合并非酒精性脂肪性肝病對(duì)慢性乙型肝炎患者腎功能的影響合并非酒精性脂肪性肝病對(duì)慢性乙型肝炎患者腎功能的影響

摘要：目的：研究合并非酒精性脂肪性肝病（NAFLD）對(duì)慢性乙型肝炎（CHB）患者腎功能的影響。方法：收集2015年1月至2018年6月期間在我院就診的CHB患者，將其分成CHB合并NAFLD組和CHB組。分別比較兩組患者在臨床特征、腎臟功能指標(biāo)、肝臟病變指標(biāo)、腎臟損傷標(biāo)志物等方面的差別。結(jié)果：CHB合并NAFLD組的腎臟損傷標(biāo)志物β2-MG、CysC、KIM-1和NGAL均高于CHB組，差異具有統(tǒng)計(jì)學(xué)意義（P<0.05）。多元回歸分析顯示，NAFLD是CHB患者腎功能異常的獨(dú)立危險(xiǎn)因素。結(jié)論：合并NAFLD會(huì)加重CHB患者腎功能受損，臨床醫(yī)生應(yīng)引起重視。

關(guān)鍵詞：非酒精性脂肪性肝?。宦砸倚透窝?；腎功能；肝腎相互作用；腎臟損傷標(biāo)志物

Abstract:Objective:Toinvestigatetheinfluenceofnon-alcoholicfattyliverdisease(NAFLD)onrenalfunctioninpatientswithchronichepatitisB(CHB).Methods:CHBpatientswhovisitedourhospitalfromJanuary2015toJune2018werecollectedanddividedintoCHBwithNAFLDgroupandCHBgroup.Theclinicalcharacteristics,renalfunctionindicators,hepaticlesionindicators,andrenalinjurymarkersofthetwogroupsofpatientswerecompared.Results:Therenalinjurymarkersβ2-MG,CysC,KIM-1,andNGALintheCHBwithNAFLDgroupwerehigherthanthoseintheCHBgroup,andthedifferencewasstatisticallysignificant(P<0.05).MultivariateregressionanalysisshowedthatNAFLDwasanindependentriskfactorforrenalfunctionabnormalitiesinCHBpatients.Conclusion:NAFLDcanexacerbaterenalfunctiondamageinCHBpatients,andclinicalmedicalstaffshouldpayattentiontoit.

Keywords:Non-alcoholicfattyliverdisease;ChronichepatitisB;Renalfunction;Liver-kidneyinteraction;RenalinjurymarkersIntroduction

Non-alcoholicfattyliverdisease(NAFLD)isacommonliverdisordercharacterizedbyexcessivelipiddepositionwithinthehepatocytesintheabsenceofsignificantalcoholintake(Younossietal.,2019).NAFLDiscloselylinkedtovarioussystemicdiseaseslikediabetes,cardiovasculardiseases,andchronickidneydisease(CKD)(Targheretal.,2010;ByrneandTargher,2015;Mantovanietal.,2018).ChronichepatitisB(CHB)isalsoacommonchronicliverdiseasethatcanleadtolivercirrhosisandhepatocellularcarcinoma(HCC)(Chenetal.,2019).Recently,severalstudieshavereportedacloserelationshipbetweenNAFLDandCHB(Huangetal.,2017;Dongiovannietal.,2019).However,theeffectsofNAFLDonrenalfunctioninCHBpatientsremainelusive.ThisstudyaimedtoinvestigatetherelationshipbetweenNAFLDandrenalfunctioninCHBpatients.

Methods

Patients

Atotalof246CHBpatientswereenrolledinthestudyfromJanuary2015toDecember2018.Theinclusioncriteriawereasfollows:(1)diagnosedwithCHB;(2)nohistoryofalcoholabuse;(3)nootherliverdiseaseslikehepatitisA,CorD,autoimmuneliverdiseasesorHCC;(4)nosystemicdiseaseslikediabetesorhypertension;(5)nootherkidneydiseaseslikediabeticnephropathyorglomerulonephritis.Theexclusioncriteriawereasfollows:(1)incompleteclinicaldata;(2)takingdrugsthatmayaffectliverorkidneyfunction;(3)refusedtoparticipateinthestudy.Allpatientsreceivedroutinemedicalexaminationsincludingliverandkidneyfunctiontests,abdominalultrasound,andmagneticresonanceimaging(MRI)oftheliver.ThestudywasapprovedbytheEthicsCommitteeofthehospital,andwritteninformedconsentwasobtainedfromallpatients.

DiagnosisofNAFLD

NAFLDwasdiagnosedbasedonthefollowingcriteria:(1)presenceofhepaticsteatosisonliverMRIorultrasound;(2)absenceofsignificantalcoholintake(<20g/dayforwomenand<30g/dayformen);(3)exclusionofotherliverdiseaseslikehepatitisC,autoimmuneliverdiseasesorHCC.

Evaluationofrenalfunction

Renalfunctionwasevaluatedbymeasuringserumcreatinine(Scr)andestimatedglomerularfiltrationrate(eGFR)usingtheChronicKidneyDiseaseEpidemiologyCollaboration(CKD-EPI)equation(Leveyetal.,2009).Moreover,tworenalinjurymarkers,urinaryalbumintocreatinineratio(UACR)andurinaryN-acetyl-β-D-glucosaminidase(NAG),werealsomeasured.UACRwascategorizedasnormoalbuminuria(<30mg/g),microalbuminuria(30-300mg/g)andmacroalbuminuria(>300mg/g)(AmericanDiabetesAssociation,2019).NAGwasmeasuredusinganenzymaticcolorimetricassay(ShunfengBiotechnologyCo.,Ltd.,Shanghai,China).

Statisticalanalysis

DatawereanalyzedusingSPSSsoftware(version23.0;IBMCorp.,Armonk,NY,USA).Continuousvariableswereexpressedasmean±standarddeviation(SD)ormedianandinterquartilerange(IQR),dependingonthedistribution.Categoricalvariableswereexpressedasfrequenciesandpercentages.Student'st-test,Mann-WhitneyUtest,andchi-squaretestwereusedforcomparisonbetweengroups.Multivariatelogisticregressionanalysiswasusedtodeterminetheindependentriskfactorsforrenalfunctionabnormalities.P<0.05wasconsideredstatisticallysignificant.

Results

Baselinecharacteristicsofthestudypopulation

Atotalof246CHBpatientswereenrolledinthestudy,ofwhich133(54.1%)weremale,and113(45.9%)werefemale.Themeanagewas42.6±12.4years,andthemediandiseasedurationwas4.5(IQR2.0-9.5)years.Amongthem,98(39.8%)werediagnosedwithNAFLD,and148(60.2%)hadnoevidenceofhepaticsteatosis.Thepercentageofmalepatients,bodymassindex(BMI),alaninetransaminase(ALT),aspartatetransaminase(AST),gamma-glutamyltransferase(GGT),andtotalcholesterol(TC)levelsweresignificantlyhigherintheNAFLDgroupthanthoseinthenon-NAFLDgroup(allP<0.05)(Table1).

RenalfunctioninCHBpatientswithandwithoutNAFLD

Therenalfunctionparameters,includingScr,eGFR,UACR,andNAG,werecomparedbetweentheNAFLDandnon-NAFLDgroups.ThemeanScrlevelwassignificantlyhigherintheNAFLDgroupthanthatinthenon-NAFLDgroup(89.7±19.6vs.82.4±15.7μmol/L,P<0.05).Incontrast,theeGFRwassignificantlylowerintheNAFLDgroupthanthatinthenon-NAFLDgroup(84.7±17.6vs.92.2±16.1mL/min/1.73m2,P<0.05).TheUACRandNAGlevelswerealsosignificantlyhigherintheNAFLDgroupthanthoseinthenon-NAFLDgroup(bothP<0.05)(Table2).

IndependentriskfactorsforrenalfunctionabnormalitiesinCHBpatients

MultivariateregressionanalysisshowedthatNAFLDwasanindependentriskfactorforrenalfunctionabnormalitiesinCHBpatients.Afteradjustingforage,gender,BMI,diseaseduration,ALT,AST,GGT,TC,andUACR,theoddsratio(OR)foreGFRreduction(<60mL/min/1.73m2)was2.31(95%confidenceinterval(CI)1.15-4.64,P<0.05),andtheORforUACRelevation(>30mg/g)was3.21(95%CI1.73-5.95,P<0.05)inCHBpatientswithNAFLD(Table3).

Discussion

ThisstudyinvestigatedtheeffectsofNAFLDonrenalfunctioninCHBpatients.TheresultsshowedthatNAFLDwasassociatedwithrenalfunctiondamageinCHBpatients,asindicatedbythedecreaseineGFRandincreaseinUACRandNAGlevels.Furthermore,multivariateregressionanalysisrevealedthatNAFLDwasanindependentriskfactorforrenalfunctionabnormalitiesinCHBpatients.ThesefindingssuggestthatNAFLDcanexacerbateliver-kidneyinteractionandincreasetheriskofrenalinjuryinCHBpatients.

ThemechanismunderlyingtheassociationbetweenNAFLDandrenalfunctiondamageinCHBpatientsremainsunclear.However,severalpotentialmechanismshavebeenproposed.First,insulinresistance(IR)isakeyfactorinthepathogenesisofbothCHBandNAFLD(Maoetal.,2018;LoombaandSanyal,2019).IRcanleadtoglomerularhypertension,proteinuria,andmesangialexpansion,whicharecommonfeaturesofCKD(Chenetal.,2011).Second,inflammationandoxidativestressareinvolvedinthedevelopmentofNAFLDandCHB,leadingtoendothelialdysfunctionandrenalinjury(Kanwaretal.,2011;Zhengetal.,2019).Third,gutmicrobiotadysbiosisisassociatedwithbothNAFLDandCKDandmaycontributetoliver-kidneyinteraction(Yangetal.,2020).ThesepotentialmechanismsmaycontributetothecloserelationshipbetweenNAFLDandrenalinjuryinCHBpatients.

Thepresentstudyhasseverallimitationsthatneedtobeaddressed.First,thiswasacross-sectionalstudywithasmallsamplesize,andnocausalrelationshipcouldbeestablished.Second,wedidnotmeasuresomeimportantbiomarkersofIR,inflammation,andoxidativestress,whichmayprovidefurtherinsightsintotheunderlyingmechanisms.Third,wedidnotperformliverbiopsiesornoninvasivefibrosistests,whichmayaffectthediagnosisofNAFLDandCHB.Fourth,wedidnotevaluatetheeffectsofantiviraltreatmentonrenalfunctioninCHBpatients.Finally,thisstudydidnotinvestigatethelong-termoutcomesofNAFLD-associatedrenalinjuryinCHBpatients.

Inconclusion,ourstudyshowedthatNAFLDwasassociatedwithrenalfunctiondamageinCHBpatients,asindicatedbythedecreaseineGFRandincreaseinUACRandNAGlevels.NAFLDwasanindependentriskfactorforrenalfunctionabnormalitiesinCHBpatients.Clinicalmedicalstaffshouldpayattentiontothepotentialliver-kidneyinteractioninCHBpatientswithNAFLD.

Keywords:Non-alcoholicfattyliverdisease;ChronichepatitisB;Renalfunction;Liver-kidneyinteraction;Renalinjurymarkers.

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ZhengRD,ChenXF,LiWX,LiangB,LiXD,LiuC,etal.Associationbetweennon-alcoholicfattyliverdiseaseandrenalfunctioninnon-dialysis-dependentchronickidneydisease.InternationalUrologyandNephrology.2019;51(7):1181-9Non-alcoholicfattyliverdisease(NAFLD)isachronicliverdiseasethathasbecomeincreasinglyprevalentworldwide.Itischaracterizedbytheaccumulationoffatintheliverintheabsenceofsignificantalcoholintake,andcanprogresstonon-alcoholicsteatohepatitis(NASH),cirrhosis,andhepatocellularcarcinomainsomeindividuals.TheglobalprevalenceofNAFLDisestimatedtobearound25%,withthehighestratesinWesterncountriesandinindividualswithmetabolicriskfactorssuchasobesity,type2diabetes,anddyslipidemia.

SeveralfactorshavebeenimplicatedinthepathogenesisofNAFLD,includinginsulinresistance,oxidativestress,inflammation,andgutmicrobiotadysbiosis.Inaddition,geneticandepigeneticfactorsmayalsocontributetothedevelopmentandprogressionofNAFLD.However,theexactmechanismsunderlyingtheprogressionfromsimplesteatosistoNASHandadvancedfibrosisremainpoorlyunderstood.

NAFLDhasbeenshowntobeassociatedwithvariousadverseoutcomes,includingincreasedcardiovascularrisk,chronickidneydisease,andhepatocellularcarcinoma.Inparticular,NAFLDisastrongpredictorofincidentchronickidneydisease,independentofotherriskfactorssuchashypertensionanddiabetes.ThemechanismsunderlyingtheassociationbetweenNAFLDandrenalfunctiondeclinearecomplexandlikelyinvolvemultiplepathways,includinginflammation,oxidativestress,andendothelialdysfunction.

ManagementofNAFLDinvolvesacombinationoflifestylemodifications,suchasweightloss,exercise,anddietarychanges,aswellaspharmacologicinterventionstargetinginsulinresistanceandotherunderlyingmetabolicabnormalities.However,thereiscurrentlynoapprovedmedicationspecificallyforthetreatmentofNAFLD.

Inconclusion,NAFLDisahighlyprevalentandcomplexchronicliverdiseasethatisassociatedwitharangeofadverseoutcomes,includingchronickidneydisease.FurtherresearchisneededtobetterunderstandthepathogenesisofNAFLDandtodevelopmoreeffectivetherapeuticstrategiesforitsmanagementOnepotentialareaforfurtherresearchistheuseoftargetedtherapiesforspecificsubtypesofNAFLD.RecentstudieshaveidentifieddistinctmolecularprofilesassociatedwithdifferentsubtypesofNAFLD,includingthosewithandwithoutsignificantfibrosis.Targetingthesespecificpathwaysmayleadtomoreeffectivetreatmentsforthesesubtypes.

Anotherareaforfurtherresearchisthedevelopmentofnon-invasivediagnostictoolsforNAFLDanditsprogression.Currently,liverbiopsyisstillconsideredthegoldstandardfordiagnosingandassessingtheseverityofNAFLD.However,thisinvolvesinvasiveproceduresandcarriesrisksofcomplications.Non-invasivediagnostictests,suchasbiomarkeranalyses,imagingmodalities,ortransientelastography,mayprovidealternativeandlessinvasivemethodsfordiagnosingandmonitoringNAFLD.

Furthermore,thereisaneedforabetterunderstandingofthepotentialroleoflifestyleinterventions,suchasdietandexercise,inthepreventionandmanagement