumin, in the detection of development nephropathy and risk  regarding of cardiovascular disease. Inflammatory mediators  including  tumour necrosis factor-α, transforming growth factor-β, vascular endothelial growth factor and Monocyte chemo-attractant protein-1(MCP-1),Oxidative Stress Markers such as 8-oxo-7,8-dihydro-2′-deoxyguanosine and Immunoglobulin M, Podocyte, Cystatin C, Ceruloplasmin are useful biomarkers for diagnosis or monitoring of diabetic complications, particularly kidney disease. Abnormal excretion of 8-dihydro-2′-deoxyguanosine results in the indication of increased systemic level of DNA damage in non –insulin dependent diabetic patients. A comprehensive literature search has been carried out in PubMed, Google scholar and articles pertaining to urinary biomarkers assessing diabetic kidney disease were selected for review.


KEYWORDS: Diabetes, diabetic kidney disease, urinary bio markers, nephropathy, dialysis.




Biomarkers are molecules which occur naturally in a living being, through which a pathological or disease conditions could be monitored and are proved. Urinary biomarkers are the molecules that plays a major role in detection of disorders of kidney  in all patients across the world.


Diabetes mellitus (DM) has emerged collectively of the main international health issues and a significant burden for all attention systems .Current predictions estimate that by 2025 over 480 million folks globally can have associate in Nursing complications altered glucose tolerance and 380 million can have developed type2 polygenic disorder . Among diabetic complications diabetic illness, renal disorder, nephrosis, uropathy (DN) has already become the leading explanation for end-stage kidney disease worldwide. Moreover, progressive decline of excretory organ perform is related to a rise in all-cause mortality and severe in patients with polygenic disorder . Use of water possesses many benefits for brand new biomarker discovery. The primary is that water is also obtained non-invasively, and in larger volumes compared with plasma. The larger volumes of water make amends for the lower concentration of proteins and peptides in water compared with plasma [9]. Secondly, the urinary protein may be a filtrate of the body fluid proteins, however additionally contains proteins arising from the shed cells of the excretory organ and system tract, from hollow secretion and secreted exosomes [10]. Numerous techniques have been used up to now so as to mirror a healthy urinary organ physiology [11] which will be distinguished from pathophysiological state caused by outlined un-wellness, victimization differentially expressed proteins or peptides . However, application of antibody techniques, at the side of Associate in Nursing understanding of the role of cytokiness, growth factors, scleraprotein matrix and macromolecule mediators have chop-chop distended the sector of latest candidates for urinary biomarkers[12].


Immunoglobulin G :            

Immunoglobulin could be a super molecule ,which is synthesized by plasma cells. The mass of immune gamma globulin is 150kDa, its quite more than simple protein. Urinary IgG excretion correlates with the rise of capillary vessel diffusion lesions. Excretion of IgG is higher in Diabetic patients compared to healthy volunteers and its excretion in diabetic patients with normoalbuminuria predicts the event of microalbuminuria[13]. IgG4 excretion is elevated in patients with micro-albuminuria, wherever the excretion of IgG and IgG4 square measure redoubled in patients with macro-albuminuria compared with normoalbuminuric patients. analysis found that urinary concentration of IgG2 in patients with normoalbuminuria is considerably higher in comparison to healthy patients and any elevation of IgG2, IgG4 and immune globulin is pronounced in ptients with microalbuminuria. Excretion of IgG2 is that the highest among all immunoglobulins. several analysis have well-tried that IgG is that the best marker fpr predicting onset of kidney disease.[14]


Cystatin c

Cystatin C could be a amino acid antiviral that is continually made by all nucleate cells. Cystatin C is recommended as a marker of capillary vessel and cannulardysfuntion for early identification of Diabetic uropathy. Levels of Cystatin C in water were higher in microalbuminuria cluster compared to normoalbuminuria, that is absolutely related to with water ACR in polygenic disorder and pre-diabetes[15]. In early stage he diagnose is that Cystatin C is raised in higher levels in diabetic and pre-diabetic uropathy , that indicates that cystatin C plays a serious role in development of uropathy in pre-diabetes. One study showed that cystatin C levels of water may be a marker of early nephritic injury in patients with sort two polygenic disorder milletus. The Zucker diabetic fatty (zdc) rats indicated that urinary cystatin C was multiplied in ZDF rats wherever nephritic injury isn't discovered by histopathological assessment and is levels in water multiplied with the progression of nephritic injury, demonstrating the first detection of diabetic uropathy[16]. Urinary cystatin C levels were known as Associate in Nursing freelance issue related to calculable capillary vessel filtration rate (eGFR)<60ml/min/1.72m2 in patients with normoalbuminuria.


Transferrin :

Transferrin, a protein, is incredibly almost like simple protein in weight. it's additional promptly filtered through capillary vessel barrier when put next to simple protein for being less anionic in nature . Urinary beta globulin is taken into account to be one among the additional sensitive marker of capillary vessel injury in diabetic patients supported theory ,analysis and experimental results[17]. Compared to healthy controls, beta globulin excretion is higher in diabetic patients, even before they develop microalbuminuri . As a result of diabetic patients are additional doubtless to own transferrinuria than proteinuria, and since the albumin/ transferrin magnitude relation was considerably smaller in normoalbuminuric and microalbuminuric compared to macroalbuminuric patients, urinary beta globulin is taken into account to be a additional sensitive marker of capillary vessel injury in diabetic patients[18]. Urinary beta globulin excretion shows an honest linear relationship with urinary simple protein excretion in diabetic patients, and inflated urinary beta globulin excretion ends up in the development of microalbuminuria in kind two diabetic patients with normoalbuminuria. A general review, together with thirteen studies, indicated that urinary beta globulin excretion was an honest marker for predicting onset of renal disorder . However, urinary beta globulin excretion isn't specific for Diabetic uropathy as a result of its elevation is found in primary nephritis .[19]


Podocytes :

Podocytes area unit key structural parts of the capillary filtration barrier.it's accepted that podocytes’ injuries play a significant role within the progression of DKD . observance excretion podocytes and podocyte-specific proteins will reveal fascinating urinary markers for the first designation of DKD . Podocytes in excretion is found in diabetic patients with micro- and macroalbuminuria[20]. Another study indicated that nephrinuria is found to be gift in 100 percent of diabetic patients with micro- and macroalbuminuria, additionally as fifty four of patients with normoalbuminuria, nephrinuria conjointly related to completely with symptom, that recommended that nephrinuria can be a biomarker of early DKD . Urinary podocalyxinis higher in fifty three.8% patients at the normoalbuminuric stage, 64.7% at the microalbuminuric stage and sixty six.7% at the macroalbu-minuric stage, that indicated that urinary podocalyxin can be a helpful biomarker for police work early podocyte injury in diabetic patients[21] . Another study found that urinary ribonucleic acid profiles of synaptopodin, podocalyxin, α-actin-4, and podocin were enhanced with the progression of DKD, that recommended that quantification of podocyte-associated molecules in excretion are a helpful biomarker of DKD .


Immunoglobulin M :

Immunoglobulin M (IgM), secreted by plasma cells, is that the largest protein within the human current system .as a result of its giant molecular radius (120 ˚A), the looks of immune gamma globulin in pee indicates that an oversized, nonselective pore exists within the capillary vessel capillary wall that implicates a severe size-selectivity defect[22] . inflated urinary immune gamma globulin excretion in patients with non-diabetic capillary vessel sickness is related to high degree of fibrosis and international glomerulo-sclerosis. inflated urinary immune gamma globulin excretion and IgG2/IgG4 magnitude relation in macroalbuminuric sort two diabetic patients compared to sort one diabetic patients suggests that the albuminuria in sort two polygenic disorder is as a result of size-selectivity defects, whereas charge property defects account for the albuminuria in sort one polygenic disorder .One study verified that pee excretion of immune gamma globulin was considerably higher in sort two DM compared to sort one DM, and patients with sort two DM with nephron-sclerosis had considerably higher pee excretion of immune gamma globulin compared to the age-matched healthy subjects[23] . An-other study found urinary organ survival of sort two diabetic patients was reciprocally related to pee immune gamma globulin excretion, that indicated that higher urinary immune gamma globulin excretion may be a higher predictor of decline in excretory organ operate than symptom in sort two DM[24]. However, urinary immune gama globulin excretion isn't been considered associate early marker of DKD, since its excretion in pee is related to severe in-jury of the capillary vessel capillary wall, whereas it's conjointly a promising marker which can predict the ultimate would like for urinary organ replacement medical aid .


Type IV Collagen

Type IV albuminoid is that the main constituent of each capillary and hollow basement membranes additionally because the mesangial matrix . Elevated aldohexose levels stimulate kind IV albuminoid synthesis that cut back its breakdown by manufacturing advanced glycosylation of proteins. As a consequence, inflated deposition of kind IV albuminoid has been noted within the capillary mesangial matrix of diabetic kidneys with diuse glomerulosclerosis .to boot, urinary kind IV albuminoid excretion has been related to mesangial enlargement and tubulointerstitial and capillary injury[25] . The urinary excretion of kind IV albuminoid correlates with the urinary excretion of different parts of the capillary basement membrane (GBM), as well as laminin a markers of hollow harm, like N-acetyl- beta-D-glucosaminidase (NAG) and alfa one microglobulin . Higher urinary concentrations of kind IV albuminoid is found in diabetics compared to healthy volunteers , even in normoalbuminuric subjects , suggesting that kind IV albuminoid can be Associate in Nursing early predictor of diabetic kidney disease. A study showed that the urinary excretion of kind IV albuminoid in diabetic patients inflated bit by bit as urinary organ diseases . Multiple studies have shown that urinary excretion of kind IV albuminoid in kind a pair of diabetics relates to UAE . In distinction, patients with nondiabetic chronic nephritis don't show this relationship[26] . though kind IV albuminoid excretion is higher in nondia- betic chronic nephropathy compared to healthy controls, kind a pair of diabetic patients with proof of nephropathy have a significantly higher kind IV collagen/albumin quantitative relation compared to patients with nondiabetic kidney disease.[27]


Monocyte chemoattractant protein-1(MCP-1)

Chemokines are involved within the pathological process of DKD, therefore, measure of protein in piss may help to diagnosing DKD. Urinary MCP-1/creatinine in patients with macroalbuminuria was considerably higher than patients with normoalbuminuria and microalbumi-nuria, and urinary MCP-1 related with the speed of eGFRdecline[28] . Another study found that urinary MCP-1 was significantly higher in patients presenting doubling of liquid body substance creatinine or death, and its levels were absolutely associated with the chance of doubling of liquid body substance creatinine or death once Cox regression; what’s a lot of, urinary MCP-1 remained as significant freelance predictors of doubling of liquid body substance creatinine or death of these information advised that urinary MCP-1 could be a prognostic marker for progression of diabetic nephrosis, whereas a lot of studies area unit required to investigate whether or not urinary MCP-1 features a role within the setting of normoalbuminuria and microalbuminuria in DKD[29].


8-oxo-7, 8-dihydro-2'-deoxyguanosine

It is documented that augmented aerophilic stress in diabetes contributes to the progression of polygenic disorder and its complications. 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxodG), a marker of living thing aerophilicstress,can be assessed non-invasively in piss. Patients with higher excretion of 8-oxodG in piss compared with those patients with moderate or lower excretion of 8-oxodG showed vital progression of diabetic nephropathy, that indicates that 8-oxodG in piss is helpful clinical marker for sleuthing uropathy.[30]



Ceruloplamin could be a ferroxidase protein that in humans is encoded by the CP sequence with a mass of 151kDa, is that the major copper-carrying supermolecule within the blood. it's additional charged compared to albumen and is additional dicult to urge filtered by the capillary. Urinary ceruloplasmin excretion is higher in sort a pair of diabetic patients compared to controls,[31] even within the normoalbuminuric part . It correlates with albumen excretion rate and predicts the event of microalbuminuria in normoalbuminuricpatients . Glycemic management and low-dose losartan revert the increased urinary ceruloplasmin excretion in normoalbuminuric patients. diurnal changes within the beat pressure significantly correlate with urinary ceruloplasmin excretion, however not with UAE . The ceruloplasmin/creatinine magnitude relation is higher in diabetic renal disorder compared to non-diabetic renal disorder patients .it's been reportable that excreta ceruloplas- min/creatinine magnitude relation includes a sensitivity of 90-91%, specificity of 61–66% and seventy fifth concordance, in diagnosis diabetic renal disorder . Ceruloplasmin could be a promising marker of diabetic renal disorder.[32]


Use of proteomic method for identification of urinary markers :

Proteomics could be a methodology geared toward discovering and identifying the whole set of proteins gift in a very given biological sample at a given time, employing a variant of 2 -dimensional gel natural process, they found excreta samples from kind two DM patients with microalbuminuria showed four main proteins incidental to with albumin: alpha-2 glycoprotein, alpha-1 acid compound protein, alpha-1 microglobulin and immunoglobulin G  found a 12-peak proteomic signature within the baseline excreta of kind two DM patients who subsequently developed DKD [33]. The reported accuracy (71% sensitivity and seventy six specificity) is encouraging in view of a future assay. Zürbig used capillary electrophoresis-coupled mass spectrum analysis to profile the low-molecular weight protein in excreta samples from a longitudinal cohort of kind one and a couple of diabetic patients. They found scleroprotein fragments were distinguished biomarkers before onset of macroalbuminuria, and there's a decrease in collagen fragments before albumen excretion starts to increase . Urinary genetic science allows noninvasive assessment of DN risk at AN early stage, whereas a lot of studies are required to research the role of urinary genetic science in diabetic nephrosis.



The current gold customary for detection and prediction of diabetic nephropathy and vas risk is albuminuria; but, it's many limitations. manufacturers that supply higher sensitivity and specificity for earlier detection of diabetic nephropathy and additional correct prediction of the progression to ESRD area unit required. we have a {tendency to|we tend to} reviewed ten biomarkers of capillary injury concerned in diabetic nephropathy Considering the results of the  studies evaluating the biomarkers reviewed here, it's appealing to start out utilizing them in clinical observe. However, the bulk of publications reviewed area unit little cross-sectional studies, and there area unit International Journal of medical specialty seven only some of longitudinal studies. Moreover, biomarkers solely have clinical value if the results area unit duplicatable, and none of the biomarkers reviewed here are studied in additional than two longitudinal trials. Hence, their clinical applicability must be confirmed in high-quality validation studies.



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Received on 16.08.2016          Modified on 17.10.2016

Accepted on 01.01.2017        © RJPT All right reserved

Research J. Pharm. and Tech. 2017; 10(9): 3242-3246.

DOI: 10.5958/0974-360X.2017.00575.3