腎移植術后的BK病毒感染

Guideline

BKPolyomavirusinSolidOrganTransplantationIntroduction

ThehumanBKpolyomavirus(BKV)islinkedtotwomajorcomplicationsintransplantrecipients,polyomavirus-associatednephropathy(PyVAN)in1–10%ofkidneytransplantpatients

andpolyomavirus-associatedhemorrhagiccystitis(PyVHC)in5–15%ofallogeneichematopoieticstemcelltransplant(HSCT)patients.Bothdiseasesoccuronlysporadicallyinpatientswithnon-kidneysolidorgantransplantation(SOT)orwithinherited,acquiredordrug-inducedimmunodeficiency.BesidesPyVANandPyVHC,BKVhasbeenimplicatedrarelyinextrarenalpathologiessuchaspneumonia,encephalitis,hepatitis,retinitis,capillary-leaksyndromeandcancer.ApotentialassociationofsustainedBKviruriawithacuteTcellmediatedrejectionhasalsobeensuggested.EpidemiologyofBKVInfectionandReplicationBKVandJCpolyomavirus(JCV)infectionsarewidespreadinthegeneralpopulation.PrimaryinfectionwithBKVoccursinthefirstdecadeoflifeasevidencedbyincreasesinBKVseroprevalenceto90%andmore.NaturalBKVtransmissionisnotresolved,butlikelyoccursviatherespiratoryororalroute.Subsequently,BKVcolonizestherenourinarytractastheprinciplesiteoflatentinfection,mostlikelyviaaprimaryviremia.InhealthyBKVseropositiveimmunocompetentindividuals,reactivationandasymptomaticurinarysheddingofBKVisdetectableinupto10%,withurineBKVloadsof5log10

genomeequivalents(geq)/mLasthe75thpercentile.BKVtypeIisfoundin70–80%,followedbyBKVtypeIVin10–20%.Inindividualswithimpairedimmunefunctions,particularlyafterSOTorHSCT,asymptomatichigh-levelurinaryBKVreplicationisobservedwithBKVloadsof>7log10

geq/mL,appearanceof“decoycells”inurinecytologyandvirusparticlesdetectablebydirectnegativestainingelectronmicroscopy.High-levelBKVviruriaonlyrarelyleadstoviremiaandPyVANinnonkidneySOT.Inkidneytransplantrecipients,however,approximatelyonethirdofpatientswithhigh-levelviruria/decoycellsdevelopBKVviremia,andintheabsenceofanyintervention,progresstohistologicallyprovenPyVAN.Thisprogressivelyaffectsgraftfunctionandincreasestheriskofgraftlossfrom<10%tomorethan90%.Becauseeffectiveandsafeantiviraltherapiesarelacking,screeningforBKVreplicationhasbecomethekeyrecommendationtoinitiateandguideastepwisereductionofimmunosuppression.ThisinterventionallowsforexpandingBKV-specificcellularimmuneresponses,curtailingofBKVreplicationinthegraftandclearanceofBKVviremia.RiskFactorsofPyVANThepreferentialoccurrenceofPyVANinkidneytransplantscomparedtoothernonkidneySOTorHSCTisstrikingandsuggeststhatfactorsspecifictotransplantingthisorganofBKVlatency,areofimportance.Theseincludedonor(organ)determinants(suchasHLA-mismatches,deceaseddonation,highBKV-specificantibodytitersinterpretedasamarkerofhigherrecentBKVexposureandpossiblygraftload,femalegender),recipientdeterminants(suchasolderage,malegender,loworabsentBKV-specificantibodytiters)andmodulatingfactorsaftertransplantation(suchasuretericstents,acuterejectionandantirejectiontreatment,steroidexposure,lymphocytedepletingantibodies,higherimmunosuppressivedruglevels,tacrolimus-mycophenolicacidcomparedtocyclosporine-mycophenolicacidortomTORinhibitor-combinations,andloworabsentBKV-specificTcellresponses)aswellasretransplantationaftergraftlossduetoPyVAN.ThereisaconsiderablevariabilityofPyVANincidenceratesindifferenttransplantcentersaswellasdiscordantresultsaboutriskfactors,whichmayreflectdifferencesintheimmunosuppressiveprotocolsoftherespectiveprograms.PreventionandProphylaxisKidneytransplantrecipientsshouldbescreenedforBKVreplicationtoidentifypatientsatincreasedriskofPyVANScreeningforBKVreplicationshouldbeperformedatleastevery3monthsduringthefirst2yearsposttransplant,andthenannuallyuntilthefifthyearposttransplant(Figure

1).Usingthisstrategy,atleast80–90%patientsatriskforPyVANcanbeidentifiedbeforesignificantfunctionalimpairmentoftherenalallograftoccurs.Morefrequentscreeningwillidentifyadditionalcasesandshouldbeperformedaccordingtothecenter-specificincidence.Thefollowingstrategieshavebeenusedsuccessfullyinalargernumberofadultandpediatricpatients:Biweeklyurinecytologyfordecoycellsforthefirst3months,thenmonthlyuntilmonth6,thenevery3monthsuntil2yearsposttransplantfollowedbyplasmatestingforBKVviremiaifpositive;ormonthlyplasmascreeningforthefirst6months,thenevery3monthsuntil2yearsposttransplant.ScreeningforBKVreplicationcanbedoneeitherbytestingurineforhigh-levelBKVviruria/decoycellsorbytestingplasmaforBKVviremia.Inasimulationmodelassumingan80%efficacytoclearPyVANanda10%riskofprecipitatingacuterejectionafterreducedimmunosuppression,screeningseemedtobecost-effectiveforPyVANincidenceratesofmorethan2.1%.AcostanalysissuggestedthatpreventingPyVANbyscreeningandreducingimmunosuppressionmaybecostsavingafterthesecondyearposttransplant.ScreeningandinterventionforBKVreplicationandnephropathyAdvantagesanddisadvantagesoftestingforBKVviruriaahighnegativepredictivevaluetoruleoutBKVnephropathyawindowperiodof6–12weeksbeforeviremiaandnephropathybeingnoninvasivelessercostsandinstrumentationrequirementsthanPCRinspecializedcenterswithexperiencedcytopathologistsavailablelowpositivepredictivevalueforPyVANthephysiologicalfluctuationsofurineBKVloadsrequiringdifferencestobegreaterthan2log10inordertobesignificantdelayeddeclineofurineBKVloads(andlackofclearance)comparedtoplasmaBKVloadsinresponsetoreducedimmunosuppressionTestingforBKVviremiapositivepredictivevalueof30–50%forprovenPyVANwithawindowperiodof2–6weeksmonthlyplasmascreeningispreferredinmanycentersasitdetectsclinicallymoresignificantreplicationprovidesawidelyacceptedtriggerfortherapeuticinterventionThepositivepredictivevalueofBKVviremiaincreasestomorethan90%whenplasmaBKVloadsareveryhigh(e.g.6log10copies/mL),renalallograftfunctionisimpairedorwhenrearrangementsintheBKVnoncodingcontrolregionappearinthebloodInpatientswithsustainedplasmaBKVDNAandloadsof>4log10

cp/mL,adiagnosisof“presumptivePyVAN”shouldbemadeinabsenceofdemonstrableBKVreplicationinbiopsies.IncreasesinserumcreatininefrombaselinearenotrequiredforthediagnosisofpresumptivePyVAN.ElectronmicroscopyDetectionofthree-dimensionalviralaggregatesinurinebyelectronmicroscopyhasbeenreportedtohavehighpositiveandnegativepredictivevaluesforBKVnephropathyreaching>90%However,electronmicroscopyisnotwidelyavailableandindependentprospectivestudiesconfirmingtheutilityofthisdiagnostictoolarewarrantedReducingimmunosuppressionshouldbeconsideredforkidneytransplantpatientswithsustainedplasmaBKVloadsStrategy1.Firstdosereductionofthecalcineurininhibitorby25–50%inoneortwosteps;followedbyreducingtheantiproliferativedrugby50%;followedbydiscontinuingthelatterStrategy2.Firstreducingtheantiproliferativedrugby50%followedbyreducingcalcineurininhibitorsby25–50%followedbydiscontinuingtheantiproliferativedrugOralprednisoneistypicallytaperedto10mgorlessperdayBothprotocolsappearsafeandeffectiveinadultandpediatricpatientsforpreventingPyVANandclearingBKVviremiawithsubsequentacuterejectionsrangingfrom8–12%allofwhichrespondedtosteroidtreatmentDiagnosisofPyVANPlasmaBKVloadsshouldbedeterminedinallkidneytransplantpatientsundergoingrenalallograftbiopsyforsurveillanceorfordeclineinfunctionThedefinitivediagnosisofPyVANshouldbesoughtbydemonstratingPyVcytopathicchangesinallografttissue,andconfirmedbyimmunohistochemistryorinsituhybridization(“provenPyVAN”)Forimmunohistochemistry,mostcentersusecross-reactingantibodiesraisedagainstthelargeT-antigenoftheSimianvirus40(clonePAb416,Calbiochem)Aminimumoftwobiopsycoresshouldbetaken,preferentiallycontainingmedullarytissuesbecauseofthefocalnatureofPyVANandthepossibilityofsamplingerrorinatleast10–36.5%ofcasesThehistologicalfindingsPyVANshouldbesemi-quantitativelyassessedThediagnosisofacuterejectionconcurrentwithPyVANisonlyconsideredsecureifonefindsendarteritis,fibrinoidvascularnecrosis,glomerulitis,orC4ddepositsalongperitubularcapillariesDeterminingwhetherinterstitialinfiltrationandtubulitisisdirectedagainstviralortubularantigenscannotbereliablydonebylightmicroscopy.InPyVAN,C4ddepositshavebeenobservedinthetubularbasementmembranes,butnotperitubularcapillaries.However,onecaseofPyVANwithintimalarteritisandonewithgeneralizedpolyomavirusvasculopathyintheskeletalmusclehasbeenreported.MHCclassIIupregulationbythetubularepitheliumhasbeenproposedasamarkerofrejectionwhichisabsentinPyVANbiopsieswithacuteviraltubularnecrosis,butrequiresindependentstudies.MolecularstudiesattempttoidentifymarkersinbiopsiesandinurinerequirefurtherinvestigationforutilityintheroutinesettingTreatmentofPyVANImmunosuppressionshouldbereducedinkidneytransplantpatientswithprovenPyVAN.ThemainstayoftherapyforPyVANinkidneytransplantpatientswithoutconcurrentacuterejectionisreducingordiscontinuingimmunosuppressivedrugsasoutlinedabove.Althoughtherearenorandomizedcontrolledtrials,anumberofobservationalstudieshavereportedsuccessfulclearanceofBKVviremiain>85%.Moreadvanceddiseasemayrequiremoreinterventionalsteps,alongertimeforrecoveryandresultinapermanentlossofrenalfunction.Tacrolimustroughlevelsarecommonlytargetedto<6ng/mLcyclosporinetroughlevelsto<150ng/mLsirolimustroughlevelsof<6ng/mLmycophenolatemofetildailydoseequivalentsof≤1000mgRecentstudiessuggestthatlowercalcineurininhibitorlevels,i.e.targetingtroughlevelsfortacrolimusof3ng/mLandcyclosporineof100ng/mLmaybeappropriateAdditionalstrategieshavebeenswitchingfromtacrolimustolow-dosecyclosporine,orswitchingfromthecalcineurininhibitortolow-dosesirolimus,orswitchingfrommycophenolicacidtoleflunomideortolow-dosesirolimusAdjuvantuseofantiviralagentsInpatientswithsustainedhigh-levelplasmaBKVloaddespiteadequatelyreducedimmunosuppression,theadjunctiveuseofantiviralagentsmaybeconsideredCidofovir,tradenameVistide?(Gilead),isanucleosideanalog,licensedbyTheFood&DrugAdministrationforthetreatmentofcytomegalovirusretinitis.Leflunomide,TradenameArava?(Aventis)isorallyadministeredasareplacementfordiscontinuedmycophenolicacidwithaloadingdoseof100mgfor5days,followedbyaninitialmaintenancedoseof40mg.Intravenousimmunoglobulin(IVIG)preparationshavebeenadministeredindosesrangingfrom0.2to2.0g/kginconjunctionwithreducedimmunosuppression.FluoroquinolonescaninhibitBKVreplicationviaaneffectonthehelicaseactivityofvirusencodedlargeTantigenbuttheselectivityindexislow.AcuterejectionafterreducedimmunosuppressionIfacuterejectionisdiagnosedinallograftbiopsies,afterclearanceofplasmaBKVDNAandPyVANbyhistology,anti-rejectiontreatmentisindicatedandajudiciousincreaseinmaintenanceimmunosuppressionbeconsidered.AdministrationoflymphocytedepletingagentsshouldbedoneaftercarefulevaluationofthecompetingrisksoffailuretocontrolrejectionandrecurrenceofPyVAN.ThenatureandthepathophysiologyofinflammatoryinfiltratesafterclearanceofBKVviremiaandPyVANmaybediverseandincludearesponsetoviralinfectiontermedimmunereconstitutioninflammatorysyndrome.Inthesettingofpersistentviruria(withoutviremiaornephropathy)biopsieswithputativeepisodesofacuterejectionthatsatisfyBanffcriteriafordiagnosis,donotalwaysrespondwelltosteroids.RetransplantationRetransplantationafterkidneyallograftlossduetoPyVANhasbeensuccessfullyperformedinatleast118cases,witha93%graftsurvivalat3years.Therapeuticinterventionforrecurrentinfectionisneededin17.5%ofpatients.Surgicalremovaloftheprimarytransplanthasbeenperformedinapproximatelyhalfofallcases,butdidnotprotectagainstrecurrentBKVreplicationandPyVAN.Saferetransplantation(withorwithoutnephrectomy)requirestheexpansionofBKV-specificimmuneeffectorsthatisfacilitatedbyreducedordiscontinuedimmunosuppression.IncaseofretransplantationofpatientswithdetectableplasmaBKVloads,asignificantdeclineofplasmaBKVloadsindicativeofemergingBKV-specificimmunityshouldbeachievedandpriorgraftnephrectomyconsidered.InductiontherapyisnotcontraindicatedafterclearanceofBKVreplication,butextendedperiodsofintensemaintenanceimmunosuppressionshouldbeavoided.SomerecentevidencesPolyomavirusBKReplicationinDeNovoKidneyTransplantPatientsReceivingTacrolimusorCyclosporine:AProspective,Randomized,MulticenterStudy.AmericanJournalofTranplantation.2013(Basel,Switzerland)Atotalof682KTpatientsreceivingbasiliximab,mycophenolicacid(MPA),corticosteroidswererandomized1:1tocyclosporine(CsA)ortacrolimus(Tac)UnivariateandmultivariateanalysisassociatedCsA-MPAwithlowerratesofviremiathanTac-MPAatmonth6(10.6%vs.16.3%,p=0.048)and12(4.8%vs.12.1%,p=0.004)Viremiaatmonth6wasalsoindependentlyassociatedwithhighersteroidexposureuntilmonth3(OR1.19per1g)Sixty-fivepatients(27%)developedBKviremia;28(12%)ofwhomhadsignificantviremiaAtotaloffive(21%)ofthe23(of28)patientswhounderwentbiopsypresentedwithsubclinicalBKVnephritisThemeanplasmaBKVDNAdeclinedby98%(range,76%-100%)at1yearafterpeakviremiaAcutecellularrejectionseeninfour(14%)of28patients,respondedtobolussteroids.Therewasnodeclineinestimatedglomerularfiltrationrateovertimefrom1monthaftertransplantationto1yearafterpeakviremiaConclusion:ReductioninimmunosuppressionaloneresultedinthesuccessfulresolutionofviremiawithpreservationofrenalfunctionandpreventionofclinicalBKVnephritisandgraftloss.ManagementandOutcomeofBKViremiainRenalTransplantRecipients:AProspectiveSingle-CenterStudy.Transplantation.2012(Milwaulkee,USA)BKviremiaandpolyomavirusnephropathyin352kidneytransplants:riskfactorsandpotentialroleofmTORinhibition.BMCNephrology.2013(Erlangen,Germany)Duringfollow-upviralreplicationwasdetectedin48patients(13.6%);22patients(6.2%)hadbiopsyprovenPyVANInmultivariatelogisticregressionanalysesriskfactorsforBK-viremiawerelackofenrolmentintorandomizedcontrolledtrials(RCTs),biopsyprovenacuterejections,cytomegalyvirus(CMV)serostatusofbothdonorandrecipientandprevioustransplantationInpatientswithoutPyVANreductionorswitchofimmunosuppressionwasassociatedwithrapidviralclearanceandstablegraftfunctionIncontrast,inmostpatientswithPyVANgraftfunctiondeterioratedand5patientsprematurelylosttheirallograftSwitchofimmunosuppressiontoalowdosecyclosporineplusmTORinhibitorbasedregimeninpatientswithPyVANwassafe,welltoleratedandtendedtobeassociatedwithabettershort-termoutcomeintermsofgraftfunctioncompar