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REVIEWOpenAccessRecentadvancesinrenalinterstitialfibrosisandtubularatrophyafterkidneytransplantationXiaojunLi1andShougangZhuang1,2*AbstractAlthoughkidneytransplantationhasbeenanimportantmeansforthetreatmentofpatientswithendstageofrenaldisease,thelong-termsurvivalrateoftherenalallograftremainsachallenge.
Thecauseoflaterenalallograftloss,onceknownaschronicallograftnephropathy,hasbeenrenamed"interstitialfibrosisandtubularatrophy"(IF/TA)toreflectthehistologicpatternseenonbiopsy.
ThemechanismsleadingtoIF/TAinthetransplantedkidneyincludeinflammation,activationofrenalfibroblasts,anddepositionofextracellularmatrixproteins.
IdentifyingthemediatorsandfactorsthattriggerIF/TAmaybeusefulinearlydiagnosisanddevelopmentofnoveltherapeuticstrategiesforimprovinglong-termrenalallograftsurvivalandpatientoutcomes.
Inthisreview,wehighlighttherecentadvancesinourunderstandingofIF/TAfromthreeaspects:pathogenesis,diagnosis,andtreatment.
Keywords:Interstitialfibrosis,Renaltransplantation,Renalallograftloss,TubularatrophyReviewFormanyyears,chronicallograftnephropathy(CAN)wasusedtodescribetheprogressivelossofrenalfunctionintransplantedkidneysovertimenotrelatedtoacuterejec-tion.
However,consensusbegantoformthatthetermdidnotsufficientlydescribetheunderlyingdiseaseprocess.
Interstitialfibrosisandtubularatrophy(IF/TA)describesthehistologiccharacteristicsofallograftdestructionovertime.
WhileIF/TAhascometoreplaceCAN[1],itisstillnotaspecificdisease,butapatternofinjurythathasmanyunderlyingcauses.
Thefundamentalmechanismofinter-stitialfibrosisistheimbalanceofextracellularmatrixmetabolismandabnormalaccumulationviainteractionofvariousinflammatorycytokines.
Itspathogenesishasnotbeenfullyelucidatedandexistingtherapyisnoteffectiveinimprovingrenaltransplantfunction.
PathogenesisofIF/TAPreviousstudiesindicatedthatIF/TAisalatefeatureoftherenalallograft.
However,increasingevidencehasshownthesamefeaturesofchronichistologicaldamageasearlyasthreemonthspost-transplant.
Moreover,thedevelopmentofIF/TAisprogressive,eventuallyresultinginchronicrenaldysfunction[2].
IF/TAisassociatedwithdecreasedgraftsurvival,especiallywhenitisaccompan-iedbytransplantvasculopathy,subclinicalrejection,ortransplantglomerulopathy.
Ina3-monthprotocolbiopsystudyinwhichbiopsieswereclassifiedaccordingtothepresenceorabsenceofarterialintimalthickening,graftsurvivalwassignificantlyreducedinpatientswithtrans-plantvasculopathy[3].
ThesimultaneouspresenceofIF/TAandincipienttransplantglomerulopathyimpliesashortergraftsurvivalthanthepresenceofIF/TAwithouttransplantglomerulopathy.
Moreover,itwasreportedthat10-yeargraftsurvivalwas95%inpatientswithnormalhistology,82%inpatientswithIF/TAwithouttransplantvasculopathy,and41%inpatientswithIF/TAandtrans-plantvasculopathy[4].
Inthepastseveraldecades,nu-merousstudieshavebeenconductedtounderstandthepathogenesisofIF/TAandmultiplefactorsandmecha-nismshavebeendemonstratedtobeinvolvedintheprogressoftheIF/TA,includingimmunosuppressivedrugtoxicity,antibody-mediatedinjury,andepithelial–mesenchymaltransition(EMT)(Figure1).
ImmunosuppressivedrugtoxicityImmunosuppressivedrugsarecloselyassociatedwiththedevelopmentofIF/TA.
Althoughthetargetsofimmunosup-pressivedrugsarecellsinvolvedintheimmuneresponse,*Correspondence:szhuang@lifespan.
org1DepartmentofNephrology,TongjiUniversitySchoolofMedicine,ShanghaiEastHospital,Shanghai,China2DepartmentofMedicine,AlpertMedicalSchoolofBrownUniversity,RhodeIslandHospital,MiddleHouse301,593EddyStreet,Providence,RI02903,USA2014LiandZhuang;licenseeBioMedCentralLtd.
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LiandZhuangFibrogenesis&TissueRepair2014,7:15http://www.
fibrogenesis.
com/content/7/1/15theyalsohavetoxiceffectsonepithelial,endothelial,andmesenchymal-origincells[5].
Chronicnephrotoxiceffectsofcalcineurininhibitorsmaybeassociatedwithlateallograftdysfunctionandreducedallografthalf-life.
Theintroductionofcalcineurininhibitor(CNI)therapy–firstcyclosporine(CsA)inthe1980sandlatertacrolimus–wasinitiallyhamperedbyearlydosingregimensthatledtoawidevarietyofsideeffects.
CNIcancausemicrovascularandglomerulardamage,arteriolarhyalinedeposition,tubularatrophy,andstripedinterstitialfibrosis.
Nephro-toxicityinthefirstyearpost-transplantcorrelateswiththe60%rateofsuchpathologyinCNI-treatedrecipients[6].
Theexactmechanismofimmunosuppressivedrug-mediatedrenaltoxicityisnotfullyunderstood.
Itisevi-dentthatbothcyclosporineandtacrolimuscancauserenalandsystemicvasoconstrictionthroughincreasedreleaseofendothelin-1,activationoftherenin-angiotensinsystem,increasedproductionofthromboxaneA2,anddecreasedproductionofvasodilatorssuchasnitricoxideandprostacyclin[7].
Cyclosporinecanalsocauseoxidativestressthroughuncouplingmitochondrialoxidativephos-phorylation,inhibitionoftheKrebscycle,andactivationofanaerobicglycolysisinthecytosol.
Inaddition,tubu-lointerstitialfibrosisassociatedwithCNItoxicityisalsorelatedtoincreasedintrarenaltransforminggrowthfactor-β(TGF-β)mRNAexpression[8].
TGF-βcanpromoteinterstitialfibrosisbydecreasingthedegradationandincreasingtheproductionofextracellularmatrixpro-teins[9,10].
ActivationofthemTORpathwayhasbeenassociatedwithextracellularmatrixsynthesisandrenalfibrosis.
IthasbeenreportedthatblockingthemTORpathwaywithrapamycincanreducerenalinterstitialfibrosisinanobstructivenephropathyrodentmodelbydiminishingthenumberofinterstitialfibroblastsandmyofibroblasts[11].
mTORinhibitorsalsodecreaseTGF-β1expressionandsignificantlyregressglomerularhypertrophy,mesangialfibrosis,andtubulointerstitialdamageinvariousanimalmodelsofkidneyinjuryandrenaltransplantpatients[12,13].
DespitethatinhibitionofthemTORpathwaycanattenuaterenalfibrosisinanimalmodels,applica-tionofrapamycininpatientswithCNIsdidnotresultinconsistentbeneficialeffects.
Pontrellietal.
[14]havereportedthatrapamycincansubstantiallyreduceintersti-tialfibrosisinrenaltransplantrecipients.
Gonzalezetal.
[15]demonstratedthatswitchingfromCNItosirolimusforkidneytransplantscouldalsoslowthecourseofIF/TA.
However,Servaisetal.
[16]didnotfindasignificantreductioninfibrosisafter1yearwhenpatientswereconvertedfromCNIstorapamycin12weeksafterrenaltransplantation.
Moreover,somerecentstudieshaveshowncertainnephrotoxicpotentialofrapamycinespeciallywhengivenincombinationwithhighdosesofCNIs[17,18].
Antibody-mediatedinjuryIF/TAisthecommonpathologicalfindingofvariouschronickidneydiseasesincludingchronicrenalallograftdysfunctionresultingfromantibody-mediatedrejection(AMR),whichiscausedbycirculatingantibodiestodonoralloantigensexpressedontheendothelium.
SeveralgroupshaverecentlyreportedthatglomerulitisandperitubularFigure1IdentifiedmechanismsinvolvedinIF/TAafterkidneytransplantation.
LiandZhuangFibrogenesis&TissueRepair2014,7:15Page2of11http://www.
fibrogenesis.
com/content/7/1/15capillaritis(microcirculationormicrovascularinflammation)correlatewithdonorspecificantibody(DSA)andgraftfailureinrenaltransplants[19-21].
Thereisalsoawealthofliteratureindicatingtheincidenceanddeleteriousim-pactofdonor-specificHLAantibodies[22].
However,gro-wingevidencesuggeststhatanti-bodiesagainstnon-HLAantigensmayalsocontributetoAMRinsolidorgantrans-plantation.
Reportsshowthat10%to23%ofrecipientsarepresensitizedtonon-HLAantigens[23,24],whereas22%formnon-HLAantibodiesaftertransplantation[25].
Themechanismsofantibody-mediatedgraftinjuryareprimar-ilydrivenbytheeffectorfunctionsoftheFcfragmentofHLAantibodies,whereasexperimentalevidenceindicatesthattheFcpromoteschronicinflammationandprolifera-tionindependentofantibodies[26-28].
ManystudieshaveshownthatC4disanimportantmarkerofcomplementactivationintheAMR,andC4dsedimentcanbefoundaroundrenaltubularcapillarybyimmunohistochemicalstainingtechniques.
Racusenetal.
re-portedthat,inbiopsiesofrenaltransplantpatientssuspectedofhavingacuterejection,depositionofC4dcomplementfragmentsonthesurfaceofendothelialcellsisobservedinmorethan50%ofperitubularcapillariesandC4d3isanimportantmarkerofanantibody-mediatedimmuneresponse[29,30].
Recently,otherstudieshaveshownthatC4dstainingofglomerulicorrelateswithglomerulitis,aninflammatorylesion[31].
Valenteetal.
furtherpointedoutthatC4dstainingofglomerularendothelialcellsindicatesglomerularendothelialdamage[32].
However,C4dasasignofAMRhascertainlimitations,becausethereisnoexpressionofC4dinAMR.
Sisetal.
proposedthatDSAtitershaveahighersensitivityandaccuracythanC4dinpredictingprogressiontograftfailure[19].
RenaltransplantrecipientswithdenovoDSA(dDSA)experiencehigherratesofrejectionandworsegraftsurvivalthandDSA-freerecipients.
Inanestedcase–controlstudyofadultkidneyandkidney-pancreasrecipientsfromJuly2007throughJuly2011inasinglecenter,Devosetal.
demonstratedthatdevelopmentofdDSAisassociatedwithincreasedinci-denceofrenalgraftloss[33]andgraftfailureafterkidneytransplantation[34].
Consequently,antibodiesplayanim-portantroleintheprogressionofrenalallograftinjury.
TheeffectofmacrophagesonrenalallograftinjuryPreviousstudiesindicatedthatmacrophagesexistwithinthetransplantedkidney.
Thesecellsarederivedfromre-cruitedmonocytes.
Inadditiontopromotionorattenu-ationofinflammationandparticipationininnateandadaptiveimmuneresponses,macrophagesmediatetissueinjuryandfibrosis,aswellastissuerepair[35].
Recruitedmacrophagesaregenerallydividedintotwophenotypes,M1andM2,whichhavedistinctfunctions.
M1phenotypesareproinflammatorymacrophagesthatexacerbaterenalcelldamage,whereasM2phenotypesareanti-inflammatorymacrophagesthatpromoteepithelialandvascularre-pair.
Insufficientvascularandepithelialhealingdespiteabundantgrowthfactorsecretionwouldpromoteswitchmacrophagestoprofibrotic'M2a/woundhealing'macro-phagesthatacceleratefibrogenesisandconsequentlyrenalallograftinjury[36].
Evidencesupportsthenotionthatmacrophagesplayanimportantroleinpromotingthisprocess.
Forexample,Qietal.
[37]haveshownthatmac-rophagesmediateendothelialcellcytotoxicityleadingtolossofrenalmicrovasculatureusingatransgeniccondi-tionalablationstrategytodepletecirculatingmonocytesandinfiltratingrenalmacrophagesafterkidneytransplant-ation.
Thus,itisevidentthatmacrophageablationreducedhistologicfeaturesofrejection(arteritis,tubulitis)andtheaccompanyingrarefactionofperitubularcapillar-ies.
Theidentificationofmacrophagesimmunopositiveforinduciblenitricoxidesynthaseimplicatednitricoxidegenerationasapossiblemechanismofendothelialcellcytotoxicity.
Thesedataindicateasignificantroleformacrophagesincausingacuterejection-relatedtissueinjury.
RenaltubularepithelialtomesenchymaltransitionIFischaracterizedbyactivationandproliferationofrenalinterstitialfibroblastsandaccumulationofexcessiveamountsofextracellularmatrix.
Theactivationandex-pansionofmatrix-producingcellsoccurthroughmultiplesourcesandmechanisms,includingactivationofintersti-tialfibroblastsandpericytes,recruitmentofcirculatingfibrocytes,andphenotypicconversionoftubularepithelialandendothelialcells[38,39].
EMThasbeenreportedtocontributetotheprocessoffibrosisinvariousorgans,includingkidney[40,41].
Severalstudieshaveshownthatepithelialcellswithanalteredphenotypehavebeenob-servedintransplantedkidneyswithfeaturesofIF/TA[42].
Amongthemanyfibrogenicfactorsthatregulaterenalfi-broticprocessesandEMT,TGF-βhasbeenconsideredtoplayacentralrole[43-48].
TGF-β1isupregulatedinani-malandhumankidneyallograftsundergoingchronicre-jectionandchronicCsA-inducedtubulointerstitialfibrosis[49,50].
TGF-β1bindingtotheTGFreceptorinducesSmad2/3phosphorylation.
Smad2/3arethentranslocatedtothenucleiwheretheypromoteexpressionofTGF-βregulatedgenesincludingcollagenI.
Incontrast,bonemorphogeneticprotein(BMP-7)hasbeenidentifiedasanaturalantagonistofTGF-β1signalingandadministrationofexogenousBMP-7alsoprotectsagainstrenalfibrosisinseveralexperimentalmodels[51-54].
Furthermore,BMP-7iseffectiveinrepressingexpressionofproinflammatorycytokinesincludinginterleukin-6andinterleukin-1,andchemokinesinhumanrenaltubularcells[55].
Thus,inhibitionofEMTmayimproveclinicaloutcomesofrenaltransplantpatients.
LiandZhuangFibrogenesis&TissueRepair2014,7:15Page3of11http://www.
fibrogenesis.
com/content/7/1/15FactorsinvolvedininflammationandfibrosisoftherenalallograftAdisintegrinandmetalloproteinase17(ADAM17)Adisintegrinandmetalloproteinase17(ADAM17)isimplicatedinbothpro-inflammatoryandpro-fibroticprocesses,whichpositionsitasapossibletargetofinterventioninavarietyofdiseases.
IthasbeenreportedthatanADAM17inhibitorwaseffectiveinreducingrenalfibrosisinangiotensinII-inducedkidneydiseaseinmice[56].
AnotherstudyhasalsoindicatedthatADAM17-mediatedproductionofsolubleheparinbindingepidermalgrowthfactor(HB-EGF)isalsoinvolvedinrenalfibrosisviaactivationofEGFreceptor(EGFR)signaling[57].
Therefore,ADAM17maybeimplicatedininterstitialrenaldamageaftertransplantation.
Hypoxia-induciblefactor-1α(HIF-1α)StudieshaveshownthatinfiltratinginflammatorycellsaredetectedinIF/TAandcontributetolong-termrenalallograftfailure[58,59].
Forexample,infiltratingmono-cytes/macrophagesandtheirrelatedchemokines/cyto-kinesinfluencethelong-termsurvivalofrenalallografts[60,61].
TheinfiltratinginflammatorycellscontributetoIF/TAofchronickidneytransplantrecipientsthroughanHIF-1αsignaling-dependentpathway.
HIF-1αparticipatesinfibrosisthroughregulatingtheexpressionofconnectivetissuegrowthfactor(CTGF).
Moreover,Yuetal.
evaluatedrenaltransplantrecipientswhounderwentrenalallograftbiopsywithIF/TA,andfoundtheexpressionofHIF-1αproteininfiltratinginflammatorycellsinareaswithIF/TAinpatientswithchronicallograftdysfunction[62].
TheexpressionofHIF-1αintheinfiltratingmacrophages/monocytesinchronicallograftdysfunctionprovidesanovelroleofHIF-1αininflammationthatmaybecausedbyhypoxiawhichisnotalloreactive[63].
HIF-1αmaypro-moteEMTdevelopmentthroughregulatingfibroticgeneexpressionduringI/Rinjuryinhumanrenaltubularepi-thelialcells,andmiR-21couldbeamongtheimportantregulatorypathwaysintheprocess[64].
Fibroblast-specificproteinchemokineCCL21andchemokinereceptorCCR7TheCCL21/CCR7signalingpathwayhasbeenshowntoparticipateinthedevelopmentofrenalfibrosis[65].
Itiswellknownthatactivationoffibroblastsisthekeymechanismofkidneyfibrosis[66].
Zhouetal.
foundthattheCCL21/CCR7signalingpathwaycon-tributestorenalallograftfibrosisthroughactivationofrenalfibroblasts.
Furthermore,fibroblastsurfaceprotein-positivefibroblastsmaybeariskfactorforacute/activecellularrejectionandchronic/sclerosingallograftnephropathy[67].
DiagnosisEarlydetectionofIF/TAisimportantforeffectivemanage-mentofpotentialchronicallyprogressiveinjuryinthetransplantedkidneybyminimizingriskfactorsassoci-atedwithgraftinjury.
Atpresent,thegoldstandardishistologicalevaluationoftissuefromrenalbiopsies.
How-ever,thecurrentlyusedmethodsareineffective,inaccur-ate,orinvasive,andsufferfromlimitationsinpredictingoutcomes.
Recentstudieshaveidentifiednumerousspe-cificbiomarkersfrombloodandurineformonitoringofgraftfunctionafterkidneytransplantationthatproveusefulinearlierdiagnosis(Table1).
BloodbiomarkersOxidativestressparametersOxidativestressmaybethemechanismresponsiblefortoxiceffectsandIF/TAcausedbyimmunosuppressivedrugs.
Itisevidentthatsomeimmunosuppressivedrugs,especiallycalcineurininhibitors,contributetoanincreaseofoxidativestress[68].
Furthermore,oxidativestressisoneofthemostimportantcomponentsofischemia/reperfusionprocessafterkidneytransplantationandincreaseswithgraftdysfunction.
Fonsecaetal.
performedaprospectivestudyof40renaltransplantationrecipientstoevaluatetime-dependentchangesinoxidativestress-relatedparameterswithinthefirstweekaftertrans-plantationandtoassesstheirperformanceinpredictingdelayedgraftfunctionatoneyear.
Theyfoundthatin-creasedmalondialdehydelevelsonday1afterrenaltrans-plantationmightbeanearlyprognosticindicatorofIF/TA,andlevelsonday7mightrepresentausefulpredictorofone-yeargraftfunction[69].
Therefore,monitoringoxidativestresswillbebeneficialtotheearlydiagnosisofprogressionofIF/TA.
Table1BiomarkersinIF/TAafterkidneytransplantationBiomarkersReferencesBloodMalondialdehyde[69]Monocytes[70–73]MMP/TIMPsystem[74-79]DNAmicrochimerism[80-87]UrinemRNA:KIM-1[91-94]miRNA:miRNA-22,mir-140-3p,mir-125b,etc.
[95-97]CCL2[98-100]CTGF[101]VitaminDbindingprotein[102]Retinolbindingprotein[103]MMP,Matrixmetalloproteinases;TIMPs,Tissueinhibitorsofmetalloproteinases;KIM-1,Kidneyinjurymolecule-1;CTGF,Connectivetissuegrowthfactor.
LiandZhuangFibrogenesis&TissueRepair2014,7:15Page4of11http://www.
fibrogenesis.
com/content/7/1/15MonitoringcirculatingmonocytesSeveralstudieshavereportedarelationshipbetweenexcessiveextracellularmatrixproteinandmacrophageinfiltrate.
Inaddition,infiltratingmacrophagescorre-latedwithformationofmyofibroblasts.
Increasingstudiesshowedtheaccumulationofmacrophagesindamagedkidneyallograftandmacrophagesareinvolvedinthedevelopmentandprogressionofkidneyfibrosis.
InanimalmodelsofchronicallograftnephropathywithIF/TA,mac-rophagesareaccumulatedinthedamagedkidney.
Inkidneyrecipients,thepresenceofmacrophagesinearlybiopsiesispredictiveofIF/TA[70,71].
Moreover,blockadeofmacrophagerecruitmentmayreducerenalfibrosis[72].
Guillén-Gómezetal.
alsoshowedthatmonitoringmono-cytescouldbeanewtoolforearlyidentificationofgraftdysfunctioninrenaltransplantpatientsbyanalyzingthephenotypeofcirculatingmonocytes[73].
However,thepropositionalsoneedsfurtherexperimentalandclinicalstudy.
Matrixmetalloproteinases(MMPs)/tissueinhibitorsofmetalloproteinases(TIMPs)systemMMPswhichbelongtothelargefamilyofmetzincins,areproducedbyrenalcells(tubularepithelialcells,mesangialcells,andendothelialcells),andplayacriticalroleinextracellularmatirxremodeling[74,75].
However,MMPscanbespecificallyinhibitedbytissueTIMPs.
IncreasingevidencerevealsthatthedysregulationofMMPsandTIMPscontributestoremodelingofkidneystructureinpatientswithchronicallograftinjury[76].
Recently,Mazanowskaetal.
proposedassessingTIMP-1plasmalevelstoestimateallograftinjuryandsuggestedthattheymaybeausefulbiomarkerinclinicalpracticetomonitorforIF/TA[77].
Inaddition,serumMMP-2andMMP-7levelsarehigherinpatientswithIF/TAcomparedtokidneytransplantpatientswithnormalallograftfunc-tion(estimatedglomerularfiltrationrate(eGFR)≥90mL/min),suggestingpotentialnon-invasivebiomarkersforIF/TA[78].
Yanetal.
havealsoreportedthatabnormalexpressionsofMMP-2andTIMP-1attributedtothedevelopmentofIF/TAinchronicactiveantibody-mediatedrejection[79].
Thus,monitoringthedysregulationofMMP/TIMPsystemmayaidinthediagnosisofrenalallograftfibrosis.
DNAmicrochimerisminbloodoftransplantrecipientsThedevelopmentofmicrochimerism,aphenomenonofthepersistenceofdonorcellsintheperipheralbloodofrenaltransplantrecipients,hasbeenconsideredtobepositivelyassociatedwiththeacceptanceoftrans-plantedorgans[80,81].
Severalcasereportsshowthatamicrochimerism-positivefindingintherecipientsofrenaltransplantationisanindexofacceptanceoftrans-plantedkidney,asshownbytherelativelongersurvivaltimeoftransplantedkidneysintherecipients[82,83].
Itwasreportedthatthesurvivaltimeoftransplantedkidneyswassignificantlylongerinmicrochimerism-positiverecipi-ents(8.
7years)thaninmicrochimerism-negativerecipi-ents(5.
4years).
Theserumcreatininelevels,measuredat1yearaftertransplantation,weresignificantlylowerinthemicrochimerism-positiverecipientsthaninthemicrochimerism-negativerecipients[84].
Althoughtheexactmechanismsbywhichmicrochimerismsformedremainlargelyunknown[85,86],themicrochimerismwasproposedtobederivedfromkidneycells,organ-containedleukocytes,orbloodstemcells[87].
Fromaclinicalpointofview,microchimerismsmightbeoneofseveralim-munologicalmechanismsassociatedwithlong-termgraftsurvival.
UrinebiomarkersUrinemRNAandmiRNANon-invasive,cost-effectivebiomarkersthatallowfrequentandaccuratemonitoringofgraftfunctionareneededinkidneytransplantation[88,89].
Asabiofluid,urineallowsrepeatedandnon-invasivecollection,anditsmolecularcompositionhighlyreflectsintrarenalevents[90].
ManyresearchersassessmRNAlevelsofurinarypelletsfortheevaluationofchronicallograftdysfunctionwithIF/TA[91,92].
Kidneyinjurymolecule-1(KIM-1)isaproteinpresentintoxicandischemicacuterenalinjuryandinchronickidneydiseases[93].
Nogareetal.
suggestedthatquantificationofKIM-1mRNAinurinarysedimentcellsmaybeusedasanon-invasivebiomarkeroffibrosisinkidneygraftswithIF/TA[94].
Recently,microRNAs(miRNAs)haveemergedasabiomarkerforavarietyofdiseases.
Severalstudiesindi-catedthatglobalmiRNAexpressionchangesareassoci-atedwithIF/TAofkidneyallografts[95,96].
Malufetal.
establishedmiRNAsignaturesinurinarycellpelletsam-plesfrompatientswithandwithoutbiopsy-provenIF/TAusingmicroarrays[97];theyidentifiedanumberofdiffer-entiallyexpressedmiRNAsinurinarycellpelletsinpa-tientshistologicallydiagnoseduponrenalbiopsyashavingIF/TA.
Moreover,throughtheanalysisofdifferentiallyexpressedmiRNAsinurinarycells,22miRNAswerefoundtobeassociatedwithIF/TAinpatients[97].
Thus,urinemRNAandmiRNAsmaybepotentialbiomarkersformonitoringallograftfunctionandanticipatingprogressionofIF/TA.
UrinaryCCL2Earlynon-invasivemarkersthatidentifypatientsatriskofrenalallograftlossmaystratifypatientsformoreinten-sivemonitoringortherapy.
CCL2isaCCR2receptorche-mokinethatisachemoattractantproteinformonocytes/macrophages,Tcells,andnaturalkillercells,andisgener-atedbymultiplecelllineages,includinglocaltubularandLiandZhuangFibrogenesis&TissueRepair2014,7:15Page5of11http://www.
fibrogenesis.
com/content/7/1/15glomerularepithelialcellsaswellasinfiltratingmonocytes/macrophagesandlymphocytes[98,99].
Inaddition,Hoetal.
havedemonstrated,inamulticenterrenaltrans-plantcohort,thaturinaryCCL2at6monthsisanin-dependentpredictorforthedevelopmentofIF/TAat24months[100].
TheyalsofoundthaturinaryCCL2:creatinineat6monthsisanindependentpredictorofdeath-censoredrenalallograftloss.
UrinaryCTGFCTGFhasbeenconsideredasabiomarkerofchronicrenalallograftinjurycharacterizedbyTA/IF.
Shietal.
havedem-onstratedthaturinaryCTGFisanearlypredictorofTA/IFusingaratmodel.
Inanallogenicratkidneytransplantmodel,theyfoundthattypicalmorphologicalchangesin-cludingTA/IFinallograftappearedatweek8andbecameverysevereatweek12post-transplantation.
Inaddition,CTGFexpressioninepitheliumwasup-regulatedearlyandurinaryCTGFwasmarkedlyelevatedfromweek4.
Serumcreatinineinrecipientswasstablebeforeweek8butin-creasedtremendouslyatweek12.
UrinaryCTGFincreasesearlierthantheappearanceofbiochemicalabnormalitiesandpathologicalchanges.
Thus,measurementofurinaryCTGFmayofferapotentialnon-invasivestrategytopre-dicttheearlyonsetofchronicrenalallograftinjury[101].
UrinaryvitaminDbindingproteinandretinolbindingproteinIncreasedurinaryproteinexcretioniscommonafterrenaltransplantationandportendsworseoutcome.
Mirkovietal.
investigatedthevalueofurinaryvitaminDbindingproteinexcretion(uVDBP)asatubulointerstitialinflam-mationandfibrosismarkerinadriamycinrats,andtestedwhetheruVDBPparallelsrenaldamageandrespondstotherapyintensificationinhumans[102].
TheyproposethatuVDBPmaybeanovelurinarybiomarkeroftubulointer-stitialdamage,independentlyofalbuminuria.
Prospectivelydesignedstudiesareneededtovalidatethesefindingsandconfirmtheirrelevanceintheclinicalsetting.
Ithasalsobeenproposedthaturinaryexcretionofretinolbindingproteinisasensitivemarkerofallograftsatrisk.
Ameretal.
analyzedurinesamplesfrom221individualsoneyearafterrenaltransplantation,showingthaturinaryretinolbindingproteinexcretionisasensitivemarkerofallograftfibrosis,whichcanpredictlong-termgraftlossindependentofhistologyandurinaryalbumin[103].
TreatmentDevelopmentofIF/TAisacomplexprocessthatin-volvesmultiplefactorsandsysteminteraction.
CurrentlyavailabletreatmentscannoteffectivelyslowtheprogressionofIF/TAandimproverenalgraftfunction.
Somenewlyde-velopedapproachesmaybebeneficialforprolongingrenalgraftsurvivalinthefuture.
Thosestrategiesincludeanti-EMTagents,antioxidanttherapy,tubularepithelialcellrepair,andmesenchymalstemcelltherapy.
Anti-EMTagentsEMTofrenaltubularepithelialcellsisthoughttocon-tributetotheprogressionofrenaltubulointerstitialfibrosis.
AntagonismofEMTcouldthuspostponeandreverserenalinterstitialfibrosis.
Norcantharidin(NCTD)isapromisingagentforinhibitingrenalinterstitialfibrosis[104].
Lietal.
suggestthatNCTDcanantagonizetubularEMTbyinhi-bitingtheSmadpathway[105];assuch,NCTDtreatmentmaypreservethenormalepithelialphenotypeandmoder-atetubularEMT.
Increasingevidencesuggeststhatrecombinanthumanerythropoietin(rHuEPO)protectsneuronsandcardio-myocytesfromacuteinsults.
Leeetal.
investigatedtheprotectiveeffectofrHuEPOoncyclosporine-inducedrenalinjury,suggestingthatrHuEPOhasarenoprotectiveeffectagainstcyclosporine-inducedchronicrenalinjury[106].
Parketal.
haveobservedthatrecombinanthumanerythropoietincouldinhibittheprogressionofrenalfibro-sisinmicewithcompleteunilateralureteralobstructionandtheTGF-β1-inducedEMTinMDCKcells[107].
KidneytransplantrecipientsusuallyhavelowvitaminDlevels,especiallyintheearlypost-transplantationperiod.
Bienaiméetal.
studiedaprospectivecohortof634kidneyrecipientswhounderwenttransplantationatasingleinsti-tutionandfoundthatlow25-hydroxyvitaminDcon-centrationmeasured3monthsaftertransplantationisanindependentriskfactorforinterstitialfibrosisprogressionandisassociatedwithalowereGFRoneyearaftertrans-plantation[108].
Inmousemodelsofrenalfibrosis,Itoetal.
havealsodemonstratedthat25-hydroxyvitaminDtreatmentpreventsrenalfibrosisthroughthesuppressionofTGF-β-SMADsignaltransduction[109].
SyntheticligandsofthevitaminDreceptorthattargettheTGF-β-SMADsignalingpathway,whichisknowntoregulatefibrosis-associatedgeneexpression,amelioratedrenalfi-brosisintwodifferentmousemodels[110].
Thus,furtherinvestigationofvitaminDandrelatedcompoundsfortreatmentofhumanswithchronickidneyfibrosiswillbeinteresting.
Studiesindicatethatrapamycinhasantiangiogenicandantiproliferativeeffects.
Wuetal.
havereportedthatrapa-mycincansignificantlyattenuatetubulointerstitialdamageinaUUO-inducedratmodelofrenalfibrosis,suggestingthatrapamycinmayhavethepotentialtodelaytheprogres-sionoftubulointerstitialrenalfibrosis[111].
Inaddition,Koetal.
havereportedthatsirolimusretardsthedevel-opmentofchronicallograftdysfunctioninaratmodel[112].
Byanalyzing20renaltransplantrecipientswhoweretreatedwithrapamycin,zdemiretal.
havealsofoundthatrapamycin-treatedpatientshavealowerin-cidenceofdiffuseinterstitialfibrosis[113].
StudiesareLiandZhuangFibrogenesis&TissueRepair2014,7:15Page6of11http://www.
fibrogenesis.
com/content/7/1/15underwaytotestwhetherusingrapamycinaspartofacalcineurin-sparingregimenactuallyaffectslongallo-graftfunction.
AsTGF-βisinvolvedinthepathogenesisofchronicrejectioninkidneytransplants[114]andcontributetodevelopmentofEMT[115-118],TGF-βmightbeakeytargetfortreatingchronicrejection[119,120].
Guanetal.
[121]haveevaluatedtheefficacyofananti-TGF-βmono-clonalantibodyinthepreventionofchronicrejectionofrenalallografts.
Theydemonstratedthatadministrationofanti-TGF-βantibodysuccessfullyreducestheseverityofchronickidneytransplantrejectioninaratmodel,suggestingthetherapeuticpotentialfortheanti-TGF-βantibodytopreventthechronicrejectionofkidneytrans-plantsorprolongkidneytransplantsurvivalinpatients.
BMP-7isanaturalTGF-βantagonistandhaspowerfulrenoprotectiveandanti-fibroticeffects[122-124].
IthasbeenreportedthatadministrationofBMP-7reducesglom-erularandtubulointerstitialfibrosisinvariousexperimen-talmodelsofacuteandchronicrenalinjury.
MostofthesestudieshavesuggestedthattheprincipaltargetofBMP-7inthekidneyarerenalepithelialcells.
ItprotectsagainstrenalfibrosisthroughcounteractingtheprofibroticeffectsofTGF-β1inglomerularmesangialcellsandrenalepithe-lialcells.
AntioxidanttherapyOxidativestressinhibitionislikelytobeinvolvedindelayingtheprogressionofrenalinterstitialfibrosis.
Evi-denceindicatesthatalpha-lipoicacid(ALA)isapowerfulantioxidantandexhibitsaprotectiveeffectagainstrenalin-jury.
ALAalsoimprovesalbuminuriaandpathologyindia-betesbyreducingoxidativestress[125].
Wongmekiatetal.
demonstratedthatALAsupplementationattenuatesrenalinterstitialfibrosisinratswithobstructivenephropathy[126].
Oxygenfreeradicalsareimportantcomponentsinvolvedinthepathophysiologicalprocessesobservedduringischemiareperfusion.
Sehirlietal.
indicatedthatALAreversesischemiareperfusion-inducedoxidantresponsesandimprovesmicroscopicdamageandrenalfunction[127].
Syndecan-1Syndecan-1,aheparansulfateproteoglycan,hasanim-portantroleinwoundhealingbybindingseveralgrowthfactorsandcytokines.
Clearly,repairofrenaltubulardam-ageisacrucialstepinrestorationofrenalfunctionupontransplantation.
Inaddition,thebalancebetweentubularepitheliumfunctionalrepairandinjuryofchronicinflam-mationandfibrosis,isadominantfactorthatdeterminesrenalallograftfunctioninthelongterm[128].
Celieetal.
haveproposedthatsyndecan-1playsanimportantroleintubularepithelialsurvivalandrepairintherenalallograft.
Up-regulatingtheexpressionofsyndecan-1mayhelpshiftingthebalanceintherenalallografttowardsfunc-tionalrestorationratherthanIF/TA[129].
EverolimusEverolimusisanimmunosuppressivemacrolide.
Theinitialclinicaltrialsofeverolimuswereconductedincombinationwithstandard-doseCsA,aregimenthatdemonstratesanequivalentefficacytostandard-doseCsAandmycopheno-latemofetilwithregardstotheincidenceofacuterejection.
Inseveralsubsequenttrials,theefficacyofeverolimushasbeenevaluatedviaCNIminimizationprotocol,astrategythatusuallymaintainstheefficacyandpreservesrenalfunction[130-132].
Thesafetyandefficacyofdifferenteverolimuslevelsincombinationwithreduced-exposureCNIhavealsobeenconfirmed[133,134].
IntheCENTRALpilotstudy,theconversionfromCNItoeverolimusover-nightatweek7afterkidneytransplantationshowedasig-nificantimprovementinrenalfunctionat6months[135].
Mesenchymalstemcell(MSC)therapyEndogenousresidentMSCshavebeenshowntoplayim-portantrolesinlocalrepairinthekidney,includingmain-tainingtheendotheliumstabilized.
Celltherapiesappliedtosolidorgantransplantationhavegainedinterestinthelastyears,andamongthem,MSCtherapyhasgainedmuchat-tention.
InadditiontotheregenerativepropertiesofresidentkidneyMSCs,exogenouslyadministeredMSCsenhancetheintrinsicreparativecapabilitiesofthekidney.
NumerousexperimentalmodelshavedemonstratedthatMSCsattenuatealloimmuneresponsesbysuppressionofallo-geneicT-cellresponsesbothinvitroandinvivo[136,137].
Inaddition,Franquesaetal.
demonstratedatherapeuticeffectofMSCinattenuatingtheprogressionofIF/TA.
MSCinjectionresultsinaneffectiveandlong-termpro-tectionagainstkidneyallografts[138].
OtherstudieshavealsoshownthatallogeneicMSCinjectioncoulddecreaseproteinuriaandfibrosisina5/6nephrectomymodel[139,140].
Moreover,inaCol4A3knock-outmodelofchronicallograftdysfunction,syngeneicMSCsareabletoreduceinterstitialfibrosis,whileallogeneicMSCsdonotamelioratetheprogressionofthedisease[141].
Arecentclinicaltrialshowedtheunexpecteddeleteriousshort-termeffectsofMSCtherapywhengivenMSCsattheearlystagesaftertransplantation[142].
Thus,MSCsmaybeeffectiveinpreventingtheprogressofIF/TA.
However,theexactmechanismanditssafetyrequirefurtherclarification.
ConclusionsLong-termrenalallograftsurvivalafterkidneytransplant-ationremainsvariable,dependingonahostoffactors.
Un-derstandingthemechanismsleadingtothefinalcommonpathwayofIF/TAinthetransplantedkidneyisimportantforearlydiagnosisanddevelopmentoftreatmentstrategiesLiandZhuangFibrogenesis&TissueRepair2014,7:15Page7of11http://www.
fibrogenesis.
com/content/7/1/15toprolongallograftlife.
Recentstudieshavesuggestedthatimmunosuppressivedrugtoxicity,antibody-mediatedin-jury,EMT,pro-inflammatory,andpro-fibrosisfactorsareinvolvedintheIF/TA.
Multipleapproaches,suchasmoni-toringbloodandurinesamples,maybepromisingtoolsforearlydetectionofIF/TA.
TreatmentsforIF/TA,suchasanti-EMTagents,antioxidanttherapy,tubularepithelialrepairing,andmesenchymalstemcelltherapy,areunderinvestigation.
Withfurtherdevelopmentoftherapiestopreventoratleastslowtheprogressionofinterstitialfibrosisandtubularatrophy,theimprovedlong-termsurvivalofrenaltransplantsanddelayingthereturntodialysiswillbehopeful.
AbbreviationsADAM17:Adisintegrinandmetalloproteinase17;ALA:Alpha-lipoicacid;AMR:Antibody-mediatedrejection;BMP-7:Bonemorphogeneticprotein7;CAN:Chronicallograftnephropathy;CNI:Calcineurininhibitor;CsA:Cyclosporine;CTGF:Connectivetissuegrowthfactor;dDSA:denovoDSA;DSA:Donorspecificantibody;EGFR:EGFreceptor;eGFR:Estimatedglomerularfiltrationrate;EMT:Epithelial–mesenchymaltransition;HB-EGF:Heparinbindingepidermalgrowthfactor;HIF-1α:Hypoxia-induciblefactor-1α;IF/TA:Interstitialfibrosisandtubularatrophy;KIM-1:Kidneyinjurymolecule-1;miRNAs:microRNAs;MMPs:Matrixmetalloproteinases;MSC:Mesenchymalstemcell;NCTD:Norcantharidin;rHuEPO:Humanerythropoietin;TGF-β:Transforminggrowthfactor-β;TIMPs:Tissueinhibitorsofmetalloproteinases;uVDBP:UrinaryvitaminDbindingprotein.
.
CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.
Authors'contributionsXLwroteandrevisedthemanuscript;SZwroteandeditedthemanuscript.
Bothauthorsreadandapprovedthefinalmanuscript.
AcknowledgmentsWeappreciateDr.
GeorgeBaylissforcriticallyreadingandrevisingthismanuscript.
FundingsourcesThisworkwassupportedbytheNationalInstitutesofHealth,USA(DK-085065toSZ),theNationalNatureScienceFoundationofChina(81270778,81470920toSZ),andKeyDisciplineConstructionProjectofPudongHealthBureauofShanghai,China(PWZx2014-06toSZ).
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