Effect of pioglitazone on decreasing of proteinuria in type 2 diabetic patients with nephropathy

Original

Article

Effect

of

pioglitazone

on

decreasing

of

proteinuria

in

type

2

diabetic

patients

with

nephropathy

$

Pejman

pourshabanan,

Ali

Momeni

*

,

Leila

Mahmoudnia,

Soleiman

Kheiri

ShahrekordUniversityofMedicalSciences,Shahrekord,Iran

ARTICLE INFO

Keywords:

Type2diabetesmellitus Nephropathy

Pioglitazone Proteinuria

ABSTRACT

Introduction:Diabeticnephropathythatmeansalbuminuriagreaterthan30mg/day,affectsaboutone thirdofdiabeticpatients.Therearemanystudiesabouttheeffectofdifferentmedicationsfordiabetic nephropathywithcontroversyintheirresults.So,theaimofthestudywastoinvestigatetheeffectof pioglitazoneondecreasingofproteinuriaintypeIIdiabeticpatientsandnephropathy.

Methodsandmaterials:Itisadoubleblindclinicaltrial.Atfirst,2356medicalcartsofthepatientswere evaluatedand76patientswithtype2diabetesmellituswithproteinuriagreaterthan250mg/daywere enrolledin2equalgroups.Inthecasegroup,pioglitazone15mg/daywasprescribedandpatientsinthe controlgroupreceivedplacebofortwomonths.Atthebeginningofthestudyandafter2months,urinary proteinduring24hwasmeasuredinallofthepatientsanddatawereenteredtoSPSS(version23)and evaluatedbyusingChi-square,McNemar,pairedt-testandlogisticregressionmodel.

Results:Atthebeginningofthestudy,urineproteinduring24hinthecaseandcontrolgroupswere 957.7385.1and972.1378.6respectively(P=.872).So,after2monthsthemeanproteinuriainthe caseandcontrolgroupswere647.3367.2and896372.4respectivelythatisvaluable(P=0.005). PioglitazonehadtheconsiderableeffectonFBS,HbA1candbloodtriglyceridetoo.

Conclusion:Thestudyshowedthatlowdoseofpioglitazoneisaneffective,safeandinexpensivemethod inreducingofproteinuriaintype2diabeticpatientswithnephropathy.

©2018PublishedbyElsevierLtdonbehalfofDiabetesIndia.

1.Introduction

Type 2 diabetes is a type of the metabolic disorderthat is recognizedwithhighlevelsofglucoseinthebloodwhichisdueto aresistancestatusagainstinsulinandrelativeinsulindeficiency. Type 2 diabetes is recognized by three pathophysiologic abnormalities:insulinsecretion,insulinresistance,andexcessive glucose production by the liver. Diabetes is common in both developedanddevelopingcountries.Obesityiscommonintype2 diabetesmellitus.Therateofdiabeteshasrisendramaticallyover the50yearsagoasobesityhasincreased.Overthetwodecades ago, the global prevalence of diabetes has increased from an estimated 30 million in 1985 to 382 million in 2013. 90% of individualswithdiabetessufferfromtype2diabetes,and10%have type1diabetesmellitusandgestationaldiabetes,respectively.The causeofresultingtype2diabetesisrelatedtolifestylesandgenetic factors.Somefactorsrelatedtolifestylesuchaslackofphysical

activity,unsuitablediet,stress,obesity,and urbanization. More-over, nutritionalfactors increase the risk of developing type 2 diabetes. Most peoplewith type 2 diabeteshave had a strong geneticbasis,andItsincidenceisamongidenticaltwinsbetween 70%and90%.Recentstudieshaverevealedtheroleofmorethan 70genesfortheappearanceofthisdisease.Diabetesisoneofthe main causes of mortality. In the United States, diabetes was reportedastheseventhmajorcauseofdeathin2010.Ithasbeen showninoneofrecentestimatesthat8%ofmortalitycausedby diabetesdiseasein2013inallovertheworld.

lifeexpectancyhasdecreased intype 2diabetes,becauseof cardiovascularandrenaldiseases.Indevelopedcountries,type2 diabetes is the major cause of blindness and renal failure. In addition,theriskofmentalimpairmentanddementiaisincreased by involving cerebrovascular accidents. Diabetic nephropathy illustrates with a progressive increase in protein excretion (proteinuria),whichisobservedinprolongeddiabetes,decrease renalfunctionandultimatelyledtorenalfailure.TypeIIdiabetes mellitus is the most important factor of chronic renal failure, followedbyfinalstageofrenalfailurethatcausesdeathindiabetic patients.About40%ofEndStageRenalDisease(ESRD)wasdueto diabetesleaded tospend morethan $4 billionperyearin the $_{Authorsdeclarethispaperhasnotsubmittedanywhereforpublish.}

*Correspondingauthor.

E-mailaddress:alimomeni@yahoo.com(A.Momeni).

https://doi.org/10.1016/j.dsx.2018.04.013

1871-4021/©2018PublishedbyElsevierLtdonbehalfofDiabetesIndia.

ContentslistsavailableatScienceDirect

Diabetes

&

Metabolic

Syndrome:

Clinical

Research

&

Reviews

UnitedStates.Also,about30%ofpatientswithtype1diabetesand lesspercentageofpatientswithtype2diabeteseventuallydevelop ESRD. Of course, because of the higher prevalence of type 2 diabetes,thenumberofcasesoftypeIIdiabetesishigher.Although infectionsandinflammatorydiseasessuchastypesof glomerulo-nephritis in the past were the most common causes of ESRD, diabetes and high blood pressure are now the most common causesofthisdisease[1].

Theprimaryevidenceofnephropathyshowstheexistenceof very low levels of albumin in the urine (30mg/day), called microalbuminuriaandthemicroalbuminuriapatientisconsidered asprimarynephropathy.Thenmicroalbuminuriamayprogressto macroalbuminuria(higherthan300mg/day)orsevere nephropa-thy.Whensevereproteinuriaisobserved,acontinuousdecreasein glomerularfiltrationrate willoccur.Hypertensioniscommonly associatedwithalbuminuriaandnephropathy[2].

Themainmechanismfordiabeticnephropathyisnotclear,but several risk factors involve. One of the serious risk factors for nephropathyindiabeticpatientsishypertension.Theotherfactor ishighhemoglobinglycosylated(higherthan9%)mentionedas increasing risk factor of nephropathy. Diabetic patients with obesityandoverweightarealsoatriskfornephropathybasedon BodyMassIndex(BMI).Also,thedurationofdiabetesandtheage of thepatient predictthe progression ofnephropathy [1]. In a study,glycosylatedhemoglobin,smoking,thedurationofdiabetes, systolic blood pressure and diastolic blood pressure showed a significantrelationshipfornephropathy[2].

Hyperglycemia makes injury toarteries by several complex mechanisms.Inflammatorycytokinesproducedbyinflammatory cells cause damage tothe renal cells and accelerate changing epithelial cells tomesenchymal cells and increase extracellular matrix. Immunological and inflammatory mechanisms play an important role in the progression of diabetic nephropathy by activating immune cells and increasing the production of inflammatorymolecules.Theexactcontrolofbloodglucoseand bloodpressurecandecreasetheprogressionofthediseaseinthe initialstagesofkidneyinvolvementinpatientswithdiabetesand especiallywhenproteinexcretionisstillinlowlevel,andevenitis possible to improve this condition. In more advanced stages, protein excretion is more. However, blood glucose control, consumptionrestriction,andbloodpressurecontrolareeffective indecreasingtheprocessofthedisease,butitdoesnotstopthe trendof the disease.Currently,diabeticnephropathyis treated with ACE inhibitors or angiotensin receptor blockers(ARBs) in additiontoblood glucosereducing drugs. Also,limited dietsof protein and sodium are used, nevertheless, the prevalence of diabeticnephropathyanddiabetes-inducedrenalfailureisstillat thehighlevel.

Byreducingproteinuria,progressionofrenaldamagetoESRD will be slowed. So, it will improve patients' life and decrease morbidityandcostsofend-stagerenaldisease.Suchstudiesare necessaryforachievingthesepurposes.

2.Materialsandmethods

Thepresentstudywasdoneintheyear2017withclinicaltrial codeIRCT2017080210222N10.Thisisadouble-blind,randomized clinicaltrial(prescribingpersonandalsopatientswhoreceivedthe drugs (placebo or pioglitazone) were not aware of these two consumeddrugtypes.Thevariableofresearchwasurineprotein excretion rate in 24h. At first, written informed consent was obtained from the patients and the research objectives were explainedtothem.Patientswereassuredthat theirinformation would remain as a secret and they are not shared with any individualorgroup.Patientswereexaminedbyanephrologist.The populationunderstudywas2356casesofpatients,documentsin

the Nephrologyward of Imam AliClinic, Shahrekord.Inclusion criteriawere:type 2diabeticpatients,24-h urineproteinmore than 250mg/day, without hypothyroidism and heart failure, HbA1C lessthan8,bloodpressurelessthan160/100,creatinine lowerthan2orGFRgreaterthan50,andexclusioncriteriawas undesirablecooperationduringthestudy,andconsiderabledrug sideeffects.SamplesizeandsamplingofpatientsreferredtoImam AliHospitalwithtype2diabetes,whohadinclusioncriteriawas76 patientsinthestudy,38patientsineachgroup.

76patientswithtype2diabetesmellituswith24-hoururine protein>250mg/day wereselectedandthentheyweredivided intotwogroups,includingthegroupreceivingpioglitazone15mg daily and the placebo group for two months with stratified randomizationthatistheywereidenticalintermsofproteinuria rates(threegroupsofproteinuria(lessthan600mg,600–1200mg and 1201mg and above), During the study, one patient in the pioglitazonegroupand twointheplacebogroupduetolackof proper cooperation were excluded. 24-h urine protein was determinedbefore interventionand 2monthslater.Theresults wererecordedinthechecklistandanalyzedbystatisticaltests. DataenteredintheSPSSsoftware(version23)andanalyzedusing descriptive statistics, Chi-square, Mc Nemar, paired t-test and logisticregressionmodel.

3.Results

Inthisstudy,thefollowingresultswereobtainedbycomparing theeffectof pioglitazoneonproteinuria inpatientswithtype 2 diabeteswithnephropathyinImamAliClinic,Shahrekord.Atotal of73diabeticpatientswithtypeIIdiabeticnephropathy(37cases and36controls)participatedinthecurrentstudy.Theagerangeof thepatientswasbetween54–71yearswithameanof62.83.8. 35 patients (47.9%) were female and the rest were male. No differencewasobservedbasedonsexinthetwogroups(P=0.73). Durationofdiabetesmellitus,glomerularfiltrationrate(GFR), systolicanddiastolicbloodpressurehadnovaluabledifferencein the case and control groups The quantitative characteristics of patientsintwogroupsweresummarizedinTable1.Itshowedthat thetwogroupswereidenticalexceptforage.

Themeanofglomerularfiltrationratewas66.98.5inthecase groupand68.38.6inthecontrolgroup.

Systolicbloodpressureinthecasegroupwas134.98.7andin thecontrolgroupwas131.78.4.Diastolicbloodpressureinthe interventiongroupwas80.98.9andintheplacebogroupwas 826.3.

Patients’ consumed drugs in two groups during the study displayedinTable2.

Consumption of ACE/ARB, statins, oral hypoglycemic drugs, diltiazemandinsulinwascomparedinthecaseandcontrolgroups. IntermsofACE/ARBconsumption,inthefirstgroup(intervention group),94.6%(35patients)useddrug,and5.4%(2patients)didnot usethedrug,andinthesecondgroup(placebo),97.2%(35patients) haddruguse,And2.8%(1people)didn'tusedrug.

Regardingtheuseofstatinintheinterventiongroup,91.9%(34 patients)usedrugsand8.1%(3non-drugusers)andintheplacebo Table1

Meanofpretestvariablesintheinterventionandcontrolgroups.

Group Case Control P-value

Variables MeanSD MeanSD

Age(year) 63.83.9 61.73.3 0.012

Durationofdiabetesmellitus(year) 11.81.8 11.52.7 0.526 Glomerularfiltrationrate 66.98.5 68.38.6 0.490 BloodpressureSystolic(mmHg) 134.98.7 131.78.4 0.114 BloodpressureDiastolic(mmHg) 80.98.9 826.3 0.530

group8.3%(3people)didnotuseand91.7%(33people)haddrug use.

Intermsoforalhypoglycemicagents,inthecasegroup2.7%(1 patients)didnotusedrugs,97.3%(36people)usedthedrug,andin the control group, 5.6% (2 patients) didn't use, and 94.4% (34 patients)haddrugusage.

Regarding the use of diltiazem in the case group, 73% (27 patients)didnotusethedrugand27%(10patients)usedthedrug, andinthecontrolgroup,66.7%(24patients)didnottakedrugsand 33.3Percentage(12people)tookmedication.

Inthecasegroup,8.1%(3patients)usedinsulinand91.9%(34 patients) didn't use insulin, and in the control group 8.3% (3 patients)usedinsulinand91.7%(33patients)didnotusethedrug. Withregardtothemeaningfulview,thereisnodifferencein patients’consumeddrugsinthesetwogroups.

The amount of measured parameters before and after interventionintwogroupsincludedinTable3.Bodymassindex (BMI)was28.032.08inthefirstgroup(receivingpioglitazone) and27.672.06inthecontrolgroup(placebo)rangedfrom24to 33.Regardingthebiochemicalparameters,therewasasignificant decreasein24hrurineproteininthecasegroupcomparedtothe controlgroup.Thismeansthattherewasnosignificantdifference betweenthe two groups beforethe intervention, but afterthe intervention,thisdifferencewassignificant(p=0.005).Theresults

indicated that the average 24-hour urine protein level at the beginningofthestudyand beforetheonsetoftheintervention (receiving the drug) was 957.7385.1mg/d, which after the interventionandconsumingpioglitazonewithintwomonthsthe 24hrurine protein reachedto647.3367.2mg/d. MeanHbA1C had a significant difference before and after the intervention (p<0.001).Themeanbeforethestudywas7.380.32andafter the intervention was 7.010.22, which was higher than the controlgroupbut therewas nosignificantdifferenceinHbA1C before and after intervention in the control group. FBS had a significantdifferencebeforeandaftertheintervention(p<0.001) inthecasegroup.Themeanbeforethestudywas125.4116.52 and afterthe interventionwas 110.6214.5, which washigher thanthecontrolgroupbuttherewasnosignificantdifferencein FBSbeforeandafterinterventioninthecontrolgroup.

Two-hourpostprandialbloodsugar(2hrppBS)andLDLhadno valuabledifferenceinthecaseandcontrolgroupsafter interven-tion(p=0.149andp=0.228respectively).

Triglyceridelevel reached from164.348.2to138.414.07 afterinterventioninthecasegroup(p<0.001),butinthecontrol groupitdecreasedfrom156.142.4to154.940.08(p=0.515) and significant difference is between these two groups after intervention(P<0.001).

The abundance of proteinuria level based on the level of proteinuriareportedbeforeandafterthestudyintwogroupsin Table4.

We observed after the intervention, the reduction level of proteinuriawasmoreintheinterventiongroup.TheMcNemartest showedthesechangesthattherewasadecreaseintheproteinuria levelinbothgroups(P<0.01)

4.Discussion

Diabeticnephropathyisamajormicrovascularcomplicationin long-standing diabetic patients who eventually undergo renal Table2

Patients’consumeddrugsintwogroupsduringthestudy.

Group Case Control P-value

Consumeddrugs Frequency Percent Frequency Percent

ACE/ARB 35 94.6 35 97.2 1

Statin 34 91.9 33 91.7 1

Oralhypoglycemicdrugs 36 97.3 34 94.4 0.615

Diltiazem 10 27 12 33.3 0.557

Insulin 3 8.1 3 8.3 1

Table3

Theaverageamountofstudiedparametersbeforeandaftertheinterventionanditschangesintwogroups.

parameter Group Case Control P-value

MeanSD MeanSD

Proteinuria(mg/d) Pretest 957.7385.1 972.1378.6 0.872

Posttest 647.3367.2 896372.4 0.005

Significantrateofpretestandposttest <0.001 0.011 – Differenceofpretestandposttest 310.5112 76.2170.9 <0.001a

FBS(mg/dl) Pretest 125.4116.52 122.9212.85 0.476

Posttest 110.6214.5 12210.24 <0.001

Significantrateofpretestandposttest <0.001 0.542 – Differenceofpretestandposttest 14.87.9 0.928.9 <0.001a

BS-2hrPP(mg/dl) Pretest 145.114.3 142.48.8 0.33

Posttest 142.313.03 142.38.82 0.994

Significantrateofpretestandposttest <0.001 0.898 – Differenceofpretestandposttest 2.84.4 0.167.74 0.149a

HbA1c(%) Pretest 7.380.32 7.360.28 0.694

Posttest 7.010.22 7.360.27 <0.001

Significantrateofpretestandposttest <0.001 0.856 – Differenceofpretestandposttest 0.370.14 0.0020.09 <0.001

Triglyceride(mg/dl) Pretest 164.348.2 156.142.4 0.445

Posttest 138.414.07 154.940.08 0.089

Significantrateofpretestandposttest <0.001 0.515 – Differenceofpretestandposttest 25.911.2 1.211.1 <0.001a

LDL(mg/dl) Pretest 98.0315.6 98.916.3 0.818

Posttest 9712.32 100.6616.77 0.289

Significantrateofpretestandposttest 0.531 0.352 –

Differenceofpretestandposttest 1.0510.15 1.7811.3 0.228a

BMI(kg/m2) Pretest 28.032.08 27.522 0.301

Posttest 28.032.08 27.672.06 0.454

Significantrateofpretestandposttest 0.324 <0.001 – Differenceofpretestandposttest 0.0050.032 0.140.099 <0.001a a

dialysisortransplantation.Achievingthebestmetaboliccontrol (A1c<7%), treating hypertension (<130/80mmHg or <125/ 75mmHgifproteinuria>1.0g/24hand increasedserum creati-nine),usingdrugswithblockadeeffectonthe renin-angiotensin-aldosterone system, and treating dyslipidemia (LDL cholesterol

<100mg/dl)are effectivestrategiesfor preventingthe develop-mentofmicroalbuminuria, indelayingtheprogression tomore advancedstages ofnephropathyand inreducing cardiovascular mortality in patients with type 1 and type 2 diabetes [1]. To prevent developmentof this disease and to improveadvanced kidney injury, effective therapies directed toward the key molecular target are required. Metabolic and hemodynamic alterationshavebeenconsideredastheclassicalfactorsinvolved in the development of renal injury in patients with diabetes mellitus. However, the exact pathogenic mechanisms and the molecularevents of diabeticnephropathy remainincompletely understood.Nowadays,thereareconvincingdatathatrelatethe diabetesinflammatorycomponentwiththedevelopmentofrenal disease[7].

ThreesubtypesofthePPARnuclearfattyacidreceptorshave been identified: alpha, beta/delta and gamma. PPAR alpha is believed to participate in fatty aciduptake (beta-and omega-oxidation)mainlyintheliverandheart.PPARbeta/deltaisinvolved infattyacidoxidationinmuscle.PPARgammaishighlyexpressed in fat to facilitate glucose and lipid uptake, stimulate glucose oxidation, decrease free fatty acidlevel and ameliorate insulin resistance.SyntheticligandsforPPARalphaandgammasuchas fibricacid,andthiazolidinedioneshavebeenusedinpatientswith type2 diabetesandpre-diabeticinsulin resistancewithsignifi -cantly improved HbA1c and glucose levels. In addition, non-hypoglycemic effects maybe elicited by PPAR agonistsor dual agonists including improved lipid metabolism, blood pressure controland endothelialfunction,as well assuppressed athero-sclerotic plaque formation and coagulation. However, issues of safetyandclinicalindicationremainundeterminedforuseofPPAR agonistsfortheincidenceofheartdiseaseinmetabolicsyndrome andtype2diabetes[10].InBrunRPandetal.study,datastrongly suggestthatPPARgammaisthepredominantreceptorregulating adipogenesis;however,theyalsosuggestthatPPARalphamayplay aroleindifferentiationofcertainadiposedepotsinresponsetoa differentsetofphysiologicactivatorsorincertaindiseasestates [8].InKoGJetalstudy,theyinvestigatedtheeffectandmolecular mechanism of the PPAR gamma agonist, pioglitazone, on the progression of diabetic nephropathyin type 2 diabetic rats. It reaveledthatpioglitazonenot onlyimprovesinsulin resistance, glycemiccontrolandlipidprofile,butalsoamelioratesrenalinjury throughananti-inflammatorymechanismintype2diabeticrats [16].Therearesomeevidencethatthiazolidinedioneshadadirect effecton thekidneys through the activation of PPAR receptors identi_fiedinthekidneys.TheanimalstudiesconductedbyMaetal. [20]andHaraguchietal.[19],Jinetal[15]havealsomentionedthe effects.Katavetinetal.[12]reportedasignificantdecreaseinthe meanoftheurinaryproteinexcretionfrom1.64to0.98g/day,that issimilartothisstudyandnosignificantdifferenceintheblood

glucosecontrolandbloodpressureinbothtreatmentandcontrol groups.InanotherstudybyAgarwaletal.,itwasfoundthatthere was a significant decrease in the proteinuria level in the pioglitazonegroup[13].

The accumulation of advanced glycosylated end-products (AGEs), the activation of isoform(s) of protein kinase C (PKC) andtheaccelerationofthealdosereductasepathwaymayexplain howhyperglycemiadamagestissue.PKCisoneofthekeysignaling moleculesintheinductionofthevascularpathologyofdiabetes.A numberofgenelocihavebeeninvestigatedtotrytoexplainthe genetic susceptibility to diabetic nephropathy [4]. Advanced glycation end products (AGEs) have been implicated in the pathogenesisof diabetickidneydisease[8].In MyintKMstudy, they examinedwhetherinhibition ofthereceptorfor advanced glycation end products (RAGE) could attenuatechanges in the diabetickidney.InactivationoftheRAGEgeneinamousemodelof diabeticnephropathyresultsinsignificantsuppressionofkidney changes,includingkidneyenlargement,increasedglomerularcell number, mesangial expansion, advanced glomerulosclerosis, increasedalbuminuria,andincreasedserumcreatininecompared withwild-typediabeticmice[5].

Theefficacyofrenin-angiotensinsystem(RAS)blockersontype 2diabetesstudiedbyFukudaM.Thisstudywasundertakentotest the hypothesis that candesartan may enhance the protective effects of pioglitazone against type 2 diabetes. Their work demonstrated that candesartan significantly potentiated the protectiveeffectsofpioglitazoneagainstcardiorenalandvascular injury, and diabetes in obese type 2 diabetic mice. Thus, the combination of pioglitazone with candesartan is potentially a promisingtherapeuticstrategyfortype2diabetes[14]. Angioten-sin-converting enzyme (ACE) is a key regulator of the renin-angiotensin system (RAS). ACE2 is a newly described enzyme identified in rodents and humans with a more restricted distributionthanACE,and isfoundmainlyinheartand kidney. ACE2mightactinacounter-regulatorymannertoACE,modulating thebalancebetweenvasoconstrictorsandvasodilatorswithinthe heart and kidney, and playing a signi_ficant role in regulating cardiovascular and renal function [5]. It was revealed that pioglitazonereducespro-inflammatorymarkersinpatientswith overtdiabeticnephropathy,whichindicatespotentiallybeneficial effects on overall cardiovascular risk. This surrogate endpoint needs to be confirmed in trials designed to demonstrate cardiovascular protection [14]. Tanimoto M, showed that the effectofpioglitazoneonmicroalbuminuriamightnotbedueto changing systemic blood pressure and blood glucose levels. It appearsthatthedecreaseofurinaryalbuminexcretionmightbe related to improvement of glomerular enlargement, including hyperfiltration,sincethelevelsof endothelialconstitutivenitric oxidesynthase(ecNOS)proteinwerereducedbypioglitazonein theglomerularvessels[17].InastudybyAbeetalin2007about theefficacyofpioglitazoneinthecontrollingbloodglucosein20 dialysispatients,patientsweretreatedwith15mgpioglitazonein thefirst 4weeks withameal inthemorning. Iftheunwanted effectsofthedrugdonotappear,thedosageofthedrugcanbe Table4

Abundanceofproteinurialevelduringthestudyintwogroupsbasedonlevelofproteinuria.

Group Case Control P-value

Stage Frequency Percent Frequency Percent

Pretest Lessorequalof600 10 27 9 25 0.981

Between601-1200 17 46 17 47.2

Equalandhigherthan1201 10 27 10 27.8

Posttest Lessorequalof600 22 59.5 8 22.2 0.005

Between601-1200 10 27 20 55.6

increaseduptotwiceasmuch. Intheresults, pioglitazonewas significantlyeffectiveinreducingHbA1c,triglycerideandsystolic anddiastolicbloodpressure[9].

A reduction of proteinuria inpatientswiththenon-diabetic renaldiseasewas observedduringthe4-monthtreatment with pioglitazonewhichcontinuedfor2monthsafterthecessationof thetreatmentwasshown in ShahidiSet al.study. However,4 monthsafterthecessationofthetreatment,alittleincreasewas detectedinthelevelofproteinuria[18].Inthisstudy,thegroup consumed pioglitazone, their urine protein levels decreased significantlycomparedtothebeginningofthetrial.

In the currentstudy regarding p-valueof less than 0.001,it indicatedapositiveeffectofthedrugonthereductionofurine protein.Theresultsoft-testshowedthattherewasasignificant decreaseinHbA1c,FBS andtriglyceridein thecasegroupafter interventionbutwithnoconsiderableeffectonLDL,2hrppBSand BMI. Therefore, the initiation of drug use at lower proteinuria levelswillbeassociatedwithanincreasedchanceoftreatment. Due to the young nature of these studies on the effect of tiazolidinedionedrugsfamilyonreducingproteinuriaofpatients with type 2 diabetes and nephropathy, consideration of the problemsandlimitationsofthesestudiesmayplayanimportant roleinthecontinuationofthepathwayofresearchers.Although thereisnospecificcomplicationinthisstudy,sincethepossibility of heart or liver complications with this drug alone and in combination with other common drugs has not yet been addressed, studies are needed to evaluate the tolerable side effectsinthesepatients.

5.Conclusion

Basedontheresultsofthisstudy,theuseofpioglitazonewas effectiveindecreasingthelevelofurineproteininpatientswith type 2 diabetes and nephropathy for two months and no side effectswereobservedusingthisdrug.Itissuggestedtoevaluate thebenefits and side effects of taking pioglitazone in Diabetic Nephropathy,a similarstudyshouldbeconductedoveralonger periodoftime.

Limitationsofresearch

Failure to follow up and not referring again patients were problemsandlimitationsofthestudy.Ifsamplesweredropped, newsampleswereselectedaccordingtothecriteriaforentering andleavingthestudyandwereincludedinthestudy.

Conflictofinterest

Thereisnoconflictofinterestinthisproject. Acknowledgment

ThisprojectapprovedbytheEthicalCommitteeinShahrekord University of Medical Sciences by number of R.SKUMS.REC.

1395039.Wealsoappreciatethehonorablestaffandstaffofthe ImamAliClinic(Shahrekord)tocooperateinthisresearch. References

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[18]ShahidiS,PakzadB,MortazaviM,AkbariM,SeirafianS,AtapourA,etal. Reductionofproteinuriabypioglitazoneinpatientswithnon-diabeticrenal disease.JResMedSci2011;16(11):1459.

[19]HaraguchiK.Suppressionofexperimentalcrescenticglomerulonephriticsby peroxisomeproliferator-activatedreceptor(PPAR)gammaactivator.ClinExp Nephrol2003;7(1):27–32.

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Furtherreading

[3]A.Raptis,G.Viberti,Pathogenesisofdiabeticnephropathy,Exp.Clin.Endocrino. Diabet.109(2)(2001)424-437.

[6]A.Flyvbjerg,L.Denner,B.F.Schrijvers,R.G.Tilton,T.H.Mogensen,S.R.Paludan, etal.,Long-termrenaleffectsofaneutralizingRAGEantibodyinobesetype2 diabeticmice,Diabetes53(1)(2004)166-172.

[11]R.Agarwal,Anti-inflammatoryeffectsofshort-termpioglitazonetherapyin menwithadvanceddiabeticnephropathy,Am.J.Physiol.Renal.Physiol.290(3) (2006)F600-F5.