Abstract

Microalbuminuria predicts the onset and progression of diabetic nephropathy. Despite its use as the conventional glomerular biomarker for early detection of diabetic kidney disease, its predictive accuracy is not optimal because of some disadvantages. Since tubular injury occurs early in the course of diabetic nephropathy, tubular biomarkers should be more sensitive than microalbuminuria as early predictors of the disease. The present review aims to discuss the tubular biomarkers currently used as diagnostic tools in diabetic nephropathy. Using a combination of terms such as ‘diabetic nephropathy and pathogenesis’, ‘biomarkers and diabetic nephropathy’, ‘tubular biomarkers and diabetic nephropathy’ and ‘diabetic nephropathy risk and predictors’, the Pubmed data base was searched for articles which met the objective of the review.

Tubular biomarkers reported as predictors of diabetic kidney disease consist of cystatin C, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, alpha 1-microglobulin, N-acetylβ-D-glucosaminidase, and liver-type fatty-acid binding protein. Several studies show that these markers are not only more sensitive, but are much earlier predictors of diabetic nephropathy than microalbuminuria. Although their advantages over microalbuminuria are evidence-based, majority still need to be validated for diagnostic purposes.

Keywords

Tubular Biomarkers; Diabetes Mellitus; Diabetic Nephropathy; Microalbuminuria; Diagnosis

Introduction

Insulin-dependent diabetes mellitus (IDDM) occurs more frequently than non-insulin-dependent diabetes mellitus (NIDDM) in childhood: the latter being the predominant form of the disease in adulthood [1]. However, there has been a global rise in reported cases of NIDDM among children as well [2]. One of the end-organ micro vascular complications of both types of diabetes is diabetic nephropathy: which is characterized by three main features namely, macro albuminuria observed twice at an interval of three to six months, raised blood pressure and an on-going drop in the glomerular filtration rate (GFR) [3]. It takes about ten to twenty years for the disease to fully develop from microalbuminuria and terminate in stage 5 chronic kidney disease (CKD) [1]. This probably explains why overt diabetic nephropathy is rare in children [4], even though its occurrence among them has also been reported in medical literature [5-7].

In IDDM and NIDDM, microalbuminuria potentially predicts the development of diabetic nephropathy, as well as future risk of cardiovascular disease [8]. Despite its use as the conventional biomarker for early prediction of diabetic kidney disease, its predictive accuracy is not optimal because of some disadvantages. Firstly, not all macroalbuminuric diabetic patients will end up with end-stage renal disease [9]. Besides, 30% of them may actually present with normoalbuminuria (urine albumin excretion of < 30 mg/day) [10], while several glomerular and tubular biomarkers do appear in the urine before microalbuminuria: which means that the latter only occurs when there is significant renal injury [11].Furthermore, recent evidence shows that many macroalbuminuric diabetic patients can become normoalbuminuric even with a decline in GFR (the concept of ‘non-albuminuric’ diabetic nephropathy) [12].

Consequently, glomerular or tubular biomarkers are presently accepted as dependable diagnostic tools for diabetic nephropathy. Given that tubular damage occurs early in the trajectory of diabetic nephropathy, tubular biomarkers should be more sensitive than glomerular biomarkers as early predictors of disease [13]. Although most of these biomarkers still need to be validated for routine clinical use, reports however indicate their usefulness in disease evaluation [14,15].

The present review aims to discuss the tubular biomarkers currently used as diagnostic tools in diabetic nephropathy. Using a combination of terms such as ‘diabetic nephropathy and pathogenesis’, ‘biomarkers and diabetic nephropathy’, ‘tubular biomarkers’ and ‘diabetic nephropathy’ and ‘diabetic nephropathy risk and predictors’, the Pubmed data base was searched for articles which met the objective of the review.

Diabetic nephropathy: Pathophysiologic pathways

Several pathways are activated in IDDM and NIDDM. Each of these pathways singly or holistically regulates the evolution of diabetic nephropathy [16]. In a sequence of complex molecular events, these pathways interact resulting in the main components of diabetic nephropathy, namely fibrotic changes in the kidney; mesangial and glomerular enlargement; oxidative stress; as well as inflammation of the tubules [13]. It is believed that the disease actually occurs following a synergistic influence between metabolic and hemodynamic factors, which activate mutual pathways leading to kidney injury [17]. During the course of diabetic nephropathy, hyperglycaemia-induced functional impairment of the kidneys and remodeling of the renal architecture, are related to several evolving intracellular reactions and activated signaling pathways [18]. Three main pathways characterized by derangement of intracellular metabolism include the activated polyol and protein kinase C pathways; the elaboration of advanced glycation end-products (AGEs), which represents a glomerular biomarker; and hypertension within the glomeruli triggered by hyper filtration [19]. At the opposing end of these pathways, hyperglycaemia appears to be the key propelling factor behind the evolution of diabetic nephropathy to end-stage renal disease, whereas in tandem with the pathways, micro inflammation and mesangial enlargement constitute the trajectories for development of diabetic kidney disease [19]. Thus, urine tubular markerto-creatinine ratio and inflammatory marker-to-creatinine ratio have been shown as early indicators of kidney damage seen in diabetic nephropathy, despite the observation of normoalbuminuria [20].

Biomarkers of diabetic nephropathy: classification

Several markers of diabetic nephropathy have been identified, leading to different methods of classification [13]. They have been categorized based on their source and the major pathogenic events which result in nephropathy: markers of kidney dysfunction, markers of inflammation, and markers of oxidative stress [11]. Other authors have suggested a classification which placed the biomarkers into three major classes: glomerular markers, tubular markers, and miscellaneous proteins [21]. Nevertheless, there is an overlap in these proposed classifications as different categories of biomarkers are interchangeably represented; for instance, some inflammatory markers can be represented as glomerular markers as well.

Tubular biomarkers: predictive role in diabetic nephropathy

As previously mentioned, tubular biomarkers can serve as much earlier predictors of diabetic nephropathy than glomerular biomarkers because tubulo-interstitial lesions are associated with and may actually precede glomerular injury in the disease [22]. Several studies have provided evidence on the predictive role of this category of biomarkers (Table 1).

Tubular biomarkers	Study (authors, year)	Predicts diabetic nephropathy	Precedes microalbuminuria	Insulin-dependent diabetes mellitus	Non-insulin-dependent diabetes mellitus
NGAL	-Yürük Yıldırım Z, et al, 2015 Lacquaniti A, et al, 2013 Zeng XF, et al, 2017	Yes Yes Yes	Yes Yes Yes	+ +	+
A1M	Shore N, et al, 2010 Hong CY, et al, 2003	Yes Yes	Yes Yes		+ +
KIM-1	- Petrica L, et al, 2014	Yes	Yes		+
NAG	Patel DN & Kalia K, 2015 Assal HS, et al, 2013 Ambade V, et al, 2006† Jones AP, et al, 1995	Yes Yes No Yes	Yes Yes No Yes	+	+ +
Cystatin C	- Jeon YK, et al, 2011	Yes	Yes		+
L-FABP	Nielsen SE, et al, 2010 Kamijo-Ikemori A, et al, 2011	Yes Yes	Yes Yes	+	+

Table 1: Tubular biomarkers as predictors of diabetic nephropathy: some study findings
NGAL=Neutrophil gelatinase-associated lipocalin, A1M= Alpha 1-microglobulin, KIM-1= Kidney injury molecule-1, NAG= N-acetyl-𝛽-D
glucosaminidase, L-FABP= Liver-type fatty acid binding protein
† The authors did not specify the type of diabetes mellitus in their study subjects

Neutrophil gelatinase-associated lipocalin (NGAL) or lipocalin-2

It is a universal iron-transporter macromolecule, expressed in the epithelium of the renal tubule which appears in the blood and urine following tubular injury. This biomarker was ab-initio identified as a 25 kDa protein in neutrophilic granules which is released into the circulation in response to bacterial infection; in innate immunity, it is involved in iron sequestration which ultimately interferes with bacterial growth [23]. In normoalbuminuric diabetic patients as well as in the assessment of tubular lesions in diabetic nephropathy, elevated urine NGAL has been demonstrated [24], and has also been shown to precede microalbuminuria in type 1 diabetes mellitus [25,26]. Furthermore, high values of this biomarker were observed in normoalbuminuric NIDDM patients; the values increased progressively in those patients who had microalbuminuria and macro albuminuria [27]. Another report has also confirmed that urine NGAL predicted the evolution of diabetic nephropathy in NIDDM patients following a prospective study [28]. In fact, a recent consecutive cohort study showed that urine NGAL and cystatin C were elevated prior to microalbuminuria in NIDDM patients [29]. Other group of investigators reported that pediatric patients with IDDM, including subjects with normoalbuminuria, showed elevated urine NGAL: a finding which is thought to confirm a pre-existent tubular damage before overt diabetic nephropathy [30]. Thus, some of these reports not only underscore the predictive accuracy of this biomarker but also its advantage over microalbuminuria as a diagnostic tool.

Alpha 1-microglobulin (A1M)

This glycoprotein biomarker usually undergoes glomerular filtration and proximal tubular reabsorption; thus, tubular lesions interfere with its re-absorptive process leading to its excretion in the urine [13]. First, some researchers have reported that urine alpha 1-microglobulin could be an alternative biomarker for early diagnosis of tubulopathy in diabetic nephropathy [31]. The finding was based on a one-year observational study of adult patients with NIDDM and their normal controls. A relatively inexpensive electrophoretic technique was used to detect this biomarker in the urine samples of the study subjects, making the authors to conclude that alpha 1-microglobulin is a cheap diagnostic tool for diabetic nephropathy [31].

In another report, the authors observed that normoalbuminuric NIDDM patients had elevated urine alpha 1-microglobulin, which again underscores the fact that tubulopathy occurs before glomerulopathy in diabetic nephropathy [32]. It was thus concluded that this tubular biomarker is useful for the early diagnosis of diabetic kidney disease [32].

Kidney injury molecule 1 (KIM-1)

This transmembrane tubular glycoprotein, up-regulated about 50-100 fold in the kidney, is excreted in the urine after an injury to the proximal tubules [33]. It is well recognized as a sensitive biomarker for acute kidney injury (AKI) with a good predictive value [34,35]. Besides, a drug-safety study shows that KIM-1 significantly performed better than serum urea and creatinine in predicting tubular damage in murine models [36]. Interestingly, elevated urine levels of this biomarker are seen in normoalbuminuric a NIDDM patient, which again suggests that a tubulopathy does occur early in diabetic nephropathy [37]. In other words, diabetic patients with microalbuminuria present with more elevated urine KIM-1 levels than their normoalbuminuric counterparts [37].

N-acetyl-β-D-glucosaminidase (NAG)

NAG is an enzyme derived from the lysosomes and found in several human cells including the renal tubules [38]. The large size (>130 kDa) of this biomarker makes glomerular filtration difficult so that its presence in urine is presumed to be of tubular origin. Thus, elevated urine NAG indicates tubular injury, but may also result from increased lysosomal activity without cell injury [33]. Regarding its sensitivity as an early predictor of diabetic nephropathy, there appears to be no unanimity in some study findings [39-42].

Some investigators report that NAG could represent an early and the most sensitive marker of tubulopathy as seen in NIDDM patients [39,40]. Conversely, another study could not demonstrate its utility as an early predictive tool for diabetic nephropathy [41]. However, increased urine NAG has also been reported as a sensitive biomarker which can precede microalbuminuria in IDDM patients [42].

Liver-type fatty-acid binding protein (L-FABP)

L-FABP is primarily seen in the liver where it plays a major part in the linkage, transport and metabolism of long-chain fatty acids; its altered expression has been linked to obesity and insulin resistance [43]. Elevated urine-FABP levels occur in normoalbuminuric IDDM patients, and can predict the onset of microalbuminuria, and progression of microalbuminuria towards macro albuminuria [44]. Furthermore, other authors have observed that normoalbuminuric NIDDM subjects also had elevated urine levels of this biomarker, which was seen as a reliable and early predictor of the onset, and evolution of diabetic nephropathy [45,46].

Cystatin C

This biomarker is a low-molecular-weight protein synthesized by nucleated cells in the body at a constant rate, with glomerular filtration and complete tubular reabsorption and catabolism [47]. Thus, elevated urine cystatin C levels are seen in tubulopathies because of impaired tubular reabsorption: making it a non-specific biomarker of AKI [48].

However, in diabetes and diabetic kidney disease, its excretion (which suggests tubular injury) is increased early in conjunction with NGAL [49]. More importantly, some authors have reported its ability to predict the progression of diabetic nephropathy [50], while its serum and urine levels are also reported as dependable markers for evaluating early nephropathy in NIDDM [51].

Conclusion

Tubular biomarkers generally represent earlier predictors of diabetic nephropathy than microalbuminuria in both IDDM and NIDDM. This is because tubular injury occurs early in diabetic kidney disease. Although their advantages over microalbuminuria are essentially evidence-based, majority still need to be validated for clinical use in disease evaluation.

References

1. Koulouridis E (2001) Diabetic nephropathy in children and adolescents and its consequences in adults. J Pediatr Endocrinol Metab 14: 1367-1377. [Ref.]
2. Jerums G, MacIsaac RJ (2002) Treatment of microalbuminuria in patients with type 2 diabetes mellitus. Treat Endocrinol 1: 163- 173. [Ref.]
3. Deferrari G, Repetto M, Calvi C, Ciabattoni M, Rossi C, et al. (1998) Diabetic nephropathy: from micro- to microalbuminuria. Nephrol Dial Transplant 13: 11-15. [Ref.]
4. Danne T, Kordonouri O, Hövener G, Weber B (1977) Diabetic angiopathy in children. Diabet Med 14: 1012-1015. [Ref.]
5. Maghribi H, Abu-Odeh A (2006) Early diabetic nephropathy in a pediatric patient. JRMS 13: 51-53.
6. Francis J, Rose SJ, Raafat F, Milford DV (1997) Early onset of diabetic nephropathy. Arch Dis Child 77: 524-525. [Ref.]
7. DeClue TJ, Campos A (1994) Diabetic nephropathy in a prepubertal diabetic female. J Pediatr Endocrinol 7: 43-46. [Ref.]
8. Uwaezuoke SN (2015) Prevention of diabetic nephropathy in children and adolescents: how effective are the current strategies? Int J Diabetol Vasc Dis Res S5: 1-5. [Ref.]
9. Remuzzi G, Schieppati A, Ruggenenti P (2002) Nephropathy in patients with type 2 diabetes. N Engl J Med 346: 1145-1151. [Ref.]
10. An JH, Cho YM, Yu HG, Jang HC, Park KS, et al. (2009) The clinical characteristics of normoalbuminuric renal insufficiency in Korean type 2 diabetic patients: a possible early stage renal complication. J Korean Med Sci 24: S75-81. [Ref.]
11. Matheson A, Willcox MDP, Flanagan J, Walsh BJ (2010) Urinary biomarkers involved in type 2 diabetes: a review. Diabetes Metab Res Rev 26: 150-171. [Ref.]
12. Currie G, McKay G, Delles C (2014) Biomarkers in diabetic nephropathy: present and future. World J Diabetes 5: 763-776. [Ref.]
13. Uwaezuoke SN (2017) The role of novel biomarkers in predicting diabetic nephropathy: a review. Int J Nephrol Renovasc Dis 10: 221-223. [Ref.]
14. Moresco RN, Sangoi MB, De Carvalho JA, Tatsch E, Bochi GV (2013) Diabetic nephropathy: traditional to proteomic markers. Clin Chim Acta 421: 17-30.
15. Gluhovschi C, Gluhovschi G, Petrica L, Timar R, Velciov S, et al. (2016) Urinary biomarkers in the assessment of early diabetic nephropathy. J Diabetes Res. [Ref.]
16. Arora MK, Singh UK (2013) Molecular mechanisms in the pathogenesis of diabetic nephropathy: an update. Vascul Pharmacol 58: 259-271. [Ref.]
17. Yamagishi S,Fukami K, Ueda S, Okuda S (2007) Molecular mechanisms of diabetic nephropathy and its therapeutic intervention. Curr Drug Targets 8: 952-959. [Ref.]
18. Tavridou A, Georgoulidou A, Roumeliotis A, Roumeliotis S, Giannakopoulou E, et al. (2015) Association of plasma adiponectin and oxidized low-density lipoprotein with carotid intima-media thickness in diabetic nephropathy. J Diabetes Res 1-8. [Ref.]
19. Wada J, Makino H (2013) Inflammation and the pathogenesis of diabetic nephropathy. Clin Sci (Lond) 124: 139-152. [Ref.]
20. Suh JS, Kim SH, Cho KS, Jung IA, Cho WK, et al. (2016) Urinary markers in the early stage of nephropathy in patients with childhood-onset type 1 diabetes. Pediatr Nephrol 31: 623-631. [Ref.]
21. Hong CY, Chia KS (1998) Markers of diabetic nephropathy. J Diabetes Complications 12: 43-60. [Ref.]
22. Mise K, Hoshino J, Ueno T, Hazue R, Hasegawa J, et al. (2016) Prognostic value of tubulointerstitial lesions, urinary N-acetylβ-d-glucosaminidase, and urinary β2-microglobulin in patients with type 2 diabetes and biopsy-proven diabetic nephropathy. Clin J Am Soc Nephrol 11: 593-601. [Ref.]
23. Yang J, Goetz D, Li JY, Wang W, Mori K, et al. (2002) An iron delivery pathway mediated by a lipocalin. Mol Cell 10: 1045- 1056. [Ref.]
24. Bolignano D, Lacquaniti A, Coppolino G, Donato V, Fazio MR, et al. (2009) Neutrophil gelatinase-associated lipocalin as an early biomarker of nephropathy in diabetic patients. Kidney Blood Press Res 32: 91-98. [Ref.]
25. Yürük Yıldırım Z, Nayır A, Yılmaz A, Gedikbaşı A, Bundak R (2015) Neutrophil gelatinase-associated lipocalin as an early sign of diabetic kidney injury in children. J Clin Res Pediatr Endocrinol 7: 274-279. [Ref.]
26. Lacquaniti A, Donato V, Pintaudi, Di Vieste G, Chirico V, et al. (2013) “Normoalbuminuric” diabetic nephropathy: tubular damage and NGAL. Acta Diabetol 50: 935-942. [Ref.]
27. de Carvalho JM, Tatsch E, Hausen BS, Bollick YS, Moretto MB, et al. (2016) Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin as indicators of tubular damage in normoalbuminuric patients with type 2 diabetes. Clin Biochem 49: 232-236. [Ref.]
28. Yang YH, He XJ, Chen SR, Wang L, Li EM, et al. (2009) Changes of serum and urine neutrophil gelatinase-associated lipocalin in type-2 diabetic patients with nephropathy: one year observational follow-up study. Endocrine 36: 45-51.
29. Zeng XF, Lu DX, Li JM, Tan Y, Li Z, et al. (2017) Performance of urinary neutrophil gelatinase-associated lipocalin, clusterin, and cystatin C in predicting diabetic kidney disease and diabetic microalbuminuria: a consecutive cohort study. BMC Nephrol 18: 233. [Ref.]
30. Hafez MH, El-Mougy FA, Makar SH, Abd El Shaheed S (2015) Detection of an earlier tubulopathy in diabetic nephropathy among children with normoalbuminuria. Iran J Kidney Dis 9: 126-131. [Ref.]
31. Shore N, Khurshid R, Saleem M (2010) Alpha-1-microglobulin: a marker for early detection of tubular disorders in diabetic nephropathy. J Ayub Med Coll Abbottabad 22: 53-55. [Ref.]
32. Hong CY, Hughes K, Chia KS, Ng V, Ling SL (2003) Urinary alpha1- microglobulin as a marker of nephropathy in type 2 diabetic Asian subjects in Singapore. Diabetes Care 26: 338-342. [Ref.]
33. Uwaezuoke SN (2016) Acute kidney injury in children: enhancing diagnosis with novel biomarkers. J Acute Dis 5: 267-270. [Ref.]
34. Bonventre JV (2014) Kidney injury molecule-1: a translational journey. Trans Am Clin Climatol Assoc 125: 293-299. [Ref.]
35. Shao X, Tian L, Xu W, Zhang Z, Wang C, et al. (2014) Diagnostic value of urinary kidney injury molecule 1 for acute kidney injury: a meta-analysis. PLoS One 9: e84131. [Ref.]
36. Bonventre JV,Vaidya VS, Schmouder R, Feig P, Dieterle F (2010) Next-generation biomarkers for detecting kidney toxicity. Nat Biotechnol 28: 436-440. [Ref.]
37. Petrica L, Vlad A , Gluhovschi G, Gadalean F, Dumitrascu V, et al. (2014) Proximal tubule dysfunction is associated with podocyte damage biomarkers nephrin and vascular endothelial growth factor in type 2 diabetes mellitus patients: a cross-sectional study. PLoS One 9: e112538. [Ref.]
38. Mårtensson J, Martling CR, Bell M (2012) Novel biomarkers of acute kidney injury and failure: clinical applicability. Br J Anaesth 109: 843-850. [Ref.]
39. Patel DN, Kalia K (2015) Efficacy of urinary N-acetyl-β-D glucosaminidase to evaluate early renal tubular damage as a consequence of type 2 diabetes mellitus: a cross-sectional study. Int J Diabetes Dev Ctries 35: S449-S457.
40. Assal HS, Tawfeek S, Rasheed EA, El-Lebedy D, Thabet EH (2013) Serum cystatin C and tubular urinary enzymes as biomarkers: a renal dysfunction in type 2 diabetes mellitus. Clin Med Insights Endocrinol Diabetes 6: 7-13. [Ref.]
41. Ambade V, Sing P, Somani BL, Basanna D (2006) Urinary N-acetyl beta glucosaminidase and gamma glutamyl transferase as early markers of diabetic nephropathy. Indian J Clin Biochem 21: 142-148. [Ref.]
42. Jones AP, Lock S, Griffiths KD (1995) Urinary N-acetyl-β- glucosaminidase activity in type 1 diabetes mellitus. Ann Clin Biochem 32: 58-62. [Ref.]
43. Shi J, Zhang Y , Gu W, Cui B, Xu M, et al. (2012) Serum liver fatty acid binding protein levels correlate positively with obesity and insulin resistance in Chinese young adults. PLOS One 7: e48777. [Ref.]
44. Nielsen SE, Sugaya T, Hovind P, Baba T, Parving H, et al. (2010) Urinary liver-type fatty acid-binding protein predicts progression to nephropathy in type 1 diabetic patients. Diabetes Care 33: 1320-1324. [Ref.]
45. Kamijo-Ikemori A, Sugaya T, Yasuda T, Kawata T, Ota A, et al. (2011) Clinical significance of urinary liver-type fatty acid-binding protein in diabetic nephropathy of type 2 diabetic patients. Diabetes Care 34: 691-696. [Ref.]
46. Panduru NM, Forsblom C, Saraheimo M, Thorn L, Bierhaus A, et al; Finn Diane Study Group (2013) Urinary liver-type fatty acidbinding protein and progression of diabetic nephropathy in type 1 diabetes. Diabetes Care 36: 2077-2083. [Ref.]
47. Srivastava RN, Bagga A (2005) Evaluation of renal function, Srivastava RN, Bagga A. (Eds), Pediatric Nephrology. 4th Ed, New Delhi: Jaypee Brothers Medical Publishers Ltd 20-29.
48. Ghys L, Paepe D, Smets P, Lefebvre H, Delanghe J, et al. (2014) Cystatin C: a new renal marker and its potential use in small animal medicine. J Vet Intern Med 28: 1152-1164. [Ref.]
49. Garg V, Kumar M, Mahapatra HS, Chitkara A, Gadpayle AK, et al. (2015) Novel urinary biomarkers in pre-diabetic nephropathy. Clin Exp Nephrol 19: 895-900. [Ref.]
50. Kim SS, Song SH, Kim IJ, Jeon YK, Kim BH et al. (2013) Urinary cystatin C and tubular proteinuria predict progression of diabetic nephropathy. Diabetes Care 36: 656-661. [Ref.]
51. Jeon YK, Kim MR, Huh JE, Mok JY, Song SH, et al. (2011) Cystatin C as an early biomarker of nephropathy in patients with type 2 diabetes. J Korean Med Sci 26: 258-263. [Ref.]

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Article Information

Article Type: REVIEW ARTICLE

Citation: Uwaezuoke SN, Muoneke VU, Mbanefo NR (2018) Tubular Biomarkers as Diagnostic Tools in Diabetic Kidney Disease: A Review of Published Evidence. Int J Nephrol Kidney Fail 4(2): dx.doi.org/10.16966/2380-5498.156

Copyright: © 2018 Uwaezuoke SN, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publication history: 

Received date: 19 Feb, 2018

Accepted date: 13 Mar, 2018

Published date: 19 Mar, 2018