Review ArticleUrinary Biomarkers in the Assessment ofEarly Diabetic Nephropathy
Cristina Gluhovschi1 Gheorghe Gluhovschi2 Ligia Petrica1 Romulus Timar3
Silvia Velciov1 Ioana Ionita4 Adriana Kaycsa5 and Bogdan Timar3
1Division of Nephrology University of Medicine and Pharmacy ldquoV Babesrdquo 300041 Timisoara Romania2Romanian Academy of Medical Sciences 300041 Timisoara Romania3Department of Diabetes and Metabolic Diseases University of Medicine and Pharmacy ldquoV Babesrdquo 300041 Timisoara Romania4Division of Hematology University of Medicine and Pharmacy ldquoV Babesrdquo 300041 Timisoara Romania5Department of Biochemistry University of Medicine and Pharmacy ldquoV Babesrdquo 300041 Timisoara Romania
Correspondence should be addressed to Cristina Gluhovschi gluhovschiyahoocom
Received 24 March 2016 Accepted 12 May 2016
Academic Editor Nikolaos Papanas
Copyright copy 2016 Cristina Gluhovschi et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited
Diabetic nephropathy (DN) is a frequent and severe complication of diabetes mellitus (DM) Its diagnosis in incipient stagesmay allow prompt interventions and an improved prognosis Towards this aim biomarkers for detecting early DN can be usedMicroalbuminuria has been proven a remarkably useful biomarker being used for diagnosis of DN for assessing its associatedconditionmdashmainly cardiovascular onesmdashand for monitoring its progression New researches are pointing that some of thesebiomarkers (ie glomerular tubular inflammation markers and biomarkers of oxidative stress) precede albuminuria in somepatients However their usefulness is widely debated in the literature and has not yet led to the validation of a new ldquogold standardrdquobiomarker for the early diagnosis of DN Currently microalbuminuria is an important biomarker for both glomerular and tubularinjury Other glomerular biomarkers (transferrin and ceruloplasmin) are under evaluation Tubular biomarkers in DN seem to beof a paramount importance in the early diagnosis of DN since tubular lesions occur early Additionally biomarkers of inflammationoxidative stress podocyte biomarkers and vascular biomarkers have been employed for assessing early DN The purpose of thisreview is to provide an overview of the current biomarkers used for the diagnosis of early DN
1 Introduction
Diabetic nephropathy (DN) represents an important causeof chronic kidney disease (CKD) that frequently leads toend stage renal disease (ESRD) Diabetes mellitus (DM) is afrequent disease and DN is one of its main complications Itis appreciated that up to 40 of the patients with type I andtype II DMpresent DN [1] InWestern countries diabetes is aleading cause of chronic kidney disease frequently leading tochronic renal replacement therapy (RRT) due to ESRD [2]
Taking into account the increased incidence of both DMand of DN the detection of early DN is of paramount impor-tance in order to provide appropriate therapy that prevents orslows evolution towards ESRD
Biomarkers play an important role in the early detectionofDNAmong them the best known ismicroalbuminuria Atthe same time microalbuminuria represents a marker of thegeneralized endothelial dysfunction present in DM linkingrenal involvement with cardiovascular and cerebral impair-ment
In time it has been demonstrated that microalbuminuriareflects not only glomerular injury but also tubular lesionsfiltered albumin being reabsorbed at tubular level Addition-ally new biomarkers have been studied in order to identifytubular lesions in DM
The new tubular biomarkers have been detected in bothtype 1 and type 2 DM early renal dysfunction that precedesmicroalbuminuria At present the assessment of early DN
Hindawi Publishing CorporationJournal of Diabetes ResearchVolume 2016 Article ID 4626125 13 pageshttpdxdoiorg10115520164626125
2 Journal of Diabetes Research
involves numerous biomarkers They span the period of nor-moalbuminuria that precedes microalbuminuria but also theevolution of renal involvement duringmicroalbuminuria andmacroalbuminuria
Until they are universally accepted they are analyzedin relationship with the levels of albuminuria especially ofmicroalbuminuria
At present markers of inflammatory and oxidative pro-cesses accompanying DM and DN are also being assessed
Since literature abounds in studies on markers highlight-ing renal dysfunction in different stages of the evolution ofDM we decided to restrict our study to the early phase ofDN
An update of the urinary biomarkers used in early DN isuseful for establishing their role in the early diagnosis of thisdisease with subsequent prophylactic and therapeutic impli-cations We insist on urinary biomarkers because they areeasily drawnwhich allows population screening and becausethey can detect tubular lesions which occur very early inDM
Proteomics is an additional tool offering great prospectsin DN assessment
The origin of the biomarkers employed for assessing renalinvolvement in DM is diverse Some of the biomarkers areconstitutive elements of the nephron such as markers at
(i) epithelial cell (podocyte) level for example nephrineand podocalyxin [3]
(ii) glomerular basement membrane level collagen andlaminin [4]
(iii) endothelial (VEGF) [5](iv) tubular cell level for example NGAL NAG and KIM
[6]
Some have mixed origin they can originate both intubular cells and in podocytes for example angiotensinogen[7 8]
Some are derived from the circulation for example trans-ferrin ceruloplasmin and immunoglobulins G and M Theypass into the urine because of glomerular lesions which resultin increased permeability for plasma proteins
There are several classifications addressing the diversityof urinary biomarkers in DM
Matheson classifies the biomarkers according to boththeir origin and the pathologic processes impairing the neph-ron kidney damage oxidative stress and inflammation
(i) biomarkers of renal dysfunction(ii) inflammatory biomarkers (cytokines and chemoki-
nes)(iii) oxidative stress biomarkers [9]
Another classification belongs to Hong and Chia whopresent 3 categories of biomarkers
(i) glomerular(ii) tubular(iii) other proteins [10]
It should be noted that products ofmetabolism inDMare alsoeliminated in the urine and they can trigger toxic effects forexample advanced glycation end products (AGE)
Since we will frequently refer to microalbuminuria inpresenting other biomarkers used in studying lesions of thenephron namely of the glomerulus and of the tubules wewill first present the main observations regarding microalbu-minuria in diagnosing DN
Recent literature uses new terms like moderatelyincreased albuminuria for microalbuminuria and severelyincreased albuminuria for macroalbuminuria However theclassical terms of microalbuminuria and microalbuminuriacontinue to be in wide use as they are more practical This iswhy we will prefer them in the present paper
Urinary biomarkers use in assessment of early diabeticnephropathy are presented in Table 1
2 Microalbuminuria (Moderately IncreasedAlbuminuria) in Type 1 DM
Microalbuminuria usually begins 5ndash10 years after the onset oftype 1 DM [11]
Kidney biopsy examination in patients with type 1 DMand microalbuminuria most frequently finds normal histo-logical aspects However DN lesions were found in a smallnumber of patients [12]
According to McKenna and Thompson microalbumin-uria is predictive element of the future development of endstage renal disease [13]
Microalbuminuria can regress towards normoalbumin-uria it can persist as such or it can progress towards albumin-uria [14 15]
The evolution of microalbuminuria towards macroal-buminuria is usually related to arterial hypertension andreduced GFR an important part being generally played byrisk factors [16]
Persistent microalbuminuria is related to future develop-ment of end stage renal disease and to cardiovascular risk [13]
It should be noted that diminution of GFR usually occursafter the development of microalbuminuria but there aresituations when even normoalbuminuria is accompanied bydiminution of the GFR [17]
3 Microalbuminuria (Moderately IncreasedAlbuminuria) in Type 2 DM
Microalbuminuria is an important biomarker in type 2 DMbeing frequently used in population-based screenings
Regarding the prevalence of microalbuminuria in type 2DM patients we highlight a review of Newman et al of 28studies on 10294 patients They found microalbuminuria in26 of the patients with ten-year duration of the disease [18]
A study on 24000 patients found that Asian andHispanicpatients with type 2 DM present more often microalbumin-uria (43) than whites (33) [19]
In China Shanghai microalbuminuria has a prevalenceof 41 among patients with type 2 DM [20]
Hypertensive patients with type 2 DM present microal-buminuria more frequently [21]
Journal of Diabetes Research 3
Table 1 Urinary biomarkers in the assessment of early diabetic nephropathy
Neutrophil gelatinase-associated lipocalin (NGAL)Immunoglobulin G Alpha-1-microglobulinCeruloplasmin Kidney injury molecule-1 (KIM-1)Type IV collagen N-acetyl-120573-D glucosaminidaseLaminin AngiotensinogenGlycosaminoglycans Cystatin CLipocalin-type prostaglandin D synthase Liver-type fatty acid binding proteinFibronectin NephrinePodocytes-podocalyxin Heart fatty binding proteinVascular endothelial growth factorVEGF Advanced glycation end productsInflammatory biomarkers Other new markers under study Oxidative stress biomarkersTumor necrosis factor alpha Retinol binding protein-4 8-Oxo-78-dihydro-21015840-deoxyguanosineOrosomucoid Vitamin D binding protein
Heme oxygenase-1Periostin
Alpha klothoMicrovesicle-bound dipeptidyl
peptidase IVMicroRNA
Adipokinesine alpha-2glycoprotein
Microalbuminuria can have a variable evolution It canregress towards normal values it can progress towardsmacroalbuminuria or it can remain unchanged In a studyon 216 patients Araki et al found after a 6-year follow-upregression of microalbuminuria in 51 cases and progressionto severely increased albuminuria in 28 cases [22]
The risk of progression to severely increased albuminuriais higher in patients with microalbuminuria as compared topatients with normoalbuminuria [18]
The diminution of GFR is also higher in patients withseverely increased albuminuria than in those with microal-buminuria [23]
Glycemic control ACE inhibitors and ARBs for bloodpressure control play an important role in the evolution ofmicroalbuminuria It should be mentioned that microalbu-minuria has been considered a glomerular biomarker Todate emerging data point to the role of the tubules in pro-ducingmicroalbuminuria [24 25] As suchwedid not includethis marker among glomerular biomarkers but approached itseparately according to its potential role as both a glomerularand tubular biomarker
31 Glomerular Biomarkers
311 Urinary Transferrin Transferrin is a protein with amolecular weight of 765 KDa Because of its low molecularweight and its less ionic load it filters easily through theglomerular barrier [26]
As increased urinary transferrin was found in type 2DMnormoalbuminuric patients concomitantly with urinary
ceruloplasmin and immunoglobulin G preceding microal-buminuria it could be considered a biomarker of early DN[27]
In microalbuminuric patients the levels of urinary trans-ferrin increase [28] They also increase in patients with type2 DM with vascular complications coronary artery diseasediabetic retinopathy and so forth [29]
Patients with initial high levels of urinary transferrinexcretion will develop microalbuminuria more frequentlythan those with normal levels [30]
312 Urinary Immunoglobulin G It is an anionic plasmaprotein with a molecular weight of 150KDa that crosses theglomerular barrier with difficulty [31]
As presented above urinary IgG can be secreted beforethe stage of microalbuminuria concomitantly with increasedvalues of urinary transferrin urinary ceruloplasmin andurinary orosomucoid [27]
Increased elimination of urinary IgG could thus predictmicroalbuminuria in DM patients [27]
313 Urinary Ceruloplasmin Ceruloplasmin is a copper-transporting serum protein It is filtered with difficulty atglomerular level because it is more negatively charged [32]
It was also found in some type 2 DM patients withnormoalbuminuria arguing in favour of its use for earlydetection of renal lesions even prior to albuminuria ceru-loplasmin could have in type 2 DM patients a DN pre-dictive effect similar to urinary transferrin and urinaryimmunoglobulin G [27] According to Yamazaki et al the
4 Journal of Diabetes Research
urinary ceruloplasmin excretion rate (CER) and clearanceof ceruloplasmin increase in parallel with the progression ofalbuminuria [33]
In fact in type 2 DM patients there could exist aparallelism between increased values of urinary transferrinurinary immunoglobulin G and urinary ceruloplasmin [27]
We conclude that urinary ceruloplasmin could be usedfor the early diagnosis of DN [34]
314 Type IV Urinary Collagen Type IV collagen is acomponent of the glomerular basementmembrane and of themesangial matrix [35]
In DN lesions are produced both at glomerular capillarylevel and at mesangial level Its excretion in urinemight serveas early indicator of renal injury associated with DN [36]
Increased levels of type IV urinary collagen are reportedfor normoalbuminuric patients with type 1 DM It could bea biomarker used for the early diagnosis of DN [37] Otherauthors also report increased excretion of type IV collagenand of laminin in patients with type 1 DM [23]
High urinary type IV collagen excretionwas also reportedin normoalbuminuric patients with impaired glucose toler-ance [38]
Urinary type IV collagen could reflect morphologicalrenal alterations in patients with type 2 DM A relationshipbetween the severity of histological lesions and urinary typeIV collagen was reported in patients with type 2 DM [39]
Type IV urinary collagen is considered to be a specificindicator of early DN [40]
It could also allow both detection of early DN in patientswith type 2 DM and differential diagnosis with glomeru-lonephritis where its levels are low [41]
315 Urinary Laminin Laminin is a component of theglomerular basement membrane Its urinary excretion isincreased in normoalbuminuric type 2 DM patients beingcorrelated with NAG (N-acetyl-beta-D-glucosaminidase)and alpha-1-microglobulin excretion Concomitantlyincreased excretion of type IV collagen is found [4]
316 Urinary Glycosaminoglycans Glycosaminoglycans arecomponents of the glomerular basementmembrane as well asof the extracellular matrix In DM alterations of these occurthe excretion of glycosaminoglycans being increased even innormoalbuminuric patients [42]
Glycosaminoglycans are also present at the level of thetubular basement membrane Urinary glycosaminoglycansare associated with other tubular biomarkers for exampleTamm-Horsfall protein which expresses a distal tubulardysfunction in diabetic patients [43]
317 Lipocalin-Type Prostaglandin-D Synthase (L-PGDS) Itis a biomarker related to lesions of the glomerular capillarywalls and reflects their increased permeability It is mainlyconsidered to predict renal lesions being less relevant as anearly marker of DN [44]
318 Urinary IgM and Urinary Fibronectin These werestudied only sporadically without sufficient data to supporttheir use as markers of early DN
Urinary fibronectin excretion is significantly increased inDMpatients only if they present microalbuminuria [45] IgMis an indicator of impaired kidney function [46]
Although the use of urinary glomerular biomarkers hasnot become current practice yet glomerular biomarkers havebeen reported in some normoalbuminuric patients leadingto the conclusion that albuminuria might not represent themost sensitive glomerular biomarker However their clinicalapplicability needs to be confirmed in high-quality validationstudies [31]
32 Tubular Biomarkers DN is manifested mainly by well-known glomerular lesions The aforementioned biomarkersare identified already precociously early in early DN Tubu-lointerstitial lesions are associated with glomerular injuryduring DN [47] Tubular biomarkers have shown that tubulardysfunction can be present early inDN sometimes precedingglomerular injury These biomarkers have proven highlysensitive as compared to microalbuminuria which is consid-ered the gold standard biomarker of DN In fact presentlymicroalbuminuria is regarded not only as a glomerularbiomarker but also as a tubular one
321 Neutrophil Gelatinase-Associated Lipocalin (NGAL)NGALmdashneutrophil gelatinase-associated lipocalinmdashis a gly-coprotein present in the kidneys at tubular cell level and isconsidered to be protective against renal damage [48]
Urinary NGAL is a biomarker used in assessing tubularlesions in DM its increased values being present even in theinitial phases of the disease namely in normoalbuminuricpatients [49]
Thus in type 1 DM high urinary NGAL can precedemicroalbuminuria [50 51]
Urinary NGAL had high values in type 2 DM patientswith normoalbuminuria increasing progressively in patientswith microalbuminuria and macroalbuminuria The valuesof KIM-1 (kidney injury molecule-1) increased in parallelindicating an early and progressive lesion [52]
However Fu et al reported in type 2 DM patientswho present hyperfiltration and increased values of urinaryNGAL as well as of urinary KIM-1 as compared to the valuesof patients with normal GFR [53]
Urinary NGAL shows the precocity of tubular lesions inpatients with prediabetes [54]
Urinary NGAL in type 2 DM patients could have a role inpredicting the evolution of disease [55]
322 Urinary Alpha-1-Microglobulin Urinary alpha-1-microglobulin is a serum protein with low molecularweight (27-kDa) which allows it to get easily filteredthrough the glomerular capillary wall Once it arrives in theproximal tubule alpha-1-microglobulin is reabsorbed andmetabolized Tubular dysfunction leads to alteration of reab-sorption with increased excretion in the urine [56]
In a cross-sectional study Hong et al analyzed 590type 2 DM patients and found that 336 patients with
Journal of Diabetes Research 5
normoalbuminuria presented increased values of urinaryalpha-1-microglobulin a fact that could be explained by tubu-lar injury that precedes the occurrence of microalbuminuriabeing a more sensitive and an earlier urinary biomarker [57]However alpha-1-microalbuminuria can be absent in somepatients with albuminuria [57] This is why assessments ofalpha-1-microglobulin are associated with the assessment ofother urinary biomarkers urinary albumin included
Petrica et al reported high values of urinary alpha-1-microglobulin in normoalbuminuric patients a fact pleadingfor an early tubular injury in type 2DM in this stageThey didnot find correlations between urinary alpha-1-microglobulinbeta-2 microglobulin and the albumincreatinine ratio withplasma asymmetric dimethyl-arginine This could plead fordissociation between tubular and endothelial dysfunction[58]
Alpha-1-microglobulin in early stages of DM could alsohave a role in predicting DN [59] It is in fact an inexpensivebiomarker of early diagnosis of DN [60]
323 Urinary KIM-1 (Kidney Injury Molecule-1) KIM-1 isa transmembrane glycoprotein located at the level of theproximal tubular cells It is eliminated in urine in case ofinjury at this level It is a sensitive biomarker used with goodresults in acute kidney injury [61]
Petrica et al reported in normoalbuminuric type 2 DMpatients high values of urinary KIM-1 which indicates lesionsof the proximal tubule in early stages of the disease Patientswith microalbuminuria have higher urinary KIM-1 valuesthan those with normoalbuminuria [62]
de Carvalho et al reported in type 2 DM normoal-buminuric patients high values of KIM-1 these valuesincreasing progressively in patients with microalbuminuriaand macroalbuminuria NGAL values studied concomitantlypresented similar evolutions [52]
Moreover KIM-1 presents higher elimination in type2 DM patients with hyperfiltration than in patients withnormal glomerular filtration NGAL has a similar evolutionThese biomarkersmdashKIM-1 and NGALmdashcould plead for adeleterious lesional effect of hyperfiltration on the proximaltubule [53]
Nielsen et al however could not demonstrate a value ofurinary KIM-1 that could be predictive of the evolution ofglomerular function (GFR) in patients with type 1 DM [63]
According to Nielsen et al it has no prognostic utility intype 2 DM patients either [64]
324 Urinary N-Acetyl-120573-D glucosaminidase (NAG) NAG isan enzyme located in the lysosomes of proximal tubular cells[65]
In case of dysfunction namely of injury of proximaltubular cells NAG is eliminated into the urine in higherquantities being a sensitive tubular biomarker This canprecede the appearance of microalbuminuria in type 1 DM[66]
Elevated serum Cys C levels and urinary NAG activitieswere found only in normoalbuminurics not in controls Inaddition elevated urinary ALP and LDH activities were alsofound in microalbuminurics [67]
Other authors like Ambade et al did not find thaturinary NAG has clinical significance as an early biomarkerof DN [68]
In type 2 DM urinary NAG excretion increases propor-tionally to the duration of diabetes It occurs much earlierthan albuminuria NAG can be considered an early tubularbiomarker [69]
Assal et al consider that urinary NAG is the mostsensitive biomarker for detecting early damage in diabeticpatients [70]
325 Urinary Angiotensinogen The renin angiotensin aldos-terone system (RAAS) is involved in the pathogenesis of DNThe constitutive elements of RAAS are present at kidney leveldefining a local RAAS
Urinary angiotensinogen can represent a biomarker forthe activation of RAAS in DM [71]
High urinary angiotensinogen precedes in type 1 DMpatients the occurrence of microalbuminuria [72]This couldhave a predictive role in normotensive type 1 DM patients[73]
Urinary angiotensinogen in normoalbuminuric type 2DM patients is higher than in controls and it increasesprogressively inmicroalbuminuric and especially inmacroal-buminuric patients [73]
Urinary angiotensinogen can be considered an earlybiomarker of DN [72]
In type 2 DM patients urinary angiotensinogen is corre-lated with alpha-1-microglobulin [8]
Kim et al did not confirm these observations in a studyon type 2 DM patients They found that the values ofurinary angiotensinogen are not different from those of thecontrols in normoalbuminuric andmicroalbuminuric type 2DM patients but higher values were described inmacroalbu-minuric patients [74]
These observations point to the need of further studiesnecessary for the validation of this biomarker
Increased urinary angiotensinogen could represent a riskfactor in renal and cardiovascular complications [75]
Since activation of RAAS could intervene in the evolutionof DN administration of ACE-I is recommended
At the same time urinary angiotensinogen could be amarker for assessing the renoprotective effects of alogliptinto type 2 DM patients [76]
326 Cystatin C It is a low molecular weight protein havingthe role of cysteine protease Cystatin is produced by thenucleated cells in the body [77]
It is filtered at glomerular level and is reabsorbed inthe tubules Cystatin is used for evaluating renal functionAssessment of GFR by means of cystatin C is considered tobe a method that is not influenced by body mass being com-parable and even better thanmethods using serum creatinine[78]
Serum cystatin is also considered a sensitive biomarker asit detects minor glomerular injury [79]
Urinary cystatin C indicates tubular injury It increasesearly in diabetes and prediabetic nephropathy [80]
6 Journal of Diabetes Research
Patients with microalbuminuria present higher values ofurinary cystatin C than those without microalbuminuriaurinary cystatin C having a predictive role for the progressionof diabetic nephropathy (DN) [81]
Urinary cystatin C level could be an independentfactor for identifying renal dysfunction in type 2 DMpatients with normoalbuminuria including patients withGFR lt60mLmin173m2 [77] Uslu et al find a significantpositive correlation between serum cystatin C urinary NAGlacticodehydrogenase alkaline phosphatase activities andserum creatinine levels [67]
Serum and urinary cystatin C are useful biomarkers forassessing early nephropathy in type 2 DM [77]
327 L-FABP (Liver-Type Fatty Acid Binding Protein) Uri-nary L-FABP is a protein with low molecular weightexpressed in the cytoplasm of human proximal tubular cells[82] It is also expressed at liver level
Increased urinary L-FABP was found in type 1 DMpatients who presented normoalbuminuria having a predic-tive role regarding the progression towards microalbumin-uria and of microalbuminuria towards macroalbuminuria[83]
Patients with type 2 DM with normoalbuminuria alsopresented high levels of urinary L-FABP this protein beingconsidered as a useful biomarker for diagnosing early diabeticnephropathy In fact urinary L-FABP has been confirmed asa tubular biomarker by the Ministry of Health andWelfare inJapan [82]
The L-FABP factor is also related to the severity of DNThe values of urinary L-FABP increase with the decline ofrenal function [84]
Although some authors like Chou et al do not ascribe apredictive role to urinary L-FABP in type 2 DM patients [85]others like Panduru et al consider that urinary L-FABP is anindependent predictor of the progression of DN [86]
328 Nephrinuria Nephrine is a transmembrane protein inthe structure of the slit diaphragm [87]
InDMpodocyte dysfunction is present DN is considereda podocytopathy [88] Injury of the slit diaphragm leads tonephrinuria
Nephrinuria can occur in some type 1 DM patients priorto microalbuminuria [89] Nephrinuria was also reported insome normoalbuminuric type 2 DM patients [62 90]
Nephrinuria is related to podocyte injury representing abiomarker of early glomerular injury [91]
Dysregulation of nephrine in podocytes in DN couldlead to nephrinuria in normoalbuminuric patients precedingmicroalbuminuria [92]
In albuminuric patients nephrinuria is positively corre-lated with albuminuria and negatively correlated with GFRbeing a biomarker of DN in other phases of DM as well
Podocyte impairment in DM involves not only nephrinebut also other podocyte elements for example VEGF Thusin normoalbuminuric DM patients nephrinuria is correlatedwith urinary elimination of VEGF [62]
Tubular biomarkers seem to play an important role inthe early diagnosis of DN They manage to show in most
cases that microalbuminuria does not represent a reliablebiomarker for diagnosing incipient lesions of DN Howeverup to now none of these biomarkers has been established asgold standard for the identification of early DN
33 Markers of Inflammation DM is accompanied bychronic inflammatory processes affecting the whole body thekidneys included Mediators of inflammation like cytokinesand chemokines are present in these processes Some of themare useful as markers of inflammation
331 Tumour Necrosis Factor Alpha (TNF Alpha) UrinaryTNF alpha presents in type 2 DM patients with microal-buminuria and macroalbuminuria higher values than inpatients with normoalbuminuria Urinary TNF alpha iscorrelatedwith urinaryNAG amarker of tubular lesions [93]
Cherney et al analyzed in a complex study on nor-moalbuminuric type 1 DM patients forty-two urinarycytokineschemokines They found that the urinary level ofIL6 and IL8 the platelet-derived growth factor and RANTESare not altered in patients with normal albumin-creatinineratio
Higher urinary excretion of these markers is associatedwith microalbuminuria Cherney et al consider that thesemarkers could have a role in assessing the risk of DN inpatients with type 1 DM [94]
In type 1 DM patients renal hyperfiltration is related toincreased excretion of inflammatory cytokineschemokines[95]
Tashiro et al found in type 2 DM patients that IL8 is highin early stages of DN andMCP-1 increases in advanced stages[96]
A study on type 2 DM patients with normoalbuminuriaand microalbuminuria found higher values of IL8 IP10MCP-1 G-CSF EOTAXIN and RANTES in patients withmicroalbuminuria than in normoalbuminurics or in controlsTheir assessment would be useful in the early diagnosis andtreatment of DN [97]
Ibrahim and Rached also found that urinary MCP-1 ishigher in patients with microalbuminuria than in normoal-buminurics or healthy controls [98]
332 Urinary Orosomucoid Orosomucoid represents a gly-coprotein involved in inflammatory processes
Urinary orosomucoid has higher values in type 1 DMpatients with normoalbuminuria than in controls These val-ues increase in patients withmicroalbuminuria andmacroal-buminuria [99] Type 2 DM patients presented increasedexcretion of orosomucoid in the urine in parallel with theexcretion of immunoglobulin G ceruloplasmin and trans-ferrin [16] El-Beblawy et al appreciate that orosomucoid isa significant independent factor for diabetic microvascularcomplications and can be considered as an early marker ofrenal injury [100]
Urinary orosomucoid excretion rate in type 2 DMpatients predicts cardiovascular mortality [101]
Urinary markers of inflammation are useful for assessinginflammatory processes in DN even in early stages
Journal of Diabetes Research 7
34 Oxidative Stress Biomarkers Oxidative stress plays animportant part in the development and progression of DN[102]
341 Urinary 8-Oxo-78-dihydro-2-deoxyguanosine (8-oHdG) 8-oHdG is produced secondary to oxidative DNAdamage It is eliminated into the urine without being meta-bolized [103] At present it is considered a marker foroxidative stress
After a 5-year follow-up Hinokio et al find that 8-oxodGin urine is a useful clinical marker to predict the developmentof diabetic nephropathy in diabetic patients There wasa significant progression of diabetic nephropathy in thepatients with higher excretion of 8-oxodG in urine comparedwith the patients with moderate or lower excretion of 8-oxodG [104]
Leinonen et al reported increased excretion of 8-oHdG intype 1 DM patients 9 years after the onset of disease mainlyrelated to poor glycemic control [105]
The urinary 8-oHdG marker of oxidation would beaccording to Broedbaek et al a predictor of long-termmortality in DM [106]
342 Heart Fatty Acid Binding Protein (H-FABP) Heart fattyacid binding protein (H-FABP) is a marker of distal tubulardamage
In a study on a cohort of type 1 and type 2DMpatients andan assessment of their markers of glomerular lesions (IgG)markers of proximal tubular lesions (urinary KIM-1 NAGNGAL and cystatin) and a marker of distal tubular lesions(urinaryH-FABP) in relationshipwith albuminuria andGFRNauta et al reported higher values of urinary NAG NGALand H-FABP in normoalbuminurics than in controls On theother hand the values of urinary cystatin C were low [107]
This shows that normoalbuminuric DM patients presentboth proximal and distal tubular lesions
343 Urinary Advanced Glycation End Products (AGE)AGE eliminated in the urine induce a toxic tubular effectproducing tubular dysfunction
In type 2 DM patients with normoalbuminuria highvalues of urinary alpha-1-microglobulin and of urinary KIM-1 were found secondary to tubular dysfunction prior to theonset of microalbuminuria At the same time urinary AGEwere high being correlated with these markers [108]
Turk et al found in type 2 DM patients high values ofurinary AGE in 50 of the patients with normoalbuminuriaand in 85 of those with microalbuminuria [109]
Pentosidine a component ofAGE is a biomarker for theirformation and accumulation [110]
Piarulli et al found in patients with microalbuminuriahigher values of pentosidine than in patients with normoal-buminuria [111]
344 Podocytes Podocyte lesions appear during DM andDN respectively the disease being considered a podocytopa-thy as mentioned above
The assessment of podocyte injury can be accomplishedby monitoring the number of podocyte cells in the urine
or more precisely by means of using podocyte urinarybiomarkers (podocalyxin and nephrine)
A study onDMpatients found that the values of the num-ber of urinary podocytes in normoalbuminuric patients arenot significantly different from those of controls In patientswithmicroalbuminuria andnephrotic syndrome the numberof urinary podocytes is higher It is correlated with urinaryosteopontin and urinary IgM [33]
Urinary podocalyxin originates in the podocyte apicalsurface occurring in vesicle form In DM patients thepodocalyxin level presented higher levels in patients withmicroalbuminuria than in patients with normoalbuminuria[112]
Another study on DM patients found high values ofurinary podocalyxin in more than half of the patients withnormoalbuminuria these values being higher in patientswith microalbuminuria and macroalbuminuria
Urinary podocalyxin is correlated with the values ofurinary NAG and of urinary beta 2 microglobulin [113]
Hara et al consider that urinary podocalyxin can bean early biomarker for detecting early podocyte injury inpatients with DM
Zheng assessed the urinary microRNA profile ofpodocyte-associated molecules (synaptopodin podocalyxinCD2-AP 120572-actin4 and podocin) as biomarkers in patientswith normoalbuminuria microalbuminuria and macro-albuminuria and they reported its increase during theprogression of DN [114]
345 Vascular Endothelial Growth Factor (VEGF) VEGF isa proangiogenic factor produced mainly by the podocytes atnephron level Urinary VEGF can be considered a podocytebiomarker
Urinary VEGF was detected in type 2 DM patientsbeing correlated in these patients with urinary alpha-1-microglobulin a biomarker for proximal tubular lesions [62]
Kim et al found that VEGF is excreted at higher valuesthan controls in normoalbuminuric type 2 DM patientsThe values increase in patients with microalbuminuria andmacroalbuminuria [115]
Fetuin A is glycosylated glycoprotein was consideredan inhibitor for ectopic calcium deposition and promoterof insulin resistance Fetuin A inhibits the calcification ofatherosclerotic plaques in diabetes mellitus [116] It wasfound that elevated urinary Fetuin A excretion is a risk fordevelopment of diabetic nephropathy [117]
35 Other Urinary Biomarkers Used in Evaluating Early DNNumerous urinarymarkers have been suggested for assessingearly DN Some of them have been introduced in use onlyrecently
Urinary retinol-binding protein is a lowmolecular weightprotein that was found to have high urinary values (togetherwith NAG) in normoalbuminuric patients reflecting tubulardysfunction in early DN [118]
The value of serum retinol-binding protein 4 as a bio-marker in assessing the severity of coronary artery disease isto be mentioned [119]
8 Journal of Diabetes Research
Urinary retinol-binding protein 4 as a biomarker in ass-essing DN needs further studies
Urinary vitamin D binding protein can plays the role asbiomarker In type 2 DM it is attributed a potential role inearly diagnosis of DN [120]
Urinary heme oxygenase-1 was found in type 2 DMpatients before the onset of significant albuminuria thusbeing a possible biomarker of early DN [121] In fact oxidativestress activation is expected in DN
Periostin is a cell adhesion molecule which is not nor-mally present in kidneys In tubulointerstitial lesions it ishowever expressed in the kidneys being eliminated in theurineThis is why urinary periostin could be used as amarkerof injury at this level
Since high levels of periostin can be identified in DMpatients before significant albuminuria periostin could rep-resent a marker of diabetic renal injury [122]
Urinary alpha klotho presents higher values in normoal-buminuric type 2 DM patients than in controls It can also bea marker of diabetic injury [123]
Analyzing a group of normoalbuminuric microalbumin-uric and macroalbuminuric type 2 DM patients Sun et alnoted that the urinary level of microvesicle-bound dipeptidylpeptidase-IV is related to the severity of DN [124]
Recent studies point to the usage of urine-specificmicroRNA as a biomarker for early stages of DN Analyzingthe studies in the literature Yang et al issued the hypothesisthat urine-specific microRNA would be a marker that can beused in the early stages of DN [125]
Recently Argyropoulos highlighted the predictive roleof urinary microRNA regarding microalbuminuria in type 1DM [126]
Adipokine zinc-alpha-2 glycoprotein is assigned to themajor histocompatibility complex class I of proteins [127]
Urinary adipokine zinc-alpha-2 glycoprotein is presentearlier than microalbuminuria in diabetic nephropathy Itcould be a useful biomarker for diagnosing early DN [128]Lim et al also appreciate adipokine zinc-alpha-2 glycoproteinas a novel urinary biomarker for normoalbuminuric diabeticnephropathy [129]
351 Proteomics At present proteomic investigations areengaged in identification of new urinary biomarkers to beused in the early diagnosis of DN
In fact proteomics studies noted the fact that microalbu-minuria is not a perfect biomarker for early detection of DN[130 131]
Urinary proteomics begins to stand out as a noninvasivemethod of detecting early DN
Among proteomics studies on diagnosing DN we canmention those of Zurbig et al who reported that collagenfragments were a prominent biomarker 3ndash5 years before theonset of microalbuminuria [132]
A potential role is also attributed to exosome proteomicsfor identifying new biomarkers for DN [133] Zubiri et alshowed a panel of 3 proteins which is differentially present inurinary exosomes fromDNpatients [134] Urinary proteomicanalysis can have an important role in the implementation ofnew biomarkers in DN [135]
At present the prospect of discovering new biomarkersin DM andDN respectively is incumbent both on proteomicsand on genomics transcriptomics and metabolomics [136]
4 Conclusions
Urinary biomarkers allow an assessment of early DNMicroalbuminuria although frequently contested as a
biomarker of early DN is used so far as reference biomarkerin assessing other urinary biomarkers in early DN Untilpresent there is no other biomarker that can substitute inpractice microalbuminuria the new biomarkers being sus-tained by limited studies and requiring validation
The concomitant assessment of several urinary biomark-ers in relationship with microalbuminuria could represent atpresent a method of diagnosing early DNThe great progressin discovering new biomarkers could lead to the developmentof an ldquoidealrdquo urinary biomarker to detect early diabetic DN inthe future
Progresses in the field of urinary biomarkers in DNpromising both in proteomics and in other modern tech-niques develop remarkably at present
Disclosure
Thesupporting source had no involvement in study design incollection analysis and interpretation of data in the writingof the report and in the decision to submit the paper forpublication
Competing Interests
The authors declare that they have no competing interests
Authorsrsquo Contributions
Cristina Gluhovschi and Gheorghe Gluhovschi contributedequally to this paper
Acknowledgments
This research received funding from an Internal Grantof ldquoVictor Babesrdquo University of Medicine and PharmacyTimisoara PIII-C1-PCFI-20142015
References
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[2] M Narres H Claessen S Droste et al ldquoThe incidence ofend-stage renal disease in the diabetic (compared to the non-diabetic) population a systematic reviewrdquo PLoS ONE vol 11no 1 Article ID e0147329 2016
[3] E Lioudaki K G Stylianou I Petrakis et al ldquoIncreased urinaryexcretion of podocyte markers in normoalbuminuric patientswith diabetesrdquo Nephron vol 131 no 1 pp 34ndash42 2015
Journal of Diabetes Research 9
[4] N Banu H Hara M Okamura G Egusa and M YamakidoldquoUrinary excretion of type IV collagen and laminin in the eval-uation of nephropathy in NIDDM comparison with urinaryalbumin and markers of tubular dysfunction andor damagerdquoDiabetes Research and Clinical Practice vol 29 no 1 pp 57ndash671995
[5] P Kubisz L Stanciakova J Stasko P Galajda and M MokanldquoEndothelial and platelet markers in diabetes mellitus type 2rdquoWorld Journal of Diabetes vol 6 no 3 pp 423ndash431 2015
[6] G Tramonti and Y S Kanwar ldquoTubular biomarkers to assessprogression of diabetic nephropathyrdquo Kidney International vol79 no 10 pp 1042ndash1044 2011
[7] T Terami J Wada K Inoue et al ldquoUrinary angiotensinogen isa marker for tubular injuries in patients with type 2 diabetesrdquoInternational Journal of Nephrology and Renovascular Diseasevol 6 pp 233ndash240 2013
[8] M Eriguchi R Yotsueda K Torisu et al ldquoAssessment ofurinary angiotensinogen as a marker of podocyte injury inproteinuric nephropathiesrdquo American Journal of PhysiologymdashRenal Physiology vol 310 no 4 pp F322ndashF333 2016
[9] A Matheson M D P Willcox J Flanagan and B J WalshldquoUrinary biomarkers involved in type 2 diabetes a reviewrdquoDiabetesMetabolism Research and Reviews vol 26 no 3 pp150ndash171 2010
[10] C Y Hong and K S Chia ldquoMarkers of diabetic nephropathyrdquoJournal of Diabetes and Its Complications vol 12 no 1 pp 43ndash60 1998
[11] J H Warram L J Scott L S Hanna et al ldquoProgression ofmicroalbuminuria to proteinuria in type 1 diabetes nonlinearrelationshipwith hyperglycemiardquoDiabetes vol 49 no 1 pp 94ndash100 2000
[12] P Fioretto M W Steffes and M Mauer ldquoGlomerular structurein nonproteinuric IDDM patients with various levels of albu-minuriardquo Diabetes vol 43 no 11 pp 1358ndash1364 1994
[13] K McKenna and C Thompson ldquoMicroalbuminuria a markerto increased renal and cardiovascular risk in diabetes mellitusrdquoScottish Medical Journal vol 42 no 4 pp 99ndash104 1997
[14] P Hovind L Tarnow P Rossing et al ldquoPredictors for thedevelopment of microalbuminuria and macroalbuminuria inpatients with type 1 diabetes inception cohort studyrdquo BritishMedical Journal vol 328 no 7448 pp 1105ndash1108 2004
[15] I H de Boer T C Rue P A Cleary et al ldquoLong-term renaloutcomes of patients with type 1 diabetes mellitus and microal-buminuria an analysis of the Diabetes Control and Complica-tions TrialEpidemiology of Diabetes Interventions and Com-plications cohortrdquo Archives of Internal Medicine vol 171 no 5pp 412ndash420 2011
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10 Journal of Diabetes Research
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[56] M H Weber and R Verwiebe ldquo1205721- microglobulin (proteinHC) features of a promising indicator of proximal tubular dys-functionrdquo European Journal of Clinical Chemistry and ClinicalBiochemistry vol 30 no 10 pp 683ndash691 1992
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nephropathyrdquoClinical and Experimental Nephrology vol 19 no5 pp 895ndash890 2015
[81] S S Kim S H Song I J Kim et al ldquoUrinary cystatin C andtubular proteinuria predict progression of diabetic nephropa-thyrdquo Diabetes Care vol 36 no 3 pp 656ndash661 2013
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[83] S E Nielsen T Sugaya P Hovind T Baba H-H Parving andP Rossing ldquoUrinary liver-type fatty acid-binding protein pre-dicts progression to nephropathy in type 1 diabetic patientsrdquoDiabetes Care vol 33 no 6 pp 1320ndash1324 2010
[84] V Viswanathan S Sivakumar V Sekar D M Umapathy andS Kumpatla ldquoClinical significance of urinary liver-type fattyacid binding protein at various stages of nephropathyrdquo IndianJournal of Nephrology vol 25 no 5 pp 269ndash273 2015
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[87] G I Welsh and M A Saleem ldquoNephrinmdashsignature moleculeof the glomerular podocyterdquoThe Journal of Pathology vol 220no 3 pp 328ndash337 2010
[88] F N Ziyadeh and G Wolf ldquoPathogenesis of the podocytopathyand proteinuria in diabetic glomerulopathyrdquo Current DiabetesReviews vol 4 no 1 pp 39ndash45 2008
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[90] D P K Ng B-C Tai E Tan et al ldquoNephrinuria associateswithmultiple renal traits in type 2 diabetesrdquoNephrology DialysisTransplantation vol 26 no 8 pp 2508ndash2514 2011
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[92] B Jim M Ghanta A Qipo et al ldquoDysregulated nephrin indiabetic nephropathy of type 2 diabetes a cross sectional studyrdquoPLoS ONE vol 7 no 5 Article ID e36041 2012
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[96] K Tashiro I Koyanagi A Saitoh et al ldquoUrinary levels ofmono-cyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) and renal injuries in patients with type 2 diabetic nephropa-thyrdquo Journal of Clinical Laboratory Analysis vol 16 no 1pp 1ndash4 2002
12 Journal of Diabetes Research
[97] J Liu Z Zhao M D P Willcox B Xu and B Shi ldquoMultiplexbead analysis of urinary cytokines of type 2 diabetic patientswith normo- and microalbuminuriardquo Journal of Immunoassayand Immunochemistry vol 31 no 4 pp 279ndash289 2010
[98] S Ibrahim and L Rashed ldquoCorrelation of urinary monocytechemo-attractant protein-1 with other parameters of renalinjury in type-II diabetes mellitusrdquo Saudi Journal of Kidney Dis-eases and Transplantation vol 19 no 6 pp 911ndash917 2008
[99] H Jiang G Guan R Zhang et al ldquoIncreased urinary excretionof orosomucoid is a risk predictor of diabetic nephropathyrdquoNephrology vol 14 no 3 pp 332ndash337 2009
[100] N M El-Beblawy N G Andrawes E A Ismail B E EnanyH S Abou El-Seoud and M A Erfan ldquoSerum and Uri-nary orosomucoid in young patients with type 1 diabetes alink between inflammation microvascular complications andsubclinical atherosclerosisrdquo Clinical and Applied ThrombosisHemostasis 2016
[101] M S Christiansen E Hommel E Magid and B Feldt-Rasmussen ldquoOrosomucoid in urine predicts cardiovascular andover-all mortality in patients with type II diabetesrdquo Diabetolo-gia vol 45 no 1 pp 115ndash120 2002
[102] H Ha and H B Lee ldquoOxidative stress in diabetic nephropathybasic and clinical informationrdquo Current Diabetes Reports vol 1no 3 pp 282ndash287 2001
[103] L L Wu C C Chiou P Y Chang and J T Wu ldquoUrinary 8-OHdG a marker of oxidative stress to DNA and a risk factorfor cancer atherosclerosis and diabeticsrdquo Clinica Chemica Actavol 339 no 1-2 pp 1ndash9 2004
[104] Y Hinokio S Suzuki M Hirai C Suzuki M Suzukiand T Toyota ldquoUrinary excretion of 8-oxo-7 8-dihydro-21015840-deoxyguanosine as a predictor of the development of diabeticnephropathyrdquo Diabetologia vol 45 no 6 pp 877ndash882 2002
[105] J Leinonen T Lehtimaki S Toyokuni et al ldquoNew biomarkerevidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitusrdquo FEBS Letters vol 417 no1 pp 150ndash152 1997
[106] K Broedbaek A Weimann E S Stovgaard and H E PoulsenldquoUrinary 8-oxo-78-dihydro-21015840-deoxyguanosine as a biomarkerin type 2 diabetesrdquo Free Radical Biology and Medicine vol 51no 8 pp 1473ndash1479 2011
[107] F L NautaW E Boertien S J L Bakker et al ldquoGlomerular andtubular damage markers are elevated in patients with diabetesrdquoDiabetes Care vol 34 no 4 pp 975ndash981 2011
[108] L Petrica A Vlad G Gluhovschi et al ldquoGlycated peptides areassociated with proximal tubule dysfunction in type 2 diabetesmellitusrdquo International Journal of Clinical and ExperimentalMedicine vol 8 no 2 pp 2516ndash2525 2015
[109] N Turk A Mornar V Mrzljak and Z Turk ldquoUrinary excre-tion of advanced glycation endproducts in patients with type2 diabetes and various stages of proteinuriardquo Diabetes andMetabolism vol 30 no 2 pp 187ndash192 2004
[110] A A Ghanem A Elewa and L F Arafa ldquoPentosidine and N-carboxymethyl-lysine biomarkers for type 2 diabetic retinopa-thyrdquo European Journal of Ophthalmology vol 21 no 1 pp 48ndash54 2011
[111] F Piarulli G Sartore A Ceriello et al ldquoRelationship betweenglyco-oxidation antioxidant status and microalbuminuria intype 2 diabetic patientsrdquo Diabetologia vol 52 no 7 pp 1419ndash1425 2009
[112] M Shoji K Kobayashi M Takemoto Y Sato and K YokoteldquoUrinary podocalyxin levels were associated with urinary albu-min levels among patients with diabetesrdquo Biomarkers vol 21no 2 pp 164ndash167 2015
[113] M Hara K Yamagata Y Tomino et al ldquoUrinary podocalyxinis an early marker for podocyte injury in patients with diabetesestablishment of a highly sensitive ELISA to detect urinarypodocalyxinrdquo Diabetologia vol 55 no 11 pp 2913ndash2919 2012
[114] M Zheng L-L Lv J Ni et al ldquoUrinary podocyte-associatedmRNA profile in various stages of diabetic nephropathyrdquo PLoSONE vol 6 no 5 Article ID e20431 2011
[115] N H Kim K B Kim D L Kim et al ldquoPlasma and urinaryvascular endothelial growth factor and diabetic nephropathy intype 2 diabetes mellitusrdquo Diabetic Medicine vol 21 no 6 pp545ndash551 2004
[116] M Emoto K Mori E Lee et al ldquoFetuin-A and atheroscleroticcalcified plaque in patients with type 2 diabetes mellitusrdquoMetabolism Clinical and Experimental vol 59 no 6 pp 873ndash878 2010
[117] K Inoue J Wada J Eguchi et al ldquoUrinary fetuin-A is a novelmarker for diabetic nephropathy in type 2 diabetes identified bylectin microarrayrdquo PLoS ONE vol 8 no 10 Article ID e771182013
[118] M A K Salem S A El-Habashy O M Saeid M M KEl-Tawil and P H Tawfik ldquoUrinary excretion of N-acetyl-120573-d-glucosaminidase and retinol binding protein as alternativeindicators of nephropathy in patients with type 1 diabetesmellitusrdquo Pediatric Diabetes vol 3 no 1 pp 37ndash41 2002
[119] V Lambadiari N P E KadoglouV Stasinos et al ldquoSerum levelsof retinol-binding protein-4 are associated with the presenceand severity of coronary artery diseaserdquo Cardiovascular Dia-betology vol 13 no 1 article 121 2014
[120] A Shoukry S E-A Bdeer and R H El-Sokkary ldquoUrinarymonocyte chemoattractant protein-1 and vitamin D-bindingprotein as biomarkers for early detection of diabetic nephropa-thy in type 2 diabetesmellitusrdquoMolecular andCellular Biochem-istry vol 408 no 1 pp 25ndash35 2015
[121] Z Li Y Xu Y Nie and Z Zhao ldquoUrinary heme oxygenase-1 as apotential biomarker for early diabetic nephropathyrdquoNephrology(Carlton Vic) 2016
[122] B Satirapoj S Tassanasorn M Charoenpitakchai and OSupasyndh ldquoPeriostin as a tissue and urinary biomarker of renalinjury in type 2 diabetes mellitusrdquo PLoS ONE vol 10 no 4Article ID e0124055 2015
[123] E Y Lee S S Kim J-S Lee et al ldquoSoluble 120572-klotho as a novelbiomarker in the early stage of nephropathy in patients withtype 2 diabetesrdquo PLoS ONE vol 9 no 8 article e102984 2014
[124] A-L Sun J-TDengG-J Guan et al ldquoDipeptidyl peptidase-IVis a potential molecular biomarker in diabetic kidney diseaserdquoDiabetes and Vascular Disease Research vol 9 no 4 pp 301ndash308 2012
[125] Y Yang L Xiao J Li Y S Kanwar F Liu and L Sun ldquoUrinemiRNAs potential biomarkers for monitoring progression ofearly stages of diabetic nephropathyrdquo Medical Hypotheses vol81 no 2 pp 274ndash278 2013
[126] C Argyropoulos K Wang J Bernardo et al ldquoUrinaryMicroRNA profiling predicts the development of microalbu-minuria in patients with type 1 Diabetesrdquo Journal of ClinicalMedicine vol 4 no 7 pp 1495ndash1517 2015
Journal of Diabetes Research 13
[127] M W Kennedy A P Heikema A Cooper P J Bjorkmanand L M Sanchez ldquoHydrophobic ligand binding by Zn-1205722-glycoprotein a soluble fat-depleting factor related to major his-tocompatibility complex proteinsrdquo Journal of Biological Chem-istry vol 276 no 37 pp 35008ndash35013 2001
[128] YWang YM Li S Zhang J Y Zhao and C Y Liu ldquoAdipokinezinc-120572-2- glycoprotein as novel urinary biomarker presentsearly than microalbuminuria in diabetic nephropathyrdquo Journalof International Medical Research vol 44 no 2 pp 278ndash2862016
[129] S C Lim D Q Liying W C Toy et al ldquoAdipocytokine zinc 1205722glycoprotein (ZAG) as a novel urinary biomarker for normo-albuminuric diabetic nephropathyrdquo Diabetic Medicine vol 29no 7 pp 945ndash949 2012
[130] V Thongboonkerd ldquoStudy of diabetic nephropathy in theproteomic erardquo Diabetes and the Kidney vol 170 pp 172ndash1832011
[131] K N Lai and S C W Tang Eds Diabetes and the Kidney vol170 Contributions to Nephrology Karger Basel Switzerland2011
[132] P Zurbig G Jerums P Hovind et al ldquoUrinary proteomics forearly diagnosis in diabetic nephropathyrdquo Diabetes vol 61 no12 pp 3304ndash3313 2012
[133] F Raimondo S Corbetta L Morosi et al ldquoUrinary exosomesand diabetic nephropathy a proteomic approachrdquo MolecularBioSystems vol 9 no 6 pp 1139ndash1146 2013
[134] I Zubiri M Posada-Ayala A Sanz-Maroto et al ldquoDiabeticnephropathy induces changes in the proteome of human uri-nary exosomes as revealed by label-free comparative analysisrdquoJournal of Proteomics vol 96 pp 92ndash102 2014
[135] A Caseiro A Barros R Ferreira et al ldquoPursuing type 1diabetes mellitus and related complications through urinaryproteomicsrdquo Translational Research vol 163 no 3 pp 188ndash1992014
[136] B Jim J Santos F Spath and J C He ldquoBiomarkers of diabeticnephropathy the present and the futurerdquo Current DiabetesReviews vol 8 no 5 pp 317ndash328 2012
involves numerous biomarkers They span the period of nor-moalbuminuria that precedes microalbuminuria but also theevolution of renal involvement duringmicroalbuminuria andmacroalbuminuria
Until they are universally accepted they are analyzedin relationship with the levels of albuminuria especially ofmicroalbuminuria
At present markers of inflammatory and oxidative pro-cesses accompanying DM and DN are also being assessed
Since literature abounds in studies on markers highlight-ing renal dysfunction in different stages of the evolution ofDM we decided to restrict our study to the early phase ofDN
An update of the urinary biomarkers used in early DN isuseful for establishing their role in the early diagnosis of thisdisease with subsequent prophylactic and therapeutic impli-cations We insist on urinary biomarkers because they areeasily drawnwhich allows population screening and becausethey can detect tubular lesions which occur very early inDM
Proteomics is an additional tool offering great prospectsin DN assessment
The origin of the biomarkers employed for assessing renalinvolvement in DM is diverse Some of the biomarkers areconstitutive elements of the nephron such as markers at
(i) epithelial cell (podocyte) level for example nephrineand podocalyxin [3]
(ii) glomerular basement membrane level collagen andlaminin [4]
(iii) endothelial (VEGF) [5](iv) tubular cell level for example NGAL NAG and KIM
[6]
Some have mixed origin they can originate both intubular cells and in podocytes for example angiotensinogen[7 8]
Some are derived from the circulation for example trans-ferrin ceruloplasmin and immunoglobulins G and M Theypass into the urine because of glomerular lesions which resultin increased permeability for plasma proteins
There are several classifications addressing the diversityof urinary biomarkers in DM
Matheson classifies the biomarkers according to boththeir origin and the pathologic processes impairing the neph-ron kidney damage oxidative stress and inflammation
(i) biomarkers of renal dysfunction(ii) inflammatory biomarkers (cytokines and chemoki-
nes)(iii) oxidative stress biomarkers [9]
Another classification belongs to Hong and Chia whopresent 3 categories of biomarkers
(i) glomerular(ii) tubular(iii) other proteins [10]
It should be noted that products ofmetabolism inDMare alsoeliminated in the urine and they can trigger toxic effects forexample advanced glycation end products (AGE)
Since we will frequently refer to microalbuminuria inpresenting other biomarkers used in studying lesions of thenephron namely of the glomerulus and of the tubules wewill first present the main observations regarding microalbu-minuria in diagnosing DN
Recent literature uses new terms like moderatelyincreased albuminuria for microalbuminuria and severelyincreased albuminuria for macroalbuminuria However theclassical terms of microalbuminuria and microalbuminuriacontinue to be in wide use as they are more practical This iswhy we will prefer them in the present paper
Urinary biomarkers use in assessment of early diabeticnephropathy are presented in Table 1
2 Microalbuminuria (Moderately IncreasedAlbuminuria) in Type 1 DM
Microalbuminuria usually begins 5ndash10 years after the onset oftype 1 DM [11]
Kidney biopsy examination in patients with type 1 DMand microalbuminuria most frequently finds normal histo-logical aspects However DN lesions were found in a smallnumber of patients [12]
According to McKenna and Thompson microalbumin-uria is predictive element of the future development of endstage renal disease [13]
Microalbuminuria can regress towards normoalbumin-uria it can persist as such or it can progress towards albumin-uria [14 15]
The evolution of microalbuminuria towards macroal-buminuria is usually related to arterial hypertension andreduced GFR an important part being generally played byrisk factors [16]
Persistent microalbuminuria is related to future develop-ment of end stage renal disease and to cardiovascular risk [13]
It should be noted that diminution of GFR usually occursafter the development of microalbuminuria but there aresituations when even normoalbuminuria is accompanied bydiminution of the GFR [17]
3 Microalbuminuria (Moderately IncreasedAlbuminuria) in Type 2 DM
Microalbuminuria is an important biomarker in type 2 DMbeing frequently used in population-based screenings
Regarding the prevalence of microalbuminuria in type 2DM patients we highlight a review of Newman et al of 28studies on 10294 patients They found microalbuminuria in26 of the patients with ten-year duration of the disease [18]
A study on 24000 patients found that Asian andHispanicpatients with type 2 DM present more often microalbumin-uria (43) than whites (33) [19]
In China Shanghai microalbuminuria has a prevalenceof 41 among patients with type 2 DM [20]
Hypertensive patients with type 2 DM present microal-buminuria more frequently [21]
Journal of Diabetes Research 3
Table 1 Urinary biomarkers in the assessment of early diabetic nephropathy
Neutrophil gelatinase-associated lipocalin (NGAL)Immunoglobulin G Alpha-1-microglobulinCeruloplasmin Kidney injury molecule-1 (KIM-1)Type IV collagen N-acetyl-120573-D glucosaminidaseLaminin AngiotensinogenGlycosaminoglycans Cystatin CLipocalin-type prostaglandin D synthase Liver-type fatty acid binding proteinFibronectin NephrinePodocytes-podocalyxin Heart fatty binding proteinVascular endothelial growth factorVEGF Advanced glycation end productsInflammatory biomarkers Other new markers under study Oxidative stress biomarkersTumor necrosis factor alpha Retinol binding protein-4 8-Oxo-78-dihydro-21015840-deoxyguanosineOrosomucoid Vitamin D binding protein
Heme oxygenase-1Periostin
Alpha klothoMicrovesicle-bound dipeptidyl
peptidase IVMicroRNA
Adipokinesine alpha-2glycoprotein
Microalbuminuria can have a variable evolution It canregress towards normal values it can progress towardsmacroalbuminuria or it can remain unchanged In a studyon 216 patients Araki et al found after a 6-year follow-upregression of microalbuminuria in 51 cases and progressionto severely increased albuminuria in 28 cases [22]
The risk of progression to severely increased albuminuriais higher in patients with microalbuminuria as compared topatients with normoalbuminuria [18]
The diminution of GFR is also higher in patients withseverely increased albuminuria than in those with microal-buminuria [23]
Glycemic control ACE inhibitors and ARBs for bloodpressure control play an important role in the evolution ofmicroalbuminuria It should be mentioned that microalbu-minuria has been considered a glomerular biomarker Todate emerging data point to the role of the tubules in pro-ducingmicroalbuminuria [24 25] As suchwedid not includethis marker among glomerular biomarkers but approached itseparately according to its potential role as both a glomerularand tubular biomarker
31 Glomerular Biomarkers
311 Urinary Transferrin Transferrin is a protein with amolecular weight of 765 KDa Because of its low molecularweight and its less ionic load it filters easily through theglomerular barrier [26]
As increased urinary transferrin was found in type 2DMnormoalbuminuric patients concomitantly with urinary
ceruloplasmin and immunoglobulin G preceding microal-buminuria it could be considered a biomarker of early DN[27]
In microalbuminuric patients the levels of urinary trans-ferrin increase [28] They also increase in patients with type2 DM with vascular complications coronary artery diseasediabetic retinopathy and so forth [29]
Patients with initial high levels of urinary transferrinexcretion will develop microalbuminuria more frequentlythan those with normal levels [30]
312 Urinary Immunoglobulin G It is an anionic plasmaprotein with a molecular weight of 150KDa that crosses theglomerular barrier with difficulty [31]
As presented above urinary IgG can be secreted beforethe stage of microalbuminuria concomitantly with increasedvalues of urinary transferrin urinary ceruloplasmin andurinary orosomucoid [27]
Increased elimination of urinary IgG could thus predictmicroalbuminuria in DM patients [27]
313 Urinary Ceruloplasmin Ceruloplasmin is a copper-transporting serum protein It is filtered with difficulty atglomerular level because it is more negatively charged [32]
It was also found in some type 2 DM patients withnormoalbuminuria arguing in favour of its use for earlydetection of renal lesions even prior to albuminuria ceru-loplasmin could have in type 2 DM patients a DN pre-dictive effect similar to urinary transferrin and urinaryimmunoglobulin G [27] According to Yamazaki et al the
4 Journal of Diabetes Research
urinary ceruloplasmin excretion rate (CER) and clearanceof ceruloplasmin increase in parallel with the progression ofalbuminuria [33]
In fact in type 2 DM patients there could exist aparallelism between increased values of urinary transferrinurinary immunoglobulin G and urinary ceruloplasmin [27]
We conclude that urinary ceruloplasmin could be usedfor the early diagnosis of DN [34]
314 Type IV Urinary Collagen Type IV collagen is acomponent of the glomerular basementmembrane and of themesangial matrix [35]
In DN lesions are produced both at glomerular capillarylevel and at mesangial level Its excretion in urinemight serveas early indicator of renal injury associated with DN [36]
Increased levels of type IV urinary collagen are reportedfor normoalbuminuric patients with type 1 DM It could bea biomarker used for the early diagnosis of DN [37] Otherauthors also report increased excretion of type IV collagenand of laminin in patients with type 1 DM [23]
High urinary type IV collagen excretionwas also reportedin normoalbuminuric patients with impaired glucose toler-ance [38]
Urinary type IV collagen could reflect morphologicalrenal alterations in patients with type 2 DM A relationshipbetween the severity of histological lesions and urinary typeIV collagen was reported in patients with type 2 DM [39]
Type IV urinary collagen is considered to be a specificindicator of early DN [40]
It could also allow both detection of early DN in patientswith type 2 DM and differential diagnosis with glomeru-lonephritis where its levels are low [41]
315 Urinary Laminin Laminin is a component of theglomerular basement membrane Its urinary excretion isincreased in normoalbuminuric type 2 DM patients beingcorrelated with NAG (N-acetyl-beta-D-glucosaminidase)and alpha-1-microglobulin excretion Concomitantlyincreased excretion of type IV collagen is found [4]
316 Urinary Glycosaminoglycans Glycosaminoglycans arecomponents of the glomerular basementmembrane as well asof the extracellular matrix In DM alterations of these occurthe excretion of glycosaminoglycans being increased even innormoalbuminuric patients [42]
Glycosaminoglycans are also present at the level of thetubular basement membrane Urinary glycosaminoglycansare associated with other tubular biomarkers for exampleTamm-Horsfall protein which expresses a distal tubulardysfunction in diabetic patients [43]
317 Lipocalin-Type Prostaglandin-D Synthase (L-PGDS) Itis a biomarker related to lesions of the glomerular capillarywalls and reflects their increased permeability It is mainlyconsidered to predict renal lesions being less relevant as anearly marker of DN [44]
318 Urinary IgM and Urinary Fibronectin These werestudied only sporadically without sufficient data to supporttheir use as markers of early DN
Urinary fibronectin excretion is significantly increased inDMpatients only if they present microalbuminuria [45] IgMis an indicator of impaired kidney function [46]
Although the use of urinary glomerular biomarkers hasnot become current practice yet glomerular biomarkers havebeen reported in some normoalbuminuric patients leadingto the conclusion that albuminuria might not represent themost sensitive glomerular biomarker However their clinicalapplicability needs to be confirmed in high-quality validationstudies [31]
32 Tubular Biomarkers DN is manifested mainly by well-known glomerular lesions The aforementioned biomarkersare identified already precociously early in early DN Tubu-lointerstitial lesions are associated with glomerular injuryduring DN [47] Tubular biomarkers have shown that tubulardysfunction can be present early inDN sometimes precedingglomerular injury These biomarkers have proven highlysensitive as compared to microalbuminuria which is consid-ered the gold standard biomarker of DN In fact presentlymicroalbuminuria is regarded not only as a glomerularbiomarker but also as a tubular one
321 Neutrophil Gelatinase-Associated Lipocalin (NGAL)NGALmdashneutrophil gelatinase-associated lipocalinmdashis a gly-coprotein present in the kidneys at tubular cell level and isconsidered to be protective against renal damage [48]
Urinary NGAL is a biomarker used in assessing tubularlesions in DM its increased values being present even in theinitial phases of the disease namely in normoalbuminuricpatients [49]
Thus in type 1 DM high urinary NGAL can precedemicroalbuminuria [50 51]
Urinary NGAL had high values in type 2 DM patientswith normoalbuminuria increasing progressively in patientswith microalbuminuria and macroalbuminuria The valuesof KIM-1 (kidney injury molecule-1) increased in parallelindicating an early and progressive lesion [52]
However Fu et al reported in type 2 DM patientswho present hyperfiltration and increased values of urinaryNGAL as well as of urinary KIM-1 as compared to the valuesof patients with normal GFR [53]
Urinary NGAL shows the precocity of tubular lesions inpatients with prediabetes [54]
Urinary NGAL in type 2 DM patients could have a role inpredicting the evolution of disease [55]
322 Urinary Alpha-1-Microglobulin Urinary alpha-1-microglobulin is a serum protein with low molecularweight (27-kDa) which allows it to get easily filteredthrough the glomerular capillary wall Once it arrives in theproximal tubule alpha-1-microglobulin is reabsorbed andmetabolized Tubular dysfunction leads to alteration of reab-sorption with increased excretion in the urine [56]
In a cross-sectional study Hong et al analyzed 590type 2 DM patients and found that 336 patients with
Journal of Diabetes Research 5
normoalbuminuria presented increased values of urinaryalpha-1-microglobulin a fact that could be explained by tubu-lar injury that precedes the occurrence of microalbuminuriabeing a more sensitive and an earlier urinary biomarker [57]However alpha-1-microalbuminuria can be absent in somepatients with albuminuria [57] This is why assessments ofalpha-1-microglobulin are associated with the assessment ofother urinary biomarkers urinary albumin included
Petrica et al reported high values of urinary alpha-1-microglobulin in normoalbuminuric patients a fact pleadingfor an early tubular injury in type 2DM in this stageThey didnot find correlations between urinary alpha-1-microglobulinbeta-2 microglobulin and the albumincreatinine ratio withplasma asymmetric dimethyl-arginine This could plead fordissociation between tubular and endothelial dysfunction[58]
Alpha-1-microglobulin in early stages of DM could alsohave a role in predicting DN [59] It is in fact an inexpensivebiomarker of early diagnosis of DN [60]
323 Urinary KIM-1 (Kidney Injury Molecule-1) KIM-1 isa transmembrane glycoprotein located at the level of theproximal tubular cells It is eliminated in urine in case ofinjury at this level It is a sensitive biomarker used with goodresults in acute kidney injury [61]
Petrica et al reported in normoalbuminuric type 2 DMpatients high values of urinary KIM-1 which indicates lesionsof the proximal tubule in early stages of the disease Patientswith microalbuminuria have higher urinary KIM-1 valuesthan those with normoalbuminuria [62]
de Carvalho et al reported in type 2 DM normoal-buminuric patients high values of KIM-1 these valuesincreasing progressively in patients with microalbuminuriaand macroalbuminuria NGAL values studied concomitantlypresented similar evolutions [52]
Moreover KIM-1 presents higher elimination in type2 DM patients with hyperfiltration than in patients withnormal glomerular filtration NGAL has a similar evolutionThese biomarkersmdashKIM-1 and NGALmdashcould plead for adeleterious lesional effect of hyperfiltration on the proximaltubule [53]
Nielsen et al however could not demonstrate a value ofurinary KIM-1 that could be predictive of the evolution ofglomerular function (GFR) in patients with type 1 DM [63]
According to Nielsen et al it has no prognostic utility intype 2 DM patients either [64]
324 Urinary N-Acetyl-120573-D glucosaminidase (NAG) NAG isan enzyme located in the lysosomes of proximal tubular cells[65]
In case of dysfunction namely of injury of proximaltubular cells NAG is eliminated into the urine in higherquantities being a sensitive tubular biomarker This canprecede the appearance of microalbuminuria in type 1 DM[66]
Elevated serum Cys C levels and urinary NAG activitieswere found only in normoalbuminurics not in controls Inaddition elevated urinary ALP and LDH activities were alsofound in microalbuminurics [67]
Other authors like Ambade et al did not find thaturinary NAG has clinical significance as an early biomarkerof DN [68]
In type 2 DM urinary NAG excretion increases propor-tionally to the duration of diabetes It occurs much earlierthan albuminuria NAG can be considered an early tubularbiomarker [69]
Assal et al consider that urinary NAG is the mostsensitive biomarker for detecting early damage in diabeticpatients [70]
325 Urinary Angiotensinogen The renin angiotensin aldos-terone system (RAAS) is involved in the pathogenesis of DNThe constitutive elements of RAAS are present at kidney leveldefining a local RAAS
Urinary angiotensinogen can represent a biomarker forthe activation of RAAS in DM [71]
High urinary angiotensinogen precedes in type 1 DMpatients the occurrence of microalbuminuria [72]This couldhave a predictive role in normotensive type 1 DM patients[73]
Urinary angiotensinogen in normoalbuminuric type 2DM patients is higher than in controls and it increasesprogressively inmicroalbuminuric and especially inmacroal-buminuric patients [73]
Urinary angiotensinogen can be considered an earlybiomarker of DN [72]
In type 2 DM patients urinary angiotensinogen is corre-lated with alpha-1-microglobulin [8]
Kim et al did not confirm these observations in a studyon type 2 DM patients They found that the values ofurinary angiotensinogen are not different from those of thecontrols in normoalbuminuric andmicroalbuminuric type 2DM patients but higher values were described inmacroalbu-minuric patients [74]
These observations point to the need of further studiesnecessary for the validation of this biomarker
Increased urinary angiotensinogen could represent a riskfactor in renal and cardiovascular complications [75]
Since activation of RAAS could intervene in the evolutionof DN administration of ACE-I is recommended
At the same time urinary angiotensinogen could be amarker for assessing the renoprotective effects of alogliptinto type 2 DM patients [76]
326 Cystatin C It is a low molecular weight protein havingthe role of cysteine protease Cystatin is produced by thenucleated cells in the body [77]
It is filtered at glomerular level and is reabsorbed inthe tubules Cystatin is used for evaluating renal functionAssessment of GFR by means of cystatin C is considered tobe a method that is not influenced by body mass being com-parable and even better thanmethods using serum creatinine[78]
Serum cystatin is also considered a sensitive biomarker asit detects minor glomerular injury [79]
Urinary cystatin C indicates tubular injury It increasesearly in diabetes and prediabetic nephropathy [80]
6 Journal of Diabetes Research
Patients with microalbuminuria present higher values ofurinary cystatin C than those without microalbuminuriaurinary cystatin C having a predictive role for the progressionof diabetic nephropathy (DN) [81]
Urinary cystatin C level could be an independentfactor for identifying renal dysfunction in type 2 DMpatients with normoalbuminuria including patients withGFR lt60mLmin173m2 [77] Uslu et al find a significantpositive correlation between serum cystatin C urinary NAGlacticodehydrogenase alkaline phosphatase activities andserum creatinine levels [67]
Serum and urinary cystatin C are useful biomarkers forassessing early nephropathy in type 2 DM [77]
327 L-FABP (Liver-Type Fatty Acid Binding Protein) Uri-nary L-FABP is a protein with low molecular weightexpressed in the cytoplasm of human proximal tubular cells[82] It is also expressed at liver level
Increased urinary L-FABP was found in type 1 DMpatients who presented normoalbuminuria having a predic-tive role regarding the progression towards microalbumin-uria and of microalbuminuria towards macroalbuminuria[83]
Patients with type 2 DM with normoalbuminuria alsopresented high levels of urinary L-FABP this protein beingconsidered as a useful biomarker for diagnosing early diabeticnephropathy In fact urinary L-FABP has been confirmed asa tubular biomarker by the Ministry of Health andWelfare inJapan [82]
The L-FABP factor is also related to the severity of DNThe values of urinary L-FABP increase with the decline ofrenal function [84]
Although some authors like Chou et al do not ascribe apredictive role to urinary L-FABP in type 2 DM patients [85]others like Panduru et al consider that urinary L-FABP is anindependent predictor of the progression of DN [86]
328 Nephrinuria Nephrine is a transmembrane protein inthe structure of the slit diaphragm [87]
InDMpodocyte dysfunction is present DN is considereda podocytopathy [88] Injury of the slit diaphragm leads tonephrinuria
Nephrinuria can occur in some type 1 DM patients priorto microalbuminuria [89] Nephrinuria was also reported insome normoalbuminuric type 2 DM patients [62 90]
Nephrinuria is related to podocyte injury representing abiomarker of early glomerular injury [91]
Dysregulation of nephrine in podocytes in DN couldlead to nephrinuria in normoalbuminuric patients precedingmicroalbuminuria [92]
In albuminuric patients nephrinuria is positively corre-lated with albuminuria and negatively correlated with GFRbeing a biomarker of DN in other phases of DM as well
Podocyte impairment in DM involves not only nephrinebut also other podocyte elements for example VEGF Thusin normoalbuminuric DM patients nephrinuria is correlatedwith urinary elimination of VEGF [62]
Tubular biomarkers seem to play an important role inthe early diagnosis of DN They manage to show in most
cases that microalbuminuria does not represent a reliablebiomarker for diagnosing incipient lesions of DN Howeverup to now none of these biomarkers has been established asgold standard for the identification of early DN
33 Markers of Inflammation DM is accompanied bychronic inflammatory processes affecting the whole body thekidneys included Mediators of inflammation like cytokinesand chemokines are present in these processes Some of themare useful as markers of inflammation
331 Tumour Necrosis Factor Alpha (TNF Alpha) UrinaryTNF alpha presents in type 2 DM patients with microal-buminuria and macroalbuminuria higher values than inpatients with normoalbuminuria Urinary TNF alpha iscorrelatedwith urinaryNAG amarker of tubular lesions [93]
Cherney et al analyzed in a complex study on nor-moalbuminuric type 1 DM patients forty-two urinarycytokineschemokines They found that the urinary level ofIL6 and IL8 the platelet-derived growth factor and RANTESare not altered in patients with normal albumin-creatinineratio
Higher urinary excretion of these markers is associatedwith microalbuminuria Cherney et al consider that thesemarkers could have a role in assessing the risk of DN inpatients with type 1 DM [94]
In type 1 DM patients renal hyperfiltration is related toincreased excretion of inflammatory cytokineschemokines[95]
Tashiro et al found in type 2 DM patients that IL8 is highin early stages of DN andMCP-1 increases in advanced stages[96]
A study on type 2 DM patients with normoalbuminuriaand microalbuminuria found higher values of IL8 IP10MCP-1 G-CSF EOTAXIN and RANTES in patients withmicroalbuminuria than in normoalbuminurics or in controlsTheir assessment would be useful in the early diagnosis andtreatment of DN [97]
Ibrahim and Rached also found that urinary MCP-1 ishigher in patients with microalbuminuria than in normoal-buminurics or healthy controls [98]
332 Urinary Orosomucoid Orosomucoid represents a gly-coprotein involved in inflammatory processes
Urinary orosomucoid has higher values in type 1 DMpatients with normoalbuminuria than in controls These val-ues increase in patients withmicroalbuminuria andmacroal-buminuria [99] Type 2 DM patients presented increasedexcretion of orosomucoid in the urine in parallel with theexcretion of immunoglobulin G ceruloplasmin and trans-ferrin [16] El-Beblawy et al appreciate that orosomucoid isa significant independent factor for diabetic microvascularcomplications and can be considered as an early marker ofrenal injury [100]
Urinary orosomucoid excretion rate in type 2 DMpatients predicts cardiovascular mortality [101]
Urinary markers of inflammation are useful for assessinginflammatory processes in DN even in early stages
Journal of Diabetes Research 7
34 Oxidative Stress Biomarkers Oxidative stress plays animportant part in the development and progression of DN[102]
341 Urinary 8-Oxo-78-dihydro-2-deoxyguanosine (8-oHdG) 8-oHdG is produced secondary to oxidative DNAdamage It is eliminated into the urine without being meta-bolized [103] At present it is considered a marker foroxidative stress
After a 5-year follow-up Hinokio et al find that 8-oxodGin urine is a useful clinical marker to predict the developmentof diabetic nephropathy in diabetic patients There wasa significant progression of diabetic nephropathy in thepatients with higher excretion of 8-oxodG in urine comparedwith the patients with moderate or lower excretion of 8-oxodG [104]
Leinonen et al reported increased excretion of 8-oHdG intype 1 DM patients 9 years after the onset of disease mainlyrelated to poor glycemic control [105]
The urinary 8-oHdG marker of oxidation would beaccording to Broedbaek et al a predictor of long-termmortality in DM [106]
342 Heart Fatty Acid Binding Protein (H-FABP) Heart fattyacid binding protein (H-FABP) is a marker of distal tubulardamage
In a study on a cohort of type 1 and type 2DMpatients andan assessment of their markers of glomerular lesions (IgG)markers of proximal tubular lesions (urinary KIM-1 NAGNGAL and cystatin) and a marker of distal tubular lesions(urinaryH-FABP) in relationshipwith albuminuria andGFRNauta et al reported higher values of urinary NAG NGALand H-FABP in normoalbuminurics than in controls On theother hand the values of urinary cystatin C were low [107]
This shows that normoalbuminuric DM patients presentboth proximal and distal tubular lesions
343 Urinary Advanced Glycation End Products (AGE)AGE eliminated in the urine induce a toxic tubular effectproducing tubular dysfunction
In type 2 DM patients with normoalbuminuria highvalues of urinary alpha-1-microglobulin and of urinary KIM-1 were found secondary to tubular dysfunction prior to theonset of microalbuminuria At the same time urinary AGEwere high being correlated with these markers [108]
Turk et al found in type 2 DM patients high values ofurinary AGE in 50 of the patients with normoalbuminuriaand in 85 of those with microalbuminuria [109]
Pentosidine a component ofAGE is a biomarker for theirformation and accumulation [110]
Piarulli et al found in patients with microalbuminuriahigher values of pentosidine than in patients with normoal-buminuria [111]
344 Podocytes Podocyte lesions appear during DM andDN respectively the disease being considered a podocytopa-thy as mentioned above
The assessment of podocyte injury can be accomplishedby monitoring the number of podocyte cells in the urine
or more precisely by means of using podocyte urinarybiomarkers (podocalyxin and nephrine)
A study onDMpatients found that the values of the num-ber of urinary podocytes in normoalbuminuric patients arenot significantly different from those of controls In patientswithmicroalbuminuria andnephrotic syndrome the numberof urinary podocytes is higher It is correlated with urinaryosteopontin and urinary IgM [33]
Urinary podocalyxin originates in the podocyte apicalsurface occurring in vesicle form In DM patients thepodocalyxin level presented higher levels in patients withmicroalbuminuria than in patients with normoalbuminuria[112]
Another study on DM patients found high values ofurinary podocalyxin in more than half of the patients withnormoalbuminuria these values being higher in patientswith microalbuminuria and macroalbuminuria
Urinary podocalyxin is correlated with the values ofurinary NAG and of urinary beta 2 microglobulin [113]
Hara et al consider that urinary podocalyxin can bean early biomarker for detecting early podocyte injury inpatients with DM
Zheng assessed the urinary microRNA profile ofpodocyte-associated molecules (synaptopodin podocalyxinCD2-AP 120572-actin4 and podocin) as biomarkers in patientswith normoalbuminuria microalbuminuria and macro-albuminuria and they reported its increase during theprogression of DN [114]
345 Vascular Endothelial Growth Factor (VEGF) VEGF isa proangiogenic factor produced mainly by the podocytes atnephron level Urinary VEGF can be considered a podocytebiomarker
Urinary VEGF was detected in type 2 DM patientsbeing correlated in these patients with urinary alpha-1-microglobulin a biomarker for proximal tubular lesions [62]
Kim et al found that VEGF is excreted at higher valuesthan controls in normoalbuminuric type 2 DM patientsThe values increase in patients with microalbuminuria andmacroalbuminuria [115]
Fetuin A is glycosylated glycoprotein was consideredan inhibitor for ectopic calcium deposition and promoterof insulin resistance Fetuin A inhibits the calcification ofatherosclerotic plaques in diabetes mellitus [116] It wasfound that elevated urinary Fetuin A excretion is a risk fordevelopment of diabetic nephropathy [117]
35 Other Urinary Biomarkers Used in Evaluating Early DNNumerous urinarymarkers have been suggested for assessingearly DN Some of them have been introduced in use onlyrecently
Urinary retinol-binding protein is a lowmolecular weightprotein that was found to have high urinary values (togetherwith NAG) in normoalbuminuric patients reflecting tubulardysfunction in early DN [118]
The value of serum retinol-binding protein 4 as a bio-marker in assessing the severity of coronary artery disease isto be mentioned [119]
8 Journal of Diabetes Research
Urinary retinol-binding protein 4 as a biomarker in ass-essing DN needs further studies
Urinary vitamin D binding protein can plays the role asbiomarker In type 2 DM it is attributed a potential role inearly diagnosis of DN [120]
Urinary heme oxygenase-1 was found in type 2 DMpatients before the onset of significant albuminuria thusbeing a possible biomarker of early DN [121] In fact oxidativestress activation is expected in DN
Periostin is a cell adhesion molecule which is not nor-mally present in kidneys In tubulointerstitial lesions it ishowever expressed in the kidneys being eliminated in theurineThis is why urinary periostin could be used as amarkerof injury at this level
Since high levels of periostin can be identified in DMpatients before significant albuminuria periostin could rep-resent a marker of diabetic renal injury [122]
Urinary alpha klotho presents higher values in normoal-buminuric type 2 DM patients than in controls It can also bea marker of diabetic injury [123]
Analyzing a group of normoalbuminuric microalbumin-uric and macroalbuminuric type 2 DM patients Sun et alnoted that the urinary level of microvesicle-bound dipeptidylpeptidase-IV is related to the severity of DN [124]
Recent studies point to the usage of urine-specificmicroRNA as a biomarker for early stages of DN Analyzingthe studies in the literature Yang et al issued the hypothesisthat urine-specific microRNA would be a marker that can beused in the early stages of DN [125]
Recently Argyropoulos highlighted the predictive roleof urinary microRNA regarding microalbuminuria in type 1DM [126]
Adipokine zinc-alpha-2 glycoprotein is assigned to themajor histocompatibility complex class I of proteins [127]
Urinary adipokine zinc-alpha-2 glycoprotein is presentearlier than microalbuminuria in diabetic nephropathy Itcould be a useful biomarker for diagnosing early DN [128]Lim et al also appreciate adipokine zinc-alpha-2 glycoproteinas a novel urinary biomarker for normoalbuminuric diabeticnephropathy [129]
351 Proteomics At present proteomic investigations areengaged in identification of new urinary biomarkers to beused in the early diagnosis of DN
In fact proteomics studies noted the fact that microalbu-minuria is not a perfect biomarker for early detection of DN[130 131]
Urinary proteomics begins to stand out as a noninvasivemethod of detecting early DN
Among proteomics studies on diagnosing DN we canmention those of Zurbig et al who reported that collagenfragments were a prominent biomarker 3ndash5 years before theonset of microalbuminuria [132]
A potential role is also attributed to exosome proteomicsfor identifying new biomarkers for DN [133] Zubiri et alshowed a panel of 3 proteins which is differentially present inurinary exosomes fromDNpatients [134] Urinary proteomicanalysis can have an important role in the implementation ofnew biomarkers in DN [135]
At present the prospect of discovering new biomarkersin DM andDN respectively is incumbent both on proteomicsand on genomics transcriptomics and metabolomics [136]
4 Conclusions
Urinary biomarkers allow an assessment of early DNMicroalbuminuria although frequently contested as a
biomarker of early DN is used so far as reference biomarkerin assessing other urinary biomarkers in early DN Untilpresent there is no other biomarker that can substitute inpractice microalbuminuria the new biomarkers being sus-tained by limited studies and requiring validation
The concomitant assessment of several urinary biomark-ers in relationship with microalbuminuria could represent atpresent a method of diagnosing early DNThe great progressin discovering new biomarkers could lead to the developmentof an ldquoidealrdquo urinary biomarker to detect early diabetic DN inthe future
Progresses in the field of urinary biomarkers in DNpromising both in proteomics and in other modern tech-niques develop remarkably at present
Disclosure
Thesupporting source had no involvement in study design incollection analysis and interpretation of data in the writingof the report and in the decision to submit the paper forpublication
Competing Interests
The authors declare that they have no competing interests
Authorsrsquo Contributions
Cristina Gluhovschi and Gheorghe Gluhovschi contributedequally to this paper
Acknowledgments
This research received funding from an Internal Grantof ldquoVictor Babesrdquo University of Medicine and PharmacyTimisoara PIII-C1-PCFI-20142015
References
[1] R J Macisaac E I Ekinci and G Jerums ldquoMarkers of and riskfactors for the development and progression of diabetic kidneydiseaserdquo American Journal of Kidney Diseases vol 63 no 2 ppS39ndashS62 2014
[2] M Narres H Claessen S Droste et al ldquoThe incidence ofend-stage renal disease in the diabetic (compared to the non-diabetic) population a systematic reviewrdquo PLoS ONE vol 11no 1 Article ID e0147329 2016
[3] E Lioudaki K G Stylianou I Petrakis et al ldquoIncreased urinaryexcretion of podocyte markers in normoalbuminuric patientswith diabetesrdquo Nephron vol 131 no 1 pp 34ndash42 2015
Journal of Diabetes Research 9
[4] N Banu H Hara M Okamura G Egusa and M YamakidoldquoUrinary excretion of type IV collagen and laminin in the eval-uation of nephropathy in NIDDM comparison with urinaryalbumin and markers of tubular dysfunction andor damagerdquoDiabetes Research and Clinical Practice vol 29 no 1 pp 57ndash671995
[5] P Kubisz L Stanciakova J Stasko P Galajda and M MokanldquoEndothelial and platelet markers in diabetes mellitus type 2rdquoWorld Journal of Diabetes vol 6 no 3 pp 423ndash431 2015
[6] G Tramonti and Y S Kanwar ldquoTubular biomarkers to assessprogression of diabetic nephropathyrdquo Kidney International vol79 no 10 pp 1042ndash1044 2011
[7] T Terami J Wada K Inoue et al ldquoUrinary angiotensinogen isa marker for tubular injuries in patients with type 2 diabetesrdquoInternational Journal of Nephrology and Renovascular Diseasevol 6 pp 233ndash240 2013
[8] M Eriguchi R Yotsueda K Torisu et al ldquoAssessment ofurinary angiotensinogen as a marker of podocyte injury inproteinuric nephropathiesrdquo American Journal of PhysiologymdashRenal Physiology vol 310 no 4 pp F322ndashF333 2016
[9] A Matheson M D P Willcox J Flanagan and B J WalshldquoUrinary biomarkers involved in type 2 diabetes a reviewrdquoDiabetesMetabolism Research and Reviews vol 26 no 3 pp150ndash171 2010
[10] C Y Hong and K S Chia ldquoMarkers of diabetic nephropathyrdquoJournal of Diabetes and Its Complications vol 12 no 1 pp 43ndash60 1998
[11] J H Warram L J Scott L S Hanna et al ldquoProgression ofmicroalbuminuria to proteinuria in type 1 diabetes nonlinearrelationshipwith hyperglycemiardquoDiabetes vol 49 no 1 pp 94ndash100 2000
[12] P Fioretto M W Steffes and M Mauer ldquoGlomerular structurein nonproteinuric IDDM patients with various levels of albu-minuriardquo Diabetes vol 43 no 11 pp 1358ndash1364 1994
[13] K McKenna and C Thompson ldquoMicroalbuminuria a markerto increased renal and cardiovascular risk in diabetes mellitusrdquoScottish Medical Journal vol 42 no 4 pp 99ndash104 1997
[14] P Hovind L Tarnow P Rossing et al ldquoPredictors for thedevelopment of microalbuminuria and macroalbuminuria inpatients with type 1 diabetes inception cohort studyrdquo BritishMedical Journal vol 328 no 7448 pp 1105ndash1108 2004
[15] I H de Boer T C Rue P A Cleary et al ldquoLong-term renaloutcomes of patients with type 1 diabetes mellitus and microal-buminuria an analysis of the Diabetes Control and Complica-tions TrialEpidemiology of Diabetes Interventions and Com-plications cohortrdquo Archives of Internal Medicine vol 171 no 5pp 412ndash420 2011
[16] G Zoppini G Targher M Chonchol et al ldquoPredictors ofestimated GFR decline in patients with type 2 diabetes andpreserved kidney functionrdquo Clinical Journal of the AmericanSociety of Nephrology vol 7 no 3 pp 401ndash408 2012
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in a referred cohort of type II diabetic patients a globalperspectiverdquoKidney International vol 69 no 11 pp 2057ndash20632006
[20] B Lu J Wen X Y Song et al ldquoHigh prevalence of albuminuriain population-based patients diagnosed with type 2 diabetesin the Shanghai downtownrdquo Diabetes Research and ClinicalPractice vol 75 no 2 pp 184ndash192 2007
[21] N Ismail B Becker P Strzelczyk and E Ritz ldquoRenal diseaseand hypertension in non-insulin-dependent diabetes mellitusrdquoKidney International vol 55 no 1 pp 1ndash28 1999
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[28] M Kanauchi Y Akai and T Hashimoto ldquoTransferrinuria intype 2 diabetic patients with early nephropathy and tubuloin-terstitial injuryrdquo European Journal of Internal Medicine vol 13no 3 pp 190ndash193 2002
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[31] A Cohen-Bucay and G Viswanathan ldquoUrinary markers ofglomerular injury in diabetic nephropathyrdquo International Jour-nal of Nephrology vol 2012 Article ID 146987 11 pages 2012
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[34] L X Qin X Zeng and G Huang ldquoChanges in serum and urineceruloplasmin concentrations in type 2 diabetesrdquo Zhong NanDa Xue Xue Bao Yi Xue Ban vol 29 no 2 pp 208ndash211 2004
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10 Journal of Diabetes Research
[36] T Fiseha ldquoUrinary biomarkers for early diabetic nephropathyin type 2 diabetic patientsrdquo Biomarker Research vol 3 article16 2015
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[38] H Takizawa T Satoh A Kurusu et al ldquoIncrease of urinarytype IV collagen in normoalbuminuric patients with impairedglucose tolerancerdquo Nephron vol 79 no 4 pp 474ndash475 1998
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[41] S Kado A Aoki S Wada et al ldquoUrinary type IV collagen as amarker for early diabetic nephropathyrdquo Diabetes Research andClinical Practice vol 31 no 1ndash3 pp 103ndash108 1996
[42] I Ueta K Takamatsu and K Hashimoto ldquoUrinary glycos-aminoglycans in patients with incipient diabetic nephropathyrdquoNihon Jinzo Gakkai Shi vol 37 no 1 pp 17ndash23 1995
[43] O Torffvit ldquoUrinary sulphated glycosaminoglycans andTamm-Horsfall protein in type 1 diabetic patientsrdquo ScandinavianJournal of Urology and Nephrology vol 33 no 5 pp 328ndash3321999
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[45] K Kuboki H Tada K Shin Y Oshima and S Isogai ldquoRela-tionship between urinary excretion of fibronectin degradationproducts and proteinuria in diabetic patients and their suppres-sion after continuous subcutaneous heparin infusionrdquoDiabetesResearch and Clinical Practice vol 21 no 1 pp 61ndash66 1993
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[48] K M Schmidt-Ott K Mori Y L Jau et al ldquoDual actionof neutrophil gelatinase-associated lipocalinrdquo Journal of theAmerican Society of Nephrology vol 18 no 2 pp 407ndash413 2007
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[50] Z Yuruk Yıldırım A Nayır A Yılmaz A Gedikbası and RBundak ldquoNeutrophil gelatinase-associated lipocalin as an earlysign of diabetic kidney injury in childrenrdquo Journal of ClinicalResearch in Pediatric Endocrinology vol 7 no 4 pp 274ndash2792015
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[56] M H Weber and R Verwiebe ldquo1205721- microglobulin (proteinHC) features of a promising indicator of proximal tubular dys-functionrdquo European Journal of Clinical Chemistry and ClinicalBiochemistry vol 30 no 10 pp 683ndash691 1992
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[59] H Wainai F Katsukawa I Takei H Maruyama K Kataokaand T Saruta ldquoInfluence of glycemic control and hypertensionon urinary microprotein excretion in non-insulin-dependentdiabetes mellitusrdquo Journal of Diabetic Complications vol 5 no2-3 pp 160ndash161 1991
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[72] T Saito M Urushihara Y Kotani S Kagami and H KoborildquoIncreased urinary angiotensinogen is precedent to increasedurinary albumin in patients with type 1 diabetesrdquo AmericanJournal of the Medical Sciences vol 338 no 6 pp 478ndash4802009
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[76] T Mizushige H Kobori Y Nishijima et al ldquoUrinaryangiotensinogen could be a prognostic marker of renoprotec-tive effects of alogliptin in patients with type 2 diabetesrdquo Journalof Diabetes Research vol 2015 Article ID 517472 7 pages 2015
[77] Y K Jeon M R Kim J E Huh et al ldquoCystatin C as an earlybiomarker of nephropathy in patients with type 2 diabetesrdquoJournal of Korean Medical Science vol 26 no 2 pp 258ndash2632011
[78] W D Comper T M Osicka and G Jerums ldquoHigh prevalenceof immuno-unreactive intact albumin in urine of diabeticpatientsrdquoAmerican Journal of Kidney Diseases vol 41 no 2 pp336ndash342 2003
[79] X Rao M Wan C Qiu and C Jiang ldquoRole of cystatin C inrenal damage and the optimum cut-off point of renal damageamong patients with type 2 diabetesmellitusrdquo Experimental andTherapeutic Medicine vol 8 no 3 pp 887ndash892 2014
[80] V Garg M Kuman H S Mahapatra A Chitkora A K Gad-poyle and V Sekhan ldquoNovel urinary biomarkers in prediabetic
nephropathyrdquoClinical and Experimental Nephrology vol 19 no5 pp 895ndash890 2015
[81] S S Kim S H Song I J Kim et al ldquoUrinary cystatin C andtubular proteinuria predict progression of diabetic nephropa-thyrdquo Diabetes Care vol 36 no 3 pp 656ndash661 2013
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[83] S E Nielsen T Sugaya P Hovind T Baba H-H Parving andP Rossing ldquoUrinary liver-type fatty acid-binding protein pre-dicts progression to nephropathy in type 1 diabetic patientsrdquoDiabetes Care vol 33 no 6 pp 1320ndash1324 2010
[84] V Viswanathan S Sivakumar V Sekar D M Umapathy andS Kumpatla ldquoClinical significance of urinary liver-type fattyacid binding protein at various stages of nephropathyrdquo IndianJournal of Nephrology vol 25 no 5 pp 269ndash273 2015
[85] K-M Chou C-C Lee C-H Chen and C-Y Sun ldquoClinicalvalue of NGAL L-FABP and albuminuria in predicting GFRdecline in type 2 diabetes mellitus patientsrdquo PLoS ONE vol 8no 1 article e54863 2013
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[87] G I Welsh and M A Saleem ldquoNephrinmdashsignature moleculeof the glomerular podocyterdquoThe Journal of Pathology vol 220no 3 pp 328ndash337 2010
[88] F N Ziyadeh and G Wolf ldquoPathogenesis of the podocytopathyand proteinuria in diabetic glomerulopathyrdquo Current DiabetesReviews vol 4 no 1 pp 39ndash45 2008
[89] A Patari C ForsblomMHavana H Taipale P-H Groop andH Holthofer ldquoNephrinuria in diabetic nephropathy of type 1diabetesrdquo Diabetes vol 52 no 12 pp 2969ndash2974 2003
[90] D P K Ng B-C Tai E Tan et al ldquoNephrinuria associateswithmultiple renal traits in type 2 diabetesrdquoNephrology DialysisTransplantation vol 26 no 8 pp 2508ndash2514 2011
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[92] B Jim M Ghanta A Qipo et al ldquoDysregulated nephrin indiabetic nephropathy of type 2 diabetes a cross sectional studyrdquoPLoS ONE vol 7 no 5 Article ID e36041 2012
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[96] K Tashiro I Koyanagi A Saitoh et al ldquoUrinary levels ofmono-cyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) and renal injuries in patients with type 2 diabetic nephropa-thyrdquo Journal of Clinical Laboratory Analysis vol 16 no 1pp 1ndash4 2002
12 Journal of Diabetes Research
[97] J Liu Z Zhao M D P Willcox B Xu and B Shi ldquoMultiplexbead analysis of urinary cytokines of type 2 diabetic patientswith normo- and microalbuminuriardquo Journal of Immunoassayand Immunochemistry vol 31 no 4 pp 279ndash289 2010
[98] S Ibrahim and L Rashed ldquoCorrelation of urinary monocytechemo-attractant protein-1 with other parameters of renalinjury in type-II diabetes mellitusrdquo Saudi Journal of Kidney Dis-eases and Transplantation vol 19 no 6 pp 911ndash917 2008
[99] H Jiang G Guan R Zhang et al ldquoIncreased urinary excretionof orosomucoid is a risk predictor of diabetic nephropathyrdquoNephrology vol 14 no 3 pp 332ndash337 2009
[100] N M El-Beblawy N G Andrawes E A Ismail B E EnanyH S Abou El-Seoud and M A Erfan ldquoSerum and Uri-nary orosomucoid in young patients with type 1 diabetes alink between inflammation microvascular complications andsubclinical atherosclerosisrdquo Clinical and Applied ThrombosisHemostasis 2016
[101] M S Christiansen E Hommel E Magid and B Feldt-Rasmussen ldquoOrosomucoid in urine predicts cardiovascular andover-all mortality in patients with type II diabetesrdquo Diabetolo-gia vol 45 no 1 pp 115ndash120 2002
[102] H Ha and H B Lee ldquoOxidative stress in diabetic nephropathybasic and clinical informationrdquo Current Diabetes Reports vol 1no 3 pp 282ndash287 2001
[103] L L Wu C C Chiou P Y Chang and J T Wu ldquoUrinary 8-OHdG a marker of oxidative stress to DNA and a risk factorfor cancer atherosclerosis and diabeticsrdquo Clinica Chemica Actavol 339 no 1-2 pp 1ndash9 2004
[104] Y Hinokio S Suzuki M Hirai C Suzuki M Suzukiand T Toyota ldquoUrinary excretion of 8-oxo-7 8-dihydro-21015840-deoxyguanosine as a predictor of the development of diabeticnephropathyrdquo Diabetologia vol 45 no 6 pp 877ndash882 2002
[105] J Leinonen T Lehtimaki S Toyokuni et al ldquoNew biomarkerevidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitusrdquo FEBS Letters vol 417 no1 pp 150ndash152 1997
[106] K Broedbaek A Weimann E S Stovgaard and H E PoulsenldquoUrinary 8-oxo-78-dihydro-21015840-deoxyguanosine as a biomarkerin type 2 diabetesrdquo Free Radical Biology and Medicine vol 51no 8 pp 1473ndash1479 2011
[107] F L NautaW E Boertien S J L Bakker et al ldquoGlomerular andtubular damage markers are elevated in patients with diabetesrdquoDiabetes Care vol 34 no 4 pp 975ndash981 2011
[108] L Petrica A Vlad G Gluhovschi et al ldquoGlycated peptides areassociated with proximal tubule dysfunction in type 2 diabetesmellitusrdquo International Journal of Clinical and ExperimentalMedicine vol 8 no 2 pp 2516ndash2525 2015
[109] N Turk A Mornar V Mrzljak and Z Turk ldquoUrinary excre-tion of advanced glycation endproducts in patients with type2 diabetes and various stages of proteinuriardquo Diabetes andMetabolism vol 30 no 2 pp 187ndash192 2004
[110] A A Ghanem A Elewa and L F Arafa ldquoPentosidine and N-carboxymethyl-lysine biomarkers for type 2 diabetic retinopa-thyrdquo European Journal of Ophthalmology vol 21 no 1 pp 48ndash54 2011
[111] F Piarulli G Sartore A Ceriello et al ldquoRelationship betweenglyco-oxidation antioxidant status and microalbuminuria intype 2 diabetic patientsrdquo Diabetologia vol 52 no 7 pp 1419ndash1425 2009
[112] M Shoji K Kobayashi M Takemoto Y Sato and K YokoteldquoUrinary podocalyxin levels were associated with urinary albu-min levels among patients with diabetesrdquo Biomarkers vol 21no 2 pp 164ndash167 2015
[113] M Hara K Yamagata Y Tomino et al ldquoUrinary podocalyxinis an early marker for podocyte injury in patients with diabetesestablishment of a highly sensitive ELISA to detect urinarypodocalyxinrdquo Diabetologia vol 55 no 11 pp 2913ndash2919 2012
[114] M Zheng L-L Lv J Ni et al ldquoUrinary podocyte-associatedmRNA profile in various stages of diabetic nephropathyrdquo PLoSONE vol 6 no 5 Article ID e20431 2011
[115] N H Kim K B Kim D L Kim et al ldquoPlasma and urinaryvascular endothelial growth factor and diabetic nephropathy intype 2 diabetes mellitusrdquo Diabetic Medicine vol 21 no 6 pp545ndash551 2004
[116] M Emoto K Mori E Lee et al ldquoFetuin-A and atheroscleroticcalcified plaque in patients with type 2 diabetes mellitusrdquoMetabolism Clinical and Experimental vol 59 no 6 pp 873ndash878 2010
[117] K Inoue J Wada J Eguchi et al ldquoUrinary fetuin-A is a novelmarker for diabetic nephropathy in type 2 diabetes identified bylectin microarrayrdquo PLoS ONE vol 8 no 10 Article ID e771182013
[118] M A K Salem S A El-Habashy O M Saeid M M KEl-Tawil and P H Tawfik ldquoUrinary excretion of N-acetyl-120573-d-glucosaminidase and retinol binding protein as alternativeindicators of nephropathy in patients with type 1 diabetesmellitusrdquo Pediatric Diabetes vol 3 no 1 pp 37ndash41 2002
[119] V Lambadiari N P E KadoglouV Stasinos et al ldquoSerum levelsof retinol-binding protein-4 are associated with the presenceand severity of coronary artery diseaserdquo Cardiovascular Dia-betology vol 13 no 1 article 121 2014
[120] A Shoukry S E-A Bdeer and R H El-Sokkary ldquoUrinarymonocyte chemoattractant protein-1 and vitamin D-bindingprotein as biomarkers for early detection of diabetic nephropa-thy in type 2 diabetesmellitusrdquoMolecular andCellular Biochem-istry vol 408 no 1 pp 25ndash35 2015
[121] Z Li Y Xu Y Nie and Z Zhao ldquoUrinary heme oxygenase-1 as apotential biomarker for early diabetic nephropathyrdquoNephrology(Carlton Vic) 2016
[122] B Satirapoj S Tassanasorn M Charoenpitakchai and OSupasyndh ldquoPeriostin as a tissue and urinary biomarker of renalinjury in type 2 diabetes mellitusrdquo PLoS ONE vol 10 no 4Article ID e0124055 2015
[123] E Y Lee S S Kim J-S Lee et al ldquoSoluble 120572-klotho as a novelbiomarker in the early stage of nephropathy in patients withtype 2 diabetesrdquo PLoS ONE vol 9 no 8 article e102984 2014
[124] A-L Sun J-TDengG-J Guan et al ldquoDipeptidyl peptidase-IVis a potential molecular biomarker in diabetic kidney diseaserdquoDiabetes and Vascular Disease Research vol 9 no 4 pp 301ndash308 2012
[125] Y Yang L Xiao J Li Y S Kanwar F Liu and L Sun ldquoUrinemiRNAs potential biomarkers for monitoring progression ofearly stages of diabetic nephropathyrdquo Medical Hypotheses vol81 no 2 pp 274ndash278 2013
[126] C Argyropoulos K Wang J Bernardo et al ldquoUrinaryMicroRNA profiling predicts the development of microalbu-minuria in patients with type 1 Diabetesrdquo Journal of ClinicalMedicine vol 4 no 7 pp 1495ndash1517 2015
Journal of Diabetes Research 13
[127] M W Kennedy A P Heikema A Cooper P J Bjorkmanand L M Sanchez ldquoHydrophobic ligand binding by Zn-1205722-glycoprotein a soluble fat-depleting factor related to major his-tocompatibility complex proteinsrdquo Journal of Biological Chem-istry vol 276 no 37 pp 35008ndash35013 2001
[128] YWang YM Li S Zhang J Y Zhao and C Y Liu ldquoAdipokinezinc-120572-2- glycoprotein as novel urinary biomarker presentsearly than microalbuminuria in diabetic nephropathyrdquo Journalof International Medical Research vol 44 no 2 pp 278ndash2862016
[129] S C Lim D Q Liying W C Toy et al ldquoAdipocytokine zinc 1205722glycoprotein (ZAG) as a novel urinary biomarker for normo-albuminuric diabetic nephropathyrdquo Diabetic Medicine vol 29no 7 pp 945ndash949 2012
[130] V Thongboonkerd ldquoStudy of diabetic nephropathy in theproteomic erardquo Diabetes and the Kidney vol 170 pp 172ndash1832011
[131] K N Lai and S C W Tang Eds Diabetes and the Kidney vol170 Contributions to Nephrology Karger Basel Switzerland2011
[132] P Zurbig G Jerums P Hovind et al ldquoUrinary proteomics forearly diagnosis in diabetic nephropathyrdquo Diabetes vol 61 no12 pp 3304ndash3313 2012
[133] F Raimondo S Corbetta L Morosi et al ldquoUrinary exosomesand diabetic nephropathy a proteomic approachrdquo MolecularBioSystems vol 9 no 6 pp 1139ndash1146 2013
[134] I Zubiri M Posada-Ayala A Sanz-Maroto et al ldquoDiabeticnephropathy induces changes in the proteome of human uri-nary exosomes as revealed by label-free comparative analysisrdquoJournal of Proteomics vol 96 pp 92ndash102 2014
[135] A Caseiro A Barros R Ferreira et al ldquoPursuing type 1diabetes mellitus and related complications through urinaryproteomicsrdquo Translational Research vol 163 no 3 pp 188ndash1992014
[136] B Jim J Santos F Spath and J C He ldquoBiomarkers of diabeticnephropathy the present and the futurerdquo Current DiabetesReviews vol 8 no 5 pp 317ndash328 2012
Neutrophil gelatinase-associated lipocalin (NGAL)Immunoglobulin G Alpha-1-microglobulinCeruloplasmin Kidney injury molecule-1 (KIM-1)Type IV collagen N-acetyl-120573-D glucosaminidaseLaminin AngiotensinogenGlycosaminoglycans Cystatin CLipocalin-type prostaglandin D synthase Liver-type fatty acid binding proteinFibronectin NephrinePodocytes-podocalyxin Heart fatty binding proteinVascular endothelial growth factorVEGF Advanced glycation end productsInflammatory biomarkers Other new markers under study Oxidative stress biomarkersTumor necrosis factor alpha Retinol binding protein-4 8-Oxo-78-dihydro-21015840-deoxyguanosineOrosomucoid Vitamin D binding protein
Heme oxygenase-1Periostin
Alpha klothoMicrovesicle-bound dipeptidyl
peptidase IVMicroRNA
Adipokinesine alpha-2glycoprotein
Microalbuminuria can have a variable evolution It canregress towards normal values it can progress towardsmacroalbuminuria or it can remain unchanged In a studyon 216 patients Araki et al found after a 6-year follow-upregression of microalbuminuria in 51 cases and progressionto severely increased albuminuria in 28 cases [22]
The risk of progression to severely increased albuminuriais higher in patients with microalbuminuria as compared topatients with normoalbuminuria [18]
The diminution of GFR is also higher in patients withseverely increased albuminuria than in those with microal-buminuria [23]
Glycemic control ACE inhibitors and ARBs for bloodpressure control play an important role in the evolution ofmicroalbuminuria It should be mentioned that microalbu-minuria has been considered a glomerular biomarker Todate emerging data point to the role of the tubules in pro-ducingmicroalbuminuria [24 25] As suchwedid not includethis marker among glomerular biomarkers but approached itseparately according to its potential role as both a glomerularand tubular biomarker
31 Glomerular Biomarkers
311 Urinary Transferrin Transferrin is a protein with amolecular weight of 765 KDa Because of its low molecularweight and its less ionic load it filters easily through theglomerular barrier [26]
As increased urinary transferrin was found in type 2DMnormoalbuminuric patients concomitantly with urinary
ceruloplasmin and immunoglobulin G preceding microal-buminuria it could be considered a biomarker of early DN[27]
In microalbuminuric patients the levels of urinary trans-ferrin increase [28] They also increase in patients with type2 DM with vascular complications coronary artery diseasediabetic retinopathy and so forth [29]
Patients with initial high levels of urinary transferrinexcretion will develop microalbuminuria more frequentlythan those with normal levels [30]
312 Urinary Immunoglobulin G It is an anionic plasmaprotein with a molecular weight of 150KDa that crosses theglomerular barrier with difficulty [31]
As presented above urinary IgG can be secreted beforethe stage of microalbuminuria concomitantly with increasedvalues of urinary transferrin urinary ceruloplasmin andurinary orosomucoid [27]
Increased elimination of urinary IgG could thus predictmicroalbuminuria in DM patients [27]
313 Urinary Ceruloplasmin Ceruloplasmin is a copper-transporting serum protein It is filtered with difficulty atglomerular level because it is more negatively charged [32]
It was also found in some type 2 DM patients withnormoalbuminuria arguing in favour of its use for earlydetection of renal lesions even prior to albuminuria ceru-loplasmin could have in type 2 DM patients a DN pre-dictive effect similar to urinary transferrin and urinaryimmunoglobulin G [27] According to Yamazaki et al the
4 Journal of Diabetes Research
urinary ceruloplasmin excretion rate (CER) and clearanceof ceruloplasmin increase in parallel with the progression ofalbuminuria [33]
In fact in type 2 DM patients there could exist aparallelism between increased values of urinary transferrinurinary immunoglobulin G and urinary ceruloplasmin [27]
We conclude that urinary ceruloplasmin could be usedfor the early diagnosis of DN [34]
314 Type IV Urinary Collagen Type IV collagen is acomponent of the glomerular basementmembrane and of themesangial matrix [35]
In DN lesions are produced both at glomerular capillarylevel and at mesangial level Its excretion in urinemight serveas early indicator of renal injury associated with DN [36]
Increased levels of type IV urinary collagen are reportedfor normoalbuminuric patients with type 1 DM It could bea biomarker used for the early diagnosis of DN [37] Otherauthors also report increased excretion of type IV collagenand of laminin in patients with type 1 DM [23]
High urinary type IV collagen excretionwas also reportedin normoalbuminuric patients with impaired glucose toler-ance [38]
Urinary type IV collagen could reflect morphologicalrenal alterations in patients with type 2 DM A relationshipbetween the severity of histological lesions and urinary typeIV collagen was reported in patients with type 2 DM [39]
Type IV urinary collagen is considered to be a specificindicator of early DN [40]
It could also allow both detection of early DN in patientswith type 2 DM and differential diagnosis with glomeru-lonephritis where its levels are low [41]
315 Urinary Laminin Laminin is a component of theglomerular basement membrane Its urinary excretion isincreased in normoalbuminuric type 2 DM patients beingcorrelated with NAG (N-acetyl-beta-D-glucosaminidase)and alpha-1-microglobulin excretion Concomitantlyincreased excretion of type IV collagen is found [4]
316 Urinary Glycosaminoglycans Glycosaminoglycans arecomponents of the glomerular basementmembrane as well asof the extracellular matrix In DM alterations of these occurthe excretion of glycosaminoglycans being increased even innormoalbuminuric patients [42]
Glycosaminoglycans are also present at the level of thetubular basement membrane Urinary glycosaminoglycansare associated with other tubular biomarkers for exampleTamm-Horsfall protein which expresses a distal tubulardysfunction in diabetic patients [43]
317 Lipocalin-Type Prostaglandin-D Synthase (L-PGDS) Itis a biomarker related to lesions of the glomerular capillarywalls and reflects their increased permeability It is mainlyconsidered to predict renal lesions being less relevant as anearly marker of DN [44]
318 Urinary IgM and Urinary Fibronectin These werestudied only sporadically without sufficient data to supporttheir use as markers of early DN
Urinary fibronectin excretion is significantly increased inDMpatients only if they present microalbuminuria [45] IgMis an indicator of impaired kidney function [46]
Although the use of urinary glomerular biomarkers hasnot become current practice yet glomerular biomarkers havebeen reported in some normoalbuminuric patients leadingto the conclusion that albuminuria might not represent themost sensitive glomerular biomarker However their clinicalapplicability needs to be confirmed in high-quality validationstudies [31]
32 Tubular Biomarkers DN is manifested mainly by well-known glomerular lesions The aforementioned biomarkersare identified already precociously early in early DN Tubu-lointerstitial lesions are associated with glomerular injuryduring DN [47] Tubular biomarkers have shown that tubulardysfunction can be present early inDN sometimes precedingglomerular injury These biomarkers have proven highlysensitive as compared to microalbuminuria which is consid-ered the gold standard biomarker of DN In fact presentlymicroalbuminuria is regarded not only as a glomerularbiomarker but also as a tubular one
321 Neutrophil Gelatinase-Associated Lipocalin (NGAL)NGALmdashneutrophil gelatinase-associated lipocalinmdashis a gly-coprotein present in the kidneys at tubular cell level and isconsidered to be protective against renal damage [48]
Urinary NGAL is a biomarker used in assessing tubularlesions in DM its increased values being present even in theinitial phases of the disease namely in normoalbuminuricpatients [49]
Thus in type 1 DM high urinary NGAL can precedemicroalbuminuria [50 51]
Urinary NGAL had high values in type 2 DM patientswith normoalbuminuria increasing progressively in patientswith microalbuminuria and macroalbuminuria The valuesof KIM-1 (kidney injury molecule-1) increased in parallelindicating an early and progressive lesion [52]
However Fu et al reported in type 2 DM patientswho present hyperfiltration and increased values of urinaryNGAL as well as of urinary KIM-1 as compared to the valuesof patients with normal GFR [53]
Urinary NGAL shows the precocity of tubular lesions inpatients with prediabetes [54]
Urinary NGAL in type 2 DM patients could have a role inpredicting the evolution of disease [55]
322 Urinary Alpha-1-Microglobulin Urinary alpha-1-microglobulin is a serum protein with low molecularweight (27-kDa) which allows it to get easily filteredthrough the glomerular capillary wall Once it arrives in theproximal tubule alpha-1-microglobulin is reabsorbed andmetabolized Tubular dysfunction leads to alteration of reab-sorption with increased excretion in the urine [56]
In a cross-sectional study Hong et al analyzed 590type 2 DM patients and found that 336 patients with
Journal of Diabetes Research 5
normoalbuminuria presented increased values of urinaryalpha-1-microglobulin a fact that could be explained by tubu-lar injury that precedes the occurrence of microalbuminuriabeing a more sensitive and an earlier urinary biomarker [57]However alpha-1-microalbuminuria can be absent in somepatients with albuminuria [57] This is why assessments ofalpha-1-microglobulin are associated with the assessment ofother urinary biomarkers urinary albumin included
Petrica et al reported high values of urinary alpha-1-microglobulin in normoalbuminuric patients a fact pleadingfor an early tubular injury in type 2DM in this stageThey didnot find correlations between urinary alpha-1-microglobulinbeta-2 microglobulin and the albumincreatinine ratio withplasma asymmetric dimethyl-arginine This could plead fordissociation between tubular and endothelial dysfunction[58]
Alpha-1-microglobulin in early stages of DM could alsohave a role in predicting DN [59] It is in fact an inexpensivebiomarker of early diagnosis of DN [60]
323 Urinary KIM-1 (Kidney Injury Molecule-1) KIM-1 isa transmembrane glycoprotein located at the level of theproximal tubular cells It is eliminated in urine in case ofinjury at this level It is a sensitive biomarker used with goodresults in acute kidney injury [61]
Petrica et al reported in normoalbuminuric type 2 DMpatients high values of urinary KIM-1 which indicates lesionsof the proximal tubule in early stages of the disease Patientswith microalbuminuria have higher urinary KIM-1 valuesthan those with normoalbuminuria [62]
de Carvalho et al reported in type 2 DM normoal-buminuric patients high values of KIM-1 these valuesincreasing progressively in patients with microalbuminuriaand macroalbuminuria NGAL values studied concomitantlypresented similar evolutions [52]
Moreover KIM-1 presents higher elimination in type2 DM patients with hyperfiltration than in patients withnormal glomerular filtration NGAL has a similar evolutionThese biomarkersmdashKIM-1 and NGALmdashcould plead for adeleterious lesional effect of hyperfiltration on the proximaltubule [53]
Nielsen et al however could not demonstrate a value ofurinary KIM-1 that could be predictive of the evolution ofglomerular function (GFR) in patients with type 1 DM [63]
According to Nielsen et al it has no prognostic utility intype 2 DM patients either [64]
324 Urinary N-Acetyl-120573-D glucosaminidase (NAG) NAG isan enzyme located in the lysosomes of proximal tubular cells[65]
In case of dysfunction namely of injury of proximaltubular cells NAG is eliminated into the urine in higherquantities being a sensitive tubular biomarker This canprecede the appearance of microalbuminuria in type 1 DM[66]
Elevated serum Cys C levels and urinary NAG activitieswere found only in normoalbuminurics not in controls Inaddition elevated urinary ALP and LDH activities were alsofound in microalbuminurics [67]
Other authors like Ambade et al did not find thaturinary NAG has clinical significance as an early biomarkerof DN [68]
In type 2 DM urinary NAG excretion increases propor-tionally to the duration of diabetes It occurs much earlierthan albuminuria NAG can be considered an early tubularbiomarker [69]
Assal et al consider that urinary NAG is the mostsensitive biomarker for detecting early damage in diabeticpatients [70]
325 Urinary Angiotensinogen The renin angiotensin aldos-terone system (RAAS) is involved in the pathogenesis of DNThe constitutive elements of RAAS are present at kidney leveldefining a local RAAS
Urinary angiotensinogen can represent a biomarker forthe activation of RAAS in DM [71]
High urinary angiotensinogen precedes in type 1 DMpatients the occurrence of microalbuminuria [72]This couldhave a predictive role in normotensive type 1 DM patients[73]
Urinary angiotensinogen in normoalbuminuric type 2DM patients is higher than in controls and it increasesprogressively inmicroalbuminuric and especially inmacroal-buminuric patients [73]
Urinary angiotensinogen can be considered an earlybiomarker of DN [72]
In type 2 DM patients urinary angiotensinogen is corre-lated with alpha-1-microglobulin [8]
Kim et al did not confirm these observations in a studyon type 2 DM patients They found that the values ofurinary angiotensinogen are not different from those of thecontrols in normoalbuminuric andmicroalbuminuric type 2DM patients but higher values were described inmacroalbu-minuric patients [74]
These observations point to the need of further studiesnecessary for the validation of this biomarker
Increased urinary angiotensinogen could represent a riskfactor in renal and cardiovascular complications [75]
Since activation of RAAS could intervene in the evolutionof DN administration of ACE-I is recommended
At the same time urinary angiotensinogen could be amarker for assessing the renoprotective effects of alogliptinto type 2 DM patients [76]
326 Cystatin C It is a low molecular weight protein havingthe role of cysteine protease Cystatin is produced by thenucleated cells in the body [77]
It is filtered at glomerular level and is reabsorbed inthe tubules Cystatin is used for evaluating renal functionAssessment of GFR by means of cystatin C is considered tobe a method that is not influenced by body mass being com-parable and even better thanmethods using serum creatinine[78]
Serum cystatin is also considered a sensitive biomarker asit detects minor glomerular injury [79]
Urinary cystatin C indicates tubular injury It increasesearly in diabetes and prediabetic nephropathy [80]
6 Journal of Diabetes Research
Patients with microalbuminuria present higher values ofurinary cystatin C than those without microalbuminuriaurinary cystatin C having a predictive role for the progressionof diabetic nephropathy (DN) [81]
Urinary cystatin C level could be an independentfactor for identifying renal dysfunction in type 2 DMpatients with normoalbuminuria including patients withGFR lt60mLmin173m2 [77] Uslu et al find a significantpositive correlation between serum cystatin C urinary NAGlacticodehydrogenase alkaline phosphatase activities andserum creatinine levels [67]
Serum and urinary cystatin C are useful biomarkers forassessing early nephropathy in type 2 DM [77]
327 L-FABP (Liver-Type Fatty Acid Binding Protein) Uri-nary L-FABP is a protein with low molecular weightexpressed in the cytoplasm of human proximal tubular cells[82] It is also expressed at liver level
Increased urinary L-FABP was found in type 1 DMpatients who presented normoalbuminuria having a predic-tive role regarding the progression towards microalbumin-uria and of microalbuminuria towards macroalbuminuria[83]
Patients with type 2 DM with normoalbuminuria alsopresented high levels of urinary L-FABP this protein beingconsidered as a useful biomarker for diagnosing early diabeticnephropathy In fact urinary L-FABP has been confirmed asa tubular biomarker by the Ministry of Health andWelfare inJapan [82]
The L-FABP factor is also related to the severity of DNThe values of urinary L-FABP increase with the decline ofrenal function [84]
Although some authors like Chou et al do not ascribe apredictive role to urinary L-FABP in type 2 DM patients [85]others like Panduru et al consider that urinary L-FABP is anindependent predictor of the progression of DN [86]
328 Nephrinuria Nephrine is a transmembrane protein inthe structure of the slit diaphragm [87]
InDMpodocyte dysfunction is present DN is considereda podocytopathy [88] Injury of the slit diaphragm leads tonephrinuria
Nephrinuria can occur in some type 1 DM patients priorto microalbuminuria [89] Nephrinuria was also reported insome normoalbuminuric type 2 DM patients [62 90]
Nephrinuria is related to podocyte injury representing abiomarker of early glomerular injury [91]
Dysregulation of nephrine in podocytes in DN couldlead to nephrinuria in normoalbuminuric patients precedingmicroalbuminuria [92]
In albuminuric patients nephrinuria is positively corre-lated with albuminuria and negatively correlated with GFRbeing a biomarker of DN in other phases of DM as well
Podocyte impairment in DM involves not only nephrinebut also other podocyte elements for example VEGF Thusin normoalbuminuric DM patients nephrinuria is correlatedwith urinary elimination of VEGF [62]
Tubular biomarkers seem to play an important role inthe early diagnosis of DN They manage to show in most
cases that microalbuminuria does not represent a reliablebiomarker for diagnosing incipient lesions of DN Howeverup to now none of these biomarkers has been established asgold standard for the identification of early DN
33 Markers of Inflammation DM is accompanied bychronic inflammatory processes affecting the whole body thekidneys included Mediators of inflammation like cytokinesand chemokines are present in these processes Some of themare useful as markers of inflammation
331 Tumour Necrosis Factor Alpha (TNF Alpha) UrinaryTNF alpha presents in type 2 DM patients with microal-buminuria and macroalbuminuria higher values than inpatients with normoalbuminuria Urinary TNF alpha iscorrelatedwith urinaryNAG amarker of tubular lesions [93]
Cherney et al analyzed in a complex study on nor-moalbuminuric type 1 DM patients forty-two urinarycytokineschemokines They found that the urinary level ofIL6 and IL8 the platelet-derived growth factor and RANTESare not altered in patients with normal albumin-creatinineratio
Higher urinary excretion of these markers is associatedwith microalbuminuria Cherney et al consider that thesemarkers could have a role in assessing the risk of DN inpatients with type 1 DM [94]
In type 1 DM patients renal hyperfiltration is related toincreased excretion of inflammatory cytokineschemokines[95]
Tashiro et al found in type 2 DM patients that IL8 is highin early stages of DN andMCP-1 increases in advanced stages[96]
A study on type 2 DM patients with normoalbuminuriaand microalbuminuria found higher values of IL8 IP10MCP-1 G-CSF EOTAXIN and RANTES in patients withmicroalbuminuria than in normoalbuminurics or in controlsTheir assessment would be useful in the early diagnosis andtreatment of DN [97]
Ibrahim and Rached also found that urinary MCP-1 ishigher in patients with microalbuminuria than in normoal-buminurics or healthy controls [98]
332 Urinary Orosomucoid Orosomucoid represents a gly-coprotein involved in inflammatory processes
Urinary orosomucoid has higher values in type 1 DMpatients with normoalbuminuria than in controls These val-ues increase in patients withmicroalbuminuria andmacroal-buminuria [99] Type 2 DM patients presented increasedexcretion of orosomucoid in the urine in parallel with theexcretion of immunoglobulin G ceruloplasmin and trans-ferrin [16] El-Beblawy et al appreciate that orosomucoid isa significant independent factor for diabetic microvascularcomplications and can be considered as an early marker ofrenal injury [100]
Urinary orosomucoid excretion rate in type 2 DMpatients predicts cardiovascular mortality [101]
Urinary markers of inflammation are useful for assessinginflammatory processes in DN even in early stages
Journal of Diabetes Research 7
34 Oxidative Stress Biomarkers Oxidative stress plays animportant part in the development and progression of DN[102]
341 Urinary 8-Oxo-78-dihydro-2-deoxyguanosine (8-oHdG) 8-oHdG is produced secondary to oxidative DNAdamage It is eliminated into the urine without being meta-bolized [103] At present it is considered a marker foroxidative stress
After a 5-year follow-up Hinokio et al find that 8-oxodGin urine is a useful clinical marker to predict the developmentof diabetic nephropathy in diabetic patients There wasa significant progression of diabetic nephropathy in thepatients with higher excretion of 8-oxodG in urine comparedwith the patients with moderate or lower excretion of 8-oxodG [104]
Leinonen et al reported increased excretion of 8-oHdG intype 1 DM patients 9 years after the onset of disease mainlyrelated to poor glycemic control [105]
The urinary 8-oHdG marker of oxidation would beaccording to Broedbaek et al a predictor of long-termmortality in DM [106]
342 Heart Fatty Acid Binding Protein (H-FABP) Heart fattyacid binding protein (H-FABP) is a marker of distal tubulardamage
In a study on a cohort of type 1 and type 2DMpatients andan assessment of their markers of glomerular lesions (IgG)markers of proximal tubular lesions (urinary KIM-1 NAGNGAL and cystatin) and a marker of distal tubular lesions(urinaryH-FABP) in relationshipwith albuminuria andGFRNauta et al reported higher values of urinary NAG NGALand H-FABP in normoalbuminurics than in controls On theother hand the values of urinary cystatin C were low [107]
This shows that normoalbuminuric DM patients presentboth proximal and distal tubular lesions
343 Urinary Advanced Glycation End Products (AGE)AGE eliminated in the urine induce a toxic tubular effectproducing tubular dysfunction
In type 2 DM patients with normoalbuminuria highvalues of urinary alpha-1-microglobulin and of urinary KIM-1 were found secondary to tubular dysfunction prior to theonset of microalbuminuria At the same time urinary AGEwere high being correlated with these markers [108]
Turk et al found in type 2 DM patients high values ofurinary AGE in 50 of the patients with normoalbuminuriaand in 85 of those with microalbuminuria [109]
Pentosidine a component ofAGE is a biomarker for theirformation and accumulation [110]
Piarulli et al found in patients with microalbuminuriahigher values of pentosidine than in patients with normoal-buminuria [111]
344 Podocytes Podocyte lesions appear during DM andDN respectively the disease being considered a podocytopa-thy as mentioned above
The assessment of podocyte injury can be accomplishedby monitoring the number of podocyte cells in the urine
or more precisely by means of using podocyte urinarybiomarkers (podocalyxin and nephrine)
A study onDMpatients found that the values of the num-ber of urinary podocytes in normoalbuminuric patients arenot significantly different from those of controls In patientswithmicroalbuminuria andnephrotic syndrome the numberof urinary podocytes is higher It is correlated with urinaryosteopontin and urinary IgM [33]
Urinary podocalyxin originates in the podocyte apicalsurface occurring in vesicle form In DM patients thepodocalyxin level presented higher levels in patients withmicroalbuminuria than in patients with normoalbuminuria[112]
Another study on DM patients found high values ofurinary podocalyxin in more than half of the patients withnormoalbuminuria these values being higher in patientswith microalbuminuria and macroalbuminuria
Urinary podocalyxin is correlated with the values ofurinary NAG and of urinary beta 2 microglobulin [113]
Hara et al consider that urinary podocalyxin can bean early biomarker for detecting early podocyte injury inpatients with DM
Zheng assessed the urinary microRNA profile ofpodocyte-associated molecules (synaptopodin podocalyxinCD2-AP 120572-actin4 and podocin) as biomarkers in patientswith normoalbuminuria microalbuminuria and macro-albuminuria and they reported its increase during theprogression of DN [114]
345 Vascular Endothelial Growth Factor (VEGF) VEGF isa proangiogenic factor produced mainly by the podocytes atnephron level Urinary VEGF can be considered a podocytebiomarker
Urinary VEGF was detected in type 2 DM patientsbeing correlated in these patients with urinary alpha-1-microglobulin a biomarker for proximal tubular lesions [62]
Kim et al found that VEGF is excreted at higher valuesthan controls in normoalbuminuric type 2 DM patientsThe values increase in patients with microalbuminuria andmacroalbuminuria [115]
Fetuin A is glycosylated glycoprotein was consideredan inhibitor for ectopic calcium deposition and promoterof insulin resistance Fetuin A inhibits the calcification ofatherosclerotic plaques in diabetes mellitus [116] It wasfound that elevated urinary Fetuin A excretion is a risk fordevelopment of diabetic nephropathy [117]
35 Other Urinary Biomarkers Used in Evaluating Early DNNumerous urinarymarkers have been suggested for assessingearly DN Some of them have been introduced in use onlyrecently
Urinary retinol-binding protein is a lowmolecular weightprotein that was found to have high urinary values (togetherwith NAG) in normoalbuminuric patients reflecting tubulardysfunction in early DN [118]
The value of serum retinol-binding protein 4 as a bio-marker in assessing the severity of coronary artery disease isto be mentioned [119]
8 Journal of Diabetes Research
Urinary retinol-binding protein 4 as a biomarker in ass-essing DN needs further studies
Urinary vitamin D binding protein can plays the role asbiomarker In type 2 DM it is attributed a potential role inearly diagnosis of DN [120]
Urinary heme oxygenase-1 was found in type 2 DMpatients before the onset of significant albuminuria thusbeing a possible biomarker of early DN [121] In fact oxidativestress activation is expected in DN
Periostin is a cell adhesion molecule which is not nor-mally present in kidneys In tubulointerstitial lesions it ishowever expressed in the kidneys being eliminated in theurineThis is why urinary periostin could be used as amarkerof injury at this level
Since high levels of periostin can be identified in DMpatients before significant albuminuria periostin could rep-resent a marker of diabetic renal injury [122]
Urinary alpha klotho presents higher values in normoal-buminuric type 2 DM patients than in controls It can also bea marker of diabetic injury [123]
Analyzing a group of normoalbuminuric microalbumin-uric and macroalbuminuric type 2 DM patients Sun et alnoted that the urinary level of microvesicle-bound dipeptidylpeptidase-IV is related to the severity of DN [124]
Recent studies point to the usage of urine-specificmicroRNA as a biomarker for early stages of DN Analyzingthe studies in the literature Yang et al issued the hypothesisthat urine-specific microRNA would be a marker that can beused in the early stages of DN [125]
Recently Argyropoulos highlighted the predictive roleof urinary microRNA regarding microalbuminuria in type 1DM [126]
Adipokine zinc-alpha-2 glycoprotein is assigned to themajor histocompatibility complex class I of proteins [127]
Urinary adipokine zinc-alpha-2 glycoprotein is presentearlier than microalbuminuria in diabetic nephropathy Itcould be a useful biomarker for diagnosing early DN [128]Lim et al also appreciate adipokine zinc-alpha-2 glycoproteinas a novel urinary biomarker for normoalbuminuric diabeticnephropathy [129]
351 Proteomics At present proteomic investigations areengaged in identification of new urinary biomarkers to beused in the early diagnosis of DN
In fact proteomics studies noted the fact that microalbu-minuria is not a perfect biomarker for early detection of DN[130 131]
Urinary proteomics begins to stand out as a noninvasivemethod of detecting early DN
Among proteomics studies on diagnosing DN we canmention those of Zurbig et al who reported that collagenfragments were a prominent biomarker 3ndash5 years before theonset of microalbuminuria [132]
A potential role is also attributed to exosome proteomicsfor identifying new biomarkers for DN [133] Zubiri et alshowed a panel of 3 proteins which is differentially present inurinary exosomes fromDNpatients [134] Urinary proteomicanalysis can have an important role in the implementation ofnew biomarkers in DN [135]
At present the prospect of discovering new biomarkersin DM andDN respectively is incumbent both on proteomicsand on genomics transcriptomics and metabolomics [136]
4 Conclusions
Urinary biomarkers allow an assessment of early DNMicroalbuminuria although frequently contested as a
biomarker of early DN is used so far as reference biomarkerin assessing other urinary biomarkers in early DN Untilpresent there is no other biomarker that can substitute inpractice microalbuminuria the new biomarkers being sus-tained by limited studies and requiring validation
The concomitant assessment of several urinary biomark-ers in relationship with microalbuminuria could represent atpresent a method of diagnosing early DNThe great progressin discovering new biomarkers could lead to the developmentof an ldquoidealrdquo urinary biomarker to detect early diabetic DN inthe future
Progresses in the field of urinary biomarkers in DNpromising both in proteomics and in other modern tech-niques develop remarkably at present
Disclosure
Thesupporting source had no involvement in study design incollection analysis and interpretation of data in the writingof the report and in the decision to submit the paper forpublication
Competing Interests
The authors declare that they have no competing interests
Authorsrsquo Contributions
Cristina Gluhovschi and Gheorghe Gluhovschi contributedequally to this paper
Acknowledgments
This research received funding from an Internal Grantof ldquoVictor Babesrdquo University of Medicine and PharmacyTimisoara PIII-C1-PCFI-20142015
References
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[2] M Narres H Claessen S Droste et al ldquoThe incidence ofend-stage renal disease in the diabetic (compared to the non-diabetic) population a systematic reviewrdquo PLoS ONE vol 11no 1 Article ID e0147329 2016
[3] E Lioudaki K G Stylianou I Petrakis et al ldquoIncreased urinaryexcretion of podocyte markers in normoalbuminuric patientswith diabetesrdquo Nephron vol 131 no 1 pp 34ndash42 2015
Journal of Diabetes Research 9
[4] N Banu H Hara M Okamura G Egusa and M YamakidoldquoUrinary excretion of type IV collagen and laminin in the eval-uation of nephropathy in NIDDM comparison with urinaryalbumin and markers of tubular dysfunction andor damagerdquoDiabetes Research and Clinical Practice vol 29 no 1 pp 57ndash671995
[5] P Kubisz L Stanciakova J Stasko P Galajda and M MokanldquoEndothelial and platelet markers in diabetes mellitus type 2rdquoWorld Journal of Diabetes vol 6 no 3 pp 423ndash431 2015
[6] G Tramonti and Y S Kanwar ldquoTubular biomarkers to assessprogression of diabetic nephropathyrdquo Kidney International vol79 no 10 pp 1042ndash1044 2011
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[8] M Eriguchi R Yotsueda K Torisu et al ldquoAssessment ofurinary angiotensinogen as a marker of podocyte injury inproteinuric nephropathiesrdquo American Journal of PhysiologymdashRenal Physiology vol 310 no 4 pp F322ndashF333 2016
[9] A Matheson M D P Willcox J Flanagan and B J WalshldquoUrinary biomarkers involved in type 2 diabetes a reviewrdquoDiabetesMetabolism Research and Reviews vol 26 no 3 pp150ndash171 2010
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10 Journal of Diabetes Research
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[88] F N Ziyadeh and G Wolf ldquoPathogenesis of the podocytopathyand proteinuria in diabetic glomerulopathyrdquo Current DiabetesReviews vol 4 no 1 pp 39ndash45 2008
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[90] D P K Ng B-C Tai E Tan et al ldquoNephrinuria associateswithmultiple renal traits in type 2 diabetesrdquoNephrology DialysisTransplantation vol 26 no 8 pp 2508ndash2514 2011
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[92] B Jim M Ghanta A Qipo et al ldquoDysregulated nephrin indiabetic nephropathy of type 2 diabetes a cross sectional studyrdquoPLoS ONE vol 7 no 5 Article ID e36041 2012
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[96] K Tashiro I Koyanagi A Saitoh et al ldquoUrinary levels ofmono-cyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) and renal injuries in patients with type 2 diabetic nephropa-thyrdquo Journal of Clinical Laboratory Analysis vol 16 no 1pp 1ndash4 2002
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[97] J Liu Z Zhao M D P Willcox B Xu and B Shi ldquoMultiplexbead analysis of urinary cytokines of type 2 diabetic patientswith normo- and microalbuminuriardquo Journal of Immunoassayand Immunochemistry vol 31 no 4 pp 279ndash289 2010
[98] S Ibrahim and L Rashed ldquoCorrelation of urinary monocytechemo-attractant protein-1 with other parameters of renalinjury in type-II diabetes mellitusrdquo Saudi Journal of Kidney Dis-eases and Transplantation vol 19 no 6 pp 911ndash917 2008
[99] H Jiang G Guan R Zhang et al ldquoIncreased urinary excretionof orosomucoid is a risk predictor of diabetic nephropathyrdquoNephrology vol 14 no 3 pp 332ndash337 2009
[100] N M El-Beblawy N G Andrawes E A Ismail B E EnanyH S Abou El-Seoud and M A Erfan ldquoSerum and Uri-nary orosomucoid in young patients with type 1 diabetes alink between inflammation microvascular complications andsubclinical atherosclerosisrdquo Clinical and Applied ThrombosisHemostasis 2016
[101] M S Christiansen E Hommel E Magid and B Feldt-Rasmussen ldquoOrosomucoid in urine predicts cardiovascular andover-all mortality in patients with type II diabetesrdquo Diabetolo-gia vol 45 no 1 pp 115ndash120 2002
[102] H Ha and H B Lee ldquoOxidative stress in diabetic nephropathybasic and clinical informationrdquo Current Diabetes Reports vol 1no 3 pp 282ndash287 2001
[103] L L Wu C C Chiou P Y Chang and J T Wu ldquoUrinary 8-OHdG a marker of oxidative stress to DNA and a risk factorfor cancer atherosclerosis and diabeticsrdquo Clinica Chemica Actavol 339 no 1-2 pp 1ndash9 2004
[104] Y Hinokio S Suzuki M Hirai C Suzuki M Suzukiand T Toyota ldquoUrinary excretion of 8-oxo-7 8-dihydro-21015840-deoxyguanosine as a predictor of the development of diabeticnephropathyrdquo Diabetologia vol 45 no 6 pp 877ndash882 2002
[105] J Leinonen T Lehtimaki S Toyokuni et al ldquoNew biomarkerevidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitusrdquo FEBS Letters vol 417 no1 pp 150ndash152 1997
[106] K Broedbaek A Weimann E S Stovgaard and H E PoulsenldquoUrinary 8-oxo-78-dihydro-21015840-deoxyguanosine as a biomarkerin type 2 diabetesrdquo Free Radical Biology and Medicine vol 51no 8 pp 1473ndash1479 2011
[107] F L NautaW E Boertien S J L Bakker et al ldquoGlomerular andtubular damage markers are elevated in patients with diabetesrdquoDiabetes Care vol 34 no 4 pp 975ndash981 2011
[108] L Petrica A Vlad G Gluhovschi et al ldquoGlycated peptides areassociated with proximal tubule dysfunction in type 2 diabetesmellitusrdquo International Journal of Clinical and ExperimentalMedicine vol 8 no 2 pp 2516ndash2525 2015
[109] N Turk A Mornar V Mrzljak and Z Turk ldquoUrinary excre-tion of advanced glycation endproducts in patients with type2 diabetes and various stages of proteinuriardquo Diabetes andMetabolism vol 30 no 2 pp 187ndash192 2004
[110] A A Ghanem A Elewa and L F Arafa ldquoPentosidine and N-carboxymethyl-lysine biomarkers for type 2 diabetic retinopa-thyrdquo European Journal of Ophthalmology vol 21 no 1 pp 48ndash54 2011
[111] F Piarulli G Sartore A Ceriello et al ldquoRelationship betweenglyco-oxidation antioxidant status and microalbuminuria intype 2 diabetic patientsrdquo Diabetologia vol 52 no 7 pp 1419ndash1425 2009
[112] M Shoji K Kobayashi M Takemoto Y Sato and K YokoteldquoUrinary podocalyxin levels were associated with urinary albu-min levels among patients with diabetesrdquo Biomarkers vol 21no 2 pp 164ndash167 2015
[113] M Hara K Yamagata Y Tomino et al ldquoUrinary podocalyxinis an early marker for podocyte injury in patients with diabetesestablishment of a highly sensitive ELISA to detect urinarypodocalyxinrdquo Diabetologia vol 55 no 11 pp 2913ndash2919 2012
[114] M Zheng L-L Lv J Ni et al ldquoUrinary podocyte-associatedmRNA profile in various stages of diabetic nephropathyrdquo PLoSONE vol 6 no 5 Article ID e20431 2011
[115] N H Kim K B Kim D L Kim et al ldquoPlasma and urinaryvascular endothelial growth factor and diabetic nephropathy intype 2 diabetes mellitusrdquo Diabetic Medicine vol 21 no 6 pp545ndash551 2004
[116] M Emoto K Mori E Lee et al ldquoFetuin-A and atheroscleroticcalcified plaque in patients with type 2 diabetes mellitusrdquoMetabolism Clinical and Experimental vol 59 no 6 pp 873ndash878 2010
[117] K Inoue J Wada J Eguchi et al ldquoUrinary fetuin-A is a novelmarker for diabetic nephropathy in type 2 diabetes identified bylectin microarrayrdquo PLoS ONE vol 8 no 10 Article ID e771182013
[118] M A K Salem S A El-Habashy O M Saeid M M KEl-Tawil and P H Tawfik ldquoUrinary excretion of N-acetyl-120573-d-glucosaminidase and retinol binding protein as alternativeindicators of nephropathy in patients with type 1 diabetesmellitusrdquo Pediatric Diabetes vol 3 no 1 pp 37ndash41 2002
[119] V Lambadiari N P E KadoglouV Stasinos et al ldquoSerum levelsof retinol-binding protein-4 are associated with the presenceand severity of coronary artery diseaserdquo Cardiovascular Dia-betology vol 13 no 1 article 121 2014
[120] A Shoukry S E-A Bdeer and R H El-Sokkary ldquoUrinarymonocyte chemoattractant protein-1 and vitamin D-bindingprotein as biomarkers for early detection of diabetic nephropa-thy in type 2 diabetesmellitusrdquoMolecular andCellular Biochem-istry vol 408 no 1 pp 25ndash35 2015
[121] Z Li Y Xu Y Nie and Z Zhao ldquoUrinary heme oxygenase-1 as apotential biomarker for early diabetic nephropathyrdquoNephrology(Carlton Vic) 2016
[122] B Satirapoj S Tassanasorn M Charoenpitakchai and OSupasyndh ldquoPeriostin as a tissue and urinary biomarker of renalinjury in type 2 diabetes mellitusrdquo PLoS ONE vol 10 no 4Article ID e0124055 2015
[123] E Y Lee S S Kim J-S Lee et al ldquoSoluble 120572-klotho as a novelbiomarker in the early stage of nephropathy in patients withtype 2 diabetesrdquo PLoS ONE vol 9 no 8 article e102984 2014
[124] A-L Sun J-TDengG-J Guan et al ldquoDipeptidyl peptidase-IVis a potential molecular biomarker in diabetic kidney diseaserdquoDiabetes and Vascular Disease Research vol 9 no 4 pp 301ndash308 2012
[125] Y Yang L Xiao J Li Y S Kanwar F Liu and L Sun ldquoUrinemiRNAs potential biomarkers for monitoring progression ofearly stages of diabetic nephropathyrdquo Medical Hypotheses vol81 no 2 pp 274ndash278 2013
[126] C Argyropoulos K Wang J Bernardo et al ldquoUrinaryMicroRNA profiling predicts the development of microalbu-minuria in patients with type 1 Diabetesrdquo Journal of ClinicalMedicine vol 4 no 7 pp 1495ndash1517 2015
Journal of Diabetes Research 13
[127] M W Kennedy A P Heikema A Cooper P J Bjorkmanand L M Sanchez ldquoHydrophobic ligand binding by Zn-1205722-glycoprotein a soluble fat-depleting factor related to major his-tocompatibility complex proteinsrdquo Journal of Biological Chem-istry vol 276 no 37 pp 35008ndash35013 2001
[128] YWang YM Li S Zhang J Y Zhao and C Y Liu ldquoAdipokinezinc-120572-2- glycoprotein as novel urinary biomarker presentsearly than microalbuminuria in diabetic nephropathyrdquo Journalof International Medical Research vol 44 no 2 pp 278ndash2862016
[129] S C Lim D Q Liying W C Toy et al ldquoAdipocytokine zinc 1205722glycoprotein (ZAG) as a novel urinary biomarker for normo-albuminuric diabetic nephropathyrdquo Diabetic Medicine vol 29no 7 pp 945ndash949 2012
[130] V Thongboonkerd ldquoStudy of diabetic nephropathy in theproteomic erardquo Diabetes and the Kidney vol 170 pp 172ndash1832011
[131] K N Lai and S C W Tang Eds Diabetes and the Kidney vol170 Contributions to Nephrology Karger Basel Switzerland2011
[132] P Zurbig G Jerums P Hovind et al ldquoUrinary proteomics forearly diagnosis in diabetic nephropathyrdquo Diabetes vol 61 no12 pp 3304ndash3313 2012
[133] F Raimondo S Corbetta L Morosi et al ldquoUrinary exosomesand diabetic nephropathy a proteomic approachrdquo MolecularBioSystems vol 9 no 6 pp 1139ndash1146 2013
[134] I Zubiri M Posada-Ayala A Sanz-Maroto et al ldquoDiabeticnephropathy induces changes in the proteome of human uri-nary exosomes as revealed by label-free comparative analysisrdquoJournal of Proteomics vol 96 pp 92ndash102 2014
[135] A Caseiro A Barros R Ferreira et al ldquoPursuing type 1diabetes mellitus and related complications through urinaryproteomicsrdquo Translational Research vol 163 no 3 pp 188ndash1992014
[136] B Jim J Santos F Spath and J C He ldquoBiomarkers of diabeticnephropathy the present and the futurerdquo Current DiabetesReviews vol 8 no 5 pp 317ndash328 2012
urinary ceruloplasmin excretion rate (CER) and clearanceof ceruloplasmin increase in parallel with the progression ofalbuminuria [33]
In fact in type 2 DM patients there could exist aparallelism between increased values of urinary transferrinurinary immunoglobulin G and urinary ceruloplasmin [27]
We conclude that urinary ceruloplasmin could be usedfor the early diagnosis of DN [34]
314 Type IV Urinary Collagen Type IV collagen is acomponent of the glomerular basementmembrane and of themesangial matrix [35]
In DN lesions are produced both at glomerular capillarylevel and at mesangial level Its excretion in urinemight serveas early indicator of renal injury associated with DN [36]
Increased levels of type IV urinary collagen are reportedfor normoalbuminuric patients with type 1 DM It could bea biomarker used for the early diagnosis of DN [37] Otherauthors also report increased excretion of type IV collagenand of laminin in patients with type 1 DM [23]
High urinary type IV collagen excretionwas also reportedin normoalbuminuric patients with impaired glucose toler-ance [38]
Urinary type IV collagen could reflect morphologicalrenal alterations in patients with type 2 DM A relationshipbetween the severity of histological lesions and urinary typeIV collagen was reported in patients with type 2 DM [39]
Type IV urinary collagen is considered to be a specificindicator of early DN [40]
It could also allow both detection of early DN in patientswith type 2 DM and differential diagnosis with glomeru-lonephritis where its levels are low [41]
315 Urinary Laminin Laminin is a component of theglomerular basement membrane Its urinary excretion isincreased in normoalbuminuric type 2 DM patients beingcorrelated with NAG (N-acetyl-beta-D-glucosaminidase)and alpha-1-microglobulin excretion Concomitantlyincreased excretion of type IV collagen is found [4]
316 Urinary Glycosaminoglycans Glycosaminoglycans arecomponents of the glomerular basementmembrane as well asof the extracellular matrix In DM alterations of these occurthe excretion of glycosaminoglycans being increased even innormoalbuminuric patients [42]
Glycosaminoglycans are also present at the level of thetubular basement membrane Urinary glycosaminoglycansare associated with other tubular biomarkers for exampleTamm-Horsfall protein which expresses a distal tubulardysfunction in diabetic patients [43]
317 Lipocalin-Type Prostaglandin-D Synthase (L-PGDS) Itis a biomarker related to lesions of the glomerular capillarywalls and reflects their increased permeability It is mainlyconsidered to predict renal lesions being less relevant as anearly marker of DN [44]
318 Urinary IgM and Urinary Fibronectin These werestudied only sporadically without sufficient data to supporttheir use as markers of early DN
Urinary fibronectin excretion is significantly increased inDMpatients only if they present microalbuminuria [45] IgMis an indicator of impaired kidney function [46]
Although the use of urinary glomerular biomarkers hasnot become current practice yet glomerular biomarkers havebeen reported in some normoalbuminuric patients leadingto the conclusion that albuminuria might not represent themost sensitive glomerular biomarker However their clinicalapplicability needs to be confirmed in high-quality validationstudies [31]
32 Tubular Biomarkers DN is manifested mainly by well-known glomerular lesions The aforementioned biomarkersare identified already precociously early in early DN Tubu-lointerstitial lesions are associated with glomerular injuryduring DN [47] Tubular biomarkers have shown that tubulardysfunction can be present early inDN sometimes precedingglomerular injury These biomarkers have proven highlysensitive as compared to microalbuminuria which is consid-ered the gold standard biomarker of DN In fact presentlymicroalbuminuria is regarded not only as a glomerularbiomarker but also as a tubular one
321 Neutrophil Gelatinase-Associated Lipocalin (NGAL)NGALmdashneutrophil gelatinase-associated lipocalinmdashis a gly-coprotein present in the kidneys at tubular cell level and isconsidered to be protective against renal damage [48]
Urinary NGAL is a biomarker used in assessing tubularlesions in DM its increased values being present even in theinitial phases of the disease namely in normoalbuminuricpatients [49]
Thus in type 1 DM high urinary NGAL can precedemicroalbuminuria [50 51]
Urinary NGAL had high values in type 2 DM patientswith normoalbuminuria increasing progressively in patientswith microalbuminuria and macroalbuminuria The valuesof KIM-1 (kidney injury molecule-1) increased in parallelindicating an early and progressive lesion [52]
However Fu et al reported in type 2 DM patientswho present hyperfiltration and increased values of urinaryNGAL as well as of urinary KIM-1 as compared to the valuesof patients with normal GFR [53]
Urinary NGAL shows the precocity of tubular lesions inpatients with prediabetes [54]
Urinary NGAL in type 2 DM patients could have a role inpredicting the evolution of disease [55]
322 Urinary Alpha-1-Microglobulin Urinary alpha-1-microglobulin is a serum protein with low molecularweight (27-kDa) which allows it to get easily filteredthrough the glomerular capillary wall Once it arrives in theproximal tubule alpha-1-microglobulin is reabsorbed andmetabolized Tubular dysfunction leads to alteration of reab-sorption with increased excretion in the urine [56]
In a cross-sectional study Hong et al analyzed 590type 2 DM patients and found that 336 patients with
Journal of Diabetes Research 5
normoalbuminuria presented increased values of urinaryalpha-1-microglobulin a fact that could be explained by tubu-lar injury that precedes the occurrence of microalbuminuriabeing a more sensitive and an earlier urinary biomarker [57]However alpha-1-microalbuminuria can be absent in somepatients with albuminuria [57] This is why assessments ofalpha-1-microglobulin are associated with the assessment ofother urinary biomarkers urinary albumin included
Petrica et al reported high values of urinary alpha-1-microglobulin in normoalbuminuric patients a fact pleadingfor an early tubular injury in type 2DM in this stageThey didnot find correlations between urinary alpha-1-microglobulinbeta-2 microglobulin and the albumincreatinine ratio withplasma asymmetric dimethyl-arginine This could plead fordissociation between tubular and endothelial dysfunction[58]
Alpha-1-microglobulin in early stages of DM could alsohave a role in predicting DN [59] It is in fact an inexpensivebiomarker of early diagnosis of DN [60]
323 Urinary KIM-1 (Kidney Injury Molecule-1) KIM-1 isa transmembrane glycoprotein located at the level of theproximal tubular cells It is eliminated in urine in case ofinjury at this level It is a sensitive biomarker used with goodresults in acute kidney injury [61]
Petrica et al reported in normoalbuminuric type 2 DMpatients high values of urinary KIM-1 which indicates lesionsof the proximal tubule in early stages of the disease Patientswith microalbuminuria have higher urinary KIM-1 valuesthan those with normoalbuminuria [62]
de Carvalho et al reported in type 2 DM normoal-buminuric patients high values of KIM-1 these valuesincreasing progressively in patients with microalbuminuriaand macroalbuminuria NGAL values studied concomitantlypresented similar evolutions [52]
Moreover KIM-1 presents higher elimination in type2 DM patients with hyperfiltration than in patients withnormal glomerular filtration NGAL has a similar evolutionThese biomarkersmdashKIM-1 and NGALmdashcould plead for adeleterious lesional effect of hyperfiltration on the proximaltubule [53]
Nielsen et al however could not demonstrate a value ofurinary KIM-1 that could be predictive of the evolution ofglomerular function (GFR) in patients with type 1 DM [63]
According to Nielsen et al it has no prognostic utility intype 2 DM patients either [64]
324 Urinary N-Acetyl-120573-D glucosaminidase (NAG) NAG isan enzyme located in the lysosomes of proximal tubular cells[65]
In case of dysfunction namely of injury of proximaltubular cells NAG is eliminated into the urine in higherquantities being a sensitive tubular biomarker This canprecede the appearance of microalbuminuria in type 1 DM[66]
Elevated serum Cys C levels and urinary NAG activitieswere found only in normoalbuminurics not in controls Inaddition elevated urinary ALP and LDH activities were alsofound in microalbuminurics [67]
Other authors like Ambade et al did not find thaturinary NAG has clinical significance as an early biomarkerof DN [68]
In type 2 DM urinary NAG excretion increases propor-tionally to the duration of diabetes It occurs much earlierthan albuminuria NAG can be considered an early tubularbiomarker [69]
Assal et al consider that urinary NAG is the mostsensitive biomarker for detecting early damage in diabeticpatients [70]
325 Urinary Angiotensinogen The renin angiotensin aldos-terone system (RAAS) is involved in the pathogenesis of DNThe constitutive elements of RAAS are present at kidney leveldefining a local RAAS
Urinary angiotensinogen can represent a biomarker forthe activation of RAAS in DM [71]
High urinary angiotensinogen precedes in type 1 DMpatients the occurrence of microalbuminuria [72]This couldhave a predictive role in normotensive type 1 DM patients[73]
Urinary angiotensinogen in normoalbuminuric type 2DM patients is higher than in controls and it increasesprogressively inmicroalbuminuric and especially inmacroal-buminuric patients [73]
Urinary angiotensinogen can be considered an earlybiomarker of DN [72]
In type 2 DM patients urinary angiotensinogen is corre-lated with alpha-1-microglobulin [8]
Kim et al did not confirm these observations in a studyon type 2 DM patients They found that the values ofurinary angiotensinogen are not different from those of thecontrols in normoalbuminuric andmicroalbuminuric type 2DM patients but higher values were described inmacroalbu-minuric patients [74]
These observations point to the need of further studiesnecessary for the validation of this biomarker
Increased urinary angiotensinogen could represent a riskfactor in renal and cardiovascular complications [75]
Since activation of RAAS could intervene in the evolutionof DN administration of ACE-I is recommended
At the same time urinary angiotensinogen could be amarker for assessing the renoprotective effects of alogliptinto type 2 DM patients [76]
326 Cystatin C It is a low molecular weight protein havingthe role of cysteine protease Cystatin is produced by thenucleated cells in the body [77]
It is filtered at glomerular level and is reabsorbed inthe tubules Cystatin is used for evaluating renal functionAssessment of GFR by means of cystatin C is considered tobe a method that is not influenced by body mass being com-parable and even better thanmethods using serum creatinine[78]
Serum cystatin is also considered a sensitive biomarker asit detects minor glomerular injury [79]
Urinary cystatin C indicates tubular injury It increasesearly in diabetes and prediabetic nephropathy [80]
6 Journal of Diabetes Research
Patients with microalbuminuria present higher values ofurinary cystatin C than those without microalbuminuriaurinary cystatin C having a predictive role for the progressionof diabetic nephropathy (DN) [81]
Urinary cystatin C level could be an independentfactor for identifying renal dysfunction in type 2 DMpatients with normoalbuminuria including patients withGFR lt60mLmin173m2 [77] Uslu et al find a significantpositive correlation between serum cystatin C urinary NAGlacticodehydrogenase alkaline phosphatase activities andserum creatinine levels [67]
Serum and urinary cystatin C are useful biomarkers forassessing early nephropathy in type 2 DM [77]
327 L-FABP (Liver-Type Fatty Acid Binding Protein) Uri-nary L-FABP is a protein with low molecular weightexpressed in the cytoplasm of human proximal tubular cells[82] It is also expressed at liver level
Increased urinary L-FABP was found in type 1 DMpatients who presented normoalbuminuria having a predic-tive role regarding the progression towards microalbumin-uria and of microalbuminuria towards macroalbuminuria[83]
Patients with type 2 DM with normoalbuminuria alsopresented high levels of urinary L-FABP this protein beingconsidered as a useful biomarker for diagnosing early diabeticnephropathy In fact urinary L-FABP has been confirmed asa tubular biomarker by the Ministry of Health andWelfare inJapan [82]
The L-FABP factor is also related to the severity of DNThe values of urinary L-FABP increase with the decline ofrenal function [84]
Although some authors like Chou et al do not ascribe apredictive role to urinary L-FABP in type 2 DM patients [85]others like Panduru et al consider that urinary L-FABP is anindependent predictor of the progression of DN [86]
328 Nephrinuria Nephrine is a transmembrane protein inthe structure of the slit diaphragm [87]
InDMpodocyte dysfunction is present DN is considereda podocytopathy [88] Injury of the slit diaphragm leads tonephrinuria
Nephrinuria can occur in some type 1 DM patients priorto microalbuminuria [89] Nephrinuria was also reported insome normoalbuminuric type 2 DM patients [62 90]
Nephrinuria is related to podocyte injury representing abiomarker of early glomerular injury [91]
Dysregulation of nephrine in podocytes in DN couldlead to nephrinuria in normoalbuminuric patients precedingmicroalbuminuria [92]
In albuminuric patients nephrinuria is positively corre-lated with albuminuria and negatively correlated with GFRbeing a biomarker of DN in other phases of DM as well
Podocyte impairment in DM involves not only nephrinebut also other podocyte elements for example VEGF Thusin normoalbuminuric DM patients nephrinuria is correlatedwith urinary elimination of VEGF [62]
Tubular biomarkers seem to play an important role inthe early diagnosis of DN They manage to show in most
cases that microalbuminuria does not represent a reliablebiomarker for diagnosing incipient lesions of DN Howeverup to now none of these biomarkers has been established asgold standard for the identification of early DN
33 Markers of Inflammation DM is accompanied bychronic inflammatory processes affecting the whole body thekidneys included Mediators of inflammation like cytokinesand chemokines are present in these processes Some of themare useful as markers of inflammation
331 Tumour Necrosis Factor Alpha (TNF Alpha) UrinaryTNF alpha presents in type 2 DM patients with microal-buminuria and macroalbuminuria higher values than inpatients with normoalbuminuria Urinary TNF alpha iscorrelatedwith urinaryNAG amarker of tubular lesions [93]
Cherney et al analyzed in a complex study on nor-moalbuminuric type 1 DM patients forty-two urinarycytokineschemokines They found that the urinary level ofIL6 and IL8 the platelet-derived growth factor and RANTESare not altered in patients with normal albumin-creatinineratio
Higher urinary excretion of these markers is associatedwith microalbuminuria Cherney et al consider that thesemarkers could have a role in assessing the risk of DN inpatients with type 1 DM [94]
In type 1 DM patients renal hyperfiltration is related toincreased excretion of inflammatory cytokineschemokines[95]
Tashiro et al found in type 2 DM patients that IL8 is highin early stages of DN andMCP-1 increases in advanced stages[96]
A study on type 2 DM patients with normoalbuminuriaand microalbuminuria found higher values of IL8 IP10MCP-1 G-CSF EOTAXIN and RANTES in patients withmicroalbuminuria than in normoalbuminurics or in controlsTheir assessment would be useful in the early diagnosis andtreatment of DN [97]
Ibrahim and Rached also found that urinary MCP-1 ishigher in patients with microalbuminuria than in normoal-buminurics or healthy controls [98]
332 Urinary Orosomucoid Orosomucoid represents a gly-coprotein involved in inflammatory processes
Urinary orosomucoid has higher values in type 1 DMpatients with normoalbuminuria than in controls These val-ues increase in patients withmicroalbuminuria andmacroal-buminuria [99] Type 2 DM patients presented increasedexcretion of orosomucoid in the urine in parallel with theexcretion of immunoglobulin G ceruloplasmin and trans-ferrin [16] El-Beblawy et al appreciate that orosomucoid isa significant independent factor for diabetic microvascularcomplications and can be considered as an early marker ofrenal injury [100]
Urinary orosomucoid excretion rate in type 2 DMpatients predicts cardiovascular mortality [101]
Urinary markers of inflammation are useful for assessinginflammatory processes in DN even in early stages
Journal of Diabetes Research 7
34 Oxidative Stress Biomarkers Oxidative stress plays animportant part in the development and progression of DN[102]
341 Urinary 8-Oxo-78-dihydro-2-deoxyguanosine (8-oHdG) 8-oHdG is produced secondary to oxidative DNAdamage It is eliminated into the urine without being meta-bolized [103] At present it is considered a marker foroxidative stress
After a 5-year follow-up Hinokio et al find that 8-oxodGin urine is a useful clinical marker to predict the developmentof diabetic nephropathy in diabetic patients There wasa significant progression of diabetic nephropathy in thepatients with higher excretion of 8-oxodG in urine comparedwith the patients with moderate or lower excretion of 8-oxodG [104]
Leinonen et al reported increased excretion of 8-oHdG intype 1 DM patients 9 years after the onset of disease mainlyrelated to poor glycemic control [105]
The urinary 8-oHdG marker of oxidation would beaccording to Broedbaek et al a predictor of long-termmortality in DM [106]
342 Heart Fatty Acid Binding Protein (H-FABP) Heart fattyacid binding protein (H-FABP) is a marker of distal tubulardamage
In a study on a cohort of type 1 and type 2DMpatients andan assessment of their markers of glomerular lesions (IgG)markers of proximal tubular lesions (urinary KIM-1 NAGNGAL and cystatin) and a marker of distal tubular lesions(urinaryH-FABP) in relationshipwith albuminuria andGFRNauta et al reported higher values of urinary NAG NGALand H-FABP in normoalbuminurics than in controls On theother hand the values of urinary cystatin C were low [107]
This shows that normoalbuminuric DM patients presentboth proximal and distal tubular lesions
343 Urinary Advanced Glycation End Products (AGE)AGE eliminated in the urine induce a toxic tubular effectproducing tubular dysfunction
In type 2 DM patients with normoalbuminuria highvalues of urinary alpha-1-microglobulin and of urinary KIM-1 were found secondary to tubular dysfunction prior to theonset of microalbuminuria At the same time urinary AGEwere high being correlated with these markers [108]
Turk et al found in type 2 DM patients high values ofurinary AGE in 50 of the patients with normoalbuminuriaand in 85 of those with microalbuminuria [109]
Pentosidine a component ofAGE is a biomarker for theirformation and accumulation [110]
Piarulli et al found in patients with microalbuminuriahigher values of pentosidine than in patients with normoal-buminuria [111]
344 Podocytes Podocyte lesions appear during DM andDN respectively the disease being considered a podocytopa-thy as mentioned above
The assessment of podocyte injury can be accomplishedby monitoring the number of podocyte cells in the urine
or more precisely by means of using podocyte urinarybiomarkers (podocalyxin and nephrine)
A study onDMpatients found that the values of the num-ber of urinary podocytes in normoalbuminuric patients arenot significantly different from those of controls In patientswithmicroalbuminuria andnephrotic syndrome the numberof urinary podocytes is higher It is correlated with urinaryosteopontin and urinary IgM [33]
Urinary podocalyxin originates in the podocyte apicalsurface occurring in vesicle form In DM patients thepodocalyxin level presented higher levels in patients withmicroalbuminuria than in patients with normoalbuminuria[112]
Another study on DM patients found high values ofurinary podocalyxin in more than half of the patients withnormoalbuminuria these values being higher in patientswith microalbuminuria and macroalbuminuria
Urinary podocalyxin is correlated with the values ofurinary NAG and of urinary beta 2 microglobulin [113]
Hara et al consider that urinary podocalyxin can bean early biomarker for detecting early podocyte injury inpatients with DM
Zheng assessed the urinary microRNA profile ofpodocyte-associated molecules (synaptopodin podocalyxinCD2-AP 120572-actin4 and podocin) as biomarkers in patientswith normoalbuminuria microalbuminuria and macro-albuminuria and they reported its increase during theprogression of DN [114]
345 Vascular Endothelial Growth Factor (VEGF) VEGF isa proangiogenic factor produced mainly by the podocytes atnephron level Urinary VEGF can be considered a podocytebiomarker
Urinary VEGF was detected in type 2 DM patientsbeing correlated in these patients with urinary alpha-1-microglobulin a biomarker for proximal tubular lesions [62]
Kim et al found that VEGF is excreted at higher valuesthan controls in normoalbuminuric type 2 DM patientsThe values increase in patients with microalbuminuria andmacroalbuminuria [115]
Fetuin A is glycosylated glycoprotein was consideredan inhibitor for ectopic calcium deposition and promoterof insulin resistance Fetuin A inhibits the calcification ofatherosclerotic plaques in diabetes mellitus [116] It wasfound that elevated urinary Fetuin A excretion is a risk fordevelopment of diabetic nephropathy [117]
35 Other Urinary Biomarkers Used in Evaluating Early DNNumerous urinarymarkers have been suggested for assessingearly DN Some of them have been introduced in use onlyrecently
Urinary retinol-binding protein is a lowmolecular weightprotein that was found to have high urinary values (togetherwith NAG) in normoalbuminuric patients reflecting tubulardysfunction in early DN [118]
The value of serum retinol-binding protein 4 as a bio-marker in assessing the severity of coronary artery disease isto be mentioned [119]
8 Journal of Diabetes Research
Urinary retinol-binding protein 4 as a biomarker in ass-essing DN needs further studies
Urinary vitamin D binding protein can plays the role asbiomarker In type 2 DM it is attributed a potential role inearly diagnosis of DN [120]
Urinary heme oxygenase-1 was found in type 2 DMpatients before the onset of significant albuminuria thusbeing a possible biomarker of early DN [121] In fact oxidativestress activation is expected in DN
Periostin is a cell adhesion molecule which is not nor-mally present in kidneys In tubulointerstitial lesions it ishowever expressed in the kidneys being eliminated in theurineThis is why urinary periostin could be used as amarkerof injury at this level
Since high levels of periostin can be identified in DMpatients before significant albuminuria periostin could rep-resent a marker of diabetic renal injury [122]
Urinary alpha klotho presents higher values in normoal-buminuric type 2 DM patients than in controls It can also bea marker of diabetic injury [123]
Analyzing a group of normoalbuminuric microalbumin-uric and macroalbuminuric type 2 DM patients Sun et alnoted that the urinary level of microvesicle-bound dipeptidylpeptidase-IV is related to the severity of DN [124]
Recent studies point to the usage of urine-specificmicroRNA as a biomarker for early stages of DN Analyzingthe studies in the literature Yang et al issued the hypothesisthat urine-specific microRNA would be a marker that can beused in the early stages of DN [125]
Recently Argyropoulos highlighted the predictive roleof urinary microRNA regarding microalbuminuria in type 1DM [126]
Adipokine zinc-alpha-2 glycoprotein is assigned to themajor histocompatibility complex class I of proteins [127]
Urinary adipokine zinc-alpha-2 glycoprotein is presentearlier than microalbuminuria in diabetic nephropathy Itcould be a useful biomarker for diagnosing early DN [128]Lim et al also appreciate adipokine zinc-alpha-2 glycoproteinas a novel urinary biomarker for normoalbuminuric diabeticnephropathy [129]
351 Proteomics At present proteomic investigations areengaged in identification of new urinary biomarkers to beused in the early diagnosis of DN
In fact proteomics studies noted the fact that microalbu-minuria is not a perfect biomarker for early detection of DN[130 131]
Urinary proteomics begins to stand out as a noninvasivemethod of detecting early DN
Among proteomics studies on diagnosing DN we canmention those of Zurbig et al who reported that collagenfragments were a prominent biomarker 3ndash5 years before theonset of microalbuminuria [132]
A potential role is also attributed to exosome proteomicsfor identifying new biomarkers for DN [133] Zubiri et alshowed a panel of 3 proteins which is differentially present inurinary exosomes fromDNpatients [134] Urinary proteomicanalysis can have an important role in the implementation ofnew biomarkers in DN [135]
At present the prospect of discovering new biomarkersin DM andDN respectively is incumbent both on proteomicsand on genomics transcriptomics and metabolomics [136]
4 Conclusions
Urinary biomarkers allow an assessment of early DNMicroalbuminuria although frequently contested as a
biomarker of early DN is used so far as reference biomarkerin assessing other urinary biomarkers in early DN Untilpresent there is no other biomarker that can substitute inpractice microalbuminuria the new biomarkers being sus-tained by limited studies and requiring validation
The concomitant assessment of several urinary biomark-ers in relationship with microalbuminuria could represent atpresent a method of diagnosing early DNThe great progressin discovering new biomarkers could lead to the developmentof an ldquoidealrdquo urinary biomarker to detect early diabetic DN inthe future
Progresses in the field of urinary biomarkers in DNpromising both in proteomics and in other modern tech-niques develop remarkably at present
Disclosure
Thesupporting source had no involvement in study design incollection analysis and interpretation of data in the writingof the report and in the decision to submit the paper forpublication
Competing Interests
The authors declare that they have no competing interests
Authorsrsquo Contributions
Cristina Gluhovschi and Gheorghe Gluhovschi contributedequally to this paper
Acknowledgments
This research received funding from an Internal Grantof ldquoVictor Babesrdquo University of Medicine and PharmacyTimisoara PIII-C1-PCFI-20142015
References
[1] R J Macisaac E I Ekinci and G Jerums ldquoMarkers of and riskfactors for the development and progression of diabetic kidneydiseaserdquo American Journal of Kidney Diseases vol 63 no 2 ppS39ndashS62 2014
[2] M Narres H Claessen S Droste et al ldquoThe incidence ofend-stage renal disease in the diabetic (compared to the non-diabetic) population a systematic reviewrdquo PLoS ONE vol 11no 1 Article ID e0147329 2016
[3] E Lioudaki K G Stylianou I Petrakis et al ldquoIncreased urinaryexcretion of podocyte markers in normoalbuminuric patientswith diabetesrdquo Nephron vol 131 no 1 pp 34ndash42 2015
Journal of Diabetes Research 9
[4] N Banu H Hara M Okamura G Egusa and M YamakidoldquoUrinary excretion of type IV collagen and laminin in the eval-uation of nephropathy in NIDDM comparison with urinaryalbumin and markers of tubular dysfunction andor damagerdquoDiabetes Research and Clinical Practice vol 29 no 1 pp 57ndash671995
[5] P Kubisz L Stanciakova J Stasko P Galajda and M MokanldquoEndothelial and platelet markers in diabetes mellitus type 2rdquoWorld Journal of Diabetes vol 6 no 3 pp 423ndash431 2015
[6] G Tramonti and Y S Kanwar ldquoTubular biomarkers to assessprogression of diabetic nephropathyrdquo Kidney International vol79 no 10 pp 1042ndash1044 2011
[7] T Terami J Wada K Inoue et al ldquoUrinary angiotensinogen isa marker for tubular injuries in patients with type 2 diabetesrdquoInternational Journal of Nephrology and Renovascular Diseasevol 6 pp 233ndash240 2013
[8] M Eriguchi R Yotsueda K Torisu et al ldquoAssessment ofurinary angiotensinogen as a marker of podocyte injury inproteinuric nephropathiesrdquo American Journal of PhysiologymdashRenal Physiology vol 310 no 4 pp F322ndashF333 2016
[9] A Matheson M D P Willcox J Flanagan and B J WalshldquoUrinary biomarkers involved in type 2 diabetes a reviewrdquoDiabetesMetabolism Research and Reviews vol 26 no 3 pp150ndash171 2010
[10] C Y Hong and K S Chia ldquoMarkers of diabetic nephropathyrdquoJournal of Diabetes and Its Complications vol 12 no 1 pp 43ndash60 1998
[11] J H Warram L J Scott L S Hanna et al ldquoProgression ofmicroalbuminuria to proteinuria in type 1 diabetes nonlinearrelationshipwith hyperglycemiardquoDiabetes vol 49 no 1 pp 94ndash100 2000
[12] P Fioretto M W Steffes and M Mauer ldquoGlomerular structurein nonproteinuric IDDM patients with various levels of albu-minuriardquo Diabetes vol 43 no 11 pp 1358ndash1364 1994
[13] K McKenna and C Thompson ldquoMicroalbuminuria a markerto increased renal and cardiovascular risk in diabetes mellitusrdquoScottish Medical Journal vol 42 no 4 pp 99ndash104 1997
[14] P Hovind L Tarnow P Rossing et al ldquoPredictors for thedevelopment of microalbuminuria and macroalbuminuria inpatients with type 1 diabetes inception cohort studyrdquo BritishMedical Journal vol 328 no 7448 pp 1105ndash1108 2004
[15] I H de Boer T C Rue P A Cleary et al ldquoLong-term renaloutcomes of patients with type 1 diabetes mellitus and microal-buminuria an analysis of the Diabetes Control and Complica-tions TrialEpidemiology of Diabetes Interventions and Com-plications cohortrdquo Archives of Internal Medicine vol 171 no 5pp 412ndash420 2011
[16] G Zoppini G Targher M Chonchol et al ldquoPredictors ofestimated GFR decline in patients with type 2 diabetes andpreserved kidney functionrdquo Clinical Journal of the AmericanSociety of Nephrology vol 7 no 3 pp 401ndash408 2012
[17] B A Perkins LH Ficociello B EOstrander et al ldquoMicroalbu-minuria and the risk for early progressive renal function declinein type 1 diabetesrdquo Journal of theAmerican Society ofNephrologyvol 18 no 4 pp 1353ndash1361 2007
[18] D J Newman M B Mattock A B Dawnay et al ldquoSystematicreview on urine albumin testing for early detection of diabeticcomplicationsrdquo Health Technology Assessment vol 9 no 302005
[19] H-H Parving J B Lewis M Ravid G Remuzzi and L GHunsicker ldquoPrevalence and risk factors for microalbuminuria
in a referred cohort of type II diabetic patients a globalperspectiverdquoKidney International vol 69 no 11 pp 2057ndash20632006
[20] B Lu J Wen X Y Song et al ldquoHigh prevalence of albuminuriain population-based patients diagnosed with type 2 diabetesin the Shanghai downtownrdquo Diabetes Research and ClinicalPractice vol 75 no 2 pp 184ndash192 2007
[21] N Ismail B Becker P Strzelczyk and E Ritz ldquoRenal diseaseand hypertension in non-insulin-dependent diabetes mellitusrdquoKidney International vol 55 no 1 pp 1ndash28 1999
[22] S-I ArakiMHaneda D Koya et al ldquoReduction inmicroalbu-minuria as an integrated indicator for renal and cardiovascularrisk reduction in patients with type 2 diabetesrdquoDiabetes vol 56no 6 pp 1727ndash1730 2007
[23] R G Nelson P H Bennett G J Beck et al ldquoDevelopment andprogression of renal disease in Pima Indians with non- insulin-dependent diabetes mellitusrdquo The New England Journal ofMedicine vol 335 no 22 pp 1636ndash1642 1996
[24] S C W Tang J C K Leung and K N Lai ldquoDiabetictubulopathy an emerging entityrdquo in Diabetes and the KidneyK N Lai and S C W Tang Eds Karger 2011
[25] K Kunika T Yamaoka and M Itakura ldquoDamage of charge-dependent renal tubular reabsorption causes diabetic micro-proteinuriardquoDiabetes Research and Clinical Practice vol 36 no1 pp 1ndash9 1997
[26] G Currie G Mc Kay and C Delles ldquoBiomarkers in diabeticnephropathy present and futurerdquoWorld Journal ofDiabetes vol5 no 6 pp 763ndash776 2014
[27] T Narita H Sasaki M Hosoba et al ldquoParallel increase inurinary excretion rates of immunoglobulin G ceruloplasmintransferrin and orosomucoid in normoalbuminuric type 2diabetic patientsrdquo Diabetes Care vol 27 no 5 pp 1176ndash11812004
[28] M Kanauchi Y Akai and T Hashimoto ldquoTransferrinuria intype 2 diabetic patients with early nephropathy and tubuloin-terstitial injuryrdquo European Journal of Internal Medicine vol 13no 3 pp 190ndash193 2002
[29] B Quiroga D Arroyo and G de Arriba ldquoPresent and futurein the treatment of diabetic kidney diseaserdquo Journal of DiabetesResearch vol 2015 Article ID 801348 13 pages 2015
[30] T Kazumi T Hozumi Y Ishida et al ldquoIncreased urinarytransferrin excretion predicts microalbuminuria in patientswith type 2 diabetesrdquoDiabetes Care vol 22 no 7 pp 1176ndash11801999
[31] A Cohen-Bucay and G Viswanathan ldquoUrinary markers ofglomerular injury in diabetic nephropathyrdquo International Jour-nal of Nephrology vol 2012 Article ID 146987 11 pages 2012
[32] C Wang C Li W Gong and T Lou ldquoNew urinary biomarkersfor diabetic kidney diseaserdquo Biomarker Research vol 1 article 92013
[33] M Yamazaki S Ito A Usami et al ldquoUrinary excretion rateof ceruloplasmin in non-insulin-dependent diabetic patientswith different stages of nephropathyrdquo European Journal of Endo-crinology vol 132 no 6 pp 681ndash687 1995
[34] L X Qin X Zeng and G Huang ldquoChanges in serum and urineceruloplasmin concentrations in type 2 diabetesrdquo Zhong NanDa Xue Xue Bao Yi Xue Ban vol 29 no 2 pp 208ndash211 2004
[35] J T Tamsma J van den Born J A Bruijn et al ldquoExpression ofglomerular extracellular matrix components in human diabeticnephropathy decrease of heparan sulphate in the glomerularbasement membranerdquo Diabetologia vol 37 no 3 pp 313ndash3201994
10 Journal of Diabetes Research
[36] T Fiseha ldquoUrinary biomarkers for early diabetic nephropathyin type 2 diabetic patientsrdquo Biomarker Research vol 3 article16 2015
[37] N Kotajima T Kimura T Kanda et al ldquoType IV collagenas an early marker for diabetic nephropathy in non-insulin-dependent diabetes mellitusrdquo Journal of Diabetes and its Com-plications vol 14 no 1 pp 13ndash17 2000
[38] H Takizawa T Satoh A Kurusu et al ldquoIncrease of urinarytype IV collagen in normoalbuminuric patients with impairedglucose tolerancerdquo Nephron vol 79 no 4 pp 474ndash475 1998
[39] H Okonogi M Nishimura Y Utsunomiya et al ldquoUrinary typeIV collagen excretion reflects renal morphological alterationsand type IV collagen expression in patients with type 2 diabetesmellitusrdquo Clinical Nephrology vol 55 no 5 pp 357ndash364 2001
[40] S Ming Z Qi L Wang and K Zhu ldquoUrinary type IV collagena specific indicator of incipient diabetic nephropathyrdquo ChineseMedical Journal vol 115 no 3 pp 389ndash394 2002
[41] S Kado A Aoki S Wada et al ldquoUrinary type IV collagen as amarker for early diabetic nephropathyrdquo Diabetes Research andClinical Practice vol 31 no 1ndash3 pp 103ndash108 1996
[42] I Ueta K Takamatsu and K Hashimoto ldquoUrinary glycos-aminoglycans in patients with incipient diabetic nephropathyrdquoNihon Jinzo Gakkai Shi vol 37 no 1 pp 17ndash23 1995
[43] O Torffvit ldquoUrinary sulphated glycosaminoglycans andTamm-Horsfall protein in type 1 diabetic patientsrdquo ScandinavianJournal of Urology and Nephrology vol 33 no 5 pp 328ndash3321999
[44] Y Uehara H Makino K Seiki and Y Urade ldquoUrinaryexcretions of lipocalin-type prostaglandin D synthase predictrenal injury in type-2 diabetes a cross-sectional and prospectivemulticentre studyrdquoNephrology Dialysis Transplantation vol 24no 2 pp 475ndash482 2009
[45] K Kuboki H Tada K Shin Y Oshima and S Isogai ldquoRela-tionship between urinary excretion of fibronectin degradationproducts and proteinuria in diabetic patients and their suppres-sion after continuous subcutaneous heparin infusionrdquoDiabetesResearch and Clinical Practice vol 21 no 1 pp 61ndash66 1993
[46] A L Al-Malki ldquoAssessment of urinary osteopontin in associa-tion with podocyte for early predication of nephropathy in dia-betic patientsrdquo Disease Markers vol 2014 Article ID 493736 5pages 2014
[47] K Mise J Hoshino T Ueno et al ldquoPrognostic value of tubu-lointerstitial lesions urinary N-acetyl-120573-d-glucosaminidaseand urinary 1205732-microglobulin in patients with type 2 diabetesand biopsy-proven diabetic nephropathyrdquoClinical Journal of theAmerican Society of Nephrology vol 11 no 4 pp 593ndash601 2016
[48] K M Schmidt-Ott K Mori Y L Jau et al ldquoDual actionof neutrophil gelatinase-associated lipocalinrdquo Journal of theAmerican Society of Nephrology vol 18 no 2 pp 407ndash413 2007
[49] D Bolignano A Lacquaniti G Coppolino et al ldquoNeu-trophil gelatinase-associated lipocalin as an early biomarker ofnephropathy in diabetic patientsrdquo Kidney amp Blood PressureResearch vol 32 no 2 pp 91ndash98 2009
[50] Z Yuruk Yıldırım A Nayır A Yılmaz A Gedikbası and RBundak ldquoNeutrophil gelatinase-associated lipocalin as an earlysign of diabetic kidney injury in childrenrdquo Journal of ClinicalResearch in Pediatric Endocrinology vol 7 no 4 pp 274ndash2792015
[51] A Lacquaniti V Donato B Pintaudi et al ldquolsquoNormoalbu-minuricrsquo diabetic nephropathy tubular damage and NGALrdquoActa Diabetologica vol 50 no 6 pp 935ndash942 2013
[52] J A de Carvalho E Tatsch B S Hausen et al ldquoUrinarykidney injury molecule-1 and neutrophil gelatinase-associatedlipocalin as indicators of tubular damage in normoalbuminuricpatients with type 2 diabetesrdquo Clinical Biochemistry vol 49 no3 pp 232ndash236 2016
[53] W-J Fu S-L Xiong Y-G Fang et al ldquoUrinary tubularbiomarkers in short-term type 2 diabetes mellitus patients across-sectional studyrdquo Endocrine vol 41 no 1 pp 82ndash88 2012
[54] V Garg M Kumar H S Mahapatra A Chitkara A KGadpayle and V Sekhar ldquoNovel urinary biomarkers in pre-diabetic nephropathyrdquo Clinical and Experimental Nephrologyvol 19 no 5 pp 895ndash900 2015
[55] Y-HYang X-JHe S-R Chen LWang E-M Li andL-Y XuldquoChanges of serum and urine neutrophil gelatinase-associatedlipocalin in type-2 diabetic patients with nephropathy one yearobservational follow-up studyrdquo Endocrine vol 36 no 1 pp 45ndash51 2009
[56] M H Weber and R Verwiebe ldquo1205721- microglobulin (proteinHC) features of a promising indicator of proximal tubular dys-functionrdquo European Journal of Clinical Chemistry and ClinicalBiochemistry vol 30 no 10 pp 683ndash691 1992
[57] C-Y Hong K Hughes K-S Chia V Ng and S-L LingldquoUrinary 1205721-microglobulin as a marker of nephropathy in type2 diabetic Asian subjects in Singaporerdquo Diabetes Care vol 26no 2 pp 338ndash342 2003
[58] L Petrica M Petrica A Vlad et al ldquoProximal tubule dysfunc-tion is dissociated from endothelial dysfunction in normoalbu-minuric patients with type 2 diabetes mellitus a cross-sectionalstudyrdquo Nephron Clinical Practice vol 118 no 2 pp c155ndashc1642011
[59] H Wainai F Katsukawa I Takei H Maruyama K Kataokaand T Saruta ldquoInfluence of glycemic control and hypertensionon urinary microprotein excretion in non-insulin-dependentdiabetes mellitusrdquo Journal of Diabetic Complications vol 5 no2-3 pp 160ndash161 1991
[60] N Shore R Khurshid and M Saleem ldquoAlpha-1 microglobulina marker for early detection of tubular disorders in diabeticnephropathyrdquo Journal of AyubMedical College Abbottabad vol22 no 4 pp 53ndash55 2010
[61] J V Bonventre ldquoKidney injury molecule-1 a translational jour-neyrdquo Transactions of the American Clinical and ClimatologicalAssociation vol 125 pp 293ndash299 2014
[62] L Petrica A Vlad G Gluhovschi et al ldquoProximal tubuledysfunction is associated with podocyte damage biomarkersnephrin and vascular endothelial growth factor in type 2diabetes mellitus patients a cross-sectional studyrdquo PLoS ONEvol 9 no 11 Article ID e112538 2014
[63] S E Nielsen K J Schjoedt A S Astrup et al ldquoNeutrophilGelatinase-Associated Lipocalin (NGAL) and Kidney InjuryMolecule 1 (KIM1) in patients with diabetic nephropathy across-sectional study and the effects of lisinoprilrdquo DiabeticMedicine vol 27 no 10 pp 1144ndash1150 2010
[64] S E Nielsen H Reinhard D Zdunek et al ldquoTubular markersare associated with decline in kidney function in proteinurictype 2 diabetic patientsrdquoDiabetes Research andClinical Practicevol 97 no 1 pp 71ndash76 2012
[65] C Bazzi C Petrini V Rizza et al ldquoUrinary N-acetyl-120573-glucosaminidase excretion is a marker of tubular cell dysfunc-tion and a predictor of outcome in primary glomerulonephri-tisrdquoNephrology Dialysis Transplantation vol 17 no 11 pp 1890ndash1896 2002
Journal of Diabetes Research 11
[66] A P Jones S Lock and K D Griffiths ldquoUrinary N-acetyl-120573-glucosaminidase activity in type I diabetes mellitusrdquo Annals ofClinical Biochemistry vol 32 no 1 pp 58ndash62 1995
[67] S Uslu B Efe O Alatas et al ldquoSerum cystatin C and urinaryenzymes as screening markers of renal dysfunction in diabeticpatientsrdquo Journal of Nephrology vol 18 no 5 pp 559ndash567 2005
[68] V Ambade P Singh B L Somani and D Basannar ldquoUrinaryN-acetyl beta glucosaminidase and gammaglutamyl transferaseas early markers of diabetic nephropathyrdquo Indian Journal ofClinical Biochemistry vol 21 no 2 pp 142ndash148 2006
[69] D N Patel and K Kalia ldquoEfficacy of urinary N-acetyl-120573-d-glucosaminidase to evaluate early renal tubular damage as aconsequence of type 2 diabetesmellitus a cross-sectional studyrdquoInternational Journal of Diabetes in Developing Countries vol35 supplement 3 pp 449ndash457 2015
[70] H S Assal S Tawfeek E A Rasheld D El-Lebedy and EH Thabet ldquoSerum cystatin C and tubular urinary enzymes asbiomarkers a renal dysfunction in type 2 diabetes mellitusrdquoClinical Medicine Insights Endocrinology and Diabetes vol 6no 7 pp 7ndash13 2013
[71] M Kamiyama A Zsombok and H Kobori ldquoUrinaryangiotensinogen as a novel early biomarker of intrarenal renin-angiotensin system activation in experimental type 1 diabetesrdquoJournal of Pharmacological Sciences vol 119 no 4 pp 314ndash3232012
[72] T Saito M Urushihara Y Kotani S Kagami and H KoborildquoIncreased urinary angiotensinogen is precedent to increasedurinary albumin in patients with type 1 diabetesrdquo AmericanJournal of the Medical Sciences vol 338 no 6 pp 478ndash4802009
[73] Z Zhuang Q Bai L A T Liang D Zheng and Y WangldquoIncreased urinary angiotensinogen precedes the onset of albu-minuria in normotensive type 2 diabetic patientsrdquo InternationalJournal of Clinical and Experimental Pathology vol 8 no 9 pp11464ndash11469 2015
[74] S S Kim S H Song I J Kim et al ldquoClinical implication ofurinary tubular markers in the early stage of nephropathy withtype 2 diabetic patientsrdquoDiabetes Research and Clinical Practicevol 97 no 2 pp 251ndash257 2012
[75] M Sawaguchi S-I ArakiHKobori et al ldquoAssociation betweenurinary angiotensinogen levels and renal and cardiovascularprognoses in patients with type 2 diabetes mellitusrdquo Journal ofDiabetes Investigation vol 3 no 3 pp 318ndash324 2012
[76] T Mizushige H Kobori Y Nishijima et al ldquoUrinaryangiotensinogen could be a prognostic marker of renoprotec-tive effects of alogliptin in patients with type 2 diabetesrdquo Journalof Diabetes Research vol 2015 Article ID 517472 7 pages 2015
[77] Y K Jeon M R Kim J E Huh et al ldquoCystatin C as an earlybiomarker of nephropathy in patients with type 2 diabetesrdquoJournal of Korean Medical Science vol 26 no 2 pp 258ndash2632011
[78] W D Comper T M Osicka and G Jerums ldquoHigh prevalenceof immuno-unreactive intact albumin in urine of diabeticpatientsrdquoAmerican Journal of Kidney Diseases vol 41 no 2 pp336ndash342 2003
[79] X Rao M Wan C Qiu and C Jiang ldquoRole of cystatin C inrenal damage and the optimum cut-off point of renal damageamong patients with type 2 diabetesmellitusrdquo Experimental andTherapeutic Medicine vol 8 no 3 pp 887ndash892 2014
[80] V Garg M Kuman H S Mahapatra A Chitkora A K Gad-poyle and V Sekhan ldquoNovel urinary biomarkers in prediabetic
nephropathyrdquoClinical and Experimental Nephrology vol 19 no5 pp 895ndash890 2015
[81] S S Kim S H Song I J Kim et al ldquoUrinary cystatin C andtubular proteinuria predict progression of diabetic nephropa-thyrdquo Diabetes Care vol 36 no 3 pp 656ndash661 2013
[82] A Kamijo-Ikemori T Sugaya T Yasuda et al ldquoClinical signifi-cance of urinary liver-type fatty acid-binding protein in diabeticnephropathy of type 2 diabetic patientsrdquo Diabetes Care vol 34no 3 pp 691ndash696 2011
[83] S E Nielsen T Sugaya P Hovind T Baba H-H Parving andP Rossing ldquoUrinary liver-type fatty acid-binding protein pre-dicts progression to nephropathy in type 1 diabetic patientsrdquoDiabetes Care vol 33 no 6 pp 1320ndash1324 2010
[84] V Viswanathan S Sivakumar V Sekar D M Umapathy andS Kumpatla ldquoClinical significance of urinary liver-type fattyacid binding protein at various stages of nephropathyrdquo IndianJournal of Nephrology vol 25 no 5 pp 269ndash273 2015
[85] K-M Chou C-C Lee C-H Chen and C-Y Sun ldquoClinicalvalue of NGAL L-FABP and albuminuria in predicting GFRdecline in type 2 diabetes mellitus patientsrdquo PLoS ONE vol 8no 1 article e54863 2013
[86] N M Panduru C Forsblom M Saraheimo et al ldquoUrinaryliver-type fatty acid-binding protein and progression of diabeticnephropathy in type 1 diabetesrdquoDiabetes Care vol 36 no 7 pp2077ndash2083 2013
[87] G I Welsh and M A Saleem ldquoNephrinmdashsignature moleculeof the glomerular podocyterdquoThe Journal of Pathology vol 220no 3 pp 328ndash337 2010
[88] F N Ziyadeh and G Wolf ldquoPathogenesis of the podocytopathyand proteinuria in diabetic glomerulopathyrdquo Current DiabetesReviews vol 4 no 1 pp 39ndash45 2008
[89] A Patari C ForsblomMHavana H Taipale P-H Groop andH Holthofer ldquoNephrinuria in diabetic nephropathy of type 1diabetesrdquo Diabetes vol 52 no 12 pp 2969ndash2974 2003
[90] D P K Ng B-C Tai E Tan et al ldquoNephrinuria associateswithmultiple renal traits in type 2 diabetesrdquoNephrology DialysisTransplantation vol 26 no 8 pp 2508ndash2514 2011
[91] Y Kandasamy R Smith E R Lumbers and D Rudd ldquoNephrina biomarker of early glomerular injuryrdquo Biomarker Researchvol 2 no 1 p 21 2014
[92] B Jim M Ghanta A Qipo et al ldquoDysregulated nephrin indiabetic nephropathy of type 2 diabetes a cross sectional studyrdquoPLoS ONE vol 7 no 5 Article ID e36041 2012
[93] J F Navarro C Mora M Gomez M Muros C Lopez-Aguilar and J Garcıa ldquoInfluence of renal involvement onperipheral blood mononuclear cell expression behaviour oftumour necrosis factor-120572 and interleukin-6 in type 2 diabeticpatientsrdquoNephrology Dialysis Transplantation vol 23 no 3 pp919ndash926 2008
[94] D Z I Cherney J W Scholey D Daneman et al ldquoUrinarymarkers of renal inflammation in adolescents with type 1 dia-betes mellitus and normoalbuminuriardquo Diabetic Medicine vol29 no 10 pp 1297ndash1302 2012
[95] R Har J W Scholey D Daneman et al ldquoThe effect of renalhyperfiltration on urinary inflammatory cytokineschemokinesin patients with uncomplicated type 1 diabetes mellitusrdquo Dia-betologia vol 56 no 5 pp 1166ndash1173 2013
[96] K Tashiro I Koyanagi A Saitoh et al ldquoUrinary levels ofmono-cyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) and renal injuries in patients with type 2 diabetic nephropa-thyrdquo Journal of Clinical Laboratory Analysis vol 16 no 1pp 1ndash4 2002
12 Journal of Diabetes Research
[97] J Liu Z Zhao M D P Willcox B Xu and B Shi ldquoMultiplexbead analysis of urinary cytokines of type 2 diabetic patientswith normo- and microalbuminuriardquo Journal of Immunoassayand Immunochemistry vol 31 no 4 pp 279ndash289 2010
[98] S Ibrahim and L Rashed ldquoCorrelation of urinary monocytechemo-attractant protein-1 with other parameters of renalinjury in type-II diabetes mellitusrdquo Saudi Journal of Kidney Dis-eases and Transplantation vol 19 no 6 pp 911ndash917 2008
[99] H Jiang G Guan R Zhang et al ldquoIncreased urinary excretionof orosomucoid is a risk predictor of diabetic nephropathyrdquoNephrology vol 14 no 3 pp 332ndash337 2009
[100] N M El-Beblawy N G Andrawes E A Ismail B E EnanyH S Abou El-Seoud and M A Erfan ldquoSerum and Uri-nary orosomucoid in young patients with type 1 diabetes alink between inflammation microvascular complications andsubclinical atherosclerosisrdquo Clinical and Applied ThrombosisHemostasis 2016
[101] M S Christiansen E Hommel E Magid and B Feldt-Rasmussen ldquoOrosomucoid in urine predicts cardiovascular andover-all mortality in patients with type II diabetesrdquo Diabetolo-gia vol 45 no 1 pp 115ndash120 2002
[102] H Ha and H B Lee ldquoOxidative stress in diabetic nephropathybasic and clinical informationrdquo Current Diabetes Reports vol 1no 3 pp 282ndash287 2001
[103] L L Wu C C Chiou P Y Chang and J T Wu ldquoUrinary 8-OHdG a marker of oxidative stress to DNA and a risk factorfor cancer atherosclerosis and diabeticsrdquo Clinica Chemica Actavol 339 no 1-2 pp 1ndash9 2004
[104] Y Hinokio S Suzuki M Hirai C Suzuki M Suzukiand T Toyota ldquoUrinary excretion of 8-oxo-7 8-dihydro-21015840-deoxyguanosine as a predictor of the development of diabeticnephropathyrdquo Diabetologia vol 45 no 6 pp 877ndash882 2002
[105] J Leinonen T Lehtimaki S Toyokuni et al ldquoNew biomarkerevidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitusrdquo FEBS Letters vol 417 no1 pp 150ndash152 1997
[106] K Broedbaek A Weimann E S Stovgaard and H E PoulsenldquoUrinary 8-oxo-78-dihydro-21015840-deoxyguanosine as a biomarkerin type 2 diabetesrdquo Free Radical Biology and Medicine vol 51no 8 pp 1473ndash1479 2011
[107] F L NautaW E Boertien S J L Bakker et al ldquoGlomerular andtubular damage markers are elevated in patients with diabetesrdquoDiabetes Care vol 34 no 4 pp 975ndash981 2011
[108] L Petrica A Vlad G Gluhovschi et al ldquoGlycated peptides areassociated with proximal tubule dysfunction in type 2 diabetesmellitusrdquo International Journal of Clinical and ExperimentalMedicine vol 8 no 2 pp 2516ndash2525 2015
[109] N Turk A Mornar V Mrzljak and Z Turk ldquoUrinary excre-tion of advanced glycation endproducts in patients with type2 diabetes and various stages of proteinuriardquo Diabetes andMetabolism vol 30 no 2 pp 187ndash192 2004
[110] A A Ghanem A Elewa and L F Arafa ldquoPentosidine and N-carboxymethyl-lysine biomarkers for type 2 diabetic retinopa-thyrdquo European Journal of Ophthalmology vol 21 no 1 pp 48ndash54 2011
[111] F Piarulli G Sartore A Ceriello et al ldquoRelationship betweenglyco-oxidation antioxidant status and microalbuminuria intype 2 diabetic patientsrdquo Diabetologia vol 52 no 7 pp 1419ndash1425 2009
[112] M Shoji K Kobayashi M Takemoto Y Sato and K YokoteldquoUrinary podocalyxin levels were associated with urinary albu-min levels among patients with diabetesrdquo Biomarkers vol 21no 2 pp 164ndash167 2015
[113] M Hara K Yamagata Y Tomino et al ldquoUrinary podocalyxinis an early marker for podocyte injury in patients with diabetesestablishment of a highly sensitive ELISA to detect urinarypodocalyxinrdquo Diabetologia vol 55 no 11 pp 2913ndash2919 2012
[114] M Zheng L-L Lv J Ni et al ldquoUrinary podocyte-associatedmRNA profile in various stages of diabetic nephropathyrdquo PLoSONE vol 6 no 5 Article ID e20431 2011
[115] N H Kim K B Kim D L Kim et al ldquoPlasma and urinaryvascular endothelial growth factor and diabetic nephropathy intype 2 diabetes mellitusrdquo Diabetic Medicine vol 21 no 6 pp545ndash551 2004
[116] M Emoto K Mori E Lee et al ldquoFetuin-A and atheroscleroticcalcified plaque in patients with type 2 diabetes mellitusrdquoMetabolism Clinical and Experimental vol 59 no 6 pp 873ndash878 2010
[117] K Inoue J Wada J Eguchi et al ldquoUrinary fetuin-A is a novelmarker for diabetic nephropathy in type 2 diabetes identified bylectin microarrayrdquo PLoS ONE vol 8 no 10 Article ID e771182013
[118] M A K Salem S A El-Habashy O M Saeid M M KEl-Tawil and P H Tawfik ldquoUrinary excretion of N-acetyl-120573-d-glucosaminidase and retinol binding protein as alternativeindicators of nephropathy in patients with type 1 diabetesmellitusrdquo Pediatric Diabetes vol 3 no 1 pp 37ndash41 2002
[119] V Lambadiari N P E KadoglouV Stasinos et al ldquoSerum levelsof retinol-binding protein-4 are associated with the presenceand severity of coronary artery diseaserdquo Cardiovascular Dia-betology vol 13 no 1 article 121 2014
[120] A Shoukry S E-A Bdeer and R H El-Sokkary ldquoUrinarymonocyte chemoattractant protein-1 and vitamin D-bindingprotein as biomarkers for early detection of diabetic nephropa-thy in type 2 diabetesmellitusrdquoMolecular andCellular Biochem-istry vol 408 no 1 pp 25ndash35 2015
[121] Z Li Y Xu Y Nie and Z Zhao ldquoUrinary heme oxygenase-1 as apotential biomarker for early diabetic nephropathyrdquoNephrology(Carlton Vic) 2016
[122] B Satirapoj S Tassanasorn M Charoenpitakchai and OSupasyndh ldquoPeriostin as a tissue and urinary biomarker of renalinjury in type 2 diabetes mellitusrdquo PLoS ONE vol 10 no 4Article ID e0124055 2015
[123] E Y Lee S S Kim J-S Lee et al ldquoSoluble 120572-klotho as a novelbiomarker in the early stage of nephropathy in patients withtype 2 diabetesrdquo PLoS ONE vol 9 no 8 article e102984 2014
[124] A-L Sun J-TDengG-J Guan et al ldquoDipeptidyl peptidase-IVis a potential molecular biomarker in diabetic kidney diseaserdquoDiabetes and Vascular Disease Research vol 9 no 4 pp 301ndash308 2012
[125] Y Yang L Xiao J Li Y S Kanwar F Liu and L Sun ldquoUrinemiRNAs potential biomarkers for monitoring progression ofearly stages of diabetic nephropathyrdquo Medical Hypotheses vol81 no 2 pp 274ndash278 2013
[126] C Argyropoulos K Wang J Bernardo et al ldquoUrinaryMicroRNA profiling predicts the development of microalbu-minuria in patients with type 1 Diabetesrdquo Journal of ClinicalMedicine vol 4 no 7 pp 1495ndash1517 2015
Journal of Diabetes Research 13
[127] M W Kennedy A P Heikema A Cooper P J Bjorkmanand L M Sanchez ldquoHydrophobic ligand binding by Zn-1205722-glycoprotein a soluble fat-depleting factor related to major his-tocompatibility complex proteinsrdquo Journal of Biological Chem-istry vol 276 no 37 pp 35008ndash35013 2001
[128] YWang YM Li S Zhang J Y Zhao and C Y Liu ldquoAdipokinezinc-120572-2- glycoprotein as novel urinary biomarker presentsearly than microalbuminuria in diabetic nephropathyrdquo Journalof International Medical Research vol 44 no 2 pp 278ndash2862016
[129] S C Lim D Q Liying W C Toy et al ldquoAdipocytokine zinc 1205722glycoprotein (ZAG) as a novel urinary biomarker for normo-albuminuric diabetic nephropathyrdquo Diabetic Medicine vol 29no 7 pp 945ndash949 2012
[130] V Thongboonkerd ldquoStudy of diabetic nephropathy in theproteomic erardquo Diabetes and the Kidney vol 170 pp 172ndash1832011
[131] K N Lai and S C W Tang Eds Diabetes and the Kidney vol170 Contributions to Nephrology Karger Basel Switzerland2011
[132] P Zurbig G Jerums P Hovind et al ldquoUrinary proteomics forearly diagnosis in diabetic nephropathyrdquo Diabetes vol 61 no12 pp 3304ndash3313 2012
[133] F Raimondo S Corbetta L Morosi et al ldquoUrinary exosomesand diabetic nephropathy a proteomic approachrdquo MolecularBioSystems vol 9 no 6 pp 1139ndash1146 2013
[134] I Zubiri M Posada-Ayala A Sanz-Maroto et al ldquoDiabeticnephropathy induces changes in the proteome of human uri-nary exosomes as revealed by label-free comparative analysisrdquoJournal of Proteomics vol 96 pp 92ndash102 2014
[135] A Caseiro A Barros R Ferreira et al ldquoPursuing type 1diabetes mellitus and related complications through urinaryproteomicsrdquo Translational Research vol 163 no 3 pp 188ndash1992014
[136] B Jim J Santos F Spath and J C He ldquoBiomarkers of diabeticnephropathy the present and the futurerdquo Current DiabetesReviews vol 8 no 5 pp 317ndash328 2012
normoalbuminuria presented increased values of urinaryalpha-1-microglobulin a fact that could be explained by tubu-lar injury that precedes the occurrence of microalbuminuriabeing a more sensitive and an earlier urinary biomarker [57]However alpha-1-microalbuminuria can be absent in somepatients with albuminuria [57] This is why assessments ofalpha-1-microglobulin are associated with the assessment ofother urinary biomarkers urinary albumin included
Petrica et al reported high values of urinary alpha-1-microglobulin in normoalbuminuric patients a fact pleadingfor an early tubular injury in type 2DM in this stageThey didnot find correlations between urinary alpha-1-microglobulinbeta-2 microglobulin and the albumincreatinine ratio withplasma asymmetric dimethyl-arginine This could plead fordissociation between tubular and endothelial dysfunction[58]
Alpha-1-microglobulin in early stages of DM could alsohave a role in predicting DN [59] It is in fact an inexpensivebiomarker of early diagnosis of DN [60]
323 Urinary KIM-1 (Kidney Injury Molecule-1) KIM-1 isa transmembrane glycoprotein located at the level of theproximal tubular cells It is eliminated in urine in case ofinjury at this level It is a sensitive biomarker used with goodresults in acute kidney injury [61]
Petrica et al reported in normoalbuminuric type 2 DMpatients high values of urinary KIM-1 which indicates lesionsof the proximal tubule in early stages of the disease Patientswith microalbuminuria have higher urinary KIM-1 valuesthan those with normoalbuminuria [62]
de Carvalho et al reported in type 2 DM normoal-buminuric patients high values of KIM-1 these valuesincreasing progressively in patients with microalbuminuriaand macroalbuminuria NGAL values studied concomitantlypresented similar evolutions [52]
Moreover KIM-1 presents higher elimination in type2 DM patients with hyperfiltration than in patients withnormal glomerular filtration NGAL has a similar evolutionThese biomarkersmdashKIM-1 and NGALmdashcould plead for adeleterious lesional effect of hyperfiltration on the proximaltubule [53]
Nielsen et al however could not demonstrate a value ofurinary KIM-1 that could be predictive of the evolution ofglomerular function (GFR) in patients with type 1 DM [63]
According to Nielsen et al it has no prognostic utility intype 2 DM patients either [64]
324 Urinary N-Acetyl-120573-D glucosaminidase (NAG) NAG isan enzyme located in the lysosomes of proximal tubular cells[65]
In case of dysfunction namely of injury of proximaltubular cells NAG is eliminated into the urine in higherquantities being a sensitive tubular biomarker This canprecede the appearance of microalbuminuria in type 1 DM[66]
Elevated serum Cys C levels and urinary NAG activitieswere found only in normoalbuminurics not in controls Inaddition elevated urinary ALP and LDH activities were alsofound in microalbuminurics [67]
Other authors like Ambade et al did not find thaturinary NAG has clinical significance as an early biomarkerof DN [68]
In type 2 DM urinary NAG excretion increases propor-tionally to the duration of diabetes It occurs much earlierthan albuminuria NAG can be considered an early tubularbiomarker [69]
Assal et al consider that urinary NAG is the mostsensitive biomarker for detecting early damage in diabeticpatients [70]
325 Urinary Angiotensinogen The renin angiotensin aldos-terone system (RAAS) is involved in the pathogenesis of DNThe constitutive elements of RAAS are present at kidney leveldefining a local RAAS
Urinary angiotensinogen can represent a biomarker forthe activation of RAAS in DM [71]
High urinary angiotensinogen precedes in type 1 DMpatients the occurrence of microalbuminuria [72]This couldhave a predictive role in normotensive type 1 DM patients[73]
Urinary angiotensinogen in normoalbuminuric type 2DM patients is higher than in controls and it increasesprogressively inmicroalbuminuric and especially inmacroal-buminuric patients [73]
Urinary angiotensinogen can be considered an earlybiomarker of DN [72]
In type 2 DM patients urinary angiotensinogen is corre-lated with alpha-1-microglobulin [8]
Kim et al did not confirm these observations in a studyon type 2 DM patients They found that the values ofurinary angiotensinogen are not different from those of thecontrols in normoalbuminuric andmicroalbuminuric type 2DM patients but higher values were described inmacroalbu-minuric patients [74]
These observations point to the need of further studiesnecessary for the validation of this biomarker
Increased urinary angiotensinogen could represent a riskfactor in renal and cardiovascular complications [75]
Since activation of RAAS could intervene in the evolutionof DN administration of ACE-I is recommended
At the same time urinary angiotensinogen could be amarker for assessing the renoprotective effects of alogliptinto type 2 DM patients [76]
326 Cystatin C It is a low molecular weight protein havingthe role of cysteine protease Cystatin is produced by thenucleated cells in the body [77]
It is filtered at glomerular level and is reabsorbed inthe tubules Cystatin is used for evaluating renal functionAssessment of GFR by means of cystatin C is considered tobe a method that is not influenced by body mass being com-parable and even better thanmethods using serum creatinine[78]
Serum cystatin is also considered a sensitive biomarker asit detects minor glomerular injury [79]
Urinary cystatin C indicates tubular injury It increasesearly in diabetes and prediabetic nephropathy [80]
6 Journal of Diabetes Research
Patients with microalbuminuria present higher values ofurinary cystatin C than those without microalbuminuriaurinary cystatin C having a predictive role for the progressionof diabetic nephropathy (DN) [81]
Urinary cystatin C level could be an independentfactor for identifying renal dysfunction in type 2 DMpatients with normoalbuminuria including patients withGFR lt60mLmin173m2 [77] Uslu et al find a significantpositive correlation between serum cystatin C urinary NAGlacticodehydrogenase alkaline phosphatase activities andserum creatinine levels [67]
Serum and urinary cystatin C are useful biomarkers forassessing early nephropathy in type 2 DM [77]
327 L-FABP (Liver-Type Fatty Acid Binding Protein) Uri-nary L-FABP is a protein with low molecular weightexpressed in the cytoplasm of human proximal tubular cells[82] It is also expressed at liver level
Increased urinary L-FABP was found in type 1 DMpatients who presented normoalbuminuria having a predic-tive role regarding the progression towards microalbumin-uria and of microalbuminuria towards macroalbuminuria[83]
Patients with type 2 DM with normoalbuminuria alsopresented high levels of urinary L-FABP this protein beingconsidered as a useful biomarker for diagnosing early diabeticnephropathy In fact urinary L-FABP has been confirmed asa tubular biomarker by the Ministry of Health andWelfare inJapan [82]
The L-FABP factor is also related to the severity of DNThe values of urinary L-FABP increase with the decline ofrenal function [84]
Although some authors like Chou et al do not ascribe apredictive role to urinary L-FABP in type 2 DM patients [85]others like Panduru et al consider that urinary L-FABP is anindependent predictor of the progression of DN [86]
328 Nephrinuria Nephrine is a transmembrane protein inthe structure of the slit diaphragm [87]
InDMpodocyte dysfunction is present DN is considereda podocytopathy [88] Injury of the slit diaphragm leads tonephrinuria
Nephrinuria can occur in some type 1 DM patients priorto microalbuminuria [89] Nephrinuria was also reported insome normoalbuminuric type 2 DM patients [62 90]
Nephrinuria is related to podocyte injury representing abiomarker of early glomerular injury [91]
Dysregulation of nephrine in podocytes in DN couldlead to nephrinuria in normoalbuminuric patients precedingmicroalbuminuria [92]
In albuminuric patients nephrinuria is positively corre-lated with albuminuria and negatively correlated with GFRbeing a biomarker of DN in other phases of DM as well
Podocyte impairment in DM involves not only nephrinebut also other podocyte elements for example VEGF Thusin normoalbuminuric DM patients nephrinuria is correlatedwith urinary elimination of VEGF [62]
Tubular biomarkers seem to play an important role inthe early diagnosis of DN They manage to show in most
cases that microalbuminuria does not represent a reliablebiomarker for diagnosing incipient lesions of DN Howeverup to now none of these biomarkers has been established asgold standard for the identification of early DN
33 Markers of Inflammation DM is accompanied bychronic inflammatory processes affecting the whole body thekidneys included Mediators of inflammation like cytokinesand chemokines are present in these processes Some of themare useful as markers of inflammation
331 Tumour Necrosis Factor Alpha (TNF Alpha) UrinaryTNF alpha presents in type 2 DM patients with microal-buminuria and macroalbuminuria higher values than inpatients with normoalbuminuria Urinary TNF alpha iscorrelatedwith urinaryNAG amarker of tubular lesions [93]
Cherney et al analyzed in a complex study on nor-moalbuminuric type 1 DM patients forty-two urinarycytokineschemokines They found that the urinary level ofIL6 and IL8 the platelet-derived growth factor and RANTESare not altered in patients with normal albumin-creatinineratio
Higher urinary excretion of these markers is associatedwith microalbuminuria Cherney et al consider that thesemarkers could have a role in assessing the risk of DN inpatients with type 1 DM [94]
In type 1 DM patients renal hyperfiltration is related toincreased excretion of inflammatory cytokineschemokines[95]
Tashiro et al found in type 2 DM patients that IL8 is highin early stages of DN andMCP-1 increases in advanced stages[96]
A study on type 2 DM patients with normoalbuminuriaand microalbuminuria found higher values of IL8 IP10MCP-1 G-CSF EOTAXIN and RANTES in patients withmicroalbuminuria than in normoalbuminurics or in controlsTheir assessment would be useful in the early diagnosis andtreatment of DN [97]
Ibrahim and Rached also found that urinary MCP-1 ishigher in patients with microalbuminuria than in normoal-buminurics or healthy controls [98]
332 Urinary Orosomucoid Orosomucoid represents a gly-coprotein involved in inflammatory processes
Urinary orosomucoid has higher values in type 1 DMpatients with normoalbuminuria than in controls These val-ues increase in patients withmicroalbuminuria andmacroal-buminuria [99] Type 2 DM patients presented increasedexcretion of orosomucoid in the urine in parallel with theexcretion of immunoglobulin G ceruloplasmin and trans-ferrin [16] El-Beblawy et al appreciate that orosomucoid isa significant independent factor for diabetic microvascularcomplications and can be considered as an early marker ofrenal injury [100]
Urinary orosomucoid excretion rate in type 2 DMpatients predicts cardiovascular mortality [101]
Urinary markers of inflammation are useful for assessinginflammatory processes in DN even in early stages
Journal of Diabetes Research 7
34 Oxidative Stress Biomarkers Oxidative stress plays animportant part in the development and progression of DN[102]
341 Urinary 8-Oxo-78-dihydro-2-deoxyguanosine (8-oHdG) 8-oHdG is produced secondary to oxidative DNAdamage It is eliminated into the urine without being meta-bolized [103] At present it is considered a marker foroxidative stress
After a 5-year follow-up Hinokio et al find that 8-oxodGin urine is a useful clinical marker to predict the developmentof diabetic nephropathy in diabetic patients There wasa significant progression of diabetic nephropathy in thepatients with higher excretion of 8-oxodG in urine comparedwith the patients with moderate or lower excretion of 8-oxodG [104]
Leinonen et al reported increased excretion of 8-oHdG intype 1 DM patients 9 years after the onset of disease mainlyrelated to poor glycemic control [105]
The urinary 8-oHdG marker of oxidation would beaccording to Broedbaek et al a predictor of long-termmortality in DM [106]
342 Heart Fatty Acid Binding Protein (H-FABP) Heart fattyacid binding protein (H-FABP) is a marker of distal tubulardamage
In a study on a cohort of type 1 and type 2DMpatients andan assessment of their markers of glomerular lesions (IgG)markers of proximal tubular lesions (urinary KIM-1 NAGNGAL and cystatin) and a marker of distal tubular lesions(urinaryH-FABP) in relationshipwith albuminuria andGFRNauta et al reported higher values of urinary NAG NGALand H-FABP in normoalbuminurics than in controls On theother hand the values of urinary cystatin C were low [107]
This shows that normoalbuminuric DM patients presentboth proximal and distal tubular lesions
343 Urinary Advanced Glycation End Products (AGE)AGE eliminated in the urine induce a toxic tubular effectproducing tubular dysfunction
In type 2 DM patients with normoalbuminuria highvalues of urinary alpha-1-microglobulin and of urinary KIM-1 were found secondary to tubular dysfunction prior to theonset of microalbuminuria At the same time urinary AGEwere high being correlated with these markers [108]
Turk et al found in type 2 DM patients high values ofurinary AGE in 50 of the patients with normoalbuminuriaand in 85 of those with microalbuminuria [109]
Pentosidine a component ofAGE is a biomarker for theirformation and accumulation [110]
Piarulli et al found in patients with microalbuminuriahigher values of pentosidine than in patients with normoal-buminuria [111]
344 Podocytes Podocyte lesions appear during DM andDN respectively the disease being considered a podocytopa-thy as mentioned above
The assessment of podocyte injury can be accomplishedby monitoring the number of podocyte cells in the urine
or more precisely by means of using podocyte urinarybiomarkers (podocalyxin and nephrine)
A study onDMpatients found that the values of the num-ber of urinary podocytes in normoalbuminuric patients arenot significantly different from those of controls In patientswithmicroalbuminuria andnephrotic syndrome the numberof urinary podocytes is higher It is correlated with urinaryosteopontin and urinary IgM [33]
Urinary podocalyxin originates in the podocyte apicalsurface occurring in vesicle form In DM patients thepodocalyxin level presented higher levels in patients withmicroalbuminuria than in patients with normoalbuminuria[112]
Another study on DM patients found high values ofurinary podocalyxin in more than half of the patients withnormoalbuminuria these values being higher in patientswith microalbuminuria and macroalbuminuria
Urinary podocalyxin is correlated with the values ofurinary NAG and of urinary beta 2 microglobulin [113]
Hara et al consider that urinary podocalyxin can bean early biomarker for detecting early podocyte injury inpatients with DM
Zheng assessed the urinary microRNA profile ofpodocyte-associated molecules (synaptopodin podocalyxinCD2-AP 120572-actin4 and podocin) as biomarkers in patientswith normoalbuminuria microalbuminuria and macro-albuminuria and they reported its increase during theprogression of DN [114]
345 Vascular Endothelial Growth Factor (VEGF) VEGF isa proangiogenic factor produced mainly by the podocytes atnephron level Urinary VEGF can be considered a podocytebiomarker
Urinary VEGF was detected in type 2 DM patientsbeing correlated in these patients with urinary alpha-1-microglobulin a biomarker for proximal tubular lesions [62]
Kim et al found that VEGF is excreted at higher valuesthan controls in normoalbuminuric type 2 DM patientsThe values increase in patients with microalbuminuria andmacroalbuminuria [115]
Fetuin A is glycosylated glycoprotein was consideredan inhibitor for ectopic calcium deposition and promoterof insulin resistance Fetuin A inhibits the calcification ofatherosclerotic plaques in diabetes mellitus [116] It wasfound that elevated urinary Fetuin A excretion is a risk fordevelopment of diabetic nephropathy [117]
35 Other Urinary Biomarkers Used in Evaluating Early DNNumerous urinarymarkers have been suggested for assessingearly DN Some of them have been introduced in use onlyrecently
Urinary retinol-binding protein is a lowmolecular weightprotein that was found to have high urinary values (togetherwith NAG) in normoalbuminuric patients reflecting tubulardysfunction in early DN [118]
The value of serum retinol-binding protein 4 as a bio-marker in assessing the severity of coronary artery disease isto be mentioned [119]
8 Journal of Diabetes Research
Urinary retinol-binding protein 4 as a biomarker in ass-essing DN needs further studies
Urinary vitamin D binding protein can plays the role asbiomarker In type 2 DM it is attributed a potential role inearly diagnosis of DN [120]
Urinary heme oxygenase-1 was found in type 2 DMpatients before the onset of significant albuminuria thusbeing a possible biomarker of early DN [121] In fact oxidativestress activation is expected in DN
Periostin is a cell adhesion molecule which is not nor-mally present in kidneys In tubulointerstitial lesions it ishowever expressed in the kidneys being eliminated in theurineThis is why urinary periostin could be used as amarkerof injury at this level
Since high levels of periostin can be identified in DMpatients before significant albuminuria periostin could rep-resent a marker of diabetic renal injury [122]
Urinary alpha klotho presents higher values in normoal-buminuric type 2 DM patients than in controls It can also bea marker of diabetic injury [123]
Analyzing a group of normoalbuminuric microalbumin-uric and macroalbuminuric type 2 DM patients Sun et alnoted that the urinary level of microvesicle-bound dipeptidylpeptidase-IV is related to the severity of DN [124]
Recent studies point to the usage of urine-specificmicroRNA as a biomarker for early stages of DN Analyzingthe studies in the literature Yang et al issued the hypothesisthat urine-specific microRNA would be a marker that can beused in the early stages of DN [125]
Recently Argyropoulos highlighted the predictive roleof urinary microRNA regarding microalbuminuria in type 1DM [126]
Adipokine zinc-alpha-2 glycoprotein is assigned to themajor histocompatibility complex class I of proteins [127]
Urinary adipokine zinc-alpha-2 glycoprotein is presentearlier than microalbuminuria in diabetic nephropathy Itcould be a useful biomarker for diagnosing early DN [128]Lim et al also appreciate adipokine zinc-alpha-2 glycoproteinas a novel urinary biomarker for normoalbuminuric diabeticnephropathy [129]
351 Proteomics At present proteomic investigations areengaged in identification of new urinary biomarkers to beused in the early diagnosis of DN
In fact proteomics studies noted the fact that microalbu-minuria is not a perfect biomarker for early detection of DN[130 131]
Urinary proteomics begins to stand out as a noninvasivemethod of detecting early DN
Among proteomics studies on diagnosing DN we canmention those of Zurbig et al who reported that collagenfragments were a prominent biomarker 3ndash5 years before theonset of microalbuminuria [132]
A potential role is also attributed to exosome proteomicsfor identifying new biomarkers for DN [133] Zubiri et alshowed a panel of 3 proteins which is differentially present inurinary exosomes fromDNpatients [134] Urinary proteomicanalysis can have an important role in the implementation ofnew biomarkers in DN [135]
At present the prospect of discovering new biomarkersin DM andDN respectively is incumbent both on proteomicsand on genomics transcriptomics and metabolomics [136]
4 Conclusions
Urinary biomarkers allow an assessment of early DNMicroalbuminuria although frequently contested as a
biomarker of early DN is used so far as reference biomarkerin assessing other urinary biomarkers in early DN Untilpresent there is no other biomarker that can substitute inpractice microalbuminuria the new biomarkers being sus-tained by limited studies and requiring validation
The concomitant assessment of several urinary biomark-ers in relationship with microalbuminuria could represent atpresent a method of diagnosing early DNThe great progressin discovering new biomarkers could lead to the developmentof an ldquoidealrdquo urinary biomarker to detect early diabetic DN inthe future
Progresses in the field of urinary biomarkers in DNpromising both in proteomics and in other modern tech-niques develop remarkably at present
Disclosure
Thesupporting source had no involvement in study design incollection analysis and interpretation of data in the writingof the report and in the decision to submit the paper forpublication
Competing Interests
The authors declare that they have no competing interests
Authorsrsquo Contributions
Cristina Gluhovschi and Gheorghe Gluhovschi contributedequally to this paper
Acknowledgments
This research received funding from an Internal Grantof ldquoVictor Babesrdquo University of Medicine and PharmacyTimisoara PIII-C1-PCFI-20142015
References
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[2] M Narres H Claessen S Droste et al ldquoThe incidence ofend-stage renal disease in the diabetic (compared to the non-diabetic) population a systematic reviewrdquo PLoS ONE vol 11no 1 Article ID e0147329 2016
[3] E Lioudaki K G Stylianou I Petrakis et al ldquoIncreased urinaryexcretion of podocyte markers in normoalbuminuric patientswith diabetesrdquo Nephron vol 131 no 1 pp 34ndash42 2015
Journal of Diabetes Research 9
[4] N Banu H Hara M Okamura G Egusa and M YamakidoldquoUrinary excretion of type IV collagen and laminin in the eval-uation of nephropathy in NIDDM comparison with urinaryalbumin and markers of tubular dysfunction andor damagerdquoDiabetes Research and Clinical Practice vol 29 no 1 pp 57ndash671995
[5] P Kubisz L Stanciakova J Stasko P Galajda and M MokanldquoEndothelial and platelet markers in diabetes mellitus type 2rdquoWorld Journal of Diabetes vol 6 no 3 pp 423ndash431 2015
[6] G Tramonti and Y S Kanwar ldquoTubular biomarkers to assessprogression of diabetic nephropathyrdquo Kidney International vol79 no 10 pp 1042ndash1044 2011
[7] T Terami J Wada K Inoue et al ldquoUrinary angiotensinogen isa marker for tubular injuries in patients with type 2 diabetesrdquoInternational Journal of Nephrology and Renovascular Diseasevol 6 pp 233ndash240 2013
[8] M Eriguchi R Yotsueda K Torisu et al ldquoAssessment ofurinary angiotensinogen as a marker of podocyte injury inproteinuric nephropathiesrdquo American Journal of PhysiologymdashRenal Physiology vol 310 no 4 pp F322ndashF333 2016
[9] A Matheson M D P Willcox J Flanagan and B J WalshldquoUrinary biomarkers involved in type 2 diabetes a reviewrdquoDiabetesMetabolism Research and Reviews vol 26 no 3 pp150ndash171 2010
[10] C Y Hong and K S Chia ldquoMarkers of diabetic nephropathyrdquoJournal of Diabetes and Its Complications vol 12 no 1 pp 43ndash60 1998
[11] J H Warram L J Scott L S Hanna et al ldquoProgression ofmicroalbuminuria to proteinuria in type 1 diabetes nonlinearrelationshipwith hyperglycemiardquoDiabetes vol 49 no 1 pp 94ndash100 2000
[12] P Fioretto M W Steffes and M Mauer ldquoGlomerular structurein nonproteinuric IDDM patients with various levels of albu-minuriardquo Diabetes vol 43 no 11 pp 1358ndash1364 1994
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[15] I H de Boer T C Rue P A Cleary et al ldquoLong-term renaloutcomes of patients with type 1 diabetes mellitus and microal-buminuria an analysis of the Diabetes Control and Complica-tions TrialEpidemiology of Diabetes Interventions and Com-plications cohortrdquo Archives of Internal Medicine vol 171 no 5pp 412ndash420 2011
[16] G Zoppini G Targher M Chonchol et al ldquoPredictors ofestimated GFR decline in patients with type 2 diabetes andpreserved kidney functionrdquo Clinical Journal of the AmericanSociety of Nephrology vol 7 no 3 pp 401ndash408 2012
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in a referred cohort of type II diabetic patients a globalperspectiverdquoKidney International vol 69 no 11 pp 2057ndash20632006
[20] B Lu J Wen X Y Song et al ldquoHigh prevalence of albuminuriain population-based patients diagnosed with type 2 diabetesin the Shanghai downtownrdquo Diabetes Research and ClinicalPractice vol 75 no 2 pp 184ndash192 2007
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[22] S-I ArakiMHaneda D Koya et al ldquoReduction inmicroalbu-minuria as an integrated indicator for renal and cardiovascularrisk reduction in patients with type 2 diabetesrdquoDiabetes vol 56no 6 pp 1727ndash1730 2007
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[28] M Kanauchi Y Akai and T Hashimoto ldquoTransferrinuria intype 2 diabetic patients with early nephropathy and tubuloin-terstitial injuryrdquo European Journal of Internal Medicine vol 13no 3 pp 190ndash193 2002
[29] B Quiroga D Arroyo and G de Arriba ldquoPresent and futurein the treatment of diabetic kidney diseaserdquo Journal of DiabetesResearch vol 2015 Article ID 801348 13 pages 2015
[30] T Kazumi T Hozumi Y Ishida et al ldquoIncreased urinarytransferrin excretion predicts microalbuminuria in patientswith type 2 diabetesrdquoDiabetes Care vol 22 no 7 pp 1176ndash11801999
[31] A Cohen-Bucay and G Viswanathan ldquoUrinary markers ofglomerular injury in diabetic nephropathyrdquo International Jour-nal of Nephrology vol 2012 Article ID 146987 11 pages 2012
[32] C Wang C Li W Gong and T Lou ldquoNew urinary biomarkersfor diabetic kidney diseaserdquo Biomarker Research vol 1 article 92013
[33] M Yamazaki S Ito A Usami et al ldquoUrinary excretion rateof ceruloplasmin in non-insulin-dependent diabetic patientswith different stages of nephropathyrdquo European Journal of Endo-crinology vol 132 no 6 pp 681ndash687 1995
[34] L X Qin X Zeng and G Huang ldquoChanges in serum and urineceruloplasmin concentrations in type 2 diabetesrdquo Zhong NanDa Xue Xue Bao Yi Xue Ban vol 29 no 2 pp 208ndash211 2004
[35] J T Tamsma J van den Born J A Bruijn et al ldquoExpression ofglomerular extracellular matrix components in human diabeticnephropathy decrease of heparan sulphate in the glomerularbasement membranerdquo Diabetologia vol 37 no 3 pp 313ndash3201994
10 Journal of Diabetes Research
[36] T Fiseha ldquoUrinary biomarkers for early diabetic nephropathyin type 2 diabetic patientsrdquo Biomarker Research vol 3 article16 2015
[37] N Kotajima T Kimura T Kanda et al ldquoType IV collagenas an early marker for diabetic nephropathy in non-insulin-dependent diabetes mellitusrdquo Journal of Diabetes and its Com-plications vol 14 no 1 pp 13ndash17 2000
[38] H Takizawa T Satoh A Kurusu et al ldquoIncrease of urinarytype IV collagen in normoalbuminuric patients with impairedglucose tolerancerdquo Nephron vol 79 no 4 pp 474ndash475 1998
[39] H Okonogi M Nishimura Y Utsunomiya et al ldquoUrinary typeIV collagen excretion reflects renal morphological alterationsand type IV collagen expression in patients with type 2 diabetesmellitusrdquo Clinical Nephrology vol 55 no 5 pp 357ndash364 2001
[40] S Ming Z Qi L Wang and K Zhu ldquoUrinary type IV collagena specific indicator of incipient diabetic nephropathyrdquo ChineseMedical Journal vol 115 no 3 pp 389ndash394 2002
[41] S Kado A Aoki S Wada et al ldquoUrinary type IV collagen as amarker for early diabetic nephropathyrdquo Diabetes Research andClinical Practice vol 31 no 1ndash3 pp 103ndash108 1996
[42] I Ueta K Takamatsu and K Hashimoto ldquoUrinary glycos-aminoglycans in patients with incipient diabetic nephropathyrdquoNihon Jinzo Gakkai Shi vol 37 no 1 pp 17ndash23 1995
[43] O Torffvit ldquoUrinary sulphated glycosaminoglycans andTamm-Horsfall protein in type 1 diabetic patientsrdquo ScandinavianJournal of Urology and Nephrology vol 33 no 5 pp 328ndash3321999
[44] Y Uehara H Makino K Seiki and Y Urade ldquoUrinaryexcretions of lipocalin-type prostaglandin D synthase predictrenal injury in type-2 diabetes a cross-sectional and prospectivemulticentre studyrdquoNephrology Dialysis Transplantation vol 24no 2 pp 475ndash482 2009
[45] K Kuboki H Tada K Shin Y Oshima and S Isogai ldquoRela-tionship between urinary excretion of fibronectin degradationproducts and proteinuria in diabetic patients and their suppres-sion after continuous subcutaneous heparin infusionrdquoDiabetesResearch and Clinical Practice vol 21 no 1 pp 61ndash66 1993
[46] A L Al-Malki ldquoAssessment of urinary osteopontin in associa-tion with podocyte for early predication of nephropathy in dia-betic patientsrdquo Disease Markers vol 2014 Article ID 493736 5pages 2014
[47] K Mise J Hoshino T Ueno et al ldquoPrognostic value of tubu-lointerstitial lesions urinary N-acetyl-120573-d-glucosaminidaseand urinary 1205732-microglobulin in patients with type 2 diabetesand biopsy-proven diabetic nephropathyrdquoClinical Journal of theAmerican Society of Nephrology vol 11 no 4 pp 593ndash601 2016
[48] K M Schmidt-Ott K Mori Y L Jau et al ldquoDual actionof neutrophil gelatinase-associated lipocalinrdquo Journal of theAmerican Society of Nephrology vol 18 no 2 pp 407ndash413 2007
[49] D Bolignano A Lacquaniti G Coppolino et al ldquoNeu-trophil gelatinase-associated lipocalin as an early biomarker ofnephropathy in diabetic patientsrdquo Kidney amp Blood PressureResearch vol 32 no 2 pp 91ndash98 2009
[50] Z Yuruk Yıldırım A Nayır A Yılmaz A Gedikbası and RBundak ldquoNeutrophil gelatinase-associated lipocalin as an earlysign of diabetic kidney injury in childrenrdquo Journal of ClinicalResearch in Pediatric Endocrinology vol 7 no 4 pp 274ndash2792015
[51] A Lacquaniti V Donato B Pintaudi et al ldquolsquoNormoalbu-minuricrsquo diabetic nephropathy tubular damage and NGALrdquoActa Diabetologica vol 50 no 6 pp 935ndash942 2013
[52] J A de Carvalho E Tatsch B S Hausen et al ldquoUrinarykidney injury molecule-1 and neutrophil gelatinase-associatedlipocalin as indicators of tubular damage in normoalbuminuricpatients with type 2 diabetesrdquo Clinical Biochemistry vol 49 no3 pp 232ndash236 2016
[53] W-J Fu S-L Xiong Y-G Fang et al ldquoUrinary tubularbiomarkers in short-term type 2 diabetes mellitus patients across-sectional studyrdquo Endocrine vol 41 no 1 pp 82ndash88 2012
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[55] Y-HYang X-JHe S-R Chen LWang E-M Li andL-Y XuldquoChanges of serum and urine neutrophil gelatinase-associatedlipocalin in type-2 diabetic patients with nephropathy one yearobservational follow-up studyrdquo Endocrine vol 36 no 1 pp 45ndash51 2009
[56] M H Weber and R Verwiebe ldquo1205721- microglobulin (proteinHC) features of a promising indicator of proximal tubular dys-functionrdquo European Journal of Clinical Chemistry and ClinicalBiochemistry vol 30 no 10 pp 683ndash691 1992
[57] C-Y Hong K Hughes K-S Chia V Ng and S-L LingldquoUrinary 1205721-microglobulin as a marker of nephropathy in type2 diabetic Asian subjects in Singaporerdquo Diabetes Care vol 26no 2 pp 338ndash342 2003
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[59] H Wainai F Katsukawa I Takei H Maruyama K Kataokaand T Saruta ldquoInfluence of glycemic control and hypertensionon urinary microprotein excretion in non-insulin-dependentdiabetes mellitusrdquo Journal of Diabetic Complications vol 5 no2-3 pp 160ndash161 1991
[60] N Shore R Khurshid and M Saleem ldquoAlpha-1 microglobulina marker for early detection of tubular disorders in diabeticnephropathyrdquo Journal of AyubMedical College Abbottabad vol22 no 4 pp 53ndash55 2010
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[62] L Petrica A Vlad G Gluhovschi et al ldquoProximal tubuledysfunction is associated with podocyte damage biomarkersnephrin and vascular endothelial growth factor in type 2diabetes mellitus patients a cross-sectional studyrdquo PLoS ONEvol 9 no 11 Article ID e112538 2014
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[64] S E Nielsen H Reinhard D Zdunek et al ldquoTubular markersare associated with decline in kidney function in proteinurictype 2 diabetic patientsrdquoDiabetes Research andClinical Practicevol 97 no 1 pp 71ndash76 2012
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[66] A P Jones S Lock and K D Griffiths ldquoUrinary N-acetyl-120573-glucosaminidase activity in type I diabetes mellitusrdquo Annals ofClinical Biochemistry vol 32 no 1 pp 58ndash62 1995
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[68] V Ambade P Singh B L Somani and D Basannar ldquoUrinaryN-acetyl beta glucosaminidase and gammaglutamyl transferaseas early markers of diabetic nephropathyrdquo Indian Journal ofClinical Biochemistry vol 21 no 2 pp 142ndash148 2006
[69] D N Patel and K Kalia ldquoEfficacy of urinary N-acetyl-120573-d-glucosaminidase to evaluate early renal tubular damage as aconsequence of type 2 diabetesmellitus a cross-sectional studyrdquoInternational Journal of Diabetes in Developing Countries vol35 supplement 3 pp 449ndash457 2015
[70] H S Assal S Tawfeek E A Rasheld D El-Lebedy and EH Thabet ldquoSerum cystatin C and tubular urinary enzymes asbiomarkers a renal dysfunction in type 2 diabetes mellitusrdquoClinical Medicine Insights Endocrinology and Diabetes vol 6no 7 pp 7ndash13 2013
[71] M Kamiyama A Zsombok and H Kobori ldquoUrinaryangiotensinogen as a novel early biomarker of intrarenal renin-angiotensin system activation in experimental type 1 diabetesrdquoJournal of Pharmacological Sciences vol 119 no 4 pp 314ndash3232012
[72] T Saito M Urushihara Y Kotani S Kagami and H KoborildquoIncreased urinary angiotensinogen is precedent to increasedurinary albumin in patients with type 1 diabetesrdquo AmericanJournal of the Medical Sciences vol 338 no 6 pp 478ndash4802009
[73] Z Zhuang Q Bai L A T Liang D Zheng and Y WangldquoIncreased urinary angiotensinogen precedes the onset of albu-minuria in normotensive type 2 diabetic patientsrdquo InternationalJournal of Clinical and Experimental Pathology vol 8 no 9 pp11464ndash11469 2015
[74] S S Kim S H Song I J Kim et al ldquoClinical implication ofurinary tubular markers in the early stage of nephropathy withtype 2 diabetic patientsrdquoDiabetes Research and Clinical Practicevol 97 no 2 pp 251ndash257 2012
[75] M Sawaguchi S-I ArakiHKobori et al ldquoAssociation betweenurinary angiotensinogen levels and renal and cardiovascularprognoses in patients with type 2 diabetes mellitusrdquo Journal ofDiabetes Investigation vol 3 no 3 pp 318ndash324 2012
[76] T Mizushige H Kobori Y Nishijima et al ldquoUrinaryangiotensinogen could be a prognostic marker of renoprotec-tive effects of alogliptin in patients with type 2 diabetesrdquo Journalof Diabetes Research vol 2015 Article ID 517472 7 pages 2015
[77] Y K Jeon M R Kim J E Huh et al ldquoCystatin C as an earlybiomarker of nephropathy in patients with type 2 diabetesrdquoJournal of Korean Medical Science vol 26 no 2 pp 258ndash2632011
[78] W D Comper T M Osicka and G Jerums ldquoHigh prevalenceof immuno-unreactive intact albumin in urine of diabeticpatientsrdquoAmerican Journal of Kidney Diseases vol 41 no 2 pp336ndash342 2003
[79] X Rao M Wan C Qiu and C Jiang ldquoRole of cystatin C inrenal damage and the optimum cut-off point of renal damageamong patients with type 2 diabetesmellitusrdquo Experimental andTherapeutic Medicine vol 8 no 3 pp 887ndash892 2014
[80] V Garg M Kuman H S Mahapatra A Chitkora A K Gad-poyle and V Sekhan ldquoNovel urinary biomarkers in prediabetic
nephropathyrdquoClinical and Experimental Nephrology vol 19 no5 pp 895ndash890 2015
[81] S S Kim S H Song I J Kim et al ldquoUrinary cystatin C andtubular proteinuria predict progression of diabetic nephropa-thyrdquo Diabetes Care vol 36 no 3 pp 656ndash661 2013
[82] A Kamijo-Ikemori T Sugaya T Yasuda et al ldquoClinical signifi-cance of urinary liver-type fatty acid-binding protein in diabeticnephropathy of type 2 diabetic patientsrdquo Diabetes Care vol 34no 3 pp 691ndash696 2011
[83] S E Nielsen T Sugaya P Hovind T Baba H-H Parving andP Rossing ldquoUrinary liver-type fatty acid-binding protein pre-dicts progression to nephropathy in type 1 diabetic patientsrdquoDiabetes Care vol 33 no 6 pp 1320ndash1324 2010
[84] V Viswanathan S Sivakumar V Sekar D M Umapathy andS Kumpatla ldquoClinical significance of urinary liver-type fattyacid binding protein at various stages of nephropathyrdquo IndianJournal of Nephrology vol 25 no 5 pp 269ndash273 2015
[85] K-M Chou C-C Lee C-H Chen and C-Y Sun ldquoClinicalvalue of NGAL L-FABP and albuminuria in predicting GFRdecline in type 2 diabetes mellitus patientsrdquo PLoS ONE vol 8no 1 article e54863 2013
[86] N M Panduru C Forsblom M Saraheimo et al ldquoUrinaryliver-type fatty acid-binding protein and progression of diabeticnephropathy in type 1 diabetesrdquoDiabetes Care vol 36 no 7 pp2077ndash2083 2013
[87] G I Welsh and M A Saleem ldquoNephrinmdashsignature moleculeof the glomerular podocyterdquoThe Journal of Pathology vol 220no 3 pp 328ndash337 2010
[88] F N Ziyadeh and G Wolf ldquoPathogenesis of the podocytopathyand proteinuria in diabetic glomerulopathyrdquo Current DiabetesReviews vol 4 no 1 pp 39ndash45 2008
[89] A Patari C ForsblomMHavana H Taipale P-H Groop andH Holthofer ldquoNephrinuria in diabetic nephropathy of type 1diabetesrdquo Diabetes vol 52 no 12 pp 2969ndash2974 2003
[90] D P K Ng B-C Tai E Tan et al ldquoNephrinuria associateswithmultiple renal traits in type 2 diabetesrdquoNephrology DialysisTransplantation vol 26 no 8 pp 2508ndash2514 2011
[91] Y Kandasamy R Smith E R Lumbers and D Rudd ldquoNephrina biomarker of early glomerular injuryrdquo Biomarker Researchvol 2 no 1 p 21 2014
[92] B Jim M Ghanta A Qipo et al ldquoDysregulated nephrin indiabetic nephropathy of type 2 diabetes a cross sectional studyrdquoPLoS ONE vol 7 no 5 Article ID e36041 2012
[93] J F Navarro C Mora M Gomez M Muros C Lopez-Aguilar and J Garcıa ldquoInfluence of renal involvement onperipheral blood mononuclear cell expression behaviour oftumour necrosis factor-120572 and interleukin-6 in type 2 diabeticpatientsrdquoNephrology Dialysis Transplantation vol 23 no 3 pp919ndash926 2008
[94] D Z I Cherney J W Scholey D Daneman et al ldquoUrinarymarkers of renal inflammation in adolescents with type 1 dia-betes mellitus and normoalbuminuriardquo Diabetic Medicine vol29 no 10 pp 1297ndash1302 2012
[95] R Har J W Scholey D Daneman et al ldquoThe effect of renalhyperfiltration on urinary inflammatory cytokineschemokinesin patients with uncomplicated type 1 diabetes mellitusrdquo Dia-betologia vol 56 no 5 pp 1166ndash1173 2013
[96] K Tashiro I Koyanagi A Saitoh et al ldquoUrinary levels ofmono-cyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) and renal injuries in patients with type 2 diabetic nephropa-thyrdquo Journal of Clinical Laboratory Analysis vol 16 no 1pp 1ndash4 2002
12 Journal of Diabetes Research
[97] J Liu Z Zhao M D P Willcox B Xu and B Shi ldquoMultiplexbead analysis of urinary cytokines of type 2 diabetic patientswith normo- and microalbuminuriardquo Journal of Immunoassayand Immunochemistry vol 31 no 4 pp 279ndash289 2010
[98] S Ibrahim and L Rashed ldquoCorrelation of urinary monocytechemo-attractant protein-1 with other parameters of renalinjury in type-II diabetes mellitusrdquo Saudi Journal of Kidney Dis-eases and Transplantation vol 19 no 6 pp 911ndash917 2008
[99] H Jiang G Guan R Zhang et al ldquoIncreased urinary excretionof orosomucoid is a risk predictor of diabetic nephropathyrdquoNephrology vol 14 no 3 pp 332ndash337 2009
[100] N M El-Beblawy N G Andrawes E A Ismail B E EnanyH S Abou El-Seoud and M A Erfan ldquoSerum and Uri-nary orosomucoid in young patients with type 1 diabetes alink between inflammation microvascular complications andsubclinical atherosclerosisrdquo Clinical and Applied ThrombosisHemostasis 2016
[101] M S Christiansen E Hommel E Magid and B Feldt-Rasmussen ldquoOrosomucoid in urine predicts cardiovascular andover-all mortality in patients with type II diabetesrdquo Diabetolo-gia vol 45 no 1 pp 115ndash120 2002
[102] H Ha and H B Lee ldquoOxidative stress in diabetic nephropathybasic and clinical informationrdquo Current Diabetes Reports vol 1no 3 pp 282ndash287 2001
[103] L L Wu C C Chiou P Y Chang and J T Wu ldquoUrinary 8-OHdG a marker of oxidative stress to DNA and a risk factorfor cancer atherosclerosis and diabeticsrdquo Clinica Chemica Actavol 339 no 1-2 pp 1ndash9 2004
[104] Y Hinokio S Suzuki M Hirai C Suzuki M Suzukiand T Toyota ldquoUrinary excretion of 8-oxo-7 8-dihydro-21015840-deoxyguanosine as a predictor of the development of diabeticnephropathyrdquo Diabetologia vol 45 no 6 pp 877ndash882 2002
[105] J Leinonen T Lehtimaki S Toyokuni et al ldquoNew biomarkerevidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitusrdquo FEBS Letters vol 417 no1 pp 150ndash152 1997
[106] K Broedbaek A Weimann E S Stovgaard and H E PoulsenldquoUrinary 8-oxo-78-dihydro-21015840-deoxyguanosine as a biomarkerin type 2 diabetesrdquo Free Radical Biology and Medicine vol 51no 8 pp 1473ndash1479 2011
[107] F L NautaW E Boertien S J L Bakker et al ldquoGlomerular andtubular damage markers are elevated in patients with diabetesrdquoDiabetes Care vol 34 no 4 pp 975ndash981 2011
[108] L Petrica A Vlad G Gluhovschi et al ldquoGlycated peptides areassociated with proximal tubule dysfunction in type 2 diabetesmellitusrdquo International Journal of Clinical and ExperimentalMedicine vol 8 no 2 pp 2516ndash2525 2015
[109] N Turk A Mornar V Mrzljak and Z Turk ldquoUrinary excre-tion of advanced glycation endproducts in patients with type2 diabetes and various stages of proteinuriardquo Diabetes andMetabolism vol 30 no 2 pp 187ndash192 2004
[110] A A Ghanem A Elewa and L F Arafa ldquoPentosidine and N-carboxymethyl-lysine biomarkers for type 2 diabetic retinopa-thyrdquo European Journal of Ophthalmology vol 21 no 1 pp 48ndash54 2011
[111] F Piarulli G Sartore A Ceriello et al ldquoRelationship betweenglyco-oxidation antioxidant status and microalbuminuria intype 2 diabetic patientsrdquo Diabetologia vol 52 no 7 pp 1419ndash1425 2009
[112] M Shoji K Kobayashi M Takemoto Y Sato and K YokoteldquoUrinary podocalyxin levels were associated with urinary albu-min levels among patients with diabetesrdquo Biomarkers vol 21no 2 pp 164ndash167 2015
[113] M Hara K Yamagata Y Tomino et al ldquoUrinary podocalyxinis an early marker for podocyte injury in patients with diabetesestablishment of a highly sensitive ELISA to detect urinarypodocalyxinrdquo Diabetologia vol 55 no 11 pp 2913ndash2919 2012
[114] M Zheng L-L Lv J Ni et al ldquoUrinary podocyte-associatedmRNA profile in various stages of diabetic nephropathyrdquo PLoSONE vol 6 no 5 Article ID e20431 2011
[115] N H Kim K B Kim D L Kim et al ldquoPlasma and urinaryvascular endothelial growth factor and diabetic nephropathy intype 2 diabetes mellitusrdquo Diabetic Medicine vol 21 no 6 pp545ndash551 2004
[116] M Emoto K Mori E Lee et al ldquoFetuin-A and atheroscleroticcalcified plaque in patients with type 2 diabetes mellitusrdquoMetabolism Clinical and Experimental vol 59 no 6 pp 873ndash878 2010
[117] K Inoue J Wada J Eguchi et al ldquoUrinary fetuin-A is a novelmarker for diabetic nephropathy in type 2 diabetes identified bylectin microarrayrdquo PLoS ONE vol 8 no 10 Article ID e771182013
[118] M A K Salem S A El-Habashy O M Saeid M M KEl-Tawil and P H Tawfik ldquoUrinary excretion of N-acetyl-120573-d-glucosaminidase and retinol binding protein as alternativeindicators of nephropathy in patients with type 1 diabetesmellitusrdquo Pediatric Diabetes vol 3 no 1 pp 37ndash41 2002
[119] V Lambadiari N P E KadoglouV Stasinos et al ldquoSerum levelsof retinol-binding protein-4 are associated with the presenceand severity of coronary artery diseaserdquo Cardiovascular Dia-betology vol 13 no 1 article 121 2014
[120] A Shoukry S E-A Bdeer and R H El-Sokkary ldquoUrinarymonocyte chemoattractant protein-1 and vitamin D-bindingprotein as biomarkers for early detection of diabetic nephropa-thy in type 2 diabetesmellitusrdquoMolecular andCellular Biochem-istry vol 408 no 1 pp 25ndash35 2015
[121] Z Li Y Xu Y Nie and Z Zhao ldquoUrinary heme oxygenase-1 as apotential biomarker for early diabetic nephropathyrdquoNephrology(Carlton Vic) 2016
[122] B Satirapoj S Tassanasorn M Charoenpitakchai and OSupasyndh ldquoPeriostin as a tissue and urinary biomarker of renalinjury in type 2 diabetes mellitusrdquo PLoS ONE vol 10 no 4Article ID e0124055 2015
[123] E Y Lee S S Kim J-S Lee et al ldquoSoluble 120572-klotho as a novelbiomarker in the early stage of nephropathy in patients withtype 2 diabetesrdquo PLoS ONE vol 9 no 8 article e102984 2014
[124] A-L Sun J-TDengG-J Guan et al ldquoDipeptidyl peptidase-IVis a potential molecular biomarker in diabetic kidney diseaserdquoDiabetes and Vascular Disease Research vol 9 no 4 pp 301ndash308 2012
[125] Y Yang L Xiao J Li Y S Kanwar F Liu and L Sun ldquoUrinemiRNAs potential biomarkers for monitoring progression ofearly stages of diabetic nephropathyrdquo Medical Hypotheses vol81 no 2 pp 274ndash278 2013
[126] C Argyropoulos K Wang J Bernardo et al ldquoUrinaryMicroRNA profiling predicts the development of microalbu-minuria in patients with type 1 Diabetesrdquo Journal of ClinicalMedicine vol 4 no 7 pp 1495ndash1517 2015
Journal of Diabetes Research 13
[127] M W Kennedy A P Heikema A Cooper P J Bjorkmanand L M Sanchez ldquoHydrophobic ligand binding by Zn-1205722-glycoprotein a soluble fat-depleting factor related to major his-tocompatibility complex proteinsrdquo Journal of Biological Chem-istry vol 276 no 37 pp 35008ndash35013 2001
[128] YWang YM Li S Zhang J Y Zhao and C Y Liu ldquoAdipokinezinc-120572-2- glycoprotein as novel urinary biomarker presentsearly than microalbuminuria in diabetic nephropathyrdquo Journalof International Medical Research vol 44 no 2 pp 278ndash2862016
[129] S C Lim D Q Liying W C Toy et al ldquoAdipocytokine zinc 1205722glycoprotein (ZAG) as a novel urinary biomarker for normo-albuminuric diabetic nephropathyrdquo Diabetic Medicine vol 29no 7 pp 945ndash949 2012
[130] V Thongboonkerd ldquoStudy of diabetic nephropathy in theproteomic erardquo Diabetes and the Kidney vol 170 pp 172ndash1832011
[131] K N Lai and S C W Tang Eds Diabetes and the Kidney vol170 Contributions to Nephrology Karger Basel Switzerland2011
[132] P Zurbig G Jerums P Hovind et al ldquoUrinary proteomics forearly diagnosis in diabetic nephropathyrdquo Diabetes vol 61 no12 pp 3304ndash3313 2012
[133] F Raimondo S Corbetta L Morosi et al ldquoUrinary exosomesand diabetic nephropathy a proteomic approachrdquo MolecularBioSystems vol 9 no 6 pp 1139ndash1146 2013
[134] I Zubiri M Posada-Ayala A Sanz-Maroto et al ldquoDiabeticnephropathy induces changes in the proteome of human uri-nary exosomes as revealed by label-free comparative analysisrdquoJournal of Proteomics vol 96 pp 92ndash102 2014
[135] A Caseiro A Barros R Ferreira et al ldquoPursuing type 1diabetes mellitus and related complications through urinaryproteomicsrdquo Translational Research vol 163 no 3 pp 188ndash1992014
[136] B Jim J Santos F Spath and J C He ldquoBiomarkers of diabeticnephropathy the present and the futurerdquo Current DiabetesReviews vol 8 no 5 pp 317ndash328 2012
Patients with microalbuminuria present higher values ofurinary cystatin C than those without microalbuminuriaurinary cystatin C having a predictive role for the progressionof diabetic nephropathy (DN) [81]
Urinary cystatin C level could be an independentfactor for identifying renal dysfunction in type 2 DMpatients with normoalbuminuria including patients withGFR lt60mLmin173m2 [77] Uslu et al find a significantpositive correlation between serum cystatin C urinary NAGlacticodehydrogenase alkaline phosphatase activities andserum creatinine levels [67]
Serum and urinary cystatin C are useful biomarkers forassessing early nephropathy in type 2 DM [77]
327 L-FABP (Liver-Type Fatty Acid Binding Protein) Uri-nary L-FABP is a protein with low molecular weightexpressed in the cytoplasm of human proximal tubular cells[82] It is also expressed at liver level
Increased urinary L-FABP was found in type 1 DMpatients who presented normoalbuminuria having a predic-tive role regarding the progression towards microalbumin-uria and of microalbuminuria towards macroalbuminuria[83]
Patients with type 2 DM with normoalbuminuria alsopresented high levels of urinary L-FABP this protein beingconsidered as a useful biomarker for diagnosing early diabeticnephropathy In fact urinary L-FABP has been confirmed asa tubular biomarker by the Ministry of Health andWelfare inJapan [82]
The L-FABP factor is also related to the severity of DNThe values of urinary L-FABP increase with the decline ofrenal function [84]
Although some authors like Chou et al do not ascribe apredictive role to urinary L-FABP in type 2 DM patients [85]others like Panduru et al consider that urinary L-FABP is anindependent predictor of the progression of DN [86]
328 Nephrinuria Nephrine is a transmembrane protein inthe structure of the slit diaphragm [87]
InDMpodocyte dysfunction is present DN is considereda podocytopathy [88] Injury of the slit diaphragm leads tonephrinuria
Nephrinuria can occur in some type 1 DM patients priorto microalbuminuria [89] Nephrinuria was also reported insome normoalbuminuric type 2 DM patients [62 90]
Nephrinuria is related to podocyte injury representing abiomarker of early glomerular injury [91]
Dysregulation of nephrine in podocytes in DN couldlead to nephrinuria in normoalbuminuric patients precedingmicroalbuminuria [92]
In albuminuric patients nephrinuria is positively corre-lated with albuminuria and negatively correlated with GFRbeing a biomarker of DN in other phases of DM as well
Podocyte impairment in DM involves not only nephrinebut also other podocyte elements for example VEGF Thusin normoalbuminuric DM patients nephrinuria is correlatedwith urinary elimination of VEGF [62]
Tubular biomarkers seem to play an important role inthe early diagnosis of DN They manage to show in most
cases that microalbuminuria does not represent a reliablebiomarker for diagnosing incipient lesions of DN Howeverup to now none of these biomarkers has been established asgold standard for the identification of early DN
33 Markers of Inflammation DM is accompanied bychronic inflammatory processes affecting the whole body thekidneys included Mediators of inflammation like cytokinesand chemokines are present in these processes Some of themare useful as markers of inflammation
331 Tumour Necrosis Factor Alpha (TNF Alpha) UrinaryTNF alpha presents in type 2 DM patients with microal-buminuria and macroalbuminuria higher values than inpatients with normoalbuminuria Urinary TNF alpha iscorrelatedwith urinaryNAG amarker of tubular lesions [93]
Cherney et al analyzed in a complex study on nor-moalbuminuric type 1 DM patients forty-two urinarycytokineschemokines They found that the urinary level ofIL6 and IL8 the platelet-derived growth factor and RANTESare not altered in patients with normal albumin-creatinineratio
Higher urinary excretion of these markers is associatedwith microalbuminuria Cherney et al consider that thesemarkers could have a role in assessing the risk of DN inpatients with type 1 DM [94]
In type 1 DM patients renal hyperfiltration is related toincreased excretion of inflammatory cytokineschemokines[95]
Tashiro et al found in type 2 DM patients that IL8 is highin early stages of DN andMCP-1 increases in advanced stages[96]
A study on type 2 DM patients with normoalbuminuriaand microalbuminuria found higher values of IL8 IP10MCP-1 G-CSF EOTAXIN and RANTES in patients withmicroalbuminuria than in normoalbuminurics or in controlsTheir assessment would be useful in the early diagnosis andtreatment of DN [97]
Ibrahim and Rached also found that urinary MCP-1 ishigher in patients with microalbuminuria than in normoal-buminurics or healthy controls [98]
332 Urinary Orosomucoid Orosomucoid represents a gly-coprotein involved in inflammatory processes
Urinary orosomucoid has higher values in type 1 DMpatients with normoalbuminuria than in controls These val-ues increase in patients withmicroalbuminuria andmacroal-buminuria [99] Type 2 DM patients presented increasedexcretion of orosomucoid in the urine in parallel with theexcretion of immunoglobulin G ceruloplasmin and trans-ferrin [16] El-Beblawy et al appreciate that orosomucoid isa significant independent factor for diabetic microvascularcomplications and can be considered as an early marker ofrenal injury [100]
Urinary orosomucoid excretion rate in type 2 DMpatients predicts cardiovascular mortality [101]
Urinary markers of inflammation are useful for assessinginflammatory processes in DN even in early stages
Journal of Diabetes Research 7
34 Oxidative Stress Biomarkers Oxidative stress plays animportant part in the development and progression of DN[102]
341 Urinary 8-Oxo-78-dihydro-2-deoxyguanosine (8-oHdG) 8-oHdG is produced secondary to oxidative DNAdamage It is eliminated into the urine without being meta-bolized [103] At present it is considered a marker foroxidative stress
After a 5-year follow-up Hinokio et al find that 8-oxodGin urine is a useful clinical marker to predict the developmentof diabetic nephropathy in diabetic patients There wasa significant progression of diabetic nephropathy in thepatients with higher excretion of 8-oxodG in urine comparedwith the patients with moderate or lower excretion of 8-oxodG [104]
Leinonen et al reported increased excretion of 8-oHdG intype 1 DM patients 9 years after the onset of disease mainlyrelated to poor glycemic control [105]
The urinary 8-oHdG marker of oxidation would beaccording to Broedbaek et al a predictor of long-termmortality in DM [106]
342 Heart Fatty Acid Binding Protein (H-FABP) Heart fattyacid binding protein (H-FABP) is a marker of distal tubulardamage
In a study on a cohort of type 1 and type 2DMpatients andan assessment of their markers of glomerular lesions (IgG)markers of proximal tubular lesions (urinary KIM-1 NAGNGAL and cystatin) and a marker of distal tubular lesions(urinaryH-FABP) in relationshipwith albuminuria andGFRNauta et al reported higher values of urinary NAG NGALand H-FABP in normoalbuminurics than in controls On theother hand the values of urinary cystatin C were low [107]
This shows that normoalbuminuric DM patients presentboth proximal and distal tubular lesions
343 Urinary Advanced Glycation End Products (AGE)AGE eliminated in the urine induce a toxic tubular effectproducing tubular dysfunction
In type 2 DM patients with normoalbuminuria highvalues of urinary alpha-1-microglobulin and of urinary KIM-1 were found secondary to tubular dysfunction prior to theonset of microalbuminuria At the same time urinary AGEwere high being correlated with these markers [108]
Turk et al found in type 2 DM patients high values ofurinary AGE in 50 of the patients with normoalbuminuriaand in 85 of those with microalbuminuria [109]
Pentosidine a component ofAGE is a biomarker for theirformation and accumulation [110]
Piarulli et al found in patients with microalbuminuriahigher values of pentosidine than in patients with normoal-buminuria [111]
344 Podocytes Podocyte lesions appear during DM andDN respectively the disease being considered a podocytopa-thy as mentioned above
The assessment of podocyte injury can be accomplishedby monitoring the number of podocyte cells in the urine
or more precisely by means of using podocyte urinarybiomarkers (podocalyxin and nephrine)
A study onDMpatients found that the values of the num-ber of urinary podocytes in normoalbuminuric patients arenot significantly different from those of controls In patientswithmicroalbuminuria andnephrotic syndrome the numberof urinary podocytes is higher It is correlated with urinaryosteopontin and urinary IgM [33]
Urinary podocalyxin originates in the podocyte apicalsurface occurring in vesicle form In DM patients thepodocalyxin level presented higher levels in patients withmicroalbuminuria than in patients with normoalbuminuria[112]
Another study on DM patients found high values ofurinary podocalyxin in more than half of the patients withnormoalbuminuria these values being higher in patientswith microalbuminuria and macroalbuminuria
Urinary podocalyxin is correlated with the values ofurinary NAG and of urinary beta 2 microglobulin [113]
Hara et al consider that urinary podocalyxin can bean early biomarker for detecting early podocyte injury inpatients with DM
Zheng assessed the urinary microRNA profile ofpodocyte-associated molecules (synaptopodin podocalyxinCD2-AP 120572-actin4 and podocin) as biomarkers in patientswith normoalbuminuria microalbuminuria and macro-albuminuria and they reported its increase during theprogression of DN [114]
345 Vascular Endothelial Growth Factor (VEGF) VEGF isa proangiogenic factor produced mainly by the podocytes atnephron level Urinary VEGF can be considered a podocytebiomarker
Urinary VEGF was detected in type 2 DM patientsbeing correlated in these patients with urinary alpha-1-microglobulin a biomarker for proximal tubular lesions [62]
Kim et al found that VEGF is excreted at higher valuesthan controls in normoalbuminuric type 2 DM patientsThe values increase in patients with microalbuminuria andmacroalbuminuria [115]
Fetuin A is glycosylated glycoprotein was consideredan inhibitor for ectopic calcium deposition and promoterof insulin resistance Fetuin A inhibits the calcification ofatherosclerotic plaques in diabetes mellitus [116] It wasfound that elevated urinary Fetuin A excretion is a risk fordevelopment of diabetic nephropathy [117]
35 Other Urinary Biomarkers Used in Evaluating Early DNNumerous urinarymarkers have been suggested for assessingearly DN Some of them have been introduced in use onlyrecently
Urinary retinol-binding protein is a lowmolecular weightprotein that was found to have high urinary values (togetherwith NAG) in normoalbuminuric patients reflecting tubulardysfunction in early DN [118]
The value of serum retinol-binding protein 4 as a bio-marker in assessing the severity of coronary artery disease isto be mentioned [119]
8 Journal of Diabetes Research
Urinary retinol-binding protein 4 as a biomarker in ass-essing DN needs further studies
Urinary vitamin D binding protein can plays the role asbiomarker In type 2 DM it is attributed a potential role inearly diagnosis of DN [120]
Urinary heme oxygenase-1 was found in type 2 DMpatients before the onset of significant albuminuria thusbeing a possible biomarker of early DN [121] In fact oxidativestress activation is expected in DN
Periostin is a cell adhesion molecule which is not nor-mally present in kidneys In tubulointerstitial lesions it ishowever expressed in the kidneys being eliminated in theurineThis is why urinary periostin could be used as amarkerof injury at this level
Since high levels of periostin can be identified in DMpatients before significant albuminuria periostin could rep-resent a marker of diabetic renal injury [122]
Urinary alpha klotho presents higher values in normoal-buminuric type 2 DM patients than in controls It can also bea marker of diabetic injury [123]
Analyzing a group of normoalbuminuric microalbumin-uric and macroalbuminuric type 2 DM patients Sun et alnoted that the urinary level of microvesicle-bound dipeptidylpeptidase-IV is related to the severity of DN [124]
Recent studies point to the usage of urine-specificmicroRNA as a biomarker for early stages of DN Analyzingthe studies in the literature Yang et al issued the hypothesisthat urine-specific microRNA would be a marker that can beused in the early stages of DN [125]
Recently Argyropoulos highlighted the predictive roleof urinary microRNA regarding microalbuminuria in type 1DM [126]
Adipokine zinc-alpha-2 glycoprotein is assigned to themajor histocompatibility complex class I of proteins [127]
Urinary adipokine zinc-alpha-2 glycoprotein is presentearlier than microalbuminuria in diabetic nephropathy Itcould be a useful biomarker for diagnosing early DN [128]Lim et al also appreciate adipokine zinc-alpha-2 glycoproteinas a novel urinary biomarker for normoalbuminuric diabeticnephropathy [129]
351 Proteomics At present proteomic investigations areengaged in identification of new urinary biomarkers to beused in the early diagnosis of DN
In fact proteomics studies noted the fact that microalbu-minuria is not a perfect biomarker for early detection of DN[130 131]
Urinary proteomics begins to stand out as a noninvasivemethod of detecting early DN
Among proteomics studies on diagnosing DN we canmention those of Zurbig et al who reported that collagenfragments were a prominent biomarker 3ndash5 years before theonset of microalbuminuria [132]
A potential role is also attributed to exosome proteomicsfor identifying new biomarkers for DN [133] Zubiri et alshowed a panel of 3 proteins which is differentially present inurinary exosomes fromDNpatients [134] Urinary proteomicanalysis can have an important role in the implementation ofnew biomarkers in DN [135]
At present the prospect of discovering new biomarkersin DM andDN respectively is incumbent both on proteomicsand on genomics transcriptomics and metabolomics [136]
4 Conclusions
Urinary biomarkers allow an assessment of early DNMicroalbuminuria although frequently contested as a
biomarker of early DN is used so far as reference biomarkerin assessing other urinary biomarkers in early DN Untilpresent there is no other biomarker that can substitute inpractice microalbuminuria the new biomarkers being sus-tained by limited studies and requiring validation
The concomitant assessment of several urinary biomark-ers in relationship with microalbuminuria could represent atpresent a method of diagnosing early DNThe great progressin discovering new biomarkers could lead to the developmentof an ldquoidealrdquo urinary biomarker to detect early diabetic DN inthe future
Progresses in the field of urinary biomarkers in DNpromising both in proteomics and in other modern tech-niques develop remarkably at present
Disclosure
Thesupporting source had no involvement in study design incollection analysis and interpretation of data in the writingof the report and in the decision to submit the paper forpublication
Competing Interests
The authors declare that they have no competing interests
Authorsrsquo Contributions
Cristina Gluhovschi and Gheorghe Gluhovschi contributedequally to this paper
Acknowledgments
This research received funding from an Internal Grantof ldquoVictor Babesrdquo University of Medicine and PharmacyTimisoara PIII-C1-PCFI-20142015
References
[1] R J Macisaac E I Ekinci and G Jerums ldquoMarkers of and riskfactors for the development and progression of diabetic kidneydiseaserdquo American Journal of Kidney Diseases vol 63 no 2 ppS39ndashS62 2014
[2] M Narres H Claessen S Droste et al ldquoThe incidence ofend-stage renal disease in the diabetic (compared to the non-diabetic) population a systematic reviewrdquo PLoS ONE vol 11no 1 Article ID e0147329 2016
[3] E Lioudaki K G Stylianou I Petrakis et al ldquoIncreased urinaryexcretion of podocyte markers in normoalbuminuric patientswith diabetesrdquo Nephron vol 131 no 1 pp 34ndash42 2015
Journal of Diabetes Research 9
[4] N Banu H Hara M Okamura G Egusa and M YamakidoldquoUrinary excretion of type IV collagen and laminin in the eval-uation of nephropathy in NIDDM comparison with urinaryalbumin and markers of tubular dysfunction andor damagerdquoDiabetes Research and Clinical Practice vol 29 no 1 pp 57ndash671995
[5] P Kubisz L Stanciakova J Stasko P Galajda and M MokanldquoEndothelial and platelet markers in diabetes mellitus type 2rdquoWorld Journal of Diabetes vol 6 no 3 pp 423ndash431 2015
[6] G Tramonti and Y S Kanwar ldquoTubular biomarkers to assessprogression of diabetic nephropathyrdquo Kidney International vol79 no 10 pp 1042ndash1044 2011
[7] T Terami J Wada K Inoue et al ldquoUrinary angiotensinogen isa marker for tubular injuries in patients with type 2 diabetesrdquoInternational Journal of Nephrology and Renovascular Diseasevol 6 pp 233ndash240 2013
[8] M Eriguchi R Yotsueda K Torisu et al ldquoAssessment ofurinary angiotensinogen as a marker of podocyte injury inproteinuric nephropathiesrdquo American Journal of PhysiologymdashRenal Physiology vol 310 no 4 pp F322ndashF333 2016
[9] A Matheson M D P Willcox J Flanagan and B J WalshldquoUrinary biomarkers involved in type 2 diabetes a reviewrdquoDiabetesMetabolism Research and Reviews vol 26 no 3 pp150ndash171 2010
[10] C Y Hong and K S Chia ldquoMarkers of diabetic nephropathyrdquoJournal of Diabetes and Its Complications vol 12 no 1 pp 43ndash60 1998
[11] J H Warram L J Scott L S Hanna et al ldquoProgression ofmicroalbuminuria to proteinuria in type 1 diabetes nonlinearrelationshipwith hyperglycemiardquoDiabetes vol 49 no 1 pp 94ndash100 2000
[12] P Fioretto M W Steffes and M Mauer ldquoGlomerular structurein nonproteinuric IDDM patients with various levels of albu-minuriardquo Diabetes vol 43 no 11 pp 1358ndash1364 1994
[13] K McKenna and C Thompson ldquoMicroalbuminuria a markerto increased renal and cardiovascular risk in diabetes mellitusrdquoScottish Medical Journal vol 42 no 4 pp 99ndash104 1997
[14] P Hovind L Tarnow P Rossing et al ldquoPredictors for thedevelopment of microalbuminuria and macroalbuminuria inpatients with type 1 diabetes inception cohort studyrdquo BritishMedical Journal vol 328 no 7448 pp 1105ndash1108 2004
[15] I H de Boer T C Rue P A Cleary et al ldquoLong-term renaloutcomes of patients with type 1 diabetes mellitus and microal-buminuria an analysis of the Diabetes Control and Complica-tions TrialEpidemiology of Diabetes Interventions and Com-plications cohortrdquo Archives of Internal Medicine vol 171 no 5pp 412ndash420 2011
[16] G Zoppini G Targher M Chonchol et al ldquoPredictors ofestimated GFR decline in patients with type 2 diabetes andpreserved kidney functionrdquo Clinical Journal of the AmericanSociety of Nephrology vol 7 no 3 pp 401ndash408 2012
[17] B A Perkins LH Ficociello B EOstrander et al ldquoMicroalbu-minuria and the risk for early progressive renal function declinein type 1 diabetesrdquo Journal of theAmerican Society ofNephrologyvol 18 no 4 pp 1353ndash1361 2007
[18] D J Newman M B Mattock A B Dawnay et al ldquoSystematicreview on urine albumin testing for early detection of diabeticcomplicationsrdquo Health Technology Assessment vol 9 no 302005
[19] H-H Parving J B Lewis M Ravid G Remuzzi and L GHunsicker ldquoPrevalence and risk factors for microalbuminuria
in a referred cohort of type II diabetic patients a globalperspectiverdquoKidney International vol 69 no 11 pp 2057ndash20632006
[20] B Lu J Wen X Y Song et al ldquoHigh prevalence of albuminuriain population-based patients diagnosed with type 2 diabetesin the Shanghai downtownrdquo Diabetes Research and ClinicalPractice vol 75 no 2 pp 184ndash192 2007
[21] N Ismail B Becker P Strzelczyk and E Ritz ldquoRenal diseaseand hypertension in non-insulin-dependent diabetes mellitusrdquoKidney International vol 55 no 1 pp 1ndash28 1999
[22] S-I ArakiMHaneda D Koya et al ldquoReduction inmicroalbu-minuria as an integrated indicator for renal and cardiovascularrisk reduction in patients with type 2 diabetesrdquoDiabetes vol 56no 6 pp 1727ndash1730 2007
[23] R G Nelson P H Bennett G J Beck et al ldquoDevelopment andprogression of renal disease in Pima Indians with non- insulin-dependent diabetes mellitusrdquo The New England Journal ofMedicine vol 335 no 22 pp 1636ndash1642 1996
[24] S C W Tang J C K Leung and K N Lai ldquoDiabetictubulopathy an emerging entityrdquo in Diabetes and the KidneyK N Lai and S C W Tang Eds Karger 2011
[25] K Kunika T Yamaoka and M Itakura ldquoDamage of charge-dependent renal tubular reabsorption causes diabetic micro-proteinuriardquoDiabetes Research and Clinical Practice vol 36 no1 pp 1ndash9 1997
[26] G Currie G Mc Kay and C Delles ldquoBiomarkers in diabeticnephropathy present and futurerdquoWorld Journal ofDiabetes vol5 no 6 pp 763ndash776 2014
[27] T Narita H Sasaki M Hosoba et al ldquoParallel increase inurinary excretion rates of immunoglobulin G ceruloplasmintransferrin and orosomucoid in normoalbuminuric type 2diabetic patientsrdquo Diabetes Care vol 27 no 5 pp 1176ndash11812004
[28] M Kanauchi Y Akai and T Hashimoto ldquoTransferrinuria intype 2 diabetic patients with early nephropathy and tubuloin-terstitial injuryrdquo European Journal of Internal Medicine vol 13no 3 pp 190ndash193 2002
[29] B Quiroga D Arroyo and G de Arriba ldquoPresent and futurein the treatment of diabetic kidney diseaserdquo Journal of DiabetesResearch vol 2015 Article ID 801348 13 pages 2015
[30] T Kazumi T Hozumi Y Ishida et al ldquoIncreased urinarytransferrin excretion predicts microalbuminuria in patientswith type 2 diabetesrdquoDiabetes Care vol 22 no 7 pp 1176ndash11801999
[31] A Cohen-Bucay and G Viswanathan ldquoUrinary markers ofglomerular injury in diabetic nephropathyrdquo International Jour-nal of Nephrology vol 2012 Article ID 146987 11 pages 2012
[32] C Wang C Li W Gong and T Lou ldquoNew urinary biomarkersfor diabetic kidney diseaserdquo Biomarker Research vol 1 article 92013
[33] M Yamazaki S Ito A Usami et al ldquoUrinary excretion rateof ceruloplasmin in non-insulin-dependent diabetic patientswith different stages of nephropathyrdquo European Journal of Endo-crinology vol 132 no 6 pp 681ndash687 1995
[34] L X Qin X Zeng and G Huang ldquoChanges in serum and urineceruloplasmin concentrations in type 2 diabetesrdquo Zhong NanDa Xue Xue Bao Yi Xue Ban vol 29 no 2 pp 208ndash211 2004
[35] J T Tamsma J van den Born J A Bruijn et al ldquoExpression ofglomerular extracellular matrix components in human diabeticnephropathy decrease of heparan sulphate in the glomerularbasement membranerdquo Diabetologia vol 37 no 3 pp 313ndash3201994
10 Journal of Diabetes Research
[36] T Fiseha ldquoUrinary biomarkers for early diabetic nephropathyin type 2 diabetic patientsrdquo Biomarker Research vol 3 article16 2015
[37] N Kotajima T Kimura T Kanda et al ldquoType IV collagenas an early marker for diabetic nephropathy in non-insulin-dependent diabetes mellitusrdquo Journal of Diabetes and its Com-plications vol 14 no 1 pp 13ndash17 2000
[38] H Takizawa T Satoh A Kurusu et al ldquoIncrease of urinarytype IV collagen in normoalbuminuric patients with impairedglucose tolerancerdquo Nephron vol 79 no 4 pp 474ndash475 1998
[39] H Okonogi M Nishimura Y Utsunomiya et al ldquoUrinary typeIV collagen excretion reflects renal morphological alterationsand type IV collagen expression in patients with type 2 diabetesmellitusrdquo Clinical Nephrology vol 55 no 5 pp 357ndash364 2001
[40] S Ming Z Qi L Wang and K Zhu ldquoUrinary type IV collagena specific indicator of incipient diabetic nephropathyrdquo ChineseMedical Journal vol 115 no 3 pp 389ndash394 2002
[41] S Kado A Aoki S Wada et al ldquoUrinary type IV collagen as amarker for early diabetic nephropathyrdquo Diabetes Research andClinical Practice vol 31 no 1ndash3 pp 103ndash108 1996
[42] I Ueta K Takamatsu and K Hashimoto ldquoUrinary glycos-aminoglycans in patients with incipient diabetic nephropathyrdquoNihon Jinzo Gakkai Shi vol 37 no 1 pp 17ndash23 1995
[43] O Torffvit ldquoUrinary sulphated glycosaminoglycans andTamm-Horsfall protein in type 1 diabetic patientsrdquo ScandinavianJournal of Urology and Nephrology vol 33 no 5 pp 328ndash3321999
[44] Y Uehara H Makino K Seiki and Y Urade ldquoUrinaryexcretions of lipocalin-type prostaglandin D synthase predictrenal injury in type-2 diabetes a cross-sectional and prospectivemulticentre studyrdquoNephrology Dialysis Transplantation vol 24no 2 pp 475ndash482 2009
[45] K Kuboki H Tada K Shin Y Oshima and S Isogai ldquoRela-tionship between urinary excretion of fibronectin degradationproducts and proteinuria in diabetic patients and their suppres-sion after continuous subcutaneous heparin infusionrdquoDiabetesResearch and Clinical Practice vol 21 no 1 pp 61ndash66 1993
[46] A L Al-Malki ldquoAssessment of urinary osteopontin in associa-tion with podocyte for early predication of nephropathy in dia-betic patientsrdquo Disease Markers vol 2014 Article ID 493736 5pages 2014
[47] K Mise J Hoshino T Ueno et al ldquoPrognostic value of tubu-lointerstitial lesions urinary N-acetyl-120573-d-glucosaminidaseand urinary 1205732-microglobulin in patients with type 2 diabetesand biopsy-proven diabetic nephropathyrdquoClinical Journal of theAmerican Society of Nephrology vol 11 no 4 pp 593ndash601 2016
[48] K M Schmidt-Ott K Mori Y L Jau et al ldquoDual actionof neutrophil gelatinase-associated lipocalinrdquo Journal of theAmerican Society of Nephrology vol 18 no 2 pp 407ndash413 2007
[49] D Bolignano A Lacquaniti G Coppolino et al ldquoNeu-trophil gelatinase-associated lipocalin as an early biomarker ofnephropathy in diabetic patientsrdquo Kidney amp Blood PressureResearch vol 32 no 2 pp 91ndash98 2009
[50] Z Yuruk Yıldırım A Nayır A Yılmaz A Gedikbası and RBundak ldquoNeutrophil gelatinase-associated lipocalin as an earlysign of diabetic kidney injury in childrenrdquo Journal of ClinicalResearch in Pediatric Endocrinology vol 7 no 4 pp 274ndash2792015
[51] A Lacquaniti V Donato B Pintaudi et al ldquolsquoNormoalbu-minuricrsquo diabetic nephropathy tubular damage and NGALrdquoActa Diabetologica vol 50 no 6 pp 935ndash942 2013
[52] J A de Carvalho E Tatsch B S Hausen et al ldquoUrinarykidney injury molecule-1 and neutrophil gelatinase-associatedlipocalin as indicators of tubular damage in normoalbuminuricpatients with type 2 diabetesrdquo Clinical Biochemistry vol 49 no3 pp 232ndash236 2016
[53] W-J Fu S-L Xiong Y-G Fang et al ldquoUrinary tubularbiomarkers in short-term type 2 diabetes mellitus patients across-sectional studyrdquo Endocrine vol 41 no 1 pp 82ndash88 2012
[54] V Garg M Kumar H S Mahapatra A Chitkara A KGadpayle and V Sekhar ldquoNovel urinary biomarkers in pre-diabetic nephropathyrdquo Clinical and Experimental Nephrologyvol 19 no 5 pp 895ndash900 2015
[55] Y-HYang X-JHe S-R Chen LWang E-M Li andL-Y XuldquoChanges of serum and urine neutrophil gelatinase-associatedlipocalin in type-2 diabetic patients with nephropathy one yearobservational follow-up studyrdquo Endocrine vol 36 no 1 pp 45ndash51 2009
[56] M H Weber and R Verwiebe ldquo1205721- microglobulin (proteinHC) features of a promising indicator of proximal tubular dys-functionrdquo European Journal of Clinical Chemistry and ClinicalBiochemistry vol 30 no 10 pp 683ndash691 1992
[57] C-Y Hong K Hughes K-S Chia V Ng and S-L LingldquoUrinary 1205721-microglobulin as a marker of nephropathy in type2 diabetic Asian subjects in Singaporerdquo Diabetes Care vol 26no 2 pp 338ndash342 2003
[58] L Petrica M Petrica A Vlad et al ldquoProximal tubule dysfunc-tion is dissociated from endothelial dysfunction in normoalbu-minuric patients with type 2 diabetes mellitus a cross-sectionalstudyrdquo Nephron Clinical Practice vol 118 no 2 pp c155ndashc1642011
[59] H Wainai F Katsukawa I Takei H Maruyama K Kataokaand T Saruta ldquoInfluence of glycemic control and hypertensionon urinary microprotein excretion in non-insulin-dependentdiabetes mellitusrdquo Journal of Diabetic Complications vol 5 no2-3 pp 160ndash161 1991
[60] N Shore R Khurshid and M Saleem ldquoAlpha-1 microglobulina marker for early detection of tubular disorders in diabeticnephropathyrdquo Journal of AyubMedical College Abbottabad vol22 no 4 pp 53ndash55 2010
[61] J V Bonventre ldquoKidney injury molecule-1 a translational jour-neyrdquo Transactions of the American Clinical and ClimatologicalAssociation vol 125 pp 293ndash299 2014
[62] L Petrica A Vlad G Gluhovschi et al ldquoProximal tubuledysfunction is associated with podocyte damage biomarkersnephrin and vascular endothelial growth factor in type 2diabetes mellitus patients a cross-sectional studyrdquo PLoS ONEvol 9 no 11 Article ID e112538 2014
[63] S E Nielsen K J Schjoedt A S Astrup et al ldquoNeutrophilGelatinase-Associated Lipocalin (NGAL) and Kidney InjuryMolecule 1 (KIM1) in patients with diabetic nephropathy across-sectional study and the effects of lisinoprilrdquo DiabeticMedicine vol 27 no 10 pp 1144ndash1150 2010
[64] S E Nielsen H Reinhard D Zdunek et al ldquoTubular markersare associated with decline in kidney function in proteinurictype 2 diabetic patientsrdquoDiabetes Research andClinical Practicevol 97 no 1 pp 71ndash76 2012
[65] C Bazzi C Petrini V Rizza et al ldquoUrinary N-acetyl-120573-glucosaminidase excretion is a marker of tubular cell dysfunc-tion and a predictor of outcome in primary glomerulonephri-tisrdquoNephrology Dialysis Transplantation vol 17 no 11 pp 1890ndash1896 2002
Journal of Diabetes Research 11
[66] A P Jones S Lock and K D Griffiths ldquoUrinary N-acetyl-120573-glucosaminidase activity in type I diabetes mellitusrdquo Annals ofClinical Biochemistry vol 32 no 1 pp 58ndash62 1995
[67] S Uslu B Efe O Alatas et al ldquoSerum cystatin C and urinaryenzymes as screening markers of renal dysfunction in diabeticpatientsrdquo Journal of Nephrology vol 18 no 5 pp 559ndash567 2005
[68] V Ambade P Singh B L Somani and D Basannar ldquoUrinaryN-acetyl beta glucosaminidase and gammaglutamyl transferaseas early markers of diabetic nephropathyrdquo Indian Journal ofClinical Biochemistry vol 21 no 2 pp 142ndash148 2006
[69] D N Patel and K Kalia ldquoEfficacy of urinary N-acetyl-120573-d-glucosaminidase to evaluate early renal tubular damage as aconsequence of type 2 diabetesmellitus a cross-sectional studyrdquoInternational Journal of Diabetes in Developing Countries vol35 supplement 3 pp 449ndash457 2015
[70] H S Assal S Tawfeek E A Rasheld D El-Lebedy and EH Thabet ldquoSerum cystatin C and tubular urinary enzymes asbiomarkers a renal dysfunction in type 2 diabetes mellitusrdquoClinical Medicine Insights Endocrinology and Diabetes vol 6no 7 pp 7ndash13 2013
[71] M Kamiyama A Zsombok and H Kobori ldquoUrinaryangiotensinogen as a novel early biomarker of intrarenal renin-angiotensin system activation in experimental type 1 diabetesrdquoJournal of Pharmacological Sciences vol 119 no 4 pp 314ndash3232012
[72] T Saito M Urushihara Y Kotani S Kagami and H KoborildquoIncreased urinary angiotensinogen is precedent to increasedurinary albumin in patients with type 1 diabetesrdquo AmericanJournal of the Medical Sciences vol 338 no 6 pp 478ndash4802009
[73] Z Zhuang Q Bai L A T Liang D Zheng and Y WangldquoIncreased urinary angiotensinogen precedes the onset of albu-minuria in normotensive type 2 diabetic patientsrdquo InternationalJournal of Clinical and Experimental Pathology vol 8 no 9 pp11464ndash11469 2015
[74] S S Kim S H Song I J Kim et al ldquoClinical implication ofurinary tubular markers in the early stage of nephropathy withtype 2 diabetic patientsrdquoDiabetes Research and Clinical Practicevol 97 no 2 pp 251ndash257 2012
[75] M Sawaguchi S-I ArakiHKobori et al ldquoAssociation betweenurinary angiotensinogen levels and renal and cardiovascularprognoses in patients with type 2 diabetes mellitusrdquo Journal ofDiabetes Investigation vol 3 no 3 pp 318ndash324 2012
[76] T Mizushige H Kobori Y Nishijima et al ldquoUrinaryangiotensinogen could be a prognostic marker of renoprotec-tive effects of alogliptin in patients with type 2 diabetesrdquo Journalof Diabetes Research vol 2015 Article ID 517472 7 pages 2015
[77] Y K Jeon M R Kim J E Huh et al ldquoCystatin C as an earlybiomarker of nephropathy in patients with type 2 diabetesrdquoJournal of Korean Medical Science vol 26 no 2 pp 258ndash2632011
[78] W D Comper T M Osicka and G Jerums ldquoHigh prevalenceof immuno-unreactive intact albumin in urine of diabeticpatientsrdquoAmerican Journal of Kidney Diseases vol 41 no 2 pp336ndash342 2003
[79] X Rao M Wan C Qiu and C Jiang ldquoRole of cystatin C inrenal damage and the optimum cut-off point of renal damageamong patients with type 2 diabetesmellitusrdquo Experimental andTherapeutic Medicine vol 8 no 3 pp 887ndash892 2014
[80] V Garg M Kuman H S Mahapatra A Chitkora A K Gad-poyle and V Sekhan ldquoNovel urinary biomarkers in prediabetic
nephropathyrdquoClinical and Experimental Nephrology vol 19 no5 pp 895ndash890 2015
[81] S S Kim S H Song I J Kim et al ldquoUrinary cystatin C andtubular proteinuria predict progression of diabetic nephropa-thyrdquo Diabetes Care vol 36 no 3 pp 656ndash661 2013
[82] A Kamijo-Ikemori T Sugaya T Yasuda et al ldquoClinical signifi-cance of urinary liver-type fatty acid-binding protein in diabeticnephropathy of type 2 diabetic patientsrdquo Diabetes Care vol 34no 3 pp 691ndash696 2011
[83] S E Nielsen T Sugaya P Hovind T Baba H-H Parving andP Rossing ldquoUrinary liver-type fatty acid-binding protein pre-dicts progression to nephropathy in type 1 diabetic patientsrdquoDiabetes Care vol 33 no 6 pp 1320ndash1324 2010
[84] V Viswanathan S Sivakumar V Sekar D M Umapathy andS Kumpatla ldquoClinical significance of urinary liver-type fattyacid binding protein at various stages of nephropathyrdquo IndianJournal of Nephrology vol 25 no 5 pp 269ndash273 2015
[85] K-M Chou C-C Lee C-H Chen and C-Y Sun ldquoClinicalvalue of NGAL L-FABP and albuminuria in predicting GFRdecline in type 2 diabetes mellitus patientsrdquo PLoS ONE vol 8no 1 article e54863 2013
[86] N M Panduru C Forsblom M Saraheimo et al ldquoUrinaryliver-type fatty acid-binding protein and progression of diabeticnephropathy in type 1 diabetesrdquoDiabetes Care vol 36 no 7 pp2077ndash2083 2013
[87] G I Welsh and M A Saleem ldquoNephrinmdashsignature moleculeof the glomerular podocyterdquoThe Journal of Pathology vol 220no 3 pp 328ndash337 2010
[88] F N Ziyadeh and G Wolf ldquoPathogenesis of the podocytopathyand proteinuria in diabetic glomerulopathyrdquo Current DiabetesReviews vol 4 no 1 pp 39ndash45 2008
[89] A Patari C ForsblomMHavana H Taipale P-H Groop andH Holthofer ldquoNephrinuria in diabetic nephropathy of type 1diabetesrdquo Diabetes vol 52 no 12 pp 2969ndash2974 2003
[90] D P K Ng B-C Tai E Tan et al ldquoNephrinuria associateswithmultiple renal traits in type 2 diabetesrdquoNephrology DialysisTransplantation vol 26 no 8 pp 2508ndash2514 2011
[91] Y Kandasamy R Smith E R Lumbers and D Rudd ldquoNephrina biomarker of early glomerular injuryrdquo Biomarker Researchvol 2 no 1 p 21 2014
[92] B Jim M Ghanta A Qipo et al ldquoDysregulated nephrin indiabetic nephropathy of type 2 diabetes a cross sectional studyrdquoPLoS ONE vol 7 no 5 Article ID e36041 2012
[93] J F Navarro C Mora M Gomez M Muros C Lopez-Aguilar and J Garcıa ldquoInfluence of renal involvement onperipheral blood mononuclear cell expression behaviour oftumour necrosis factor-120572 and interleukin-6 in type 2 diabeticpatientsrdquoNephrology Dialysis Transplantation vol 23 no 3 pp919ndash926 2008
[94] D Z I Cherney J W Scholey D Daneman et al ldquoUrinarymarkers of renal inflammation in adolescents with type 1 dia-betes mellitus and normoalbuminuriardquo Diabetic Medicine vol29 no 10 pp 1297ndash1302 2012
[95] R Har J W Scholey D Daneman et al ldquoThe effect of renalhyperfiltration on urinary inflammatory cytokineschemokinesin patients with uncomplicated type 1 diabetes mellitusrdquo Dia-betologia vol 56 no 5 pp 1166ndash1173 2013
[96] K Tashiro I Koyanagi A Saitoh et al ldquoUrinary levels ofmono-cyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) and renal injuries in patients with type 2 diabetic nephropa-thyrdquo Journal of Clinical Laboratory Analysis vol 16 no 1pp 1ndash4 2002
12 Journal of Diabetes Research
[97] J Liu Z Zhao M D P Willcox B Xu and B Shi ldquoMultiplexbead analysis of urinary cytokines of type 2 diabetic patientswith normo- and microalbuminuriardquo Journal of Immunoassayand Immunochemistry vol 31 no 4 pp 279ndash289 2010
[98] S Ibrahim and L Rashed ldquoCorrelation of urinary monocytechemo-attractant protein-1 with other parameters of renalinjury in type-II diabetes mellitusrdquo Saudi Journal of Kidney Dis-eases and Transplantation vol 19 no 6 pp 911ndash917 2008
[99] H Jiang G Guan R Zhang et al ldquoIncreased urinary excretionof orosomucoid is a risk predictor of diabetic nephropathyrdquoNephrology vol 14 no 3 pp 332ndash337 2009
[100] N M El-Beblawy N G Andrawes E A Ismail B E EnanyH S Abou El-Seoud and M A Erfan ldquoSerum and Uri-nary orosomucoid in young patients with type 1 diabetes alink between inflammation microvascular complications andsubclinical atherosclerosisrdquo Clinical and Applied ThrombosisHemostasis 2016
[101] M S Christiansen E Hommel E Magid and B Feldt-Rasmussen ldquoOrosomucoid in urine predicts cardiovascular andover-all mortality in patients with type II diabetesrdquo Diabetolo-gia vol 45 no 1 pp 115ndash120 2002
[102] H Ha and H B Lee ldquoOxidative stress in diabetic nephropathybasic and clinical informationrdquo Current Diabetes Reports vol 1no 3 pp 282ndash287 2001
[103] L L Wu C C Chiou P Y Chang and J T Wu ldquoUrinary 8-OHdG a marker of oxidative stress to DNA and a risk factorfor cancer atherosclerosis and diabeticsrdquo Clinica Chemica Actavol 339 no 1-2 pp 1ndash9 2004
[104] Y Hinokio S Suzuki M Hirai C Suzuki M Suzukiand T Toyota ldquoUrinary excretion of 8-oxo-7 8-dihydro-21015840-deoxyguanosine as a predictor of the development of diabeticnephropathyrdquo Diabetologia vol 45 no 6 pp 877ndash882 2002
[105] J Leinonen T Lehtimaki S Toyokuni et al ldquoNew biomarkerevidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitusrdquo FEBS Letters vol 417 no1 pp 150ndash152 1997
[106] K Broedbaek A Weimann E S Stovgaard and H E PoulsenldquoUrinary 8-oxo-78-dihydro-21015840-deoxyguanosine as a biomarkerin type 2 diabetesrdquo Free Radical Biology and Medicine vol 51no 8 pp 1473ndash1479 2011
[107] F L NautaW E Boertien S J L Bakker et al ldquoGlomerular andtubular damage markers are elevated in patients with diabetesrdquoDiabetes Care vol 34 no 4 pp 975ndash981 2011
[108] L Petrica A Vlad G Gluhovschi et al ldquoGlycated peptides areassociated with proximal tubule dysfunction in type 2 diabetesmellitusrdquo International Journal of Clinical and ExperimentalMedicine vol 8 no 2 pp 2516ndash2525 2015
[109] N Turk A Mornar V Mrzljak and Z Turk ldquoUrinary excre-tion of advanced glycation endproducts in patients with type2 diabetes and various stages of proteinuriardquo Diabetes andMetabolism vol 30 no 2 pp 187ndash192 2004
[110] A A Ghanem A Elewa and L F Arafa ldquoPentosidine and N-carboxymethyl-lysine biomarkers for type 2 diabetic retinopa-thyrdquo European Journal of Ophthalmology vol 21 no 1 pp 48ndash54 2011
[111] F Piarulli G Sartore A Ceriello et al ldquoRelationship betweenglyco-oxidation antioxidant status and microalbuminuria intype 2 diabetic patientsrdquo Diabetologia vol 52 no 7 pp 1419ndash1425 2009
[112] M Shoji K Kobayashi M Takemoto Y Sato and K YokoteldquoUrinary podocalyxin levels were associated with urinary albu-min levels among patients with diabetesrdquo Biomarkers vol 21no 2 pp 164ndash167 2015
[113] M Hara K Yamagata Y Tomino et al ldquoUrinary podocalyxinis an early marker for podocyte injury in patients with diabetesestablishment of a highly sensitive ELISA to detect urinarypodocalyxinrdquo Diabetologia vol 55 no 11 pp 2913ndash2919 2012
[114] M Zheng L-L Lv J Ni et al ldquoUrinary podocyte-associatedmRNA profile in various stages of diabetic nephropathyrdquo PLoSONE vol 6 no 5 Article ID e20431 2011
[115] N H Kim K B Kim D L Kim et al ldquoPlasma and urinaryvascular endothelial growth factor and diabetic nephropathy intype 2 diabetes mellitusrdquo Diabetic Medicine vol 21 no 6 pp545ndash551 2004
[116] M Emoto K Mori E Lee et al ldquoFetuin-A and atheroscleroticcalcified plaque in patients with type 2 diabetes mellitusrdquoMetabolism Clinical and Experimental vol 59 no 6 pp 873ndash878 2010
[117] K Inoue J Wada J Eguchi et al ldquoUrinary fetuin-A is a novelmarker for diabetic nephropathy in type 2 diabetes identified bylectin microarrayrdquo PLoS ONE vol 8 no 10 Article ID e771182013
[118] M A K Salem S A El-Habashy O M Saeid M M KEl-Tawil and P H Tawfik ldquoUrinary excretion of N-acetyl-120573-d-glucosaminidase and retinol binding protein as alternativeindicators of nephropathy in patients with type 1 diabetesmellitusrdquo Pediatric Diabetes vol 3 no 1 pp 37ndash41 2002
[119] V Lambadiari N P E KadoglouV Stasinos et al ldquoSerum levelsof retinol-binding protein-4 are associated with the presenceand severity of coronary artery diseaserdquo Cardiovascular Dia-betology vol 13 no 1 article 121 2014
[120] A Shoukry S E-A Bdeer and R H El-Sokkary ldquoUrinarymonocyte chemoattractant protein-1 and vitamin D-bindingprotein as biomarkers for early detection of diabetic nephropa-thy in type 2 diabetesmellitusrdquoMolecular andCellular Biochem-istry vol 408 no 1 pp 25ndash35 2015
[121] Z Li Y Xu Y Nie and Z Zhao ldquoUrinary heme oxygenase-1 as apotential biomarker for early diabetic nephropathyrdquoNephrology(Carlton Vic) 2016
[122] B Satirapoj S Tassanasorn M Charoenpitakchai and OSupasyndh ldquoPeriostin as a tissue and urinary biomarker of renalinjury in type 2 diabetes mellitusrdquo PLoS ONE vol 10 no 4Article ID e0124055 2015
[123] E Y Lee S S Kim J-S Lee et al ldquoSoluble 120572-klotho as a novelbiomarker in the early stage of nephropathy in patients withtype 2 diabetesrdquo PLoS ONE vol 9 no 8 article e102984 2014
[124] A-L Sun J-TDengG-J Guan et al ldquoDipeptidyl peptidase-IVis a potential molecular biomarker in diabetic kidney diseaserdquoDiabetes and Vascular Disease Research vol 9 no 4 pp 301ndash308 2012
[125] Y Yang L Xiao J Li Y S Kanwar F Liu and L Sun ldquoUrinemiRNAs potential biomarkers for monitoring progression ofearly stages of diabetic nephropathyrdquo Medical Hypotheses vol81 no 2 pp 274ndash278 2013
[126] C Argyropoulos K Wang J Bernardo et al ldquoUrinaryMicroRNA profiling predicts the development of microalbu-minuria in patients with type 1 Diabetesrdquo Journal of ClinicalMedicine vol 4 no 7 pp 1495ndash1517 2015
Journal of Diabetes Research 13
[127] M W Kennedy A P Heikema A Cooper P J Bjorkmanand L M Sanchez ldquoHydrophobic ligand binding by Zn-1205722-glycoprotein a soluble fat-depleting factor related to major his-tocompatibility complex proteinsrdquo Journal of Biological Chem-istry vol 276 no 37 pp 35008ndash35013 2001
[128] YWang YM Li S Zhang J Y Zhao and C Y Liu ldquoAdipokinezinc-120572-2- glycoprotein as novel urinary biomarker presentsearly than microalbuminuria in diabetic nephropathyrdquo Journalof International Medical Research vol 44 no 2 pp 278ndash2862016
[129] S C Lim D Q Liying W C Toy et al ldquoAdipocytokine zinc 1205722glycoprotein (ZAG) as a novel urinary biomarker for normo-albuminuric diabetic nephropathyrdquo Diabetic Medicine vol 29no 7 pp 945ndash949 2012
[130] V Thongboonkerd ldquoStudy of diabetic nephropathy in theproteomic erardquo Diabetes and the Kidney vol 170 pp 172ndash1832011
[131] K N Lai and S C W Tang Eds Diabetes and the Kidney vol170 Contributions to Nephrology Karger Basel Switzerland2011
[132] P Zurbig G Jerums P Hovind et al ldquoUrinary proteomics forearly diagnosis in diabetic nephropathyrdquo Diabetes vol 61 no12 pp 3304ndash3313 2012
[133] F Raimondo S Corbetta L Morosi et al ldquoUrinary exosomesand diabetic nephropathy a proteomic approachrdquo MolecularBioSystems vol 9 no 6 pp 1139ndash1146 2013
[134] I Zubiri M Posada-Ayala A Sanz-Maroto et al ldquoDiabeticnephropathy induces changes in the proteome of human uri-nary exosomes as revealed by label-free comparative analysisrdquoJournal of Proteomics vol 96 pp 92ndash102 2014
[135] A Caseiro A Barros R Ferreira et al ldquoPursuing type 1diabetes mellitus and related complications through urinaryproteomicsrdquo Translational Research vol 163 no 3 pp 188ndash1992014
[136] B Jim J Santos F Spath and J C He ldquoBiomarkers of diabeticnephropathy the present and the futurerdquo Current DiabetesReviews vol 8 no 5 pp 317ndash328 2012
34 Oxidative Stress Biomarkers Oxidative stress plays animportant part in the development and progression of DN[102]
341 Urinary 8-Oxo-78-dihydro-2-deoxyguanosine (8-oHdG) 8-oHdG is produced secondary to oxidative DNAdamage It is eliminated into the urine without being meta-bolized [103] At present it is considered a marker foroxidative stress
After a 5-year follow-up Hinokio et al find that 8-oxodGin urine is a useful clinical marker to predict the developmentof diabetic nephropathy in diabetic patients There wasa significant progression of diabetic nephropathy in thepatients with higher excretion of 8-oxodG in urine comparedwith the patients with moderate or lower excretion of 8-oxodG [104]
Leinonen et al reported increased excretion of 8-oHdG intype 1 DM patients 9 years after the onset of disease mainlyrelated to poor glycemic control [105]
The urinary 8-oHdG marker of oxidation would beaccording to Broedbaek et al a predictor of long-termmortality in DM [106]
342 Heart Fatty Acid Binding Protein (H-FABP) Heart fattyacid binding protein (H-FABP) is a marker of distal tubulardamage
In a study on a cohort of type 1 and type 2DMpatients andan assessment of their markers of glomerular lesions (IgG)markers of proximal tubular lesions (urinary KIM-1 NAGNGAL and cystatin) and a marker of distal tubular lesions(urinaryH-FABP) in relationshipwith albuminuria andGFRNauta et al reported higher values of urinary NAG NGALand H-FABP in normoalbuminurics than in controls On theother hand the values of urinary cystatin C were low [107]
This shows that normoalbuminuric DM patients presentboth proximal and distal tubular lesions
343 Urinary Advanced Glycation End Products (AGE)AGE eliminated in the urine induce a toxic tubular effectproducing tubular dysfunction
In type 2 DM patients with normoalbuminuria highvalues of urinary alpha-1-microglobulin and of urinary KIM-1 were found secondary to tubular dysfunction prior to theonset of microalbuminuria At the same time urinary AGEwere high being correlated with these markers [108]
Turk et al found in type 2 DM patients high values ofurinary AGE in 50 of the patients with normoalbuminuriaand in 85 of those with microalbuminuria [109]
Pentosidine a component ofAGE is a biomarker for theirformation and accumulation [110]
Piarulli et al found in patients with microalbuminuriahigher values of pentosidine than in patients with normoal-buminuria [111]
344 Podocytes Podocyte lesions appear during DM andDN respectively the disease being considered a podocytopa-thy as mentioned above
The assessment of podocyte injury can be accomplishedby monitoring the number of podocyte cells in the urine
or more precisely by means of using podocyte urinarybiomarkers (podocalyxin and nephrine)
A study onDMpatients found that the values of the num-ber of urinary podocytes in normoalbuminuric patients arenot significantly different from those of controls In patientswithmicroalbuminuria andnephrotic syndrome the numberof urinary podocytes is higher It is correlated with urinaryosteopontin and urinary IgM [33]
Urinary podocalyxin originates in the podocyte apicalsurface occurring in vesicle form In DM patients thepodocalyxin level presented higher levels in patients withmicroalbuminuria than in patients with normoalbuminuria[112]
Another study on DM patients found high values ofurinary podocalyxin in more than half of the patients withnormoalbuminuria these values being higher in patientswith microalbuminuria and macroalbuminuria
Urinary podocalyxin is correlated with the values ofurinary NAG and of urinary beta 2 microglobulin [113]
Hara et al consider that urinary podocalyxin can bean early biomarker for detecting early podocyte injury inpatients with DM
Zheng assessed the urinary microRNA profile ofpodocyte-associated molecules (synaptopodin podocalyxinCD2-AP 120572-actin4 and podocin) as biomarkers in patientswith normoalbuminuria microalbuminuria and macro-albuminuria and they reported its increase during theprogression of DN [114]
345 Vascular Endothelial Growth Factor (VEGF) VEGF isa proangiogenic factor produced mainly by the podocytes atnephron level Urinary VEGF can be considered a podocytebiomarker
Urinary VEGF was detected in type 2 DM patientsbeing correlated in these patients with urinary alpha-1-microglobulin a biomarker for proximal tubular lesions [62]
Kim et al found that VEGF is excreted at higher valuesthan controls in normoalbuminuric type 2 DM patientsThe values increase in patients with microalbuminuria andmacroalbuminuria [115]
Fetuin A is glycosylated glycoprotein was consideredan inhibitor for ectopic calcium deposition and promoterof insulin resistance Fetuin A inhibits the calcification ofatherosclerotic plaques in diabetes mellitus [116] It wasfound that elevated urinary Fetuin A excretion is a risk fordevelopment of diabetic nephropathy [117]
35 Other Urinary Biomarkers Used in Evaluating Early DNNumerous urinarymarkers have been suggested for assessingearly DN Some of them have been introduced in use onlyrecently
Urinary retinol-binding protein is a lowmolecular weightprotein that was found to have high urinary values (togetherwith NAG) in normoalbuminuric patients reflecting tubulardysfunction in early DN [118]
The value of serum retinol-binding protein 4 as a bio-marker in assessing the severity of coronary artery disease isto be mentioned [119]
8 Journal of Diabetes Research
Urinary retinol-binding protein 4 as a biomarker in ass-essing DN needs further studies
Urinary vitamin D binding protein can plays the role asbiomarker In type 2 DM it is attributed a potential role inearly diagnosis of DN [120]
Urinary heme oxygenase-1 was found in type 2 DMpatients before the onset of significant albuminuria thusbeing a possible biomarker of early DN [121] In fact oxidativestress activation is expected in DN
Periostin is a cell adhesion molecule which is not nor-mally present in kidneys In tubulointerstitial lesions it ishowever expressed in the kidneys being eliminated in theurineThis is why urinary periostin could be used as amarkerof injury at this level
Since high levels of periostin can be identified in DMpatients before significant albuminuria periostin could rep-resent a marker of diabetic renal injury [122]
Urinary alpha klotho presents higher values in normoal-buminuric type 2 DM patients than in controls It can also bea marker of diabetic injury [123]
Analyzing a group of normoalbuminuric microalbumin-uric and macroalbuminuric type 2 DM patients Sun et alnoted that the urinary level of microvesicle-bound dipeptidylpeptidase-IV is related to the severity of DN [124]
Recent studies point to the usage of urine-specificmicroRNA as a biomarker for early stages of DN Analyzingthe studies in the literature Yang et al issued the hypothesisthat urine-specific microRNA would be a marker that can beused in the early stages of DN [125]
Recently Argyropoulos highlighted the predictive roleof urinary microRNA regarding microalbuminuria in type 1DM [126]
Adipokine zinc-alpha-2 glycoprotein is assigned to themajor histocompatibility complex class I of proteins [127]
Urinary adipokine zinc-alpha-2 glycoprotein is presentearlier than microalbuminuria in diabetic nephropathy Itcould be a useful biomarker for diagnosing early DN [128]Lim et al also appreciate adipokine zinc-alpha-2 glycoproteinas a novel urinary biomarker for normoalbuminuric diabeticnephropathy [129]
351 Proteomics At present proteomic investigations areengaged in identification of new urinary biomarkers to beused in the early diagnosis of DN
In fact proteomics studies noted the fact that microalbu-minuria is not a perfect biomarker for early detection of DN[130 131]
Urinary proteomics begins to stand out as a noninvasivemethod of detecting early DN
Among proteomics studies on diagnosing DN we canmention those of Zurbig et al who reported that collagenfragments were a prominent biomarker 3ndash5 years before theonset of microalbuminuria [132]
A potential role is also attributed to exosome proteomicsfor identifying new biomarkers for DN [133] Zubiri et alshowed a panel of 3 proteins which is differentially present inurinary exosomes fromDNpatients [134] Urinary proteomicanalysis can have an important role in the implementation ofnew biomarkers in DN [135]
At present the prospect of discovering new biomarkersin DM andDN respectively is incumbent both on proteomicsand on genomics transcriptomics and metabolomics [136]
4 Conclusions
Urinary biomarkers allow an assessment of early DNMicroalbuminuria although frequently contested as a
biomarker of early DN is used so far as reference biomarkerin assessing other urinary biomarkers in early DN Untilpresent there is no other biomarker that can substitute inpractice microalbuminuria the new biomarkers being sus-tained by limited studies and requiring validation
The concomitant assessment of several urinary biomark-ers in relationship with microalbuminuria could represent atpresent a method of diagnosing early DNThe great progressin discovering new biomarkers could lead to the developmentof an ldquoidealrdquo urinary biomarker to detect early diabetic DN inthe future
Progresses in the field of urinary biomarkers in DNpromising both in proteomics and in other modern tech-niques develop remarkably at present
Disclosure
Thesupporting source had no involvement in study design incollection analysis and interpretation of data in the writingof the report and in the decision to submit the paper forpublication
Competing Interests
The authors declare that they have no competing interests
Authorsrsquo Contributions
Cristina Gluhovschi and Gheorghe Gluhovschi contributedequally to this paper
Acknowledgments
This research received funding from an Internal Grantof ldquoVictor Babesrdquo University of Medicine and PharmacyTimisoara PIII-C1-PCFI-20142015
References
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[2] M Narres H Claessen S Droste et al ldquoThe incidence ofend-stage renal disease in the diabetic (compared to the non-diabetic) population a systematic reviewrdquo PLoS ONE vol 11no 1 Article ID e0147329 2016
[3] E Lioudaki K G Stylianou I Petrakis et al ldquoIncreased urinaryexcretion of podocyte markers in normoalbuminuric patientswith diabetesrdquo Nephron vol 131 no 1 pp 34ndash42 2015
Journal of Diabetes Research 9
[4] N Banu H Hara M Okamura G Egusa and M YamakidoldquoUrinary excretion of type IV collagen and laminin in the eval-uation of nephropathy in NIDDM comparison with urinaryalbumin and markers of tubular dysfunction andor damagerdquoDiabetes Research and Clinical Practice vol 29 no 1 pp 57ndash671995
[5] P Kubisz L Stanciakova J Stasko P Galajda and M MokanldquoEndothelial and platelet markers in diabetes mellitus type 2rdquoWorld Journal of Diabetes vol 6 no 3 pp 423ndash431 2015
[6] G Tramonti and Y S Kanwar ldquoTubular biomarkers to assessprogression of diabetic nephropathyrdquo Kidney International vol79 no 10 pp 1042ndash1044 2011
[7] T Terami J Wada K Inoue et al ldquoUrinary angiotensinogen isa marker for tubular injuries in patients with type 2 diabetesrdquoInternational Journal of Nephrology and Renovascular Diseasevol 6 pp 233ndash240 2013
[8] M Eriguchi R Yotsueda K Torisu et al ldquoAssessment ofurinary angiotensinogen as a marker of podocyte injury inproteinuric nephropathiesrdquo American Journal of PhysiologymdashRenal Physiology vol 310 no 4 pp F322ndashF333 2016
[9] A Matheson M D P Willcox J Flanagan and B J WalshldquoUrinary biomarkers involved in type 2 diabetes a reviewrdquoDiabetesMetabolism Research and Reviews vol 26 no 3 pp150ndash171 2010
[10] C Y Hong and K S Chia ldquoMarkers of diabetic nephropathyrdquoJournal of Diabetes and Its Complications vol 12 no 1 pp 43ndash60 1998
[11] J H Warram L J Scott L S Hanna et al ldquoProgression ofmicroalbuminuria to proteinuria in type 1 diabetes nonlinearrelationshipwith hyperglycemiardquoDiabetes vol 49 no 1 pp 94ndash100 2000
[12] P Fioretto M W Steffes and M Mauer ldquoGlomerular structurein nonproteinuric IDDM patients with various levels of albu-minuriardquo Diabetes vol 43 no 11 pp 1358ndash1364 1994
[13] K McKenna and C Thompson ldquoMicroalbuminuria a markerto increased renal and cardiovascular risk in diabetes mellitusrdquoScottish Medical Journal vol 42 no 4 pp 99ndash104 1997
[14] P Hovind L Tarnow P Rossing et al ldquoPredictors for thedevelopment of microalbuminuria and macroalbuminuria inpatients with type 1 diabetes inception cohort studyrdquo BritishMedical Journal vol 328 no 7448 pp 1105ndash1108 2004
[15] I H de Boer T C Rue P A Cleary et al ldquoLong-term renaloutcomes of patients with type 1 diabetes mellitus and microal-buminuria an analysis of the Diabetes Control and Complica-tions TrialEpidemiology of Diabetes Interventions and Com-plications cohortrdquo Archives of Internal Medicine vol 171 no 5pp 412ndash420 2011
[16] G Zoppini G Targher M Chonchol et al ldquoPredictors ofestimated GFR decline in patients with type 2 diabetes andpreserved kidney functionrdquo Clinical Journal of the AmericanSociety of Nephrology vol 7 no 3 pp 401ndash408 2012
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[18] D J Newman M B Mattock A B Dawnay et al ldquoSystematicreview on urine albumin testing for early detection of diabeticcomplicationsrdquo Health Technology Assessment vol 9 no 302005
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in a referred cohort of type II diabetic patients a globalperspectiverdquoKidney International vol 69 no 11 pp 2057ndash20632006
[20] B Lu J Wen X Y Song et al ldquoHigh prevalence of albuminuriain population-based patients diagnosed with type 2 diabetesin the Shanghai downtownrdquo Diabetes Research and ClinicalPractice vol 75 no 2 pp 184ndash192 2007
[21] N Ismail B Becker P Strzelczyk and E Ritz ldquoRenal diseaseand hypertension in non-insulin-dependent diabetes mellitusrdquoKidney International vol 55 no 1 pp 1ndash28 1999
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[28] M Kanauchi Y Akai and T Hashimoto ldquoTransferrinuria intype 2 diabetic patients with early nephropathy and tubuloin-terstitial injuryrdquo European Journal of Internal Medicine vol 13no 3 pp 190ndash193 2002
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[31] A Cohen-Bucay and G Viswanathan ldquoUrinary markers ofglomerular injury in diabetic nephropathyrdquo International Jour-nal of Nephrology vol 2012 Article ID 146987 11 pages 2012
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[34] L X Qin X Zeng and G Huang ldquoChanges in serum and urineceruloplasmin concentrations in type 2 diabetesrdquo Zhong NanDa Xue Xue Bao Yi Xue Ban vol 29 no 2 pp 208ndash211 2004
[35] J T Tamsma J van den Born J A Bruijn et al ldquoExpression ofglomerular extracellular matrix components in human diabeticnephropathy decrease of heparan sulphate in the glomerularbasement membranerdquo Diabetologia vol 37 no 3 pp 313ndash3201994
10 Journal of Diabetes Research
[36] T Fiseha ldquoUrinary biomarkers for early diabetic nephropathyin type 2 diabetic patientsrdquo Biomarker Research vol 3 article16 2015
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[38] H Takizawa T Satoh A Kurusu et al ldquoIncrease of urinarytype IV collagen in normoalbuminuric patients with impairedglucose tolerancerdquo Nephron vol 79 no 4 pp 474ndash475 1998
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[40] S Ming Z Qi L Wang and K Zhu ldquoUrinary type IV collagena specific indicator of incipient diabetic nephropathyrdquo ChineseMedical Journal vol 115 no 3 pp 389ndash394 2002
[41] S Kado A Aoki S Wada et al ldquoUrinary type IV collagen as amarker for early diabetic nephropathyrdquo Diabetes Research andClinical Practice vol 31 no 1ndash3 pp 103ndash108 1996
[42] I Ueta K Takamatsu and K Hashimoto ldquoUrinary glycos-aminoglycans in patients with incipient diabetic nephropathyrdquoNihon Jinzo Gakkai Shi vol 37 no 1 pp 17ndash23 1995
[43] O Torffvit ldquoUrinary sulphated glycosaminoglycans andTamm-Horsfall protein in type 1 diabetic patientsrdquo ScandinavianJournal of Urology and Nephrology vol 33 no 5 pp 328ndash3321999
[44] Y Uehara H Makino K Seiki and Y Urade ldquoUrinaryexcretions of lipocalin-type prostaglandin D synthase predictrenal injury in type-2 diabetes a cross-sectional and prospectivemulticentre studyrdquoNephrology Dialysis Transplantation vol 24no 2 pp 475ndash482 2009
[45] K Kuboki H Tada K Shin Y Oshima and S Isogai ldquoRela-tionship between urinary excretion of fibronectin degradationproducts and proteinuria in diabetic patients and their suppres-sion after continuous subcutaneous heparin infusionrdquoDiabetesResearch and Clinical Practice vol 21 no 1 pp 61ndash66 1993
[46] A L Al-Malki ldquoAssessment of urinary osteopontin in associa-tion with podocyte for early predication of nephropathy in dia-betic patientsrdquo Disease Markers vol 2014 Article ID 493736 5pages 2014
[47] K Mise J Hoshino T Ueno et al ldquoPrognostic value of tubu-lointerstitial lesions urinary N-acetyl-120573-d-glucosaminidaseand urinary 1205732-microglobulin in patients with type 2 diabetesand biopsy-proven diabetic nephropathyrdquoClinical Journal of theAmerican Society of Nephrology vol 11 no 4 pp 593ndash601 2016
[48] K M Schmidt-Ott K Mori Y L Jau et al ldquoDual actionof neutrophil gelatinase-associated lipocalinrdquo Journal of theAmerican Society of Nephrology vol 18 no 2 pp 407ndash413 2007
[49] D Bolignano A Lacquaniti G Coppolino et al ldquoNeu-trophil gelatinase-associated lipocalin as an early biomarker ofnephropathy in diabetic patientsrdquo Kidney amp Blood PressureResearch vol 32 no 2 pp 91ndash98 2009
[50] Z Yuruk Yıldırım A Nayır A Yılmaz A Gedikbası and RBundak ldquoNeutrophil gelatinase-associated lipocalin as an earlysign of diabetic kidney injury in childrenrdquo Journal of ClinicalResearch in Pediatric Endocrinology vol 7 no 4 pp 274ndash2792015
[51] A Lacquaniti V Donato B Pintaudi et al ldquolsquoNormoalbu-minuricrsquo diabetic nephropathy tubular damage and NGALrdquoActa Diabetologica vol 50 no 6 pp 935ndash942 2013
[52] J A de Carvalho E Tatsch B S Hausen et al ldquoUrinarykidney injury molecule-1 and neutrophil gelatinase-associatedlipocalin as indicators of tubular damage in normoalbuminuricpatients with type 2 diabetesrdquo Clinical Biochemistry vol 49 no3 pp 232ndash236 2016
[53] W-J Fu S-L Xiong Y-G Fang et al ldquoUrinary tubularbiomarkers in short-term type 2 diabetes mellitus patients across-sectional studyrdquo Endocrine vol 41 no 1 pp 82ndash88 2012
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[56] M H Weber and R Verwiebe ldquo1205721- microglobulin (proteinHC) features of a promising indicator of proximal tubular dys-functionrdquo European Journal of Clinical Chemistry and ClinicalBiochemistry vol 30 no 10 pp 683ndash691 1992
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[66] A P Jones S Lock and K D Griffiths ldquoUrinary N-acetyl-120573-glucosaminidase activity in type I diabetes mellitusrdquo Annals ofClinical Biochemistry vol 32 no 1 pp 58ndash62 1995
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[69] D N Patel and K Kalia ldquoEfficacy of urinary N-acetyl-120573-d-glucosaminidase to evaluate early renal tubular damage as aconsequence of type 2 diabetesmellitus a cross-sectional studyrdquoInternational Journal of Diabetes in Developing Countries vol35 supplement 3 pp 449ndash457 2015
[70] H S Assal S Tawfeek E A Rasheld D El-Lebedy and EH Thabet ldquoSerum cystatin C and tubular urinary enzymes asbiomarkers a renal dysfunction in type 2 diabetes mellitusrdquoClinical Medicine Insights Endocrinology and Diabetes vol 6no 7 pp 7ndash13 2013
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[72] T Saito M Urushihara Y Kotani S Kagami and H KoborildquoIncreased urinary angiotensinogen is precedent to increasedurinary albumin in patients with type 1 diabetesrdquo AmericanJournal of the Medical Sciences vol 338 no 6 pp 478ndash4802009
[73] Z Zhuang Q Bai L A T Liang D Zheng and Y WangldquoIncreased urinary angiotensinogen precedes the onset of albu-minuria in normotensive type 2 diabetic patientsrdquo InternationalJournal of Clinical and Experimental Pathology vol 8 no 9 pp11464ndash11469 2015
[74] S S Kim S H Song I J Kim et al ldquoClinical implication ofurinary tubular markers in the early stage of nephropathy withtype 2 diabetic patientsrdquoDiabetes Research and Clinical Practicevol 97 no 2 pp 251ndash257 2012
[75] M Sawaguchi S-I ArakiHKobori et al ldquoAssociation betweenurinary angiotensinogen levels and renal and cardiovascularprognoses in patients with type 2 diabetes mellitusrdquo Journal ofDiabetes Investigation vol 3 no 3 pp 318ndash324 2012
[76] T Mizushige H Kobori Y Nishijima et al ldquoUrinaryangiotensinogen could be a prognostic marker of renoprotec-tive effects of alogliptin in patients with type 2 diabetesrdquo Journalof Diabetes Research vol 2015 Article ID 517472 7 pages 2015
[77] Y K Jeon M R Kim J E Huh et al ldquoCystatin C as an earlybiomarker of nephropathy in patients with type 2 diabetesrdquoJournal of Korean Medical Science vol 26 no 2 pp 258ndash2632011
[78] W D Comper T M Osicka and G Jerums ldquoHigh prevalenceof immuno-unreactive intact albumin in urine of diabeticpatientsrdquoAmerican Journal of Kidney Diseases vol 41 no 2 pp336ndash342 2003
[79] X Rao M Wan C Qiu and C Jiang ldquoRole of cystatin C inrenal damage and the optimum cut-off point of renal damageamong patients with type 2 diabetesmellitusrdquo Experimental andTherapeutic Medicine vol 8 no 3 pp 887ndash892 2014
[80] V Garg M Kuman H S Mahapatra A Chitkora A K Gad-poyle and V Sekhan ldquoNovel urinary biomarkers in prediabetic
nephropathyrdquoClinical and Experimental Nephrology vol 19 no5 pp 895ndash890 2015
[81] S S Kim S H Song I J Kim et al ldquoUrinary cystatin C andtubular proteinuria predict progression of diabetic nephropa-thyrdquo Diabetes Care vol 36 no 3 pp 656ndash661 2013
[82] A Kamijo-Ikemori T Sugaya T Yasuda et al ldquoClinical signifi-cance of urinary liver-type fatty acid-binding protein in diabeticnephropathy of type 2 diabetic patientsrdquo Diabetes Care vol 34no 3 pp 691ndash696 2011
[83] S E Nielsen T Sugaya P Hovind T Baba H-H Parving andP Rossing ldquoUrinary liver-type fatty acid-binding protein pre-dicts progression to nephropathy in type 1 diabetic patientsrdquoDiabetes Care vol 33 no 6 pp 1320ndash1324 2010
[84] V Viswanathan S Sivakumar V Sekar D M Umapathy andS Kumpatla ldquoClinical significance of urinary liver-type fattyacid binding protein at various stages of nephropathyrdquo IndianJournal of Nephrology vol 25 no 5 pp 269ndash273 2015
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[87] G I Welsh and M A Saleem ldquoNephrinmdashsignature moleculeof the glomerular podocyterdquoThe Journal of Pathology vol 220no 3 pp 328ndash337 2010
[88] F N Ziyadeh and G Wolf ldquoPathogenesis of the podocytopathyand proteinuria in diabetic glomerulopathyrdquo Current DiabetesReviews vol 4 no 1 pp 39ndash45 2008
[89] A Patari C ForsblomMHavana H Taipale P-H Groop andH Holthofer ldquoNephrinuria in diabetic nephropathy of type 1diabetesrdquo Diabetes vol 52 no 12 pp 2969ndash2974 2003
[90] D P K Ng B-C Tai E Tan et al ldquoNephrinuria associateswithmultiple renal traits in type 2 diabetesrdquoNephrology DialysisTransplantation vol 26 no 8 pp 2508ndash2514 2011
[91] Y Kandasamy R Smith E R Lumbers and D Rudd ldquoNephrina biomarker of early glomerular injuryrdquo Biomarker Researchvol 2 no 1 p 21 2014
[92] B Jim M Ghanta A Qipo et al ldquoDysregulated nephrin indiabetic nephropathy of type 2 diabetes a cross sectional studyrdquoPLoS ONE vol 7 no 5 Article ID e36041 2012
[93] J F Navarro C Mora M Gomez M Muros C Lopez-Aguilar and J Garcıa ldquoInfluence of renal involvement onperipheral blood mononuclear cell expression behaviour oftumour necrosis factor-120572 and interleukin-6 in type 2 diabeticpatientsrdquoNephrology Dialysis Transplantation vol 23 no 3 pp919ndash926 2008
[94] D Z I Cherney J W Scholey D Daneman et al ldquoUrinarymarkers of renal inflammation in adolescents with type 1 dia-betes mellitus and normoalbuminuriardquo Diabetic Medicine vol29 no 10 pp 1297ndash1302 2012
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[96] K Tashiro I Koyanagi A Saitoh et al ldquoUrinary levels ofmono-cyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) and renal injuries in patients with type 2 diabetic nephropa-thyrdquo Journal of Clinical Laboratory Analysis vol 16 no 1pp 1ndash4 2002
12 Journal of Diabetes Research
[97] J Liu Z Zhao M D P Willcox B Xu and B Shi ldquoMultiplexbead analysis of urinary cytokines of type 2 diabetic patientswith normo- and microalbuminuriardquo Journal of Immunoassayand Immunochemistry vol 31 no 4 pp 279ndash289 2010
[98] S Ibrahim and L Rashed ldquoCorrelation of urinary monocytechemo-attractant protein-1 with other parameters of renalinjury in type-II diabetes mellitusrdquo Saudi Journal of Kidney Dis-eases and Transplantation vol 19 no 6 pp 911ndash917 2008
[99] H Jiang G Guan R Zhang et al ldquoIncreased urinary excretionof orosomucoid is a risk predictor of diabetic nephropathyrdquoNephrology vol 14 no 3 pp 332ndash337 2009
[100] N M El-Beblawy N G Andrawes E A Ismail B E EnanyH S Abou El-Seoud and M A Erfan ldquoSerum and Uri-nary orosomucoid in young patients with type 1 diabetes alink between inflammation microvascular complications andsubclinical atherosclerosisrdquo Clinical and Applied ThrombosisHemostasis 2016
[101] M S Christiansen E Hommel E Magid and B Feldt-Rasmussen ldquoOrosomucoid in urine predicts cardiovascular andover-all mortality in patients with type II diabetesrdquo Diabetolo-gia vol 45 no 1 pp 115ndash120 2002
[102] H Ha and H B Lee ldquoOxidative stress in diabetic nephropathybasic and clinical informationrdquo Current Diabetes Reports vol 1no 3 pp 282ndash287 2001
[103] L L Wu C C Chiou P Y Chang and J T Wu ldquoUrinary 8-OHdG a marker of oxidative stress to DNA and a risk factorfor cancer atherosclerosis and diabeticsrdquo Clinica Chemica Actavol 339 no 1-2 pp 1ndash9 2004
[104] Y Hinokio S Suzuki M Hirai C Suzuki M Suzukiand T Toyota ldquoUrinary excretion of 8-oxo-7 8-dihydro-21015840-deoxyguanosine as a predictor of the development of diabeticnephropathyrdquo Diabetologia vol 45 no 6 pp 877ndash882 2002
[105] J Leinonen T Lehtimaki S Toyokuni et al ldquoNew biomarkerevidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitusrdquo FEBS Letters vol 417 no1 pp 150ndash152 1997
[106] K Broedbaek A Weimann E S Stovgaard and H E PoulsenldquoUrinary 8-oxo-78-dihydro-21015840-deoxyguanosine as a biomarkerin type 2 diabetesrdquo Free Radical Biology and Medicine vol 51no 8 pp 1473ndash1479 2011
[107] F L NautaW E Boertien S J L Bakker et al ldquoGlomerular andtubular damage markers are elevated in patients with diabetesrdquoDiabetes Care vol 34 no 4 pp 975ndash981 2011
[108] L Petrica A Vlad G Gluhovschi et al ldquoGlycated peptides areassociated with proximal tubule dysfunction in type 2 diabetesmellitusrdquo International Journal of Clinical and ExperimentalMedicine vol 8 no 2 pp 2516ndash2525 2015
[109] N Turk A Mornar V Mrzljak and Z Turk ldquoUrinary excre-tion of advanced glycation endproducts in patients with type2 diabetes and various stages of proteinuriardquo Diabetes andMetabolism vol 30 no 2 pp 187ndash192 2004
[110] A A Ghanem A Elewa and L F Arafa ldquoPentosidine and N-carboxymethyl-lysine biomarkers for type 2 diabetic retinopa-thyrdquo European Journal of Ophthalmology vol 21 no 1 pp 48ndash54 2011
[111] F Piarulli G Sartore A Ceriello et al ldquoRelationship betweenglyco-oxidation antioxidant status and microalbuminuria intype 2 diabetic patientsrdquo Diabetologia vol 52 no 7 pp 1419ndash1425 2009
[112] M Shoji K Kobayashi M Takemoto Y Sato and K YokoteldquoUrinary podocalyxin levels were associated with urinary albu-min levels among patients with diabetesrdquo Biomarkers vol 21no 2 pp 164ndash167 2015
[113] M Hara K Yamagata Y Tomino et al ldquoUrinary podocalyxinis an early marker for podocyte injury in patients with diabetesestablishment of a highly sensitive ELISA to detect urinarypodocalyxinrdquo Diabetologia vol 55 no 11 pp 2913ndash2919 2012
[114] M Zheng L-L Lv J Ni et al ldquoUrinary podocyte-associatedmRNA profile in various stages of diabetic nephropathyrdquo PLoSONE vol 6 no 5 Article ID e20431 2011
[115] N H Kim K B Kim D L Kim et al ldquoPlasma and urinaryvascular endothelial growth factor and diabetic nephropathy intype 2 diabetes mellitusrdquo Diabetic Medicine vol 21 no 6 pp545ndash551 2004
[116] M Emoto K Mori E Lee et al ldquoFetuin-A and atheroscleroticcalcified plaque in patients with type 2 diabetes mellitusrdquoMetabolism Clinical and Experimental vol 59 no 6 pp 873ndash878 2010
[117] K Inoue J Wada J Eguchi et al ldquoUrinary fetuin-A is a novelmarker for diabetic nephropathy in type 2 diabetes identified bylectin microarrayrdquo PLoS ONE vol 8 no 10 Article ID e771182013
[118] M A K Salem S A El-Habashy O M Saeid M M KEl-Tawil and P H Tawfik ldquoUrinary excretion of N-acetyl-120573-d-glucosaminidase and retinol binding protein as alternativeindicators of nephropathy in patients with type 1 diabetesmellitusrdquo Pediatric Diabetes vol 3 no 1 pp 37ndash41 2002
[119] V Lambadiari N P E KadoglouV Stasinos et al ldquoSerum levelsof retinol-binding protein-4 are associated with the presenceand severity of coronary artery diseaserdquo Cardiovascular Dia-betology vol 13 no 1 article 121 2014
[120] A Shoukry S E-A Bdeer and R H El-Sokkary ldquoUrinarymonocyte chemoattractant protein-1 and vitamin D-bindingprotein as biomarkers for early detection of diabetic nephropa-thy in type 2 diabetesmellitusrdquoMolecular andCellular Biochem-istry vol 408 no 1 pp 25ndash35 2015
[121] Z Li Y Xu Y Nie and Z Zhao ldquoUrinary heme oxygenase-1 as apotential biomarker for early diabetic nephropathyrdquoNephrology(Carlton Vic) 2016
[122] B Satirapoj S Tassanasorn M Charoenpitakchai and OSupasyndh ldquoPeriostin as a tissue and urinary biomarker of renalinjury in type 2 diabetes mellitusrdquo PLoS ONE vol 10 no 4Article ID e0124055 2015
[123] E Y Lee S S Kim J-S Lee et al ldquoSoluble 120572-klotho as a novelbiomarker in the early stage of nephropathy in patients withtype 2 diabetesrdquo PLoS ONE vol 9 no 8 article e102984 2014
[124] A-L Sun J-TDengG-J Guan et al ldquoDipeptidyl peptidase-IVis a potential molecular biomarker in diabetic kidney diseaserdquoDiabetes and Vascular Disease Research vol 9 no 4 pp 301ndash308 2012
[125] Y Yang L Xiao J Li Y S Kanwar F Liu and L Sun ldquoUrinemiRNAs potential biomarkers for monitoring progression ofearly stages of diabetic nephropathyrdquo Medical Hypotheses vol81 no 2 pp 274ndash278 2013
[126] C Argyropoulos K Wang J Bernardo et al ldquoUrinaryMicroRNA profiling predicts the development of microalbu-minuria in patients with type 1 Diabetesrdquo Journal of ClinicalMedicine vol 4 no 7 pp 1495ndash1517 2015
Journal of Diabetes Research 13
[127] M W Kennedy A P Heikema A Cooper P J Bjorkmanand L M Sanchez ldquoHydrophobic ligand binding by Zn-1205722-glycoprotein a soluble fat-depleting factor related to major his-tocompatibility complex proteinsrdquo Journal of Biological Chem-istry vol 276 no 37 pp 35008ndash35013 2001
[128] YWang YM Li S Zhang J Y Zhao and C Y Liu ldquoAdipokinezinc-120572-2- glycoprotein as novel urinary biomarker presentsearly than microalbuminuria in diabetic nephropathyrdquo Journalof International Medical Research vol 44 no 2 pp 278ndash2862016
[129] S C Lim D Q Liying W C Toy et al ldquoAdipocytokine zinc 1205722glycoprotein (ZAG) as a novel urinary biomarker for normo-albuminuric diabetic nephropathyrdquo Diabetic Medicine vol 29no 7 pp 945ndash949 2012
[130] V Thongboonkerd ldquoStudy of diabetic nephropathy in theproteomic erardquo Diabetes and the Kidney vol 170 pp 172ndash1832011
[131] K N Lai and S C W Tang Eds Diabetes and the Kidney vol170 Contributions to Nephrology Karger Basel Switzerland2011
[132] P Zurbig G Jerums P Hovind et al ldquoUrinary proteomics forearly diagnosis in diabetic nephropathyrdquo Diabetes vol 61 no12 pp 3304ndash3313 2012
[133] F Raimondo S Corbetta L Morosi et al ldquoUrinary exosomesand diabetic nephropathy a proteomic approachrdquo MolecularBioSystems vol 9 no 6 pp 1139ndash1146 2013
[134] I Zubiri M Posada-Ayala A Sanz-Maroto et al ldquoDiabeticnephropathy induces changes in the proteome of human uri-nary exosomes as revealed by label-free comparative analysisrdquoJournal of Proteomics vol 96 pp 92ndash102 2014
[135] A Caseiro A Barros R Ferreira et al ldquoPursuing type 1diabetes mellitus and related complications through urinaryproteomicsrdquo Translational Research vol 163 no 3 pp 188ndash1992014
[136] B Jim J Santos F Spath and J C He ldquoBiomarkers of diabeticnephropathy the present and the futurerdquo Current DiabetesReviews vol 8 no 5 pp 317ndash328 2012
Urinary retinol-binding protein 4 as a biomarker in ass-essing DN needs further studies
Urinary vitamin D binding protein can plays the role asbiomarker In type 2 DM it is attributed a potential role inearly diagnosis of DN [120]
Urinary heme oxygenase-1 was found in type 2 DMpatients before the onset of significant albuminuria thusbeing a possible biomarker of early DN [121] In fact oxidativestress activation is expected in DN
Periostin is a cell adhesion molecule which is not nor-mally present in kidneys In tubulointerstitial lesions it ishowever expressed in the kidneys being eliminated in theurineThis is why urinary periostin could be used as amarkerof injury at this level
Since high levels of periostin can be identified in DMpatients before significant albuminuria periostin could rep-resent a marker of diabetic renal injury [122]
Urinary alpha klotho presents higher values in normoal-buminuric type 2 DM patients than in controls It can also bea marker of diabetic injury [123]
Analyzing a group of normoalbuminuric microalbumin-uric and macroalbuminuric type 2 DM patients Sun et alnoted that the urinary level of microvesicle-bound dipeptidylpeptidase-IV is related to the severity of DN [124]
Recent studies point to the usage of urine-specificmicroRNA as a biomarker for early stages of DN Analyzingthe studies in the literature Yang et al issued the hypothesisthat urine-specific microRNA would be a marker that can beused in the early stages of DN [125]
Recently Argyropoulos highlighted the predictive roleof urinary microRNA regarding microalbuminuria in type 1DM [126]
Adipokine zinc-alpha-2 glycoprotein is assigned to themajor histocompatibility complex class I of proteins [127]
Urinary adipokine zinc-alpha-2 glycoprotein is presentearlier than microalbuminuria in diabetic nephropathy Itcould be a useful biomarker for diagnosing early DN [128]Lim et al also appreciate adipokine zinc-alpha-2 glycoproteinas a novel urinary biomarker for normoalbuminuric diabeticnephropathy [129]
351 Proteomics At present proteomic investigations areengaged in identification of new urinary biomarkers to beused in the early diagnosis of DN
In fact proteomics studies noted the fact that microalbu-minuria is not a perfect biomarker for early detection of DN[130 131]
Urinary proteomics begins to stand out as a noninvasivemethod of detecting early DN
Among proteomics studies on diagnosing DN we canmention those of Zurbig et al who reported that collagenfragments were a prominent biomarker 3ndash5 years before theonset of microalbuminuria [132]
A potential role is also attributed to exosome proteomicsfor identifying new biomarkers for DN [133] Zubiri et alshowed a panel of 3 proteins which is differentially present inurinary exosomes fromDNpatients [134] Urinary proteomicanalysis can have an important role in the implementation ofnew biomarkers in DN [135]
At present the prospect of discovering new biomarkersin DM andDN respectively is incumbent both on proteomicsand on genomics transcriptomics and metabolomics [136]
4 Conclusions
Urinary biomarkers allow an assessment of early DNMicroalbuminuria although frequently contested as a
biomarker of early DN is used so far as reference biomarkerin assessing other urinary biomarkers in early DN Untilpresent there is no other biomarker that can substitute inpractice microalbuminuria the new biomarkers being sus-tained by limited studies and requiring validation
The concomitant assessment of several urinary biomark-ers in relationship with microalbuminuria could represent atpresent a method of diagnosing early DNThe great progressin discovering new biomarkers could lead to the developmentof an ldquoidealrdquo urinary biomarker to detect early diabetic DN inthe future
Progresses in the field of urinary biomarkers in DNpromising both in proteomics and in other modern tech-niques develop remarkably at present
Disclosure
Thesupporting source had no involvement in study design incollection analysis and interpretation of data in the writingof the report and in the decision to submit the paper forpublication
Competing Interests
The authors declare that they have no competing interests
Authorsrsquo Contributions
Cristina Gluhovschi and Gheorghe Gluhovschi contributedequally to this paper
Acknowledgments
This research received funding from an Internal Grantof ldquoVictor Babesrdquo University of Medicine and PharmacyTimisoara PIII-C1-PCFI-20142015
References
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[2] M Narres H Claessen S Droste et al ldquoThe incidence ofend-stage renal disease in the diabetic (compared to the non-diabetic) population a systematic reviewrdquo PLoS ONE vol 11no 1 Article ID e0147329 2016
[3] E Lioudaki K G Stylianou I Petrakis et al ldquoIncreased urinaryexcretion of podocyte markers in normoalbuminuric patientswith diabetesrdquo Nephron vol 131 no 1 pp 34ndash42 2015
Journal of Diabetes Research 9
[4] N Banu H Hara M Okamura G Egusa and M YamakidoldquoUrinary excretion of type IV collagen and laminin in the eval-uation of nephropathy in NIDDM comparison with urinaryalbumin and markers of tubular dysfunction andor damagerdquoDiabetes Research and Clinical Practice vol 29 no 1 pp 57ndash671995
[5] P Kubisz L Stanciakova J Stasko P Galajda and M MokanldquoEndothelial and platelet markers in diabetes mellitus type 2rdquoWorld Journal of Diabetes vol 6 no 3 pp 423ndash431 2015
[6] G Tramonti and Y S Kanwar ldquoTubular biomarkers to assessprogression of diabetic nephropathyrdquo Kidney International vol79 no 10 pp 1042ndash1044 2011
[7] T Terami J Wada K Inoue et al ldquoUrinary angiotensinogen isa marker for tubular injuries in patients with type 2 diabetesrdquoInternational Journal of Nephrology and Renovascular Diseasevol 6 pp 233ndash240 2013
[8] M Eriguchi R Yotsueda K Torisu et al ldquoAssessment ofurinary angiotensinogen as a marker of podocyte injury inproteinuric nephropathiesrdquo American Journal of PhysiologymdashRenal Physiology vol 310 no 4 pp F322ndashF333 2016
[9] A Matheson M D P Willcox J Flanagan and B J WalshldquoUrinary biomarkers involved in type 2 diabetes a reviewrdquoDiabetesMetabolism Research and Reviews vol 26 no 3 pp150ndash171 2010
[10] C Y Hong and K S Chia ldquoMarkers of diabetic nephropathyrdquoJournal of Diabetes and Its Complications vol 12 no 1 pp 43ndash60 1998
[11] J H Warram L J Scott L S Hanna et al ldquoProgression ofmicroalbuminuria to proteinuria in type 1 diabetes nonlinearrelationshipwith hyperglycemiardquoDiabetes vol 49 no 1 pp 94ndash100 2000
[12] P Fioretto M W Steffes and M Mauer ldquoGlomerular structurein nonproteinuric IDDM patients with various levels of albu-minuriardquo Diabetes vol 43 no 11 pp 1358ndash1364 1994
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[14] P Hovind L Tarnow P Rossing et al ldquoPredictors for thedevelopment of microalbuminuria and macroalbuminuria inpatients with type 1 diabetes inception cohort studyrdquo BritishMedical Journal vol 328 no 7448 pp 1105ndash1108 2004
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in a referred cohort of type II diabetic patients a globalperspectiverdquoKidney International vol 69 no 11 pp 2057ndash20632006
[20] B Lu J Wen X Y Song et al ldquoHigh prevalence of albuminuriain population-based patients diagnosed with type 2 diabetesin the Shanghai downtownrdquo Diabetes Research and ClinicalPractice vol 75 no 2 pp 184ndash192 2007
[21] N Ismail B Becker P Strzelczyk and E Ritz ldquoRenal diseaseand hypertension in non-insulin-dependent diabetes mellitusrdquoKidney International vol 55 no 1 pp 1ndash28 1999
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[28] M Kanauchi Y Akai and T Hashimoto ldquoTransferrinuria intype 2 diabetic patients with early nephropathy and tubuloin-terstitial injuryrdquo European Journal of Internal Medicine vol 13no 3 pp 190ndash193 2002
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[34] L X Qin X Zeng and G Huang ldquoChanges in serum and urineceruloplasmin concentrations in type 2 diabetesrdquo Zhong NanDa Xue Xue Bao Yi Xue Ban vol 29 no 2 pp 208ndash211 2004
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10 Journal of Diabetes Research
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[38] H Takizawa T Satoh A Kurusu et al ldquoIncrease of urinarytype IV collagen in normoalbuminuric patients with impairedglucose tolerancerdquo Nephron vol 79 no 4 pp 474ndash475 1998
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[41] S Kado A Aoki S Wada et al ldquoUrinary type IV collagen as amarker for early diabetic nephropathyrdquo Diabetes Research andClinical Practice vol 31 no 1ndash3 pp 103ndash108 1996
[42] I Ueta K Takamatsu and K Hashimoto ldquoUrinary glycos-aminoglycans in patients with incipient diabetic nephropathyrdquoNihon Jinzo Gakkai Shi vol 37 no 1 pp 17ndash23 1995
[43] O Torffvit ldquoUrinary sulphated glycosaminoglycans andTamm-Horsfall protein in type 1 diabetic patientsrdquo ScandinavianJournal of Urology and Nephrology vol 33 no 5 pp 328ndash3321999
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[48] K M Schmidt-Ott K Mori Y L Jau et al ldquoDual actionof neutrophil gelatinase-associated lipocalinrdquo Journal of theAmerican Society of Nephrology vol 18 no 2 pp 407ndash413 2007
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[50] Z Yuruk Yıldırım A Nayır A Yılmaz A Gedikbası and RBundak ldquoNeutrophil gelatinase-associated lipocalin as an earlysign of diabetic kidney injury in childrenrdquo Journal of ClinicalResearch in Pediatric Endocrinology vol 7 no 4 pp 274ndash2792015
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[52] J A de Carvalho E Tatsch B S Hausen et al ldquoUrinarykidney injury molecule-1 and neutrophil gelatinase-associatedlipocalin as indicators of tubular damage in normoalbuminuricpatients with type 2 diabetesrdquo Clinical Biochemistry vol 49 no3 pp 232ndash236 2016
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[56] M H Weber and R Verwiebe ldquo1205721- microglobulin (proteinHC) features of a promising indicator of proximal tubular dys-functionrdquo European Journal of Clinical Chemistry and ClinicalBiochemistry vol 30 no 10 pp 683ndash691 1992
[57] C-Y Hong K Hughes K-S Chia V Ng and S-L LingldquoUrinary 1205721-microglobulin as a marker of nephropathy in type2 diabetic Asian subjects in Singaporerdquo Diabetes Care vol 26no 2 pp 338ndash342 2003
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[59] H Wainai F Katsukawa I Takei H Maruyama K Kataokaand T Saruta ldquoInfluence of glycemic control and hypertensionon urinary microprotein excretion in non-insulin-dependentdiabetes mellitusrdquo Journal of Diabetic Complications vol 5 no2-3 pp 160ndash161 1991
[60] N Shore R Khurshid and M Saleem ldquoAlpha-1 microglobulina marker for early detection of tubular disorders in diabeticnephropathyrdquo Journal of AyubMedical College Abbottabad vol22 no 4 pp 53ndash55 2010
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[66] A P Jones S Lock and K D Griffiths ldquoUrinary N-acetyl-120573-glucosaminidase activity in type I diabetes mellitusrdquo Annals ofClinical Biochemistry vol 32 no 1 pp 58ndash62 1995
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[68] V Ambade P Singh B L Somani and D Basannar ldquoUrinaryN-acetyl beta glucosaminidase and gammaglutamyl transferaseas early markers of diabetic nephropathyrdquo Indian Journal ofClinical Biochemistry vol 21 no 2 pp 142ndash148 2006
[69] D N Patel and K Kalia ldquoEfficacy of urinary N-acetyl-120573-d-glucosaminidase to evaluate early renal tubular damage as aconsequence of type 2 diabetesmellitus a cross-sectional studyrdquoInternational Journal of Diabetes in Developing Countries vol35 supplement 3 pp 449ndash457 2015
[70] H S Assal S Tawfeek E A Rasheld D El-Lebedy and EH Thabet ldquoSerum cystatin C and tubular urinary enzymes asbiomarkers a renal dysfunction in type 2 diabetes mellitusrdquoClinical Medicine Insights Endocrinology and Diabetes vol 6no 7 pp 7ndash13 2013
[71] M Kamiyama A Zsombok and H Kobori ldquoUrinaryangiotensinogen as a novel early biomarker of intrarenal renin-angiotensin system activation in experimental type 1 diabetesrdquoJournal of Pharmacological Sciences vol 119 no 4 pp 314ndash3232012
[72] T Saito M Urushihara Y Kotani S Kagami and H KoborildquoIncreased urinary angiotensinogen is precedent to increasedurinary albumin in patients with type 1 diabetesrdquo AmericanJournal of the Medical Sciences vol 338 no 6 pp 478ndash4802009
[73] Z Zhuang Q Bai L A T Liang D Zheng and Y WangldquoIncreased urinary angiotensinogen precedes the onset of albu-minuria in normotensive type 2 diabetic patientsrdquo InternationalJournal of Clinical and Experimental Pathology vol 8 no 9 pp11464ndash11469 2015
[74] S S Kim S H Song I J Kim et al ldquoClinical implication ofurinary tubular markers in the early stage of nephropathy withtype 2 diabetic patientsrdquoDiabetes Research and Clinical Practicevol 97 no 2 pp 251ndash257 2012
[75] M Sawaguchi S-I ArakiHKobori et al ldquoAssociation betweenurinary angiotensinogen levels and renal and cardiovascularprognoses in patients with type 2 diabetes mellitusrdquo Journal ofDiabetes Investigation vol 3 no 3 pp 318ndash324 2012
[76] T Mizushige H Kobori Y Nishijima et al ldquoUrinaryangiotensinogen could be a prognostic marker of renoprotec-tive effects of alogliptin in patients with type 2 diabetesrdquo Journalof Diabetes Research vol 2015 Article ID 517472 7 pages 2015
[77] Y K Jeon M R Kim J E Huh et al ldquoCystatin C as an earlybiomarker of nephropathy in patients with type 2 diabetesrdquoJournal of Korean Medical Science vol 26 no 2 pp 258ndash2632011
[78] W D Comper T M Osicka and G Jerums ldquoHigh prevalenceof immuno-unreactive intact albumin in urine of diabeticpatientsrdquoAmerican Journal of Kidney Diseases vol 41 no 2 pp336ndash342 2003
[79] X Rao M Wan C Qiu and C Jiang ldquoRole of cystatin C inrenal damage and the optimum cut-off point of renal damageamong patients with type 2 diabetesmellitusrdquo Experimental andTherapeutic Medicine vol 8 no 3 pp 887ndash892 2014
[80] V Garg M Kuman H S Mahapatra A Chitkora A K Gad-poyle and V Sekhan ldquoNovel urinary biomarkers in prediabetic
nephropathyrdquoClinical and Experimental Nephrology vol 19 no5 pp 895ndash890 2015
[81] S S Kim S H Song I J Kim et al ldquoUrinary cystatin C andtubular proteinuria predict progression of diabetic nephropa-thyrdquo Diabetes Care vol 36 no 3 pp 656ndash661 2013
[82] A Kamijo-Ikemori T Sugaya T Yasuda et al ldquoClinical signifi-cance of urinary liver-type fatty acid-binding protein in diabeticnephropathy of type 2 diabetic patientsrdquo Diabetes Care vol 34no 3 pp 691ndash696 2011
[83] S E Nielsen T Sugaya P Hovind T Baba H-H Parving andP Rossing ldquoUrinary liver-type fatty acid-binding protein pre-dicts progression to nephropathy in type 1 diabetic patientsrdquoDiabetes Care vol 33 no 6 pp 1320ndash1324 2010
[84] V Viswanathan S Sivakumar V Sekar D M Umapathy andS Kumpatla ldquoClinical significance of urinary liver-type fattyacid binding protein at various stages of nephropathyrdquo IndianJournal of Nephrology vol 25 no 5 pp 269ndash273 2015
[85] K-M Chou C-C Lee C-H Chen and C-Y Sun ldquoClinicalvalue of NGAL L-FABP and albuminuria in predicting GFRdecline in type 2 diabetes mellitus patientsrdquo PLoS ONE vol 8no 1 article e54863 2013
[86] N M Panduru C Forsblom M Saraheimo et al ldquoUrinaryliver-type fatty acid-binding protein and progression of diabeticnephropathy in type 1 diabetesrdquoDiabetes Care vol 36 no 7 pp2077ndash2083 2013
[87] G I Welsh and M A Saleem ldquoNephrinmdashsignature moleculeof the glomerular podocyterdquoThe Journal of Pathology vol 220no 3 pp 328ndash337 2010
[88] F N Ziyadeh and G Wolf ldquoPathogenesis of the podocytopathyand proteinuria in diabetic glomerulopathyrdquo Current DiabetesReviews vol 4 no 1 pp 39ndash45 2008
[89] A Patari C ForsblomMHavana H Taipale P-H Groop andH Holthofer ldquoNephrinuria in diabetic nephropathy of type 1diabetesrdquo Diabetes vol 52 no 12 pp 2969ndash2974 2003
[90] D P K Ng B-C Tai E Tan et al ldquoNephrinuria associateswithmultiple renal traits in type 2 diabetesrdquoNephrology DialysisTransplantation vol 26 no 8 pp 2508ndash2514 2011
[91] Y Kandasamy R Smith E R Lumbers and D Rudd ldquoNephrina biomarker of early glomerular injuryrdquo Biomarker Researchvol 2 no 1 p 21 2014
[92] B Jim M Ghanta A Qipo et al ldquoDysregulated nephrin indiabetic nephropathy of type 2 diabetes a cross sectional studyrdquoPLoS ONE vol 7 no 5 Article ID e36041 2012
[93] J F Navarro C Mora M Gomez M Muros C Lopez-Aguilar and J Garcıa ldquoInfluence of renal involvement onperipheral blood mononuclear cell expression behaviour oftumour necrosis factor-120572 and interleukin-6 in type 2 diabeticpatientsrdquoNephrology Dialysis Transplantation vol 23 no 3 pp919ndash926 2008
[94] D Z I Cherney J W Scholey D Daneman et al ldquoUrinarymarkers of renal inflammation in adolescents with type 1 dia-betes mellitus and normoalbuminuriardquo Diabetic Medicine vol29 no 10 pp 1297ndash1302 2012
[95] R Har J W Scholey D Daneman et al ldquoThe effect of renalhyperfiltration on urinary inflammatory cytokineschemokinesin patients with uncomplicated type 1 diabetes mellitusrdquo Dia-betologia vol 56 no 5 pp 1166ndash1173 2013
[96] K Tashiro I Koyanagi A Saitoh et al ldquoUrinary levels ofmono-cyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) and renal injuries in patients with type 2 diabetic nephropa-thyrdquo Journal of Clinical Laboratory Analysis vol 16 no 1pp 1ndash4 2002
12 Journal of Diabetes Research
[97] J Liu Z Zhao M D P Willcox B Xu and B Shi ldquoMultiplexbead analysis of urinary cytokines of type 2 diabetic patientswith normo- and microalbuminuriardquo Journal of Immunoassayand Immunochemistry vol 31 no 4 pp 279ndash289 2010
[98] S Ibrahim and L Rashed ldquoCorrelation of urinary monocytechemo-attractant protein-1 with other parameters of renalinjury in type-II diabetes mellitusrdquo Saudi Journal of Kidney Dis-eases and Transplantation vol 19 no 6 pp 911ndash917 2008
[99] H Jiang G Guan R Zhang et al ldquoIncreased urinary excretionof orosomucoid is a risk predictor of diabetic nephropathyrdquoNephrology vol 14 no 3 pp 332ndash337 2009
[100] N M El-Beblawy N G Andrawes E A Ismail B E EnanyH S Abou El-Seoud and M A Erfan ldquoSerum and Uri-nary orosomucoid in young patients with type 1 diabetes alink between inflammation microvascular complications andsubclinical atherosclerosisrdquo Clinical and Applied ThrombosisHemostasis 2016
[101] M S Christiansen E Hommel E Magid and B Feldt-Rasmussen ldquoOrosomucoid in urine predicts cardiovascular andover-all mortality in patients with type II diabetesrdquo Diabetolo-gia vol 45 no 1 pp 115ndash120 2002
[102] H Ha and H B Lee ldquoOxidative stress in diabetic nephropathybasic and clinical informationrdquo Current Diabetes Reports vol 1no 3 pp 282ndash287 2001
[103] L L Wu C C Chiou P Y Chang and J T Wu ldquoUrinary 8-OHdG a marker of oxidative stress to DNA and a risk factorfor cancer atherosclerosis and diabeticsrdquo Clinica Chemica Actavol 339 no 1-2 pp 1ndash9 2004
[104] Y Hinokio S Suzuki M Hirai C Suzuki M Suzukiand T Toyota ldquoUrinary excretion of 8-oxo-7 8-dihydro-21015840-deoxyguanosine as a predictor of the development of diabeticnephropathyrdquo Diabetologia vol 45 no 6 pp 877ndash882 2002
[105] J Leinonen T Lehtimaki S Toyokuni et al ldquoNew biomarkerevidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitusrdquo FEBS Letters vol 417 no1 pp 150ndash152 1997
[106] K Broedbaek A Weimann E S Stovgaard and H E PoulsenldquoUrinary 8-oxo-78-dihydro-21015840-deoxyguanosine as a biomarkerin type 2 diabetesrdquo Free Radical Biology and Medicine vol 51no 8 pp 1473ndash1479 2011
[107] F L NautaW E Boertien S J L Bakker et al ldquoGlomerular andtubular damage markers are elevated in patients with diabetesrdquoDiabetes Care vol 34 no 4 pp 975ndash981 2011
[108] L Petrica A Vlad G Gluhovschi et al ldquoGlycated peptides areassociated with proximal tubule dysfunction in type 2 diabetesmellitusrdquo International Journal of Clinical and ExperimentalMedicine vol 8 no 2 pp 2516ndash2525 2015
[109] N Turk A Mornar V Mrzljak and Z Turk ldquoUrinary excre-tion of advanced glycation endproducts in patients with type2 diabetes and various stages of proteinuriardquo Diabetes andMetabolism vol 30 no 2 pp 187ndash192 2004
[110] A A Ghanem A Elewa and L F Arafa ldquoPentosidine and N-carboxymethyl-lysine biomarkers for type 2 diabetic retinopa-thyrdquo European Journal of Ophthalmology vol 21 no 1 pp 48ndash54 2011
[111] F Piarulli G Sartore A Ceriello et al ldquoRelationship betweenglyco-oxidation antioxidant status and microalbuminuria intype 2 diabetic patientsrdquo Diabetologia vol 52 no 7 pp 1419ndash1425 2009
[112] M Shoji K Kobayashi M Takemoto Y Sato and K YokoteldquoUrinary podocalyxin levels were associated with urinary albu-min levels among patients with diabetesrdquo Biomarkers vol 21no 2 pp 164ndash167 2015
[113] M Hara K Yamagata Y Tomino et al ldquoUrinary podocalyxinis an early marker for podocyte injury in patients with diabetesestablishment of a highly sensitive ELISA to detect urinarypodocalyxinrdquo Diabetologia vol 55 no 11 pp 2913ndash2919 2012
[114] M Zheng L-L Lv J Ni et al ldquoUrinary podocyte-associatedmRNA profile in various stages of diabetic nephropathyrdquo PLoSONE vol 6 no 5 Article ID e20431 2011
[115] N H Kim K B Kim D L Kim et al ldquoPlasma and urinaryvascular endothelial growth factor and diabetic nephropathy intype 2 diabetes mellitusrdquo Diabetic Medicine vol 21 no 6 pp545ndash551 2004
[116] M Emoto K Mori E Lee et al ldquoFetuin-A and atheroscleroticcalcified plaque in patients with type 2 diabetes mellitusrdquoMetabolism Clinical and Experimental vol 59 no 6 pp 873ndash878 2010
[117] K Inoue J Wada J Eguchi et al ldquoUrinary fetuin-A is a novelmarker for diabetic nephropathy in type 2 diabetes identified bylectin microarrayrdquo PLoS ONE vol 8 no 10 Article ID e771182013
[118] M A K Salem S A El-Habashy O M Saeid M M KEl-Tawil and P H Tawfik ldquoUrinary excretion of N-acetyl-120573-d-glucosaminidase and retinol binding protein as alternativeindicators of nephropathy in patients with type 1 diabetesmellitusrdquo Pediatric Diabetes vol 3 no 1 pp 37ndash41 2002
[119] V Lambadiari N P E KadoglouV Stasinos et al ldquoSerum levelsof retinol-binding protein-4 are associated with the presenceand severity of coronary artery diseaserdquo Cardiovascular Dia-betology vol 13 no 1 article 121 2014
[120] A Shoukry S E-A Bdeer and R H El-Sokkary ldquoUrinarymonocyte chemoattractant protein-1 and vitamin D-bindingprotein as biomarkers for early detection of diabetic nephropa-thy in type 2 diabetesmellitusrdquoMolecular andCellular Biochem-istry vol 408 no 1 pp 25ndash35 2015
[121] Z Li Y Xu Y Nie and Z Zhao ldquoUrinary heme oxygenase-1 as apotential biomarker for early diabetic nephropathyrdquoNephrology(Carlton Vic) 2016
[122] B Satirapoj S Tassanasorn M Charoenpitakchai and OSupasyndh ldquoPeriostin as a tissue and urinary biomarker of renalinjury in type 2 diabetes mellitusrdquo PLoS ONE vol 10 no 4Article ID e0124055 2015
[123] E Y Lee S S Kim J-S Lee et al ldquoSoluble 120572-klotho as a novelbiomarker in the early stage of nephropathy in patients withtype 2 diabetesrdquo PLoS ONE vol 9 no 8 article e102984 2014
[124] A-L Sun J-TDengG-J Guan et al ldquoDipeptidyl peptidase-IVis a potential molecular biomarker in diabetic kidney diseaserdquoDiabetes and Vascular Disease Research vol 9 no 4 pp 301ndash308 2012
[125] Y Yang L Xiao J Li Y S Kanwar F Liu and L Sun ldquoUrinemiRNAs potential biomarkers for monitoring progression ofearly stages of diabetic nephropathyrdquo Medical Hypotheses vol81 no 2 pp 274ndash278 2013
[126] C Argyropoulos K Wang J Bernardo et al ldquoUrinaryMicroRNA profiling predicts the development of microalbu-minuria in patients with type 1 Diabetesrdquo Journal of ClinicalMedicine vol 4 no 7 pp 1495ndash1517 2015
Journal of Diabetes Research 13
[127] M W Kennedy A P Heikema A Cooper P J Bjorkmanand L M Sanchez ldquoHydrophobic ligand binding by Zn-1205722-glycoprotein a soluble fat-depleting factor related to major his-tocompatibility complex proteinsrdquo Journal of Biological Chem-istry vol 276 no 37 pp 35008ndash35013 2001
[128] YWang YM Li S Zhang J Y Zhao and C Y Liu ldquoAdipokinezinc-120572-2- glycoprotein as novel urinary biomarker presentsearly than microalbuminuria in diabetic nephropathyrdquo Journalof International Medical Research vol 44 no 2 pp 278ndash2862016
[129] S C Lim D Q Liying W C Toy et al ldquoAdipocytokine zinc 1205722glycoprotein (ZAG) as a novel urinary biomarker for normo-albuminuric diabetic nephropathyrdquo Diabetic Medicine vol 29no 7 pp 945ndash949 2012
[130] V Thongboonkerd ldquoStudy of diabetic nephropathy in theproteomic erardquo Diabetes and the Kidney vol 170 pp 172ndash1832011
[131] K N Lai and S C W Tang Eds Diabetes and the Kidney vol170 Contributions to Nephrology Karger Basel Switzerland2011
[132] P Zurbig G Jerums P Hovind et al ldquoUrinary proteomics forearly diagnosis in diabetic nephropathyrdquo Diabetes vol 61 no12 pp 3304ndash3313 2012
[133] F Raimondo S Corbetta L Morosi et al ldquoUrinary exosomesand diabetic nephropathy a proteomic approachrdquo MolecularBioSystems vol 9 no 6 pp 1139ndash1146 2013
[134] I Zubiri M Posada-Ayala A Sanz-Maroto et al ldquoDiabeticnephropathy induces changes in the proteome of human uri-nary exosomes as revealed by label-free comparative analysisrdquoJournal of Proteomics vol 96 pp 92ndash102 2014
[135] A Caseiro A Barros R Ferreira et al ldquoPursuing type 1diabetes mellitus and related complications through urinaryproteomicsrdquo Translational Research vol 163 no 3 pp 188ndash1992014
[136] B Jim J Santos F Spath and J C He ldquoBiomarkers of diabeticnephropathy the present and the futurerdquo Current DiabetesReviews vol 8 no 5 pp 317ndash328 2012
[4] N Banu H Hara M Okamura G Egusa and M YamakidoldquoUrinary excretion of type IV collagen and laminin in the eval-uation of nephropathy in NIDDM comparison with urinaryalbumin and markers of tubular dysfunction andor damagerdquoDiabetes Research and Clinical Practice vol 29 no 1 pp 57ndash671995
[5] P Kubisz L Stanciakova J Stasko P Galajda and M MokanldquoEndothelial and platelet markers in diabetes mellitus type 2rdquoWorld Journal of Diabetes vol 6 no 3 pp 423ndash431 2015
[6] G Tramonti and Y S Kanwar ldquoTubular biomarkers to assessprogression of diabetic nephropathyrdquo Kidney International vol79 no 10 pp 1042ndash1044 2011
[7] T Terami J Wada K Inoue et al ldquoUrinary angiotensinogen isa marker for tubular injuries in patients with type 2 diabetesrdquoInternational Journal of Nephrology and Renovascular Diseasevol 6 pp 233ndash240 2013
[8] M Eriguchi R Yotsueda K Torisu et al ldquoAssessment ofurinary angiotensinogen as a marker of podocyte injury inproteinuric nephropathiesrdquo American Journal of PhysiologymdashRenal Physiology vol 310 no 4 pp F322ndashF333 2016
[9] A Matheson M D P Willcox J Flanagan and B J WalshldquoUrinary biomarkers involved in type 2 diabetes a reviewrdquoDiabetesMetabolism Research and Reviews vol 26 no 3 pp150ndash171 2010
[10] C Y Hong and K S Chia ldquoMarkers of diabetic nephropathyrdquoJournal of Diabetes and Its Complications vol 12 no 1 pp 43ndash60 1998
[11] J H Warram L J Scott L S Hanna et al ldquoProgression ofmicroalbuminuria to proteinuria in type 1 diabetes nonlinearrelationshipwith hyperglycemiardquoDiabetes vol 49 no 1 pp 94ndash100 2000
[12] P Fioretto M W Steffes and M Mauer ldquoGlomerular structurein nonproteinuric IDDM patients with various levels of albu-minuriardquo Diabetes vol 43 no 11 pp 1358ndash1364 1994
[13] K McKenna and C Thompson ldquoMicroalbuminuria a markerto increased renal and cardiovascular risk in diabetes mellitusrdquoScottish Medical Journal vol 42 no 4 pp 99ndash104 1997
[14] P Hovind L Tarnow P Rossing et al ldquoPredictors for thedevelopment of microalbuminuria and macroalbuminuria inpatients with type 1 diabetes inception cohort studyrdquo BritishMedical Journal vol 328 no 7448 pp 1105ndash1108 2004
[15] I H de Boer T C Rue P A Cleary et al ldquoLong-term renaloutcomes of patients with type 1 diabetes mellitus and microal-buminuria an analysis of the Diabetes Control and Complica-tions TrialEpidemiology of Diabetes Interventions and Com-plications cohortrdquo Archives of Internal Medicine vol 171 no 5pp 412ndash420 2011
[16] G Zoppini G Targher M Chonchol et al ldquoPredictors ofestimated GFR decline in patients with type 2 diabetes andpreserved kidney functionrdquo Clinical Journal of the AmericanSociety of Nephrology vol 7 no 3 pp 401ndash408 2012
[17] B A Perkins LH Ficociello B EOstrander et al ldquoMicroalbu-minuria and the risk for early progressive renal function declinein type 1 diabetesrdquo Journal of theAmerican Society ofNephrologyvol 18 no 4 pp 1353ndash1361 2007
[18] D J Newman M B Mattock A B Dawnay et al ldquoSystematicreview on urine albumin testing for early detection of diabeticcomplicationsrdquo Health Technology Assessment vol 9 no 302005
[19] H-H Parving J B Lewis M Ravid G Remuzzi and L GHunsicker ldquoPrevalence and risk factors for microalbuminuria
in a referred cohort of type II diabetic patients a globalperspectiverdquoKidney International vol 69 no 11 pp 2057ndash20632006
[20] B Lu J Wen X Y Song et al ldquoHigh prevalence of albuminuriain population-based patients diagnosed with type 2 diabetesin the Shanghai downtownrdquo Diabetes Research and ClinicalPractice vol 75 no 2 pp 184ndash192 2007
[21] N Ismail B Becker P Strzelczyk and E Ritz ldquoRenal diseaseand hypertension in non-insulin-dependent diabetes mellitusrdquoKidney International vol 55 no 1 pp 1ndash28 1999
[22] S-I ArakiMHaneda D Koya et al ldquoReduction inmicroalbu-minuria as an integrated indicator for renal and cardiovascularrisk reduction in patients with type 2 diabetesrdquoDiabetes vol 56no 6 pp 1727ndash1730 2007
[23] R G Nelson P H Bennett G J Beck et al ldquoDevelopment andprogression of renal disease in Pima Indians with non- insulin-dependent diabetes mellitusrdquo The New England Journal ofMedicine vol 335 no 22 pp 1636ndash1642 1996
[24] S C W Tang J C K Leung and K N Lai ldquoDiabetictubulopathy an emerging entityrdquo in Diabetes and the KidneyK N Lai and S C W Tang Eds Karger 2011
[25] K Kunika T Yamaoka and M Itakura ldquoDamage of charge-dependent renal tubular reabsorption causes diabetic micro-proteinuriardquoDiabetes Research and Clinical Practice vol 36 no1 pp 1ndash9 1997
[26] G Currie G Mc Kay and C Delles ldquoBiomarkers in diabeticnephropathy present and futurerdquoWorld Journal ofDiabetes vol5 no 6 pp 763ndash776 2014
[27] T Narita H Sasaki M Hosoba et al ldquoParallel increase inurinary excretion rates of immunoglobulin G ceruloplasmintransferrin and orosomucoid in normoalbuminuric type 2diabetic patientsrdquo Diabetes Care vol 27 no 5 pp 1176ndash11812004
[28] M Kanauchi Y Akai and T Hashimoto ldquoTransferrinuria intype 2 diabetic patients with early nephropathy and tubuloin-terstitial injuryrdquo European Journal of Internal Medicine vol 13no 3 pp 190ndash193 2002
[29] B Quiroga D Arroyo and G de Arriba ldquoPresent and futurein the treatment of diabetic kidney diseaserdquo Journal of DiabetesResearch vol 2015 Article ID 801348 13 pages 2015
[30] T Kazumi T Hozumi Y Ishida et al ldquoIncreased urinarytransferrin excretion predicts microalbuminuria in patientswith type 2 diabetesrdquoDiabetes Care vol 22 no 7 pp 1176ndash11801999
[31] A Cohen-Bucay and G Viswanathan ldquoUrinary markers ofglomerular injury in diabetic nephropathyrdquo International Jour-nal of Nephrology vol 2012 Article ID 146987 11 pages 2012
[32] C Wang C Li W Gong and T Lou ldquoNew urinary biomarkersfor diabetic kidney diseaserdquo Biomarker Research vol 1 article 92013
[33] M Yamazaki S Ito A Usami et al ldquoUrinary excretion rateof ceruloplasmin in non-insulin-dependent diabetic patientswith different stages of nephropathyrdquo European Journal of Endo-crinology vol 132 no 6 pp 681ndash687 1995
[34] L X Qin X Zeng and G Huang ldquoChanges in serum and urineceruloplasmin concentrations in type 2 diabetesrdquo Zhong NanDa Xue Xue Bao Yi Xue Ban vol 29 no 2 pp 208ndash211 2004
[35] J T Tamsma J van den Born J A Bruijn et al ldquoExpression ofglomerular extracellular matrix components in human diabeticnephropathy decrease of heparan sulphate in the glomerularbasement membranerdquo Diabetologia vol 37 no 3 pp 313ndash3201994
10 Journal of Diabetes Research
[36] T Fiseha ldquoUrinary biomarkers for early diabetic nephropathyin type 2 diabetic patientsrdquo Biomarker Research vol 3 article16 2015
[37] N Kotajima T Kimura T Kanda et al ldquoType IV collagenas an early marker for diabetic nephropathy in non-insulin-dependent diabetes mellitusrdquo Journal of Diabetes and its Com-plications vol 14 no 1 pp 13ndash17 2000
[38] H Takizawa T Satoh A Kurusu et al ldquoIncrease of urinarytype IV collagen in normoalbuminuric patients with impairedglucose tolerancerdquo Nephron vol 79 no 4 pp 474ndash475 1998
[39] H Okonogi M Nishimura Y Utsunomiya et al ldquoUrinary typeIV collagen excretion reflects renal morphological alterationsand type IV collagen expression in patients with type 2 diabetesmellitusrdquo Clinical Nephrology vol 55 no 5 pp 357ndash364 2001
[40] S Ming Z Qi L Wang and K Zhu ldquoUrinary type IV collagena specific indicator of incipient diabetic nephropathyrdquo ChineseMedical Journal vol 115 no 3 pp 389ndash394 2002
[41] S Kado A Aoki S Wada et al ldquoUrinary type IV collagen as amarker for early diabetic nephropathyrdquo Diabetes Research andClinical Practice vol 31 no 1ndash3 pp 103ndash108 1996
[42] I Ueta K Takamatsu and K Hashimoto ldquoUrinary glycos-aminoglycans in patients with incipient diabetic nephropathyrdquoNihon Jinzo Gakkai Shi vol 37 no 1 pp 17ndash23 1995
[43] O Torffvit ldquoUrinary sulphated glycosaminoglycans andTamm-Horsfall protein in type 1 diabetic patientsrdquo ScandinavianJournal of Urology and Nephrology vol 33 no 5 pp 328ndash3321999
[44] Y Uehara H Makino K Seiki and Y Urade ldquoUrinaryexcretions of lipocalin-type prostaglandin D synthase predictrenal injury in type-2 diabetes a cross-sectional and prospectivemulticentre studyrdquoNephrology Dialysis Transplantation vol 24no 2 pp 475ndash482 2009
[45] K Kuboki H Tada K Shin Y Oshima and S Isogai ldquoRela-tionship between urinary excretion of fibronectin degradationproducts and proteinuria in diabetic patients and their suppres-sion after continuous subcutaneous heparin infusionrdquoDiabetesResearch and Clinical Practice vol 21 no 1 pp 61ndash66 1993
[46] A L Al-Malki ldquoAssessment of urinary osteopontin in associa-tion with podocyte for early predication of nephropathy in dia-betic patientsrdquo Disease Markers vol 2014 Article ID 493736 5pages 2014
[47] K Mise J Hoshino T Ueno et al ldquoPrognostic value of tubu-lointerstitial lesions urinary N-acetyl-120573-d-glucosaminidaseand urinary 1205732-microglobulin in patients with type 2 diabetesand biopsy-proven diabetic nephropathyrdquoClinical Journal of theAmerican Society of Nephrology vol 11 no 4 pp 593ndash601 2016
[48] K M Schmidt-Ott K Mori Y L Jau et al ldquoDual actionof neutrophil gelatinase-associated lipocalinrdquo Journal of theAmerican Society of Nephrology vol 18 no 2 pp 407ndash413 2007
[49] D Bolignano A Lacquaniti G Coppolino et al ldquoNeu-trophil gelatinase-associated lipocalin as an early biomarker ofnephropathy in diabetic patientsrdquo Kidney amp Blood PressureResearch vol 32 no 2 pp 91ndash98 2009
[50] Z Yuruk Yıldırım A Nayır A Yılmaz A Gedikbası and RBundak ldquoNeutrophil gelatinase-associated lipocalin as an earlysign of diabetic kidney injury in childrenrdquo Journal of ClinicalResearch in Pediatric Endocrinology vol 7 no 4 pp 274ndash2792015
[51] A Lacquaniti V Donato B Pintaudi et al ldquolsquoNormoalbu-minuricrsquo diabetic nephropathy tubular damage and NGALrdquoActa Diabetologica vol 50 no 6 pp 935ndash942 2013
[52] J A de Carvalho E Tatsch B S Hausen et al ldquoUrinarykidney injury molecule-1 and neutrophil gelatinase-associatedlipocalin as indicators of tubular damage in normoalbuminuricpatients with type 2 diabetesrdquo Clinical Biochemistry vol 49 no3 pp 232ndash236 2016
[53] W-J Fu S-L Xiong Y-G Fang et al ldquoUrinary tubularbiomarkers in short-term type 2 diabetes mellitus patients across-sectional studyrdquo Endocrine vol 41 no 1 pp 82ndash88 2012
[54] V Garg M Kumar H S Mahapatra A Chitkara A KGadpayle and V Sekhar ldquoNovel urinary biomarkers in pre-diabetic nephropathyrdquo Clinical and Experimental Nephrologyvol 19 no 5 pp 895ndash900 2015
[55] Y-HYang X-JHe S-R Chen LWang E-M Li andL-Y XuldquoChanges of serum and urine neutrophil gelatinase-associatedlipocalin in type-2 diabetic patients with nephropathy one yearobservational follow-up studyrdquo Endocrine vol 36 no 1 pp 45ndash51 2009
[56] M H Weber and R Verwiebe ldquo1205721- microglobulin (proteinHC) features of a promising indicator of proximal tubular dys-functionrdquo European Journal of Clinical Chemistry and ClinicalBiochemistry vol 30 no 10 pp 683ndash691 1992
[57] C-Y Hong K Hughes K-S Chia V Ng and S-L LingldquoUrinary 1205721-microglobulin as a marker of nephropathy in type2 diabetic Asian subjects in Singaporerdquo Diabetes Care vol 26no 2 pp 338ndash342 2003
[58] L Petrica M Petrica A Vlad et al ldquoProximal tubule dysfunc-tion is dissociated from endothelial dysfunction in normoalbu-minuric patients with type 2 diabetes mellitus a cross-sectionalstudyrdquo Nephron Clinical Practice vol 118 no 2 pp c155ndashc1642011
[59] H Wainai F Katsukawa I Takei H Maruyama K Kataokaand T Saruta ldquoInfluence of glycemic control and hypertensionon urinary microprotein excretion in non-insulin-dependentdiabetes mellitusrdquo Journal of Diabetic Complications vol 5 no2-3 pp 160ndash161 1991
[60] N Shore R Khurshid and M Saleem ldquoAlpha-1 microglobulina marker for early detection of tubular disorders in diabeticnephropathyrdquo Journal of AyubMedical College Abbottabad vol22 no 4 pp 53ndash55 2010
[61] J V Bonventre ldquoKidney injury molecule-1 a translational jour-neyrdquo Transactions of the American Clinical and ClimatologicalAssociation vol 125 pp 293ndash299 2014
[62] L Petrica A Vlad G Gluhovschi et al ldquoProximal tubuledysfunction is associated with podocyte damage biomarkersnephrin and vascular endothelial growth factor in type 2diabetes mellitus patients a cross-sectional studyrdquo PLoS ONEvol 9 no 11 Article ID e112538 2014
[63] S E Nielsen K J Schjoedt A S Astrup et al ldquoNeutrophilGelatinase-Associated Lipocalin (NGAL) and Kidney InjuryMolecule 1 (KIM1) in patients with diabetic nephropathy across-sectional study and the effects of lisinoprilrdquo DiabeticMedicine vol 27 no 10 pp 1144ndash1150 2010
[64] S E Nielsen H Reinhard D Zdunek et al ldquoTubular markersare associated with decline in kidney function in proteinurictype 2 diabetic patientsrdquoDiabetes Research andClinical Practicevol 97 no 1 pp 71ndash76 2012
[65] C Bazzi C Petrini V Rizza et al ldquoUrinary N-acetyl-120573-glucosaminidase excretion is a marker of tubular cell dysfunc-tion and a predictor of outcome in primary glomerulonephri-tisrdquoNephrology Dialysis Transplantation vol 17 no 11 pp 1890ndash1896 2002
Journal of Diabetes Research 11
[66] A P Jones S Lock and K D Griffiths ldquoUrinary N-acetyl-120573-glucosaminidase activity in type I diabetes mellitusrdquo Annals ofClinical Biochemistry vol 32 no 1 pp 58ndash62 1995
[67] S Uslu B Efe O Alatas et al ldquoSerum cystatin C and urinaryenzymes as screening markers of renal dysfunction in diabeticpatientsrdquo Journal of Nephrology vol 18 no 5 pp 559ndash567 2005
[68] V Ambade P Singh B L Somani and D Basannar ldquoUrinaryN-acetyl beta glucosaminidase and gammaglutamyl transferaseas early markers of diabetic nephropathyrdquo Indian Journal ofClinical Biochemistry vol 21 no 2 pp 142ndash148 2006
[69] D N Patel and K Kalia ldquoEfficacy of urinary N-acetyl-120573-d-glucosaminidase to evaluate early renal tubular damage as aconsequence of type 2 diabetesmellitus a cross-sectional studyrdquoInternational Journal of Diabetes in Developing Countries vol35 supplement 3 pp 449ndash457 2015
[70] H S Assal S Tawfeek E A Rasheld D El-Lebedy and EH Thabet ldquoSerum cystatin C and tubular urinary enzymes asbiomarkers a renal dysfunction in type 2 diabetes mellitusrdquoClinical Medicine Insights Endocrinology and Diabetes vol 6no 7 pp 7ndash13 2013
[71] M Kamiyama A Zsombok and H Kobori ldquoUrinaryangiotensinogen as a novel early biomarker of intrarenal renin-angiotensin system activation in experimental type 1 diabetesrdquoJournal of Pharmacological Sciences vol 119 no 4 pp 314ndash3232012
[72] T Saito M Urushihara Y Kotani S Kagami and H KoborildquoIncreased urinary angiotensinogen is precedent to increasedurinary albumin in patients with type 1 diabetesrdquo AmericanJournal of the Medical Sciences vol 338 no 6 pp 478ndash4802009
[73] Z Zhuang Q Bai L A T Liang D Zheng and Y WangldquoIncreased urinary angiotensinogen precedes the onset of albu-minuria in normotensive type 2 diabetic patientsrdquo InternationalJournal of Clinical and Experimental Pathology vol 8 no 9 pp11464ndash11469 2015
[74] S S Kim S H Song I J Kim et al ldquoClinical implication ofurinary tubular markers in the early stage of nephropathy withtype 2 diabetic patientsrdquoDiabetes Research and Clinical Practicevol 97 no 2 pp 251ndash257 2012
[75] M Sawaguchi S-I ArakiHKobori et al ldquoAssociation betweenurinary angiotensinogen levels and renal and cardiovascularprognoses in patients with type 2 diabetes mellitusrdquo Journal ofDiabetes Investigation vol 3 no 3 pp 318ndash324 2012
[76] T Mizushige H Kobori Y Nishijima et al ldquoUrinaryangiotensinogen could be a prognostic marker of renoprotec-tive effects of alogliptin in patients with type 2 diabetesrdquo Journalof Diabetes Research vol 2015 Article ID 517472 7 pages 2015
[77] Y K Jeon M R Kim J E Huh et al ldquoCystatin C as an earlybiomarker of nephropathy in patients with type 2 diabetesrdquoJournal of Korean Medical Science vol 26 no 2 pp 258ndash2632011
[78] W D Comper T M Osicka and G Jerums ldquoHigh prevalenceof immuno-unreactive intact albumin in urine of diabeticpatientsrdquoAmerican Journal of Kidney Diseases vol 41 no 2 pp336ndash342 2003
[79] X Rao M Wan C Qiu and C Jiang ldquoRole of cystatin C inrenal damage and the optimum cut-off point of renal damageamong patients with type 2 diabetesmellitusrdquo Experimental andTherapeutic Medicine vol 8 no 3 pp 887ndash892 2014
[80] V Garg M Kuman H S Mahapatra A Chitkora A K Gad-poyle and V Sekhan ldquoNovel urinary biomarkers in prediabetic
nephropathyrdquoClinical and Experimental Nephrology vol 19 no5 pp 895ndash890 2015
[81] S S Kim S H Song I J Kim et al ldquoUrinary cystatin C andtubular proteinuria predict progression of diabetic nephropa-thyrdquo Diabetes Care vol 36 no 3 pp 656ndash661 2013
[82] A Kamijo-Ikemori T Sugaya T Yasuda et al ldquoClinical signifi-cance of urinary liver-type fatty acid-binding protein in diabeticnephropathy of type 2 diabetic patientsrdquo Diabetes Care vol 34no 3 pp 691ndash696 2011
[83] S E Nielsen T Sugaya P Hovind T Baba H-H Parving andP Rossing ldquoUrinary liver-type fatty acid-binding protein pre-dicts progression to nephropathy in type 1 diabetic patientsrdquoDiabetes Care vol 33 no 6 pp 1320ndash1324 2010
[84] V Viswanathan S Sivakumar V Sekar D M Umapathy andS Kumpatla ldquoClinical significance of urinary liver-type fattyacid binding protein at various stages of nephropathyrdquo IndianJournal of Nephrology vol 25 no 5 pp 269ndash273 2015
[85] K-M Chou C-C Lee C-H Chen and C-Y Sun ldquoClinicalvalue of NGAL L-FABP and albuminuria in predicting GFRdecline in type 2 diabetes mellitus patientsrdquo PLoS ONE vol 8no 1 article e54863 2013
[86] N M Panduru C Forsblom M Saraheimo et al ldquoUrinaryliver-type fatty acid-binding protein and progression of diabeticnephropathy in type 1 diabetesrdquoDiabetes Care vol 36 no 7 pp2077ndash2083 2013
[87] G I Welsh and M A Saleem ldquoNephrinmdashsignature moleculeof the glomerular podocyterdquoThe Journal of Pathology vol 220no 3 pp 328ndash337 2010
[88] F N Ziyadeh and G Wolf ldquoPathogenesis of the podocytopathyand proteinuria in diabetic glomerulopathyrdquo Current DiabetesReviews vol 4 no 1 pp 39ndash45 2008
[89] A Patari C ForsblomMHavana H Taipale P-H Groop andH Holthofer ldquoNephrinuria in diabetic nephropathy of type 1diabetesrdquo Diabetes vol 52 no 12 pp 2969ndash2974 2003
[90] D P K Ng B-C Tai E Tan et al ldquoNephrinuria associateswithmultiple renal traits in type 2 diabetesrdquoNephrology DialysisTransplantation vol 26 no 8 pp 2508ndash2514 2011
[91] Y Kandasamy R Smith E R Lumbers and D Rudd ldquoNephrina biomarker of early glomerular injuryrdquo Biomarker Researchvol 2 no 1 p 21 2014
[92] B Jim M Ghanta A Qipo et al ldquoDysregulated nephrin indiabetic nephropathy of type 2 diabetes a cross sectional studyrdquoPLoS ONE vol 7 no 5 Article ID e36041 2012
[93] J F Navarro C Mora M Gomez M Muros C Lopez-Aguilar and J Garcıa ldquoInfluence of renal involvement onperipheral blood mononuclear cell expression behaviour oftumour necrosis factor-120572 and interleukin-6 in type 2 diabeticpatientsrdquoNephrology Dialysis Transplantation vol 23 no 3 pp919ndash926 2008
[94] D Z I Cherney J W Scholey D Daneman et al ldquoUrinarymarkers of renal inflammation in adolescents with type 1 dia-betes mellitus and normoalbuminuriardquo Diabetic Medicine vol29 no 10 pp 1297ndash1302 2012
[95] R Har J W Scholey D Daneman et al ldquoThe effect of renalhyperfiltration on urinary inflammatory cytokineschemokinesin patients with uncomplicated type 1 diabetes mellitusrdquo Dia-betologia vol 56 no 5 pp 1166ndash1173 2013
[96] K Tashiro I Koyanagi A Saitoh et al ldquoUrinary levels ofmono-cyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) and renal injuries in patients with type 2 diabetic nephropa-thyrdquo Journal of Clinical Laboratory Analysis vol 16 no 1pp 1ndash4 2002
12 Journal of Diabetes Research
[97] J Liu Z Zhao M D P Willcox B Xu and B Shi ldquoMultiplexbead analysis of urinary cytokines of type 2 diabetic patientswith normo- and microalbuminuriardquo Journal of Immunoassayand Immunochemistry vol 31 no 4 pp 279ndash289 2010
[98] S Ibrahim and L Rashed ldquoCorrelation of urinary monocytechemo-attractant protein-1 with other parameters of renalinjury in type-II diabetes mellitusrdquo Saudi Journal of Kidney Dis-eases and Transplantation vol 19 no 6 pp 911ndash917 2008
[99] H Jiang G Guan R Zhang et al ldquoIncreased urinary excretionof orosomucoid is a risk predictor of diabetic nephropathyrdquoNephrology vol 14 no 3 pp 332ndash337 2009
[100] N M El-Beblawy N G Andrawes E A Ismail B E EnanyH S Abou El-Seoud and M A Erfan ldquoSerum and Uri-nary orosomucoid in young patients with type 1 diabetes alink between inflammation microvascular complications andsubclinical atherosclerosisrdquo Clinical and Applied ThrombosisHemostasis 2016
[101] M S Christiansen E Hommel E Magid and B Feldt-Rasmussen ldquoOrosomucoid in urine predicts cardiovascular andover-all mortality in patients with type II diabetesrdquo Diabetolo-gia vol 45 no 1 pp 115ndash120 2002
[102] H Ha and H B Lee ldquoOxidative stress in diabetic nephropathybasic and clinical informationrdquo Current Diabetes Reports vol 1no 3 pp 282ndash287 2001
[103] L L Wu C C Chiou P Y Chang and J T Wu ldquoUrinary 8-OHdG a marker of oxidative stress to DNA and a risk factorfor cancer atherosclerosis and diabeticsrdquo Clinica Chemica Actavol 339 no 1-2 pp 1ndash9 2004
[104] Y Hinokio S Suzuki M Hirai C Suzuki M Suzukiand T Toyota ldquoUrinary excretion of 8-oxo-7 8-dihydro-21015840-deoxyguanosine as a predictor of the development of diabeticnephropathyrdquo Diabetologia vol 45 no 6 pp 877ndash882 2002
[105] J Leinonen T Lehtimaki S Toyokuni et al ldquoNew biomarkerevidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitusrdquo FEBS Letters vol 417 no1 pp 150ndash152 1997
[106] K Broedbaek A Weimann E S Stovgaard and H E PoulsenldquoUrinary 8-oxo-78-dihydro-21015840-deoxyguanosine as a biomarkerin type 2 diabetesrdquo Free Radical Biology and Medicine vol 51no 8 pp 1473ndash1479 2011
[107] F L NautaW E Boertien S J L Bakker et al ldquoGlomerular andtubular damage markers are elevated in patients with diabetesrdquoDiabetes Care vol 34 no 4 pp 975ndash981 2011
[108] L Petrica A Vlad G Gluhovschi et al ldquoGlycated peptides areassociated with proximal tubule dysfunction in type 2 diabetesmellitusrdquo International Journal of Clinical and ExperimentalMedicine vol 8 no 2 pp 2516ndash2525 2015
[109] N Turk A Mornar V Mrzljak and Z Turk ldquoUrinary excre-tion of advanced glycation endproducts in patients with type2 diabetes and various stages of proteinuriardquo Diabetes andMetabolism vol 30 no 2 pp 187ndash192 2004
[110] A A Ghanem A Elewa and L F Arafa ldquoPentosidine and N-carboxymethyl-lysine biomarkers for type 2 diabetic retinopa-thyrdquo European Journal of Ophthalmology vol 21 no 1 pp 48ndash54 2011
[111] F Piarulli G Sartore A Ceriello et al ldquoRelationship betweenglyco-oxidation antioxidant status and microalbuminuria intype 2 diabetic patientsrdquo Diabetologia vol 52 no 7 pp 1419ndash1425 2009
[112] M Shoji K Kobayashi M Takemoto Y Sato and K YokoteldquoUrinary podocalyxin levels were associated with urinary albu-min levels among patients with diabetesrdquo Biomarkers vol 21no 2 pp 164ndash167 2015
[113] M Hara K Yamagata Y Tomino et al ldquoUrinary podocalyxinis an early marker for podocyte injury in patients with diabetesestablishment of a highly sensitive ELISA to detect urinarypodocalyxinrdquo Diabetologia vol 55 no 11 pp 2913ndash2919 2012
[114] M Zheng L-L Lv J Ni et al ldquoUrinary podocyte-associatedmRNA profile in various stages of diabetic nephropathyrdquo PLoSONE vol 6 no 5 Article ID e20431 2011
[115] N H Kim K B Kim D L Kim et al ldquoPlasma and urinaryvascular endothelial growth factor and diabetic nephropathy intype 2 diabetes mellitusrdquo Diabetic Medicine vol 21 no 6 pp545ndash551 2004
[116] M Emoto K Mori E Lee et al ldquoFetuin-A and atheroscleroticcalcified plaque in patients with type 2 diabetes mellitusrdquoMetabolism Clinical and Experimental vol 59 no 6 pp 873ndash878 2010
[117] K Inoue J Wada J Eguchi et al ldquoUrinary fetuin-A is a novelmarker for diabetic nephropathy in type 2 diabetes identified bylectin microarrayrdquo PLoS ONE vol 8 no 10 Article ID e771182013
[118] M A K Salem S A El-Habashy O M Saeid M M KEl-Tawil and P H Tawfik ldquoUrinary excretion of N-acetyl-120573-d-glucosaminidase and retinol binding protein as alternativeindicators of nephropathy in patients with type 1 diabetesmellitusrdquo Pediatric Diabetes vol 3 no 1 pp 37ndash41 2002
[119] V Lambadiari N P E KadoglouV Stasinos et al ldquoSerum levelsof retinol-binding protein-4 are associated with the presenceand severity of coronary artery diseaserdquo Cardiovascular Dia-betology vol 13 no 1 article 121 2014
[120] A Shoukry S E-A Bdeer and R H El-Sokkary ldquoUrinarymonocyte chemoattractant protein-1 and vitamin D-bindingprotein as biomarkers for early detection of diabetic nephropa-thy in type 2 diabetesmellitusrdquoMolecular andCellular Biochem-istry vol 408 no 1 pp 25ndash35 2015
[121] Z Li Y Xu Y Nie and Z Zhao ldquoUrinary heme oxygenase-1 as apotential biomarker for early diabetic nephropathyrdquoNephrology(Carlton Vic) 2016
[122] B Satirapoj S Tassanasorn M Charoenpitakchai and OSupasyndh ldquoPeriostin as a tissue and urinary biomarker of renalinjury in type 2 diabetes mellitusrdquo PLoS ONE vol 10 no 4Article ID e0124055 2015
[123] E Y Lee S S Kim J-S Lee et al ldquoSoluble 120572-klotho as a novelbiomarker in the early stage of nephropathy in patients withtype 2 diabetesrdquo PLoS ONE vol 9 no 8 article e102984 2014
[124] A-L Sun J-TDengG-J Guan et al ldquoDipeptidyl peptidase-IVis a potential molecular biomarker in diabetic kidney diseaserdquoDiabetes and Vascular Disease Research vol 9 no 4 pp 301ndash308 2012
[125] Y Yang L Xiao J Li Y S Kanwar F Liu and L Sun ldquoUrinemiRNAs potential biomarkers for monitoring progression ofearly stages of diabetic nephropathyrdquo Medical Hypotheses vol81 no 2 pp 274ndash278 2013
[126] C Argyropoulos K Wang J Bernardo et al ldquoUrinaryMicroRNA profiling predicts the development of microalbu-minuria in patients with type 1 Diabetesrdquo Journal of ClinicalMedicine vol 4 no 7 pp 1495ndash1517 2015
Journal of Diabetes Research 13
[127] M W Kennedy A P Heikema A Cooper P J Bjorkmanand L M Sanchez ldquoHydrophobic ligand binding by Zn-1205722-glycoprotein a soluble fat-depleting factor related to major his-tocompatibility complex proteinsrdquo Journal of Biological Chem-istry vol 276 no 37 pp 35008ndash35013 2001
[128] YWang YM Li S Zhang J Y Zhao and C Y Liu ldquoAdipokinezinc-120572-2- glycoprotein as novel urinary biomarker presentsearly than microalbuminuria in diabetic nephropathyrdquo Journalof International Medical Research vol 44 no 2 pp 278ndash2862016
[129] S C Lim D Q Liying W C Toy et al ldquoAdipocytokine zinc 1205722glycoprotein (ZAG) as a novel urinary biomarker for normo-albuminuric diabetic nephropathyrdquo Diabetic Medicine vol 29no 7 pp 945ndash949 2012
[130] V Thongboonkerd ldquoStudy of diabetic nephropathy in theproteomic erardquo Diabetes and the Kidney vol 170 pp 172ndash1832011
[131] K N Lai and S C W Tang Eds Diabetes and the Kidney vol170 Contributions to Nephrology Karger Basel Switzerland2011
[132] P Zurbig G Jerums P Hovind et al ldquoUrinary proteomics forearly diagnosis in diabetic nephropathyrdquo Diabetes vol 61 no12 pp 3304ndash3313 2012
[133] F Raimondo S Corbetta L Morosi et al ldquoUrinary exosomesand diabetic nephropathy a proteomic approachrdquo MolecularBioSystems vol 9 no 6 pp 1139ndash1146 2013
[134] I Zubiri M Posada-Ayala A Sanz-Maroto et al ldquoDiabeticnephropathy induces changes in the proteome of human uri-nary exosomes as revealed by label-free comparative analysisrdquoJournal of Proteomics vol 96 pp 92ndash102 2014
[135] A Caseiro A Barros R Ferreira et al ldquoPursuing type 1diabetes mellitus and related complications through urinaryproteomicsrdquo Translational Research vol 163 no 3 pp 188ndash1992014
[136] B Jim J Santos F Spath and J C He ldquoBiomarkers of diabeticnephropathy the present and the futurerdquo Current DiabetesReviews vol 8 no 5 pp 317ndash328 2012
[36] T Fiseha ldquoUrinary biomarkers for early diabetic nephropathyin type 2 diabetic patientsrdquo Biomarker Research vol 3 article16 2015
[37] N Kotajima T Kimura T Kanda et al ldquoType IV collagenas an early marker for diabetic nephropathy in non-insulin-dependent diabetes mellitusrdquo Journal of Diabetes and its Com-plications vol 14 no 1 pp 13ndash17 2000
[38] H Takizawa T Satoh A Kurusu et al ldquoIncrease of urinarytype IV collagen in normoalbuminuric patients with impairedglucose tolerancerdquo Nephron vol 79 no 4 pp 474ndash475 1998
[39] H Okonogi M Nishimura Y Utsunomiya et al ldquoUrinary typeIV collagen excretion reflects renal morphological alterationsand type IV collagen expression in patients with type 2 diabetesmellitusrdquo Clinical Nephrology vol 55 no 5 pp 357ndash364 2001
[40] S Ming Z Qi L Wang and K Zhu ldquoUrinary type IV collagena specific indicator of incipient diabetic nephropathyrdquo ChineseMedical Journal vol 115 no 3 pp 389ndash394 2002
[41] S Kado A Aoki S Wada et al ldquoUrinary type IV collagen as amarker for early diabetic nephropathyrdquo Diabetes Research andClinical Practice vol 31 no 1ndash3 pp 103ndash108 1996
[42] I Ueta K Takamatsu and K Hashimoto ldquoUrinary glycos-aminoglycans in patients with incipient diabetic nephropathyrdquoNihon Jinzo Gakkai Shi vol 37 no 1 pp 17ndash23 1995
[43] O Torffvit ldquoUrinary sulphated glycosaminoglycans andTamm-Horsfall protein in type 1 diabetic patientsrdquo ScandinavianJournal of Urology and Nephrology vol 33 no 5 pp 328ndash3321999
[44] Y Uehara H Makino K Seiki and Y Urade ldquoUrinaryexcretions of lipocalin-type prostaglandin D synthase predictrenal injury in type-2 diabetes a cross-sectional and prospectivemulticentre studyrdquoNephrology Dialysis Transplantation vol 24no 2 pp 475ndash482 2009
[45] K Kuboki H Tada K Shin Y Oshima and S Isogai ldquoRela-tionship between urinary excretion of fibronectin degradationproducts and proteinuria in diabetic patients and their suppres-sion after continuous subcutaneous heparin infusionrdquoDiabetesResearch and Clinical Practice vol 21 no 1 pp 61ndash66 1993
[46] A L Al-Malki ldquoAssessment of urinary osteopontin in associa-tion with podocyte for early predication of nephropathy in dia-betic patientsrdquo Disease Markers vol 2014 Article ID 493736 5pages 2014
[47] K Mise J Hoshino T Ueno et al ldquoPrognostic value of tubu-lointerstitial lesions urinary N-acetyl-120573-d-glucosaminidaseand urinary 1205732-microglobulin in patients with type 2 diabetesand biopsy-proven diabetic nephropathyrdquoClinical Journal of theAmerican Society of Nephrology vol 11 no 4 pp 593ndash601 2016
[48] K M Schmidt-Ott K Mori Y L Jau et al ldquoDual actionof neutrophil gelatinase-associated lipocalinrdquo Journal of theAmerican Society of Nephrology vol 18 no 2 pp 407ndash413 2007
[49] D Bolignano A Lacquaniti G Coppolino et al ldquoNeu-trophil gelatinase-associated lipocalin as an early biomarker ofnephropathy in diabetic patientsrdquo Kidney amp Blood PressureResearch vol 32 no 2 pp 91ndash98 2009
[50] Z Yuruk Yıldırım A Nayır A Yılmaz A Gedikbası and RBundak ldquoNeutrophil gelatinase-associated lipocalin as an earlysign of diabetic kidney injury in childrenrdquo Journal of ClinicalResearch in Pediatric Endocrinology vol 7 no 4 pp 274ndash2792015
[51] A Lacquaniti V Donato B Pintaudi et al ldquolsquoNormoalbu-minuricrsquo diabetic nephropathy tubular damage and NGALrdquoActa Diabetologica vol 50 no 6 pp 935ndash942 2013
[52] J A de Carvalho E Tatsch B S Hausen et al ldquoUrinarykidney injury molecule-1 and neutrophil gelatinase-associatedlipocalin as indicators of tubular damage in normoalbuminuricpatients with type 2 diabetesrdquo Clinical Biochemistry vol 49 no3 pp 232ndash236 2016
[53] W-J Fu S-L Xiong Y-G Fang et al ldquoUrinary tubularbiomarkers in short-term type 2 diabetes mellitus patients across-sectional studyrdquo Endocrine vol 41 no 1 pp 82ndash88 2012
[54] V Garg M Kumar H S Mahapatra A Chitkara A KGadpayle and V Sekhar ldquoNovel urinary biomarkers in pre-diabetic nephropathyrdquo Clinical and Experimental Nephrologyvol 19 no 5 pp 895ndash900 2015
[55] Y-HYang X-JHe S-R Chen LWang E-M Li andL-Y XuldquoChanges of serum and urine neutrophil gelatinase-associatedlipocalin in type-2 diabetic patients with nephropathy one yearobservational follow-up studyrdquo Endocrine vol 36 no 1 pp 45ndash51 2009
[56] M H Weber and R Verwiebe ldquo1205721- microglobulin (proteinHC) features of a promising indicator of proximal tubular dys-functionrdquo European Journal of Clinical Chemistry and ClinicalBiochemistry vol 30 no 10 pp 683ndash691 1992
[57] C-Y Hong K Hughes K-S Chia V Ng and S-L LingldquoUrinary 1205721-microglobulin as a marker of nephropathy in type2 diabetic Asian subjects in Singaporerdquo Diabetes Care vol 26no 2 pp 338ndash342 2003
[58] L Petrica M Petrica A Vlad et al ldquoProximal tubule dysfunc-tion is dissociated from endothelial dysfunction in normoalbu-minuric patients with type 2 diabetes mellitus a cross-sectionalstudyrdquo Nephron Clinical Practice vol 118 no 2 pp c155ndashc1642011
[59] H Wainai F Katsukawa I Takei H Maruyama K Kataokaand T Saruta ldquoInfluence of glycemic control and hypertensionon urinary microprotein excretion in non-insulin-dependentdiabetes mellitusrdquo Journal of Diabetic Complications vol 5 no2-3 pp 160ndash161 1991
[60] N Shore R Khurshid and M Saleem ldquoAlpha-1 microglobulina marker for early detection of tubular disorders in diabeticnephropathyrdquo Journal of AyubMedical College Abbottabad vol22 no 4 pp 53ndash55 2010
[61] J V Bonventre ldquoKidney injury molecule-1 a translational jour-neyrdquo Transactions of the American Clinical and ClimatologicalAssociation vol 125 pp 293ndash299 2014
[62] L Petrica A Vlad G Gluhovschi et al ldquoProximal tubuledysfunction is associated with podocyte damage biomarkersnephrin and vascular endothelial growth factor in type 2diabetes mellitus patients a cross-sectional studyrdquo PLoS ONEvol 9 no 11 Article ID e112538 2014
[63] S E Nielsen K J Schjoedt A S Astrup et al ldquoNeutrophilGelatinase-Associated Lipocalin (NGAL) and Kidney InjuryMolecule 1 (KIM1) in patients with diabetic nephropathy across-sectional study and the effects of lisinoprilrdquo DiabeticMedicine vol 27 no 10 pp 1144ndash1150 2010
[64] S E Nielsen H Reinhard D Zdunek et al ldquoTubular markersare associated with decline in kidney function in proteinurictype 2 diabetic patientsrdquoDiabetes Research andClinical Practicevol 97 no 1 pp 71ndash76 2012
[65] C Bazzi C Petrini V Rizza et al ldquoUrinary N-acetyl-120573-glucosaminidase excretion is a marker of tubular cell dysfunc-tion and a predictor of outcome in primary glomerulonephri-tisrdquoNephrology Dialysis Transplantation vol 17 no 11 pp 1890ndash1896 2002
Journal of Diabetes Research 11
[66] A P Jones S Lock and K D Griffiths ldquoUrinary N-acetyl-120573-glucosaminidase activity in type I diabetes mellitusrdquo Annals ofClinical Biochemistry vol 32 no 1 pp 58ndash62 1995
[67] S Uslu B Efe O Alatas et al ldquoSerum cystatin C and urinaryenzymes as screening markers of renal dysfunction in diabeticpatientsrdquo Journal of Nephrology vol 18 no 5 pp 559ndash567 2005
[68] V Ambade P Singh B L Somani and D Basannar ldquoUrinaryN-acetyl beta glucosaminidase and gammaglutamyl transferaseas early markers of diabetic nephropathyrdquo Indian Journal ofClinical Biochemistry vol 21 no 2 pp 142ndash148 2006
[69] D N Patel and K Kalia ldquoEfficacy of urinary N-acetyl-120573-d-glucosaminidase to evaluate early renal tubular damage as aconsequence of type 2 diabetesmellitus a cross-sectional studyrdquoInternational Journal of Diabetes in Developing Countries vol35 supplement 3 pp 449ndash457 2015
[70] H S Assal S Tawfeek E A Rasheld D El-Lebedy and EH Thabet ldquoSerum cystatin C and tubular urinary enzymes asbiomarkers a renal dysfunction in type 2 diabetes mellitusrdquoClinical Medicine Insights Endocrinology and Diabetes vol 6no 7 pp 7ndash13 2013
[71] M Kamiyama A Zsombok and H Kobori ldquoUrinaryangiotensinogen as a novel early biomarker of intrarenal renin-angiotensin system activation in experimental type 1 diabetesrdquoJournal of Pharmacological Sciences vol 119 no 4 pp 314ndash3232012
[72] T Saito M Urushihara Y Kotani S Kagami and H KoborildquoIncreased urinary angiotensinogen is precedent to increasedurinary albumin in patients with type 1 diabetesrdquo AmericanJournal of the Medical Sciences vol 338 no 6 pp 478ndash4802009
[73] Z Zhuang Q Bai L A T Liang D Zheng and Y WangldquoIncreased urinary angiotensinogen precedes the onset of albu-minuria in normotensive type 2 diabetic patientsrdquo InternationalJournal of Clinical and Experimental Pathology vol 8 no 9 pp11464ndash11469 2015
[74] S S Kim S H Song I J Kim et al ldquoClinical implication ofurinary tubular markers in the early stage of nephropathy withtype 2 diabetic patientsrdquoDiabetes Research and Clinical Practicevol 97 no 2 pp 251ndash257 2012
[75] M Sawaguchi S-I ArakiHKobori et al ldquoAssociation betweenurinary angiotensinogen levels and renal and cardiovascularprognoses in patients with type 2 diabetes mellitusrdquo Journal ofDiabetes Investigation vol 3 no 3 pp 318ndash324 2012
[76] T Mizushige H Kobori Y Nishijima et al ldquoUrinaryangiotensinogen could be a prognostic marker of renoprotec-tive effects of alogliptin in patients with type 2 diabetesrdquo Journalof Diabetes Research vol 2015 Article ID 517472 7 pages 2015
[77] Y K Jeon M R Kim J E Huh et al ldquoCystatin C as an earlybiomarker of nephropathy in patients with type 2 diabetesrdquoJournal of Korean Medical Science vol 26 no 2 pp 258ndash2632011
[78] W D Comper T M Osicka and G Jerums ldquoHigh prevalenceof immuno-unreactive intact albumin in urine of diabeticpatientsrdquoAmerican Journal of Kidney Diseases vol 41 no 2 pp336ndash342 2003
[79] X Rao M Wan C Qiu and C Jiang ldquoRole of cystatin C inrenal damage and the optimum cut-off point of renal damageamong patients with type 2 diabetesmellitusrdquo Experimental andTherapeutic Medicine vol 8 no 3 pp 887ndash892 2014
[80] V Garg M Kuman H S Mahapatra A Chitkora A K Gad-poyle and V Sekhan ldquoNovel urinary biomarkers in prediabetic
nephropathyrdquoClinical and Experimental Nephrology vol 19 no5 pp 895ndash890 2015
[81] S S Kim S H Song I J Kim et al ldquoUrinary cystatin C andtubular proteinuria predict progression of diabetic nephropa-thyrdquo Diabetes Care vol 36 no 3 pp 656ndash661 2013
[82] A Kamijo-Ikemori T Sugaya T Yasuda et al ldquoClinical signifi-cance of urinary liver-type fatty acid-binding protein in diabeticnephropathy of type 2 diabetic patientsrdquo Diabetes Care vol 34no 3 pp 691ndash696 2011
[83] S E Nielsen T Sugaya P Hovind T Baba H-H Parving andP Rossing ldquoUrinary liver-type fatty acid-binding protein pre-dicts progression to nephropathy in type 1 diabetic patientsrdquoDiabetes Care vol 33 no 6 pp 1320ndash1324 2010
[84] V Viswanathan S Sivakumar V Sekar D M Umapathy andS Kumpatla ldquoClinical significance of urinary liver-type fattyacid binding protein at various stages of nephropathyrdquo IndianJournal of Nephrology vol 25 no 5 pp 269ndash273 2015
[85] K-M Chou C-C Lee C-H Chen and C-Y Sun ldquoClinicalvalue of NGAL L-FABP and albuminuria in predicting GFRdecline in type 2 diabetes mellitus patientsrdquo PLoS ONE vol 8no 1 article e54863 2013
[86] N M Panduru C Forsblom M Saraheimo et al ldquoUrinaryliver-type fatty acid-binding protein and progression of diabeticnephropathy in type 1 diabetesrdquoDiabetes Care vol 36 no 7 pp2077ndash2083 2013
[87] G I Welsh and M A Saleem ldquoNephrinmdashsignature moleculeof the glomerular podocyterdquoThe Journal of Pathology vol 220no 3 pp 328ndash337 2010
[88] F N Ziyadeh and G Wolf ldquoPathogenesis of the podocytopathyand proteinuria in diabetic glomerulopathyrdquo Current DiabetesReviews vol 4 no 1 pp 39ndash45 2008
[89] A Patari C ForsblomMHavana H Taipale P-H Groop andH Holthofer ldquoNephrinuria in diabetic nephropathy of type 1diabetesrdquo Diabetes vol 52 no 12 pp 2969ndash2974 2003
[90] D P K Ng B-C Tai E Tan et al ldquoNephrinuria associateswithmultiple renal traits in type 2 diabetesrdquoNephrology DialysisTransplantation vol 26 no 8 pp 2508ndash2514 2011
[91] Y Kandasamy R Smith E R Lumbers and D Rudd ldquoNephrina biomarker of early glomerular injuryrdquo Biomarker Researchvol 2 no 1 p 21 2014
[92] B Jim M Ghanta A Qipo et al ldquoDysregulated nephrin indiabetic nephropathy of type 2 diabetes a cross sectional studyrdquoPLoS ONE vol 7 no 5 Article ID e36041 2012
[93] J F Navarro C Mora M Gomez M Muros C Lopez-Aguilar and J Garcıa ldquoInfluence of renal involvement onperipheral blood mononuclear cell expression behaviour oftumour necrosis factor-120572 and interleukin-6 in type 2 diabeticpatientsrdquoNephrology Dialysis Transplantation vol 23 no 3 pp919ndash926 2008
[94] D Z I Cherney J W Scholey D Daneman et al ldquoUrinarymarkers of renal inflammation in adolescents with type 1 dia-betes mellitus and normoalbuminuriardquo Diabetic Medicine vol29 no 10 pp 1297ndash1302 2012
[95] R Har J W Scholey D Daneman et al ldquoThe effect of renalhyperfiltration on urinary inflammatory cytokineschemokinesin patients with uncomplicated type 1 diabetes mellitusrdquo Dia-betologia vol 56 no 5 pp 1166ndash1173 2013
[96] K Tashiro I Koyanagi A Saitoh et al ldquoUrinary levels ofmono-cyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) and renal injuries in patients with type 2 diabetic nephropa-thyrdquo Journal of Clinical Laboratory Analysis vol 16 no 1pp 1ndash4 2002
12 Journal of Diabetes Research
[97] J Liu Z Zhao M D P Willcox B Xu and B Shi ldquoMultiplexbead analysis of urinary cytokines of type 2 diabetic patientswith normo- and microalbuminuriardquo Journal of Immunoassayand Immunochemistry vol 31 no 4 pp 279ndash289 2010
[98] S Ibrahim and L Rashed ldquoCorrelation of urinary monocytechemo-attractant protein-1 with other parameters of renalinjury in type-II diabetes mellitusrdquo Saudi Journal of Kidney Dis-eases and Transplantation vol 19 no 6 pp 911ndash917 2008
[99] H Jiang G Guan R Zhang et al ldquoIncreased urinary excretionof orosomucoid is a risk predictor of diabetic nephropathyrdquoNephrology vol 14 no 3 pp 332ndash337 2009
[100] N M El-Beblawy N G Andrawes E A Ismail B E EnanyH S Abou El-Seoud and M A Erfan ldquoSerum and Uri-nary orosomucoid in young patients with type 1 diabetes alink between inflammation microvascular complications andsubclinical atherosclerosisrdquo Clinical and Applied ThrombosisHemostasis 2016
[101] M S Christiansen E Hommel E Magid and B Feldt-Rasmussen ldquoOrosomucoid in urine predicts cardiovascular andover-all mortality in patients with type II diabetesrdquo Diabetolo-gia vol 45 no 1 pp 115ndash120 2002
[102] H Ha and H B Lee ldquoOxidative stress in diabetic nephropathybasic and clinical informationrdquo Current Diabetes Reports vol 1no 3 pp 282ndash287 2001
[103] L L Wu C C Chiou P Y Chang and J T Wu ldquoUrinary 8-OHdG a marker of oxidative stress to DNA and a risk factorfor cancer atherosclerosis and diabeticsrdquo Clinica Chemica Actavol 339 no 1-2 pp 1ndash9 2004
[104] Y Hinokio S Suzuki M Hirai C Suzuki M Suzukiand T Toyota ldquoUrinary excretion of 8-oxo-7 8-dihydro-21015840-deoxyguanosine as a predictor of the development of diabeticnephropathyrdquo Diabetologia vol 45 no 6 pp 877ndash882 2002
[105] J Leinonen T Lehtimaki S Toyokuni et al ldquoNew biomarkerevidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitusrdquo FEBS Letters vol 417 no1 pp 150ndash152 1997
[106] K Broedbaek A Weimann E S Stovgaard and H E PoulsenldquoUrinary 8-oxo-78-dihydro-21015840-deoxyguanosine as a biomarkerin type 2 diabetesrdquo Free Radical Biology and Medicine vol 51no 8 pp 1473ndash1479 2011
[107] F L NautaW E Boertien S J L Bakker et al ldquoGlomerular andtubular damage markers are elevated in patients with diabetesrdquoDiabetes Care vol 34 no 4 pp 975ndash981 2011
[108] L Petrica A Vlad G Gluhovschi et al ldquoGlycated peptides areassociated with proximal tubule dysfunction in type 2 diabetesmellitusrdquo International Journal of Clinical and ExperimentalMedicine vol 8 no 2 pp 2516ndash2525 2015
[109] N Turk A Mornar V Mrzljak and Z Turk ldquoUrinary excre-tion of advanced glycation endproducts in patients with type2 diabetes and various stages of proteinuriardquo Diabetes andMetabolism vol 30 no 2 pp 187ndash192 2004
[110] A A Ghanem A Elewa and L F Arafa ldquoPentosidine and N-carboxymethyl-lysine biomarkers for type 2 diabetic retinopa-thyrdquo European Journal of Ophthalmology vol 21 no 1 pp 48ndash54 2011
[111] F Piarulli G Sartore A Ceriello et al ldquoRelationship betweenglyco-oxidation antioxidant status and microalbuminuria intype 2 diabetic patientsrdquo Diabetologia vol 52 no 7 pp 1419ndash1425 2009
[112] M Shoji K Kobayashi M Takemoto Y Sato and K YokoteldquoUrinary podocalyxin levels were associated with urinary albu-min levels among patients with diabetesrdquo Biomarkers vol 21no 2 pp 164ndash167 2015
[113] M Hara K Yamagata Y Tomino et al ldquoUrinary podocalyxinis an early marker for podocyte injury in patients with diabetesestablishment of a highly sensitive ELISA to detect urinarypodocalyxinrdquo Diabetologia vol 55 no 11 pp 2913ndash2919 2012
[114] M Zheng L-L Lv J Ni et al ldquoUrinary podocyte-associatedmRNA profile in various stages of diabetic nephropathyrdquo PLoSONE vol 6 no 5 Article ID e20431 2011
[115] N H Kim K B Kim D L Kim et al ldquoPlasma and urinaryvascular endothelial growth factor and diabetic nephropathy intype 2 diabetes mellitusrdquo Diabetic Medicine vol 21 no 6 pp545ndash551 2004
[116] M Emoto K Mori E Lee et al ldquoFetuin-A and atheroscleroticcalcified plaque in patients with type 2 diabetes mellitusrdquoMetabolism Clinical and Experimental vol 59 no 6 pp 873ndash878 2010
[117] K Inoue J Wada J Eguchi et al ldquoUrinary fetuin-A is a novelmarker for diabetic nephropathy in type 2 diabetes identified bylectin microarrayrdquo PLoS ONE vol 8 no 10 Article ID e771182013
[118] M A K Salem S A El-Habashy O M Saeid M M KEl-Tawil and P H Tawfik ldquoUrinary excretion of N-acetyl-120573-d-glucosaminidase and retinol binding protein as alternativeindicators of nephropathy in patients with type 1 diabetesmellitusrdquo Pediatric Diabetes vol 3 no 1 pp 37ndash41 2002
[119] V Lambadiari N P E KadoglouV Stasinos et al ldquoSerum levelsof retinol-binding protein-4 are associated with the presenceand severity of coronary artery diseaserdquo Cardiovascular Dia-betology vol 13 no 1 article 121 2014
[120] A Shoukry S E-A Bdeer and R H El-Sokkary ldquoUrinarymonocyte chemoattractant protein-1 and vitamin D-bindingprotein as biomarkers for early detection of diabetic nephropa-thy in type 2 diabetesmellitusrdquoMolecular andCellular Biochem-istry vol 408 no 1 pp 25ndash35 2015
[121] Z Li Y Xu Y Nie and Z Zhao ldquoUrinary heme oxygenase-1 as apotential biomarker for early diabetic nephropathyrdquoNephrology(Carlton Vic) 2016
[122] B Satirapoj S Tassanasorn M Charoenpitakchai and OSupasyndh ldquoPeriostin as a tissue and urinary biomarker of renalinjury in type 2 diabetes mellitusrdquo PLoS ONE vol 10 no 4Article ID e0124055 2015
[123] E Y Lee S S Kim J-S Lee et al ldquoSoluble 120572-klotho as a novelbiomarker in the early stage of nephropathy in patients withtype 2 diabetesrdquo PLoS ONE vol 9 no 8 article e102984 2014
[124] A-L Sun J-TDengG-J Guan et al ldquoDipeptidyl peptidase-IVis a potential molecular biomarker in diabetic kidney diseaserdquoDiabetes and Vascular Disease Research vol 9 no 4 pp 301ndash308 2012
[125] Y Yang L Xiao J Li Y S Kanwar F Liu and L Sun ldquoUrinemiRNAs potential biomarkers for monitoring progression ofearly stages of diabetic nephropathyrdquo Medical Hypotheses vol81 no 2 pp 274ndash278 2013
[126] C Argyropoulos K Wang J Bernardo et al ldquoUrinaryMicroRNA profiling predicts the development of microalbu-minuria in patients with type 1 Diabetesrdquo Journal of ClinicalMedicine vol 4 no 7 pp 1495ndash1517 2015
Journal of Diabetes Research 13
[127] M W Kennedy A P Heikema A Cooper P J Bjorkmanand L M Sanchez ldquoHydrophobic ligand binding by Zn-1205722-glycoprotein a soluble fat-depleting factor related to major his-tocompatibility complex proteinsrdquo Journal of Biological Chem-istry vol 276 no 37 pp 35008ndash35013 2001
[128] YWang YM Li S Zhang J Y Zhao and C Y Liu ldquoAdipokinezinc-120572-2- glycoprotein as novel urinary biomarker presentsearly than microalbuminuria in diabetic nephropathyrdquo Journalof International Medical Research vol 44 no 2 pp 278ndash2862016
[129] S C Lim D Q Liying W C Toy et al ldquoAdipocytokine zinc 1205722glycoprotein (ZAG) as a novel urinary biomarker for normo-albuminuric diabetic nephropathyrdquo Diabetic Medicine vol 29no 7 pp 945ndash949 2012
[130] V Thongboonkerd ldquoStudy of diabetic nephropathy in theproteomic erardquo Diabetes and the Kidney vol 170 pp 172ndash1832011
[131] K N Lai and S C W Tang Eds Diabetes and the Kidney vol170 Contributions to Nephrology Karger Basel Switzerland2011
[132] P Zurbig G Jerums P Hovind et al ldquoUrinary proteomics forearly diagnosis in diabetic nephropathyrdquo Diabetes vol 61 no12 pp 3304ndash3313 2012
[133] F Raimondo S Corbetta L Morosi et al ldquoUrinary exosomesand diabetic nephropathy a proteomic approachrdquo MolecularBioSystems vol 9 no 6 pp 1139ndash1146 2013
[134] I Zubiri M Posada-Ayala A Sanz-Maroto et al ldquoDiabeticnephropathy induces changes in the proteome of human uri-nary exosomes as revealed by label-free comparative analysisrdquoJournal of Proteomics vol 96 pp 92ndash102 2014
[135] A Caseiro A Barros R Ferreira et al ldquoPursuing type 1diabetes mellitus and related complications through urinaryproteomicsrdquo Translational Research vol 163 no 3 pp 188ndash1992014
[136] B Jim J Santos F Spath and J C He ldquoBiomarkers of diabeticnephropathy the present and the futurerdquo Current DiabetesReviews vol 8 no 5 pp 317ndash328 2012
[66] A P Jones S Lock and K D Griffiths ldquoUrinary N-acetyl-120573-glucosaminidase activity in type I diabetes mellitusrdquo Annals ofClinical Biochemistry vol 32 no 1 pp 58ndash62 1995
[67] S Uslu B Efe O Alatas et al ldquoSerum cystatin C and urinaryenzymes as screening markers of renal dysfunction in diabeticpatientsrdquo Journal of Nephrology vol 18 no 5 pp 559ndash567 2005
[68] V Ambade P Singh B L Somani and D Basannar ldquoUrinaryN-acetyl beta glucosaminidase and gammaglutamyl transferaseas early markers of diabetic nephropathyrdquo Indian Journal ofClinical Biochemistry vol 21 no 2 pp 142ndash148 2006
[69] D N Patel and K Kalia ldquoEfficacy of urinary N-acetyl-120573-d-glucosaminidase to evaluate early renal tubular damage as aconsequence of type 2 diabetesmellitus a cross-sectional studyrdquoInternational Journal of Diabetes in Developing Countries vol35 supplement 3 pp 449ndash457 2015
[70] H S Assal S Tawfeek E A Rasheld D El-Lebedy and EH Thabet ldquoSerum cystatin C and tubular urinary enzymes asbiomarkers a renal dysfunction in type 2 diabetes mellitusrdquoClinical Medicine Insights Endocrinology and Diabetes vol 6no 7 pp 7ndash13 2013
[71] M Kamiyama A Zsombok and H Kobori ldquoUrinaryangiotensinogen as a novel early biomarker of intrarenal renin-angiotensin system activation in experimental type 1 diabetesrdquoJournal of Pharmacological Sciences vol 119 no 4 pp 314ndash3232012
[72] T Saito M Urushihara Y Kotani S Kagami and H KoborildquoIncreased urinary angiotensinogen is precedent to increasedurinary albumin in patients with type 1 diabetesrdquo AmericanJournal of the Medical Sciences vol 338 no 6 pp 478ndash4802009
[73] Z Zhuang Q Bai L A T Liang D Zheng and Y WangldquoIncreased urinary angiotensinogen precedes the onset of albu-minuria in normotensive type 2 diabetic patientsrdquo InternationalJournal of Clinical and Experimental Pathology vol 8 no 9 pp11464ndash11469 2015
[74] S S Kim S H Song I J Kim et al ldquoClinical implication ofurinary tubular markers in the early stage of nephropathy withtype 2 diabetic patientsrdquoDiabetes Research and Clinical Practicevol 97 no 2 pp 251ndash257 2012
[75] M Sawaguchi S-I ArakiHKobori et al ldquoAssociation betweenurinary angiotensinogen levels and renal and cardiovascularprognoses in patients with type 2 diabetes mellitusrdquo Journal ofDiabetes Investigation vol 3 no 3 pp 318ndash324 2012
[76] T Mizushige H Kobori Y Nishijima et al ldquoUrinaryangiotensinogen could be a prognostic marker of renoprotec-tive effects of alogliptin in patients with type 2 diabetesrdquo Journalof Diabetes Research vol 2015 Article ID 517472 7 pages 2015
[77] Y K Jeon M R Kim J E Huh et al ldquoCystatin C as an earlybiomarker of nephropathy in patients with type 2 diabetesrdquoJournal of Korean Medical Science vol 26 no 2 pp 258ndash2632011
[78] W D Comper T M Osicka and G Jerums ldquoHigh prevalenceof immuno-unreactive intact albumin in urine of diabeticpatientsrdquoAmerican Journal of Kidney Diseases vol 41 no 2 pp336ndash342 2003
[79] X Rao M Wan C Qiu and C Jiang ldquoRole of cystatin C inrenal damage and the optimum cut-off point of renal damageamong patients with type 2 diabetesmellitusrdquo Experimental andTherapeutic Medicine vol 8 no 3 pp 887ndash892 2014
[80] V Garg M Kuman H S Mahapatra A Chitkora A K Gad-poyle and V Sekhan ldquoNovel urinary biomarkers in prediabetic
nephropathyrdquoClinical and Experimental Nephrology vol 19 no5 pp 895ndash890 2015
[81] S S Kim S H Song I J Kim et al ldquoUrinary cystatin C andtubular proteinuria predict progression of diabetic nephropa-thyrdquo Diabetes Care vol 36 no 3 pp 656ndash661 2013
[82] A Kamijo-Ikemori T Sugaya T Yasuda et al ldquoClinical signifi-cance of urinary liver-type fatty acid-binding protein in diabeticnephropathy of type 2 diabetic patientsrdquo Diabetes Care vol 34no 3 pp 691ndash696 2011
[83] S E Nielsen T Sugaya P Hovind T Baba H-H Parving andP Rossing ldquoUrinary liver-type fatty acid-binding protein pre-dicts progression to nephropathy in type 1 diabetic patientsrdquoDiabetes Care vol 33 no 6 pp 1320ndash1324 2010
[84] V Viswanathan S Sivakumar V Sekar D M Umapathy andS Kumpatla ldquoClinical significance of urinary liver-type fattyacid binding protein at various stages of nephropathyrdquo IndianJournal of Nephrology vol 25 no 5 pp 269ndash273 2015
[85] K-M Chou C-C Lee C-H Chen and C-Y Sun ldquoClinicalvalue of NGAL L-FABP and albuminuria in predicting GFRdecline in type 2 diabetes mellitus patientsrdquo PLoS ONE vol 8no 1 article e54863 2013
[86] N M Panduru C Forsblom M Saraheimo et al ldquoUrinaryliver-type fatty acid-binding protein and progression of diabeticnephropathy in type 1 diabetesrdquoDiabetes Care vol 36 no 7 pp2077ndash2083 2013
[87] G I Welsh and M A Saleem ldquoNephrinmdashsignature moleculeof the glomerular podocyterdquoThe Journal of Pathology vol 220no 3 pp 328ndash337 2010
[88] F N Ziyadeh and G Wolf ldquoPathogenesis of the podocytopathyand proteinuria in diabetic glomerulopathyrdquo Current DiabetesReviews vol 4 no 1 pp 39ndash45 2008
[89] A Patari C ForsblomMHavana H Taipale P-H Groop andH Holthofer ldquoNephrinuria in diabetic nephropathy of type 1diabetesrdquo Diabetes vol 52 no 12 pp 2969ndash2974 2003
[90] D P K Ng B-C Tai E Tan et al ldquoNephrinuria associateswithmultiple renal traits in type 2 diabetesrdquoNephrology DialysisTransplantation vol 26 no 8 pp 2508ndash2514 2011
[91] Y Kandasamy R Smith E R Lumbers and D Rudd ldquoNephrina biomarker of early glomerular injuryrdquo Biomarker Researchvol 2 no 1 p 21 2014
[92] B Jim M Ghanta A Qipo et al ldquoDysregulated nephrin indiabetic nephropathy of type 2 diabetes a cross sectional studyrdquoPLoS ONE vol 7 no 5 Article ID e36041 2012
[93] J F Navarro C Mora M Gomez M Muros C Lopez-Aguilar and J Garcıa ldquoInfluence of renal involvement onperipheral blood mononuclear cell expression behaviour oftumour necrosis factor-120572 and interleukin-6 in type 2 diabeticpatientsrdquoNephrology Dialysis Transplantation vol 23 no 3 pp919ndash926 2008
[94] D Z I Cherney J W Scholey D Daneman et al ldquoUrinarymarkers of renal inflammation in adolescents with type 1 dia-betes mellitus and normoalbuminuriardquo Diabetic Medicine vol29 no 10 pp 1297ndash1302 2012
[95] R Har J W Scholey D Daneman et al ldquoThe effect of renalhyperfiltration on urinary inflammatory cytokineschemokinesin patients with uncomplicated type 1 diabetes mellitusrdquo Dia-betologia vol 56 no 5 pp 1166ndash1173 2013
[96] K Tashiro I Koyanagi A Saitoh et al ldquoUrinary levels ofmono-cyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) and renal injuries in patients with type 2 diabetic nephropa-thyrdquo Journal of Clinical Laboratory Analysis vol 16 no 1pp 1ndash4 2002
12 Journal of Diabetes Research
[97] J Liu Z Zhao M D P Willcox B Xu and B Shi ldquoMultiplexbead analysis of urinary cytokines of type 2 diabetic patientswith normo- and microalbuminuriardquo Journal of Immunoassayand Immunochemistry vol 31 no 4 pp 279ndash289 2010
[98] S Ibrahim and L Rashed ldquoCorrelation of urinary monocytechemo-attractant protein-1 with other parameters of renalinjury in type-II diabetes mellitusrdquo Saudi Journal of Kidney Dis-eases and Transplantation vol 19 no 6 pp 911ndash917 2008
[99] H Jiang G Guan R Zhang et al ldquoIncreased urinary excretionof orosomucoid is a risk predictor of diabetic nephropathyrdquoNephrology vol 14 no 3 pp 332ndash337 2009
[100] N M El-Beblawy N G Andrawes E A Ismail B E EnanyH S Abou El-Seoud and M A Erfan ldquoSerum and Uri-nary orosomucoid in young patients with type 1 diabetes alink between inflammation microvascular complications andsubclinical atherosclerosisrdquo Clinical and Applied ThrombosisHemostasis 2016
[101] M S Christiansen E Hommel E Magid and B Feldt-Rasmussen ldquoOrosomucoid in urine predicts cardiovascular andover-all mortality in patients with type II diabetesrdquo Diabetolo-gia vol 45 no 1 pp 115ndash120 2002
[102] H Ha and H B Lee ldquoOxidative stress in diabetic nephropathybasic and clinical informationrdquo Current Diabetes Reports vol 1no 3 pp 282ndash287 2001
[103] L L Wu C C Chiou P Y Chang and J T Wu ldquoUrinary 8-OHdG a marker of oxidative stress to DNA and a risk factorfor cancer atherosclerosis and diabeticsrdquo Clinica Chemica Actavol 339 no 1-2 pp 1ndash9 2004
[104] Y Hinokio S Suzuki M Hirai C Suzuki M Suzukiand T Toyota ldquoUrinary excretion of 8-oxo-7 8-dihydro-21015840-deoxyguanosine as a predictor of the development of diabeticnephropathyrdquo Diabetologia vol 45 no 6 pp 877ndash882 2002
[105] J Leinonen T Lehtimaki S Toyokuni et al ldquoNew biomarkerevidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitusrdquo FEBS Letters vol 417 no1 pp 150ndash152 1997
[106] K Broedbaek A Weimann E S Stovgaard and H E PoulsenldquoUrinary 8-oxo-78-dihydro-21015840-deoxyguanosine as a biomarkerin type 2 diabetesrdquo Free Radical Biology and Medicine vol 51no 8 pp 1473ndash1479 2011
[107] F L NautaW E Boertien S J L Bakker et al ldquoGlomerular andtubular damage markers are elevated in patients with diabetesrdquoDiabetes Care vol 34 no 4 pp 975ndash981 2011
[108] L Petrica A Vlad G Gluhovschi et al ldquoGlycated peptides areassociated with proximal tubule dysfunction in type 2 diabetesmellitusrdquo International Journal of Clinical and ExperimentalMedicine vol 8 no 2 pp 2516ndash2525 2015
[109] N Turk A Mornar V Mrzljak and Z Turk ldquoUrinary excre-tion of advanced glycation endproducts in patients with type2 diabetes and various stages of proteinuriardquo Diabetes andMetabolism vol 30 no 2 pp 187ndash192 2004
[110] A A Ghanem A Elewa and L F Arafa ldquoPentosidine and N-carboxymethyl-lysine biomarkers for type 2 diabetic retinopa-thyrdquo European Journal of Ophthalmology vol 21 no 1 pp 48ndash54 2011
[111] F Piarulli G Sartore A Ceriello et al ldquoRelationship betweenglyco-oxidation antioxidant status and microalbuminuria intype 2 diabetic patientsrdquo Diabetologia vol 52 no 7 pp 1419ndash1425 2009
[112] M Shoji K Kobayashi M Takemoto Y Sato and K YokoteldquoUrinary podocalyxin levels were associated with urinary albu-min levels among patients with diabetesrdquo Biomarkers vol 21no 2 pp 164ndash167 2015
[113] M Hara K Yamagata Y Tomino et al ldquoUrinary podocalyxinis an early marker for podocyte injury in patients with diabetesestablishment of a highly sensitive ELISA to detect urinarypodocalyxinrdquo Diabetologia vol 55 no 11 pp 2913ndash2919 2012
[114] M Zheng L-L Lv J Ni et al ldquoUrinary podocyte-associatedmRNA profile in various stages of diabetic nephropathyrdquo PLoSONE vol 6 no 5 Article ID e20431 2011
[115] N H Kim K B Kim D L Kim et al ldquoPlasma and urinaryvascular endothelial growth factor and diabetic nephropathy intype 2 diabetes mellitusrdquo Diabetic Medicine vol 21 no 6 pp545ndash551 2004
[116] M Emoto K Mori E Lee et al ldquoFetuin-A and atheroscleroticcalcified plaque in patients with type 2 diabetes mellitusrdquoMetabolism Clinical and Experimental vol 59 no 6 pp 873ndash878 2010
[117] K Inoue J Wada J Eguchi et al ldquoUrinary fetuin-A is a novelmarker for diabetic nephropathy in type 2 diabetes identified bylectin microarrayrdquo PLoS ONE vol 8 no 10 Article ID e771182013
[118] M A K Salem S A El-Habashy O M Saeid M M KEl-Tawil and P H Tawfik ldquoUrinary excretion of N-acetyl-120573-d-glucosaminidase and retinol binding protein as alternativeindicators of nephropathy in patients with type 1 diabetesmellitusrdquo Pediatric Diabetes vol 3 no 1 pp 37ndash41 2002
[119] V Lambadiari N P E KadoglouV Stasinos et al ldquoSerum levelsof retinol-binding protein-4 are associated with the presenceand severity of coronary artery diseaserdquo Cardiovascular Dia-betology vol 13 no 1 article 121 2014
[120] A Shoukry S E-A Bdeer and R H El-Sokkary ldquoUrinarymonocyte chemoattractant protein-1 and vitamin D-bindingprotein as biomarkers for early detection of diabetic nephropa-thy in type 2 diabetesmellitusrdquoMolecular andCellular Biochem-istry vol 408 no 1 pp 25ndash35 2015
[121] Z Li Y Xu Y Nie and Z Zhao ldquoUrinary heme oxygenase-1 as apotential biomarker for early diabetic nephropathyrdquoNephrology(Carlton Vic) 2016
[122] B Satirapoj S Tassanasorn M Charoenpitakchai and OSupasyndh ldquoPeriostin as a tissue and urinary biomarker of renalinjury in type 2 diabetes mellitusrdquo PLoS ONE vol 10 no 4Article ID e0124055 2015
[123] E Y Lee S S Kim J-S Lee et al ldquoSoluble 120572-klotho as a novelbiomarker in the early stage of nephropathy in patients withtype 2 diabetesrdquo PLoS ONE vol 9 no 8 article e102984 2014
[124] A-L Sun J-TDengG-J Guan et al ldquoDipeptidyl peptidase-IVis a potential molecular biomarker in diabetic kidney diseaserdquoDiabetes and Vascular Disease Research vol 9 no 4 pp 301ndash308 2012
[125] Y Yang L Xiao J Li Y S Kanwar F Liu and L Sun ldquoUrinemiRNAs potential biomarkers for monitoring progression ofearly stages of diabetic nephropathyrdquo Medical Hypotheses vol81 no 2 pp 274ndash278 2013
[126] C Argyropoulos K Wang J Bernardo et al ldquoUrinaryMicroRNA profiling predicts the development of microalbu-minuria in patients with type 1 Diabetesrdquo Journal of ClinicalMedicine vol 4 no 7 pp 1495ndash1517 2015
Journal of Diabetes Research 13
[127] M W Kennedy A P Heikema A Cooper P J Bjorkmanand L M Sanchez ldquoHydrophobic ligand binding by Zn-1205722-glycoprotein a soluble fat-depleting factor related to major his-tocompatibility complex proteinsrdquo Journal of Biological Chem-istry vol 276 no 37 pp 35008ndash35013 2001
[128] YWang YM Li S Zhang J Y Zhao and C Y Liu ldquoAdipokinezinc-120572-2- glycoprotein as novel urinary biomarker presentsearly than microalbuminuria in diabetic nephropathyrdquo Journalof International Medical Research vol 44 no 2 pp 278ndash2862016
[129] S C Lim D Q Liying W C Toy et al ldquoAdipocytokine zinc 1205722glycoprotein (ZAG) as a novel urinary biomarker for normo-albuminuric diabetic nephropathyrdquo Diabetic Medicine vol 29no 7 pp 945ndash949 2012
[130] V Thongboonkerd ldquoStudy of diabetic nephropathy in theproteomic erardquo Diabetes and the Kidney vol 170 pp 172ndash1832011
[131] K N Lai and S C W Tang Eds Diabetes and the Kidney vol170 Contributions to Nephrology Karger Basel Switzerland2011
[132] P Zurbig G Jerums P Hovind et al ldquoUrinary proteomics forearly diagnosis in diabetic nephropathyrdquo Diabetes vol 61 no12 pp 3304ndash3313 2012
[133] F Raimondo S Corbetta L Morosi et al ldquoUrinary exosomesand diabetic nephropathy a proteomic approachrdquo MolecularBioSystems vol 9 no 6 pp 1139ndash1146 2013
[134] I Zubiri M Posada-Ayala A Sanz-Maroto et al ldquoDiabeticnephropathy induces changes in the proteome of human uri-nary exosomes as revealed by label-free comparative analysisrdquoJournal of Proteomics vol 96 pp 92ndash102 2014
[135] A Caseiro A Barros R Ferreira et al ldquoPursuing type 1diabetes mellitus and related complications through urinaryproteomicsrdquo Translational Research vol 163 no 3 pp 188ndash1992014
[136] B Jim J Santos F Spath and J C He ldquoBiomarkers of diabeticnephropathy the present and the futurerdquo Current DiabetesReviews vol 8 no 5 pp 317ndash328 2012
[97] J Liu Z Zhao M D P Willcox B Xu and B Shi ldquoMultiplexbead analysis of urinary cytokines of type 2 diabetic patientswith normo- and microalbuminuriardquo Journal of Immunoassayand Immunochemistry vol 31 no 4 pp 279ndash289 2010
[98] S Ibrahim and L Rashed ldquoCorrelation of urinary monocytechemo-attractant protein-1 with other parameters of renalinjury in type-II diabetes mellitusrdquo Saudi Journal of Kidney Dis-eases and Transplantation vol 19 no 6 pp 911ndash917 2008
[99] H Jiang G Guan R Zhang et al ldquoIncreased urinary excretionof orosomucoid is a risk predictor of diabetic nephropathyrdquoNephrology vol 14 no 3 pp 332ndash337 2009
[100] N M El-Beblawy N G Andrawes E A Ismail B E EnanyH S Abou El-Seoud and M A Erfan ldquoSerum and Uri-nary orosomucoid in young patients with type 1 diabetes alink between inflammation microvascular complications andsubclinical atherosclerosisrdquo Clinical and Applied ThrombosisHemostasis 2016
[101] M S Christiansen E Hommel E Magid and B Feldt-Rasmussen ldquoOrosomucoid in urine predicts cardiovascular andover-all mortality in patients with type II diabetesrdquo Diabetolo-gia vol 45 no 1 pp 115ndash120 2002
[102] H Ha and H B Lee ldquoOxidative stress in diabetic nephropathybasic and clinical informationrdquo Current Diabetes Reports vol 1no 3 pp 282ndash287 2001
[103] L L Wu C C Chiou P Y Chang and J T Wu ldquoUrinary 8-OHdG a marker of oxidative stress to DNA and a risk factorfor cancer atherosclerosis and diabeticsrdquo Clinica Chemica Actavol 339 no 1-2 pp 1ndash9 2004
[104] Y Hinokio S Suzuki M Hirai C Suzuki M Suzukiand T Toyota ldquoUrinary excretion of 8-oxo-7 8-dihydro-21015840-deoxyguanosine as a predictor of the development of diabeticnephropathyrdquo Diabetologia vol 45 no 6 pp 877ndash882 2002
[105] J Leinonen T Lehtimaki S Toyokuni et al ldquoNew biomarkerevidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitusrdquo FEBS Letters vol 417 no1 pp 150ndash152 1997
[106] K Broedbaek A Weimann E S Stovgaard and H E PoulsenldquoUrinary 8-oxo-78-dihydro-21015840-deoxyguanosine as a biomarkerin type 2 diabetesrdquo Free Radical Biology and Medicine vol 51no 8 pp 1473ndash1479 2011
[107] F L NautaW E Boertien S J L Bakker et al ldquoGlomerular andtubular damage markers are elevated in patients with diabetesrdquoDiabetes Care vol 34 no 4 pp 975ndash981 2011
[108] L Petrica A Vlad G Gluhovschi et al ldquoGlycated peptides areassociated with proximal tubule dysfunction in type 2 diabetesmellitusrdquo International Journal of Clinical and ExperimentalMedicine vol 8 no 2 pp 2516ndash2525 2015
[109] N Turk A Mornar V Mrzljak and Z Turk ldquoUrinary excre-tion of advanced glycation endproducts in patients with type2 diabetes and various stages of proteinuriardquo Diabetes andMetabolism vol 30 no 2 pp 187ndash192 2004
[110] A A Ghanem A Elewa and L F Arafa ldquoPentosidine and N-carboxymethyl-lysine biomarkers for type 2 diabetic retinopa-thyrdquo European Journal of Ophthalmology vol 21 no 1 pp 48ndash54 2011
[111] F Piarulli G Sartore A Ceriello et al ldquoRelationship betweenglyco-oxidation antioxidant status and microalbuminuria intype 2 diabetic patientsrdquo Diabetologia vol 52 no 7 pp 1419ndash1425 2009
[112] M Shoji K Kobayashi M Takemoto Y Sato and K YokoteldquoUrinary podocalyxin levels were associated with urinary albu-min levels among patients with diabetesrdquo Biomarkers vol 21no 2 pp 164ndash167 2015
[113] M Hara K Yamagata Y Tomino et al ldquoUrinary podocalyxinis an early marker for podocyte injury in patients with diabetesestablishment of a highly sensitive ELISA to detect urinarypodocalyxinrdquo Diabetologia vol 55 no 11 pp 2913ndash2919 2012
[114] M Zheng L-L Lv J Ni et al ldquoUrinary podocyte-associatedmRNA profile in various stages of diabetic nephropathyrdquo PLoSONE vol 6 no 5 Article ID e20431 2011
[115] N H Kim K B Kim D L Kim et al ldquoPlasma and urinaryvascular endothelial growth factor and diabetic nephropathy intype 2 diabetes mellitusrdquo Diabetic Medicine vol 21 no 6 pp545ndash551 2004
[116] M Emoto K Mori E Lee et al ldquoFetuin-A and atheroscleroticcalcified plaque in patients with type 2 diabetes mellitusrdquoMetabolism Clinical and Experimental vol 59 no 6 pp 873ndash878 2010
[117] K Inoue J Wada J Eguchi et al ldquoUrinary fetuin-A is a novelmarker for diabetic nephropathy in type 2 diabetes identified bylectin microarrayrdquo PLoS ONE vol 8 no 10 Article ID e771182013
[118] M A K Salem S A El-Habashy O M Saeid M M KEl-Tawil and P H Tawfik ldquoUrinary excretion of N-acetyl-120573-d-glucosaminidase and retinol binding protein as alternativeindicators of nephropathy in patients with type 1 diabetesmellitusrdquo Pediatric Diabetes vol 3 no 1 pp 37ndash41 2002
[119] V Lambadiari N P E KadoglouV Stasinos et al ldquoSerum levelsof retinol-binding protein-4 are associated with the presenceand severity of coronary artery diseaserdquo Cardiovascular Dia-betology vol 13 no 1 article 121 2014
[120] A Shoukry S E-A Bdeer and R H El-Sokkary ldquoUrinarymonocyte chemoattractant protein-1 and vitamin D-bindingprotein as biomarkers for early detection of diabetic nephropa-thy in type 2 diabetesmellitusrdquoMolecular andCellular Biochem-istry vol 408 no 1 pp 25ndash35 2015
[121] Z Li Y Xu Y Nie and Z Zhao ldquoUrinary heme oxygenase-1 as apotential biomarker for early diabetic nephropathyrdquoNephrology(Carlton Vic) 2016
[122] B Satirapoj S Tassanasorn M Charoenpitakchai and OSupasyndh ldquoPeriostin as a tissue and urinary biomarker of renalinjury in type 2 diabetes mellitusrdquo PLoS ONE vol 10 no 4Article ID e0124055 2015
[123] E Y Lee S S Kim J-S Lee et al ldquoSoluble 120572-klotho as a novelbiomarker in the early stage of nephropathy in patients withtype 2 diabetesrdquo PLoS ONE vol 9 no 8 article e102984 2014
[124] A-L Sun J-TDengG-J Guan et al ldquoDipeptidyl peptidase-IVis a potential molecular biomarker in diabetic kidney diseaserdquoDiabetes and Vascular Disease Research vol 9 no 4 pp 301ndash308 2012
[125] Y Yang L Xiao J Li Y S Kanwar F Liu and L Sun ldquoUrinemiRNAs potential biomarkers for monitoring progression ofearly stages of diabetic nephropathyrdquo Medical Hypotheses vol81 no 2 pp 274ndash278 2013
[126] C Argyropoulos K Wang J Bernardo et al ldquoUrinaryMicroRNA profiling predicts the development of microalbu-minuria in patients with type 1 Diabetesrdquo Journal of ClinicalMedicine vol 4 no 7 pp 1495ndash1517 2015
Journal of Diabetes Research 13
[127] M W Kennedy A P Heikema A Cooper P J Bjorkmanand L M Sanchez ldquoHydrophobic ligand binding by Zn-1205722-glycoprotein a soluble fat-depleting factor related to major his-tocompatibility complex proteinsrdquo Journal of Biological Chem-istry vol 276 no 37 pp 35008ndash35013 2001
[128] YWang YM Li S Zhang J Y Zhao and C Y Liu ldquoAdipokinezinc-120572-2- glycoprotein as novel urinary biomarker presentsearly than microalbuminuria in diabetic nephropathyrdquo Journalof International Medical Research vol 44 no 2 pp 278ndash2862016
[129] S C Lim D Q Liying W C Toy et al ldquoAdipocytokine zinc 1205722glycoprotein (ZAG) as a novel urinary biomarker for normo-albuminuric diabetic nephropathyrdquo Diabetic Medicine vol 29no 7 pp 945ndash949 2012
[130] V Thongboonkerd ldquoStudy of diabetic nephropathy in theproteomic erardquo Diabetes and the Kidney vol 170 pp 172ndash1832011
[131] K N Lai and S C W Tang Eds Diabetes and the Kidney vol170 Contributions to Nephrology Karger Basel Switzerland2011
[132] P Zurbig G Jerums P Hovind et al ldquoUrinary proteomics forearly diagnosis in diabetic nephropathyrdquo Diabetes vol 61 no12 pp 3304ndash3313 2012
[133] F Raimondo S Corbetta L Morosi et al ldquoUrinary exosomesand diabetic nephropathy a proteomic approachrdquo MolecularBioSystems vol 9 no 6 pp 1139ndash1146 2013
[134] I Zubiri M Posada-Ayala A Sanz-Maroto et al ldquoDiabeticnephropathy induces changes in the proteome of human uri-nary exosomes as revealed by label-free comparative analysisrdquoJournal of Proteomics vol 96 pp 92ndash102 2014
[135] A Caseiro A Barros R Ferreira et al ldquoPursuing type 1diabetes mellitus and related complications through urinaryproteomicsrdquo Translational Research vol 163 no 3 pp 188ndash1992014
[136] B Jim J Santos F Spath and J C He ldquoBiomarkers of diabeticnephropathy the present and the futurerdquo Current DiabetesReviews vol 8 no 5 pp 317ndash328 2012
[127] M W Kennedy A P Heikema A Cooper P J Bjorkmanand L M Sanchez ldquoHydrophobic ligand binding by Zn-1205722-glycoprotein a soluble fat-depleting factor related to major his-tocompatibility complex proteinsrdquo Journal of Biological Chem-istry vol 276 no 37 pp 35008ndash35013 2001
[128] YWang YM Li S Zhang J Y Zhao and C Y Liu ldquoAdipokinezinc-120572-2- glycoprotein as novel urinary biomarker presentsearly than microalbuminuria in diabetic nephropathyrdquo Journalof International Medical Research vol 44 no 2 pp 278ndash2862016
[129] S C Lim D Q Liying W C Toy et al ldquoAdipocytokine zinc 1205722glycoprotein (ZAG) as a novel urinary biomarker for normo-albuminuric diabetic nephropathyrdquo Diabetic Medicine vol 29no 7 pp 945ndash949 2012
[130] V Thongboonkerd ldquoStudy of diabetic nephropathy in theproteomic erardquo Diabetes and the Kidney vol 170 pp 172ndash1832011
[131] K N Lai and S C W Tang Eds Diabetes and the Kidney vol170 Contributions to Nephrology Karger Basel Switzerland2011
[132] P Zurbig G Jerums P Hovind et al ldquoUrinary proteomics forearly diagnosis in diabetic nephropathyrdquo Diabetes vol 61 no12 pp 3304ndash3313 2012
[133] F Raimondo S Corbetta L Morosi et al ldquoUrinary exosomesand diabetic nephropathy a proteomic approachrdquo MolecularBioSystems vol 9 no 6 pp 1139ndash1146 2013
[134] I Zubiri M Posada-Ayala A Sanz-Maroto et al ldquoDiabeticnephropathy induces changes in the proteome of human uri-nary exosomes as revealed by label-free comparative analysisrdquoJournal of Proteomics vol 96 pp 92ndash102 2014
[135] A Caseiro A Barros R Ferreira et al ldquoPursuing type 1diabetes mellitus and related complications through urinaryproteomicsrdquo Translational Research vol 163 no 3 pp 188ndash1992014
[136] B Jim J Santos F Spath and J C He ldquoBiomarkers of diabeticnephropathy the present and the futurerdquo Current DiabetesReviews vol 8 no 5 pp 317ndash328 2012
