醫(yī)、技學(xué)院(華盛頓醫(yī)療手冊(cè)培訓(xùn)器官移植)

SolidOrganTransplantMedicine

Dr.BaiXue-liTheDepartmentofHBPSurgeryandLiverTransplantationContentsSolidOrganTransplantBasics1GraftRejection2Complications3SpecialConsiderations4In1954,Prof.JosephMurrayachievedthefirstsuccessfulkidneytransplantationfromoneidenticaltwintoanotherwithoutusinganti-rejectiondrugsThefirstsuccessfulkidneytransplantation；Thefirstlivingorgantransplantation；Thefirstrelativekidneytransplantation;Thefirstorgantransplantationbetweenidenticaltwins1990HistoryHistoryDr.ThomasE.Starzl1963firstlivertransplantationProf.ChristiaanBarnard

1967firsthearttransplantationDr.JamesD.Hardy1963

firstlungtransplantationGeneralPrinciplesAsurgicaloperationwhereafailingordamagedorganinthehumanbodyisremovedandreplacedwithanewoneAtreatment,notacure,forend-stageorganfailureofthekidney,liver,pancreas,heartandlung

SolidOrganTransplantBasicsOrthotopic:lung/heart/liverHeterotopic:kidneySurgicalOptionsAutograft:

fromonepartofthebodytoanotherIsograft,Syngenic:betweentwogeneticallyidenticalindividualsAllograft:betweentwogeneticallydissimilarindividualsofthesamespeciesXenograft:betweentwospecies

GraftAllorgansremaininshortsupplywithincreasingwaitingtimesforpotentialrecipients

Living-donortransplantsareconsideredasapartialsolutiontoorganshortage

XenotransplantationisnotaviableoptioninthenearfutureGeneralPrinciples

ImmunologicconsiderationspriortothetransplantmustbefullyevaluatedIncludingABOcompatibility,

HLAtyping,andsomedegreeofimmuneresponsetestingtotheproposeddonorGeneralPrinciples

EvaluationoftherecipientCauseoforganfailureTreatmentfororganfailurepriortotransplantationTypeanddateoftransplantCMVstatusofdonorandrecipientInitialimmunosuppression,particularlyuseofantibody-basedinductiontherapyEvaluationoftherecipientInitialandcurrentfunctionoftransplant：nadircreatinine,FEV1,ejectionfraction,syntheticfunctionandtransaminases,etc.Complicationsoftransplantation：surgicalproblems,acuterejection,infections,chronicorgandysfunction,etc.CurrentimmunosuppressionregimenandrecentdruglevelsTreatmentImmunosuppressionpromoteacceptanceofagraft(inductiontherapy)preventrejection(maintenancetherapy)reverseepisodesofacuterejection(rejectiontherapy)Complicationsinfectionmalignancynonimmunetoxicity：nephrotoxicity,diabetesmellitus,bonedisease,gout,hyperlipidemia,cardiovasculardisease,orneurotoxicityImmunosuppressiveagents

1、Glucocorticoids：methylprednisolone

mechanismsimmunosuppressiveandanti-inflammatoryinhibitionofcytokinetranscriptioninductionoflymphocyteapoptosisdownregulationofadhesionmoleculeandMHCexpression

sideeffectsdiabetesmellitusCushingsyndromeosteoporosisPepticulcer2、Antiproliferativeagents:Azathioprine,MPAAzathioprinemechanisms:

metabolizedto6-mercaptopurineinhibitsthesynthesisofDNA;suppressestheproliferationofactivatedlymphocytesadverseeffects:

myelosuppressionMPA:MPA,MMFmechanisms:inhibitstherate-limitingstepindenovopurinesynthesis;selectivelyinhibitslymphocytesproliferationadverseeffects:

gastrointestinaldisturbances,hematologicdisturbances3、Calcineurininhibitors(CNI)：Cyclosporine(CsA),TacrolimusCsAmechanisms：blockadeofinterleukin-2andothercytokinetranscription;inhibitionofT-lymphocyteactivationandproliferationsideeffect：nephrotoxicity(30%),hirsutism,hypertension,glucoseintolerance,hyperlipidemiaFK506(firstchoiceforlivertranspl)mechanisms：blockadeofinterleukin-2transcription,inhibitionofT-lymphocyteactivationandproliferationsideeffect：nephrotoxicity,neurotoxicanddiabetogenic(morethanCsA),hypertension4、Sirolimusmechanisms：inhibitstheactivationofaregulatorykinase,mammaliantargetofrapamycin(mTOR);

prohibitsT-cellprogressionfromtheG1totheSphaseofthecell;Anti-HCCsideeffect：Nonephrotoxicityandneurotoxicitygastrointestinalsymptomshyperlipidemiaanemia5、Polyclonalantibodies:Antithymocyteglobulin（ATG）,Antilymphocyteglobulin（ALG）

6、Monoclonalantibodies:OKT3，Anti-interleukin-2receptormonoclonalantibodies（Daclizumab,

Basiliximab）mechanisms：competitivelyinhibitCD25andtherebyinhibitactivationofTcellsPreventinginfectionTrimethoprim/sulfamethoxazole：preventsurinarytractinfections,Pneumocystisjirovecipneumonia,andNocardiainfectionsAcyclovir：preventsHSVandvaricella-zoster，ineffectiveinCMVprophylaxisGanciclovirorvalganciclovir:

preventsreactivationofCMVinfection

Fluconazoleorketoconazole：systemicfungalinfectionsorrecurrentlocalizedfungalinfectionsGraftRejectionHyperacuteRejectionGraftRejectionChronicRejectionAcuteRejectionGraftRejectionHyperacuterejection:occurswithin24hoursaftertransplantationmediatedbypre-existingantibodiesspecificforgraftantigensmassiverecruitmentofneutrophilsoccursfollowedbyrapidinflammationABOincompatibilityGraftRejectionAcuterejection:occursinthefirstfewdaystomonthsaftertransplantation,80-90%inthefirstmonthMediatedbyTcellsimmuneresponseMassiveinfiltrationbymacrophagesandlymphocytesGraftRejectionChronicrejection:occursinmonthstoyearsaftertransplantationmediatedbyhumoralandcellresponseschronicvascularrejectionandvascularendothelialinjury;organdegenerationanddysfunctionnotinducedbyimmuneresponseAcuteRejection,Kidneyoccurinthe1styearaftertransplantation，inonly10%ofpatients;ifdonotreceiveinductiontherapy,20-30%Reasons：inadequatedruglevels,noncompliance,orlesscommonformsofrejection(suchasantibody-mediatedrejectionorplasmacellrejection)

mediatedbythecellularimmunesystemandTlymphocytesspecificpathologicchanges:

lymphocyticinterstitialinfiltrates,tubulitis,andarteritisAcuteRejection,KidneyDiagnosis:

percutaneousrenalbiopsy;

excludingcalcineurininhibitornephrotoxicity

(troughand/orpeaklevelsandassociatedsigns),infection(urinalysisandculture),andobstruction(renalultrasound)Manifestations:elevatedserumcreatinine(initialsymptom),decreasedurineoutput,increasededema,orworseninghypertension；Constitutionalsymptoms(fever,malaise,arthralgia,painfulorswollenallograft)areuncommonAcuteRejection,Lung

Ofthesolidorgantransplants,thelungisthemost

immunogenicorgan.

Themajorityofpatientshaveatleastoneepisodeofacuterejection.developmentofchronicrejection(bronchiolitisobliteranssyndrome)occursfrequentlyandmostcommonlyinthefirstfewmonthsaftertransplantationDiagnosis:

fiberopticbronchoscopywithbronchoalveolarlavageandtransbronchialbiopsiesAcuteRejection,LungManifestations:

nonspecific;fever,dyspnea,andanonproductivecough；chestradiographisusuallyunchanged；Changeinpulmonaryfunctiontestingisnotspecificforrejection,buta10%orgreaterdeclineinforcedvitalcapacityorforcedexpiratoryvolumein1second,orboth,isusuallyclinicallysignificantmustdistinguishrejectionfrominfection!Toughsymptomsaresimilar,treatmentsaremarkedlydifferentAcuteRejection,Hearttwotothreeepisodesofacuterejectioninthefirstyearaftertransplantation;50%to80%,atleastonerejectionepisode,mostcommonlyinthefirst6months.Diagnosis:endomyocardialbiopsyperformedduringroutinesurveillanceoraspromptedbysymptoms；irreplaceable;repeatedendomyocardialbiopsies,severetricuspidregurgitationManifestations:symptomsandsignsofleftventriculardysfunction----dyspnea,paroxysmalnocturnaldyspnea,orthopnea,syncope,palpitations,newgallops,andelevatedjugularvenouspressureManypatientsareasymptomaticAcuteRejection,Liveroccurswithinthefirst3monthsaftertransplantandofteninthefirst2weeksaftertheoperationgenerallyreversibleanddoesnotportendapotentiallyseriousadverseoutcome

asinotherorganscommonlyexperienceacuteallograftrejection,withatleast60%havingoneepisodeAcuteRejection,LiverDiagnosis:liverbiopsy

Manifestations:

mild,onlyaslightelevationintransaminases；severe,developto

liverfailure:fever,malaise,anorexia,abdominalpain,ascites,decreasedbileoutput,elevatedbilirubin,andelevatedtransaminases.Differentialdiagnosis:primarygraftnonfunction,preservationinjury,vascularthrombosis,biliaryanastomoticleak,orstenosis肝匯管區(qū)內(nèi)大量以淋巴細(xì)胞為主的炎性細(xì)胞浸潤(rùn)，并可見(jiàn)小葉間膽管上皮炎性細(xì)胞浸潤(rùn)形成導(dǎo)管上皮炎損傷肝小葉間靜脈血管內(nèi)皮炎，內(nèi)皮層有淋巴細(xì)胞浸潤(rùn)并呈內(nèi)皮水腫ChronicAllograftDysfunction

accountsforthevastmajorityoflategraftlosses;mediatedbyimmuneandnonimmunefactorsslowlyprogressive,insidious;majorobstacletolong-termgraftsurvivalPathologic

characterization：gradualvascularandductalobliteration,parenchymalatrophy,andinterstitialfibrosisDiagnosis:oftendifficultandgenerallyrequiresabiopsyTreatment:

ifestablished,

noeffectivetherapy;requireasecondsolidorgantransplant;aimedatprevention

CompanyLogoGraftRejectionGeneralPrinciplesDiagnosisManifestationsTreatment-----ChronicAllograftDysfunctionAccountsforthevastmajorityoflategraftlossesandisthemajorobstacletolong-termgraftsurvival?Difficult?Requireabiopsy?MediatedbyimmuneandnonimmunefactorsUnique?Noeffectivetherapy?Asecondsolidorgantransplant?PreventionComplications

InfectionsRenalDiseaseMalignancyCMVHepatitisBHepatitisCEBVFungusParasiteComplications●Skincancer●LipCancer●LymphoproliferativeDisease●BronchogenicCarcinoma●KaposiSarcoma●Uterine/CervicalCarcinoma●RenalCellCarcinoma●AnogenitalNeoplasmsCompanyLogoComplications----InfectionsTreatmentTreatmentDiagnosisPolymeraseChainReaction(PCR)----BloodSample?Valganciclovir

?450to900mg

PObid

?Ganciclovir

?2.5to5.0mg/kgbidIVadjustedforRenalFunctionCMV?Hyperimmuneglobulin+Ganciclovir

☆

OrganInvolvement

?Foscarnet/Cidofovir

☆

GanciclovirResistantComplications----InfectionsHepatitisLamivudinTextRibavirinInterferonHepatitisBHepatitisCOralFluconazole●Playaroleinthedevelopmentofposttransplantlymphoproliferativedisease●Immunosuppression↓OralFluconazoleComplications----InfectionsEBVFungusParasiteCompanyLogoTimingandEtiologyofPosttransplantInfectionsTimePeriodInfectiousComplicationEtiology<1monthposttransplantNosocomialpneumonia,woundinfection,urinarytractinfection,catheter-relatedsepsisBacterialorfungalinfections1-6monthposttransplantOpportunisticinfectionsCytomegalovirus,Pneumocystisjiroveci,Aspergillusspp.,Toxoplasmagondii,Listeriamonocytogenes,Strongyloidesstercoralis,WestNilevirus,Varicella-zostervirusReactivationofpreexistinginfectionsMycobacteriaspp.,Endemicmycoses>6monthposttransplantCommunity-acquiredinfectionsBacterialTick-bornediseaseChronicprogressiveinfectionHepatitisB,HepatitisC,CytomegalovirusEpstein-Barrvirus,PapillomavirusPolyomavirus(BK)OpportunisticinfectionsP.Jiroveci,L.monocytogenesNocardiaasteroides,CryptococcusneoformansAspergillusspp.,WestNilevirusCompanyLogoComplicationsRenaldiseaseTheleadingcauseofallograftlossinrenaltransplantrecipientsCalcineurininhibitor(CsA,Tacrolimus)

NephrotoxicityChronicrenalinsufficiencyEnd-stagerenaldisease(ESRD)CompanyLogoComplicationsMalignancyThree-tofourfoldhigherthangeneralpopulationSkinandlipcancers

?40-50%intransplantrecipients?Riskfactors:immunosuppression,UVradiation,HPV?Developatyoungerage?Recommend:protectiveclothing,sunscreensavoidsunexposure?Diagnosis:examinationoftheskinCompanyLogoComplicationsMalignancyPosttransplantlymphoproliferativedisease

?1/5ofallmalignanciesaftertransplantation?Riskfactors:antilymphocytetherapy?Majority:large-cellnon-HodgkinlymphomasoftheB-celltype?Presentation:atypical?Diagnosis:requiresahighindexofsuspicionfollowedbyatissuebiopsy?Treatment:reductionorwithdrawalofimmunosuppressionchemotherapyCompanyLogoSpecialConsiderationsDrugInteractionsImportantdruginteractionsarealwaysaconcerngiventhepolypharmacyassociatedwithtransplantpatients.prescribinganewmedicationtoatransplantrecipient,alwaysinvestigatedruginteractions..Specialconsieration

druginteractions

allopurinol+azathioprine:

avoidedorusedcautiously;profoundmyelosuppressionCsA/tacrolimus:

metabolizedbycytochromeP-450；