Immunological Challenges in Kidney...

Immunological Challenges in Kidney Transplantation

Andreea Mirela Caragea1; Ion Maruntelu1; Ileana Constantinescu1,2*

1Immunology and Transplant Immunology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

2Centre for Immunogenetics and Virology, Fundeni Clinical Institute, Bucharest, Romania

*Correspondence to: Ileana Constantinescu, Immunology and Transplant Immunology, Carol Davila University of

Medicine and Pharmacy, Bucharest, Romania

Email: [email protected]

Chapter 1

Kidney Transplantation

1. Matching Donor and Recipient

End stage renal disease (ESRD) is an epidemiological notion that starts from the idea that persistent kidney damage may be the consequence of many etiological factors. ESRD consists of the progressive nephron loss and renal function damage.

When the glomerular filtration rate (GFR) reaches a critical level below 60 ml/minute/1.73m2,adaptiverenalandsystemicmechanismsbecomeharmfulresultinginare-ductioninthenumberofnephronswhichleadstochronickidneydisease(CKD).

TherearemanyetiologiesforCKDbutthemostcommoncauseisglomerulonephritis(60%),followedbychronicpyelonephritis(30%),vesicoureteralrefluxandpolycystickidneydiseaseandtheremaining10%isrepresentedbydiabeticnephropathies,collagendiseasesandHenoch–Schönleinpurpura[1].Inpediatricpatients,ismorelikelytohavehereditaryneph-ropathyandcongenital kidneyhypoplasia.Focal sclerosingglomerulonephritis is themostcommon form of glomerulonephritis leading to end stage renal disease in childhood.

ESRDmaybenefitfromtwotreatmentmethods:hemodialysisandkidneytransplant.Hemodialysis improves survival rates until transplantation and is also useful after transplant in theeventoffailure.However,long-termdialysistreatmentformorethanoneyearconferredahigher riskofgraft rejection.Forchildrenwhoaredependentondialysis, therearewelldocumentedadverseeffectsoncognitivefunction,growth,anemia,osteodystrophyandmanyothereffectsduetothelackofendocrinefunction.Thefirstlineoftreatmentinapatientwith

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KidneyTransplantationConstantinescuI

endstagerenaldiseaseiskidneytransplantation.Itisthemosteffective,acceptedandrequiredtreatment method (Figure 1).

KidneytransplantationrepresentstheoptimaltreatmentforpatientswithESRDandof-fersmoresubstantialbenefitsincomparisonwithdialysis.Thesebenefitsincludereplacementoftheregulatory,excretoryandendocrinefunctionsofthekidney.Itcorrectsproblemssuchasrenalanemia,improvessocialadjustmentandqualityoflife.Fortheseadvantages,preemp-tivetransplantation,definedastransplantationpriortotheinitiationofdialysis,isthepreferredtreatmentforpediatricpatientswithkidneydisease.

Recent advances in pre and post-transplantation management, immunosuppressivemedications,surgical techniquesanddonorselectionhavecontributedtoimprovedpatientsand graft survival among kidney transplant recipients.

2. Tissue Typing

Clinicalengraftmentofhistocompatibilitymismatchedorgansbetweentwogeneticallydifferentindividualsofthesamespeciesproducesanimmuneresponsebythehostimmunesystem.Theallorecognitionisdeterminatebyalloantigensofthehostwhichareencodedwith-inthemajorhistocompatibilitycomplex(MHC)[2].

Figure 1: Kidneytransplant

Figure 2: Chromosome6

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KidneyTransplantation

Themajorhistocompatibilitycomplexrepresentsaclusterofgenesandislocatedontheshortarmofchromosome6(Figure 2). This is the most polymorphic and the most studied region inthehumangenomebecausevariantsatthislociareassociatedwithtransplantcompatibility,autoimmunediseases,infectiousandinflammatorydiseases[3].TheMHCencodesthehumanleukocyteantigens(HLA)genes,whichisdividedintofourregionsA,B,CandD.ClassIisrepresentedbyA,B,CregionsandtheycodeforclassImolecules(HLA-A,-B,-C).ClassIIisrepresentedbyDregionandcodeforclassIImolecules(HLA-DR,-DP,-DQ).TheMHCalsocontainsclassIIIregion,themostgene-denseregioninthegenome,thatcodeformoleculessuchascomplementproteins,C2,complementfactorB(CFB),C4,TNF,heatshockproteincluster,growthproteins,thatarecalledclassIIIMHCmolecules.

ClassIHLAmoleculesareexpressedinallnucleatedcellsandplateletswhileclassIIHLAmoleculesareexpressedonantigenpresentingcells(APC)likedendriticcells,Blym-phocytes,macrophages.

ThefundamentalroleofclassIandclassIImoleculesistobindtotheirselfandnon-selfpeptideswhichthentransportstotheplasmamembraneofthecellsforTcellantigenreceptorrecognition[4].

ClassIHLAmoleculesbindpeptidesmadeof8-10aminoacidsandpresentthesepep-tidestoCD8cytotoxicTlymphocytes.ClassIproteinsarehighlypolymorphic.HLA-Bisthemostpolymorphicgeneknowninthehumangenome.ClassIIHLAmoleculesbindpeptidesmadeof13-25aminoacidsandpresentpeptidestoCD4helperTlymphocytes.

ActivationofCD4andCD8Tcellsbythesetwopathwaysleadstocelldivisionanddifferentiationresultinginacellularandhumoralimmuneresponse.

Anallelerepresentsavariantofagivengenewhichisfoundatthesameplaceonachro-mosome.ThenomenclatureofHLAallelesiscomposedofthelocusandthegenenamewhichareseparatedbyahyphenandanasterisk,followedbytwodigitswhichdefinethealleleofthegene and this number frequently but

Notalwaysmatchestheserologicaltype[5].Thethirdandfourthdigitsareusedtolistthe subtypes (Figure 3).

Figure 3: HLA nomenclature

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EachindividualinheritsfromparentsonesetofHLAgenesinaMendeliantransmission(Figure 4).

HLA genes are normally inherited “en bloc” from parents because of their close physi-cal linkage.

Despitetheimmensecomplexityofthesegenesclusters,therearenormallyfourgeno-types transmitted. All children inherit a haplotype from their mother and a haplotype from theirfather.Thechancetofindbetweensiblingsa100%HLAcompatibledonoris25%.Thereisa50%chanceoftwosiblingssharing1haplotype(50%HLAcompatibledonor)anda25%chanceoftwosiblingsnotsharingahaplotype(0%HLAcompatibledonor).

Inthecaseofconsanguineousmarriages,thereisachancethatparentsandchildrencanbe100%compatible.

Inthecaseofheart/liver/kidneyorganfailure,thebesttherapyisanorgantransplant.The kidney graft is perceived by the recipient immune system as non-self so the allograft is infiltratedwithhostcellswithinseventotendaysresultingingraftloss.

HLA has an important role in long-term graft preservation.

Inkidneyallografts,themostimportantdeterminantsofearlytransplantationsuccessorfailureare:

- methodoforganpreservation,

- coldischemiatime,

Figure 4: MendelianTransmission

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- number of blood transfusions

- recipient’s age

- theprimarycauseforkidneyfailure,

- priororgantransplant,

- immunosuppressive therapy.

The role of a histocompatibility test in organ transplant is to select the best donor for a recipient. HLA laboratories perform various tests to support transplant programs like HLA typing,detectionofHLAantibodiesandthecross-matchingtest.

HLAmatchingimproveslong-termgraftsurvivalrates(GSRs).Thisisanimportantfactbecausethetreatmentoforganfailurewithatransplantislimitedbythenumberofavailabledonors.Toincreasethechancesforaretransplant,whennecessary,weneedtoincreasetheduration of graft survival.

Thehighestsurvivalrateoccurswhenallsixantigensarematched(6/6match).KidneytransplantsmaybedonewithanHLAcompatibilitybelow50%buttheDRlocusmustmatchbetweendonorandrecipient.

Beforeatransplant,allpatientswhoareonthewaitinglistaretestedforHLAantibod-ies.Thisoffersvaluableinformationfordonorselection.

Sera are collected and screened for the presence of HLA antibodies on a regular basis. HLAantibodiesdevelopduringbloodtransfusions,pregnancyorpreviousorgantransplants.All immunization can occur prior to kidney transplant thus continuous patient monitoring is required.

Antibodydeterminationinvolvestwosteps.Inthefirststep,theserumisputincontactwithpurifiedlymphocytesfromadonororHLAantigensofadonortoseethereactivityex-pressedinpercentoftheantibodies.Inthesecondstep,weneedtoidentifythespecificityofHLA antibodies present in the serum.

HLAantibodiesareinvolvedingraftrejection,sotheirperiodicdeterminationisveryimportant (Figure 5).

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Wemayconsiderapossibleantibody-mediatedrejectionwhenwehavealowerrenalfunction.

Kidneyallograftrejectioniscategorizedinto4categoriesaccordingtothetimeofpost-transplantation,clinicalandanatomo-pathologicalmanifestations,responsetoanti-rejectiontreatment (Figure 6).

1.Hyperacuterejection:Occurswithinthefirstfewhoursoreventhefirstfewminutesafterrenaltransplantation.Thegraftstopsfunctioningandmustberemoved.Anti-HLAclassIan-tibodies attack the donor cells thinking of it as a non-self or foreign antigen. Antigen-antibody interactionwithinglomerularcapillariesresultsinthedevelopmentneutrophil-infiltratedcom-plementdeposits,plateletaggregation,andintracapillarythrombusformation.Attheanatomo-pathologicalexamthekidneyiscongestedandedematous,withblue-violetorcyanoticbluecolorchanges.Microscopically,extensivecorticalinfarctionisreportedinglomeruliandtherenaltubules.Studiesinimmunofluorescenceshowexcessfibrinandimmunoglobulins(IgG)aswellascomplementdepositsinglomerularcapillaries.

Clinically,thepatienthasanuria,hypertension,hyperkaliemia,metabolicacidosisandpulmonaryedema.ThethromboticprocessinitiatedatthekidneycanexpandandprogresstoDisseminatedIntravascularCoagulation(DIC).DICisaconditionwhichiscausedbysmallthrombiwhichblockthesmallbloodvessels.Itcausesthrombocytopeniaanddepletesclottingfactorswhichinturnleadstointernalhemorrhages.

Renal artery thrombosis or renal artery embolism have the same appearance on kidney radi-ography.

Figure 5: HLA antibodies cause graft injury in the donor vasculature

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Hyper acute rejection should be distinguished from other anuria causes such as urinary tractobstruction,ureternecrosiswithurinaryfistula,acuteischemictubularnecrosisorsevereintravenous volume depletion.

2.Acceleratedacuterejection:Appearsdaysorweeksaftertransplantation.Inmostcases,pa-tientshavegoodurinevolumeandnormalkidneyfunctionatfirstandthendevelopacutekid-neyfailurewitholiguriaduetoimmunologicalrejection.Themechanismbehindthisisduetograftlesionscausedbydonor-specificantibodiesthatdevelopedafterthetransplant.Clinicallyand anatomo-pathologically acute accelerated rejection and hyper acute rejection are hard to distinguish,thedifferentiationcriteriaareasfollows:

- The time span of post-transplant rejection;

- The presence or absence of anti-donor antibodies at the time of transplantation.

3.Acuterejection:Thisisacell-mediatedrejection.ThekeyplayersaremainlyTlymphocytes,Blymphocytes,macrophagesandtherestofthecellpopulationcomposedofneutrophilsandnatural killer cells.

4.Chronicrejection:Thetriadofhypertension,proteinuria,andprogressivedeteriorationofrenal function is commonly attributed to chronic renal allograft rejection. This complication mayoccurattheearliest6monthspost-transplantandisthemostcommoncauseofgraftlossmorethan1yearaftertransplant.Theexactpathogenesisofchronicrejectionisunknownbutimmunofluorescence shows thepresenceof immunoglobulins (IgG, IgM) and complementdeposits in glomerular capillaries.

3. Blood Group Matching

Bloodgroupcompatibilityisessentialforsuccessfulkidneytransplantation(Figure7).KidneystransplantwithABOincompatiblebloodgroupsarelargelyunsuccessfulduetothe

Figure 6: HLA antibodies cause graft injury in the donor vasculature

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hyperacuterejectionphenomenoncausedbyanti-Aand/oranti-Bantibodies.AntibodiesbindtoAand/orBantigensfromtheendotheliumofthegraft,activatingthecomplementcascade,inducing platelet aggregation and intravascular thrombosis. The most important blood antigens areA,BandOgroupantigens.Theseantigensarefoundinmanycellsincludingerythrocytes,plateletsandendothelialcellsofallvascularvessels.Bloodgroupantigensarepolysaccha-rides and they do not need T cell sensitization for antibody induction.

BloodgroupmatchinginABOsystemattherecipientanddonoristhefirstconditiontoperformakidneytransplant.PatientswhoarecandidatesforrenalgraftwillbedeterminederythrocyteantigensinABO,Rh,Lewis,P,Ss,Iisystemsandwillbeinvestigatedthepresenceof irregular antibodies.

WhenABOcompatibledonorsarenotavailable,crossingtheABObloodtypebarrieristheonlychanceforsomepatientstoreceivearenalgraft[6].KidneytransplantfromABOincompatiblebloodgroup(ABOi)donorsbecametheonlyoptionforthepatientswhoareonthewaitinglist.AlthoughABOirenaltransplantisnowfeasible,antibody-mediatedrejectionofthegraftremainsanimportantissue.BecausethenumberofpatientswithESRDisincreas-ingandthereisalackofkidneydonors,researchersinJapandevelopednewtherapeuticstrate-gies.

CurrentstrategiesofABOirenaltransplantconsistinpretransplantremovalofisoag-glutinin titers to prevent antibody mediated rejection. Desensitization protocols are based on plasmapheresisorplasmaexchangepreoperativelyortheuseofanti–CD20monoclonalan-tibody(Rituximab)reducedthehightitersofisoagglutinin.

Splenectomy is another procedure that can be used to reduce the high titers of isoag-glutininwhich are responsible for hyperacute rejection inABOibloodgrouppatients.Butsplenectomyalsoincreasestheriskofsepsisinpatientswithaggressiveimmunosuppressiontherapyandplasmaexchange[7].

ThenumberofABOikidneytransplantshasincreasedworldwidebecauseofthegoodresultsandimprovedoutcomesobtainedbyJapanesesurgeons.

Figure 7: ABOmatching.

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4. Cross Matching

Thepurposeofcross-matchingtestistodetectinthepatient’sserum,thepresenceofantibodiesdirectedagainstdonorHLAantigens.Cross-matchingisperformedonTcelllym-phocyteswhichexpressHLAclassImoleculesandonBcellswhichexpressclassIandclassIImolecules[8].

Ifantibodiesarepresent,itshowsthattherecipient’simmunesystemhasbeensensi-tized to thedonorantigensand is susceptible toallografthyperacute rejectionand/orearlygraft loss (Figure 8).

Theseraofsomepatientswithanautoimmunediseaselikesystematiclupuserythema-tosusandpatientsonbloodpressuremedication(hydralazineandprocainamide),canoftencontain autoantibodies.

Theseautoantibodiesdonotaffectthegraftandareimportantbecausetheycanmimicdonorspecificantibodiesandsubsequentlydeprivearecipientofagraftdonor.Thedonorspe-cificantibodiesandtheautoantibodiescanberemovedwithdithiothreitol(DTT)treatment.Thecrossmatchtestshouldneverbeinterpretedalone,withoutanyinformationaboutthepa-tient’s history.

The virtual crossmatch (v-XM) decrease theworkload inHLA-laboratories and facilitatestheorganallocationeveninsensitizedrecipients[9].InastudypublishedinSeptember2014

Figure 8: Antibody mediated rejection.

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Piazzaetal.showedthatV-XMprotocolhadagoodsensitivityinpredictingdonor-recipientimmunologiccompatibility[10].

5. Highly Sensitized and Regraft Recipients

SensitizationisaprocesswherethepatientisexposedtononselfHLAantigens.Sensi-tizationcanoccurduringbloodtransfusions,Pregnancyorapriororgantransplant[11].

Thenumberofpatientswaitingforakidneyretransplantsafterafailedkidneygrafthasincreasedovertime.Theapproachtotheretransplantrecipientswithhighsensitization,repre-sent a challenge for organ transplantation.

Recipients of kidney retransplant are at high immunological risk for graft rejection. Causesincludepriorsurgery,sideeffectsfromchronicimmunosuppressiontherapy–nephro-toxicdrugs,theriskofsensitizationwithanelaboratedpanelofreactiveantibodylevelsandother comorbidities.

Outcomesinretransplantpatientsincludemanyfactorslikethesourceofthedonor(liv-ingordeceaseddonor),functionaldurationofthefirstgraftandelapsedtimebetweenfirstandsecond graft.

Therateofkidneygraftfailureishigherinpatientswhoreceiveagraftfromadeceaseddonorcomparedwithpatientswithagraft froma livingdonor [12].Oneof the reasons isprolongedcoldischemiatime(CIT)whichleadstodelayedgraftfunction(DGF).DGFafterprimarytransplantsisassociatedwithanincreasedprobabilityofrecurrence.

Long-termgraftsurvivaldecreaseswithsubsequentretransplants.Graftsurvivalisaf-fectedbyfactorssuchasrepeatedsurgery,acuterejection,anon-functionalprimarygraft,theimmunosuppressiveregimen,thenumberofHLAmismatchesandsurgicalcomplications.

Failedgraftnephrectomymaybeindicatedbeforekidneyretransplantifitisassociatedwith refractoryhypertension,urinary tract infections, urinary tuberculosis, andproteinuria.Itisnotyetclearifthepresenceofafailedgraftcanstimulatetheproductionofantibodies,thereforenephrectomydecisionshouldbebasedonclinicalindications.Betweenkidneyre-transplantandhemodialysis,retransplantationremainsthetreatmentofchoice.

6. Networks and Tissue Type Matching

Manypatientswithend-stagekidneyfailurehavedifficultiesinfindingadonorintheirowncountry.Tofix thisproblem, internationalorganprocurementand transplantationnet-worksappeared.

Worldwidetransplantationnetworksplayanimportantroleintheallocationanddistri-

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butionofdonororgansfortransplantationbaseduponmedical,ethicalcriteriaandincompli-ancewiththenationallegislationofthemembers’countries.

Intheworldaremanytransplantationnetworkssuchas:

Eurotransplant(Austria,Germany,Belgium,Croatia,Hungary,Luxembourg,theNeth-erlands and Slovenia).

Scandiatransplant(Iceland,Norway,Finland,DenmarkandSweden),

Baltransplant(Estonia,LatviaandLithuania)

NHSBloodandTransplantintheUK

UnitedNetworkforOrganSharing(UNOS)intheUSA

Theyserveasacommonorganexchangeorganizationandallocationresourcefortheirmemberhospitalsincludingkidney,liver,heartandlung.

7. Immunosuppressive Agents

The integrity of humoral and cellular immune response is essential for preventing in-fections.Insomesituations,suchasautoimmunediseasesandsolidorgantransplantation,theactivity of humoral and cellular immune system has to be suppressed.

Post-transplant status involves cellular immunity. Both for graft-versus-host disease(GvHD)andhost-versus-graftreactions,CD4+Tlymphocytesareactivatedwhenaforeignantigenbinds toHLAclass II antigenson the surfaceofmacrophages (antigenpresentingcells).

SpecificT-cellcloneswillbindtotheantigenviatheTcellreceptor(TCR).TCRacti-vationresultsinasignaltransductioncascadethatwilleventuallyleadtoendocytosisoftheantigen inmacrophagesand itsdestruction in lysosomes. In thiscascade,calcium ionsareactivatedtoactivatecalcineurin,aphosphatasethatformsacalmodulincomplex.

ActivatedcalcineurindephosphorylatesT-cellcytosolicfactor(NF-AT)Candthusac-tivatesit.TheactivatedT-cellcytosolicfactor(NF-AT)Cmigratestothenucleusandbindstoitscounterpart(NF-AT)N.Theresultingtranscriptionallyactivecomplexwillinducethesynthesisofinterleukin-2(IL-2)thatissecretedasanextracellularmitogen.

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IL-2bindstoitsTlymphocytereceptor,whichitactivatesbybindingaprotein,termedra-pamycintarget(TOR).TORactivatescyclinkinasesthatfacilitatecellcycleprogressionfromG1toSandstimulatenucleotidesynthesis.Theprocessresultsinthedifferentiationandpro-liferationofTcellsandwilleventuallyleadtothedestructionoftheantigen.

Specificdrugshavebeendeveloped.Theyblockoneormoreoftheabove-mentionedsteps,thusinhibitingthedestructionoftheantigen.

Cyclosporineandtacrolimusarecyclicpolypeptidesthatbindtointracellularproteinscalledimmunophilins(whiletacrolimusbindstotheimmunophilincalledFKBP12),resultingincomplexesthatsubsequentlyblocktheactivationofcalcineurin-inducedNF-ATandconse-quentlythesynthesisofIL-2.

Cyclosporine

CyclosporineAisrecommendedtopreventgraftrejectioninallogeneictransplantationofkidney,liver,heart,andlung-heart.

itisalsousedasamedicineofthefirstorsecondlineinthetreatmentofacutegraft-versus-hostdisease(acuteGvHD)forbonemarrowarisingafter thetransplantation,severerheumatoidarthritis,andinsomesevereformsofpsoriasis.

Themaximum blood level is reached approximately 3.5 hours after administration;about20-40%oftheadministereddoseisabsorbedintestinallyandit ismetabolizedat thefirstpassageoftheliver.TheisoenzymeCYP3A4ofcytochromeP450isresponsibleforthemetabolismofcyclosporineinatleast30metabolites.BecausealargenumberofdrugscaninducetheenzymeormaybemetabolizedbyCYP3A4(antibiotic,antifungalorotherimmu-

Figure 9: ImmunosuppressivedrugsaffectingIL-2

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nosuppressant’s) the combination could alter the levels of cyclosporine in the blood and thus complicate treatment.

Cyclosporinehasanarrowtherapeuticintervalwithfrequentsideeffects,whichmakesmonitoring of its blood concentration essential.

Since80%ofcyclosporineissequesteredinerythrocytes,itisrecommendedthatdruglevelsweredeterminedinwholebloodsamples.Inthefirst2monthspost-transplant,thedosesareadjustedtomaintainconcentrationsbetween150ug/Land400ug/L.Troughconcentra-tionsobtainedsamplescanbevariedaccordingtotheclinicalprotocol,suchasallograftrejec-tionrisk,concomitantuseofotherimmunosuppressant’sandtoxicity.Afterthefirst2months,thetherapeutictargetisgenerallylower(between75and300ug/L).

Thesideeffectsofcyclosporinemayoccurinanyorgan;maximumconcentrationvalues(troughsamples)>500mg/L.Themostcommonadversereactionisnephrotoxicityfollowedbyhyperkalemia,hyperuricemia,hypertensionandgingivalhyperplasia.

Tacrolimus

Itisamacrolideclassantibioticwithamechanismofactionsimilartocyclosporinebutwithamorepotentinhibitoryeffectthanit.Itisusedtopreventorganrejection.

TacrolimusismetabolizedintheliverbyCYP3A4,soitsbloodlevelsareaffectedbothbydrugsthatinhibitthisenzyme(calciumchannelblockers,antifungals,someantibiotics)andthosethatinduceenzymeactivity(anticonvulsants,rifampicin).

Since90%oftacrolimusisfoundinbloodcellcomponents,itisrecommendedthatdruglevelsweredeterminedinwholebloodsamples.Concentrationsintroughsamplesmayvarydependingontheclinicalprotocol,allografttype,riskofrejection,concomitantadministrationofotherimmunosuppressant’sandtoxicity(mainlynephrotoxicity)butshouldnotexceed20ug/L.

The toxic potential is similar to that of cyclosporine: nephrotoxicity, neurotoxicity(tremor, headache), gastrointestinal disorders (nausea, diarrhea),HAT, glucosemetabolismdisorder,hyperkalemia,andinfectiousdiseases.However,thereisnogingivalhypertrophyorhirsutism.Anaphylaxisisdescribedonlyforintravenousadministration[13].

Rapamycin (sirolimus)

Anotherimmunosuppressiveagent-rapamycin(sirolimus)-doesnotexertanyeffecton T cells.

RapamycinisasimilarantibiotictotacrolimusthatsuppressestheproliferationofBand

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T lymphocytes; also has anti-neoplastic and antifungal activity.

ItinhibitsTORproteinkinaseandblocksthecellcycle.Ithasnoeffectoncalcineurinandcan,therefore,beusedwithcyclosporineandtacrolimus.

SirolimusismetabolizedbyCYP3A4,soitsbloodlevelsareaffectedbothbydrugsthatinhibit this enzyme and those that induce enzyme activity.

Thepharmacokineticinteractionbetweensirolimusandcyclosporineortacrolimusin-creasesboththerapeutic immunosuppressionandthetoxicityof theseagents;asaresultofcombineduse,lowerdosesareneeded.

Adversereactionsaregenerallydose-dependent,somonitoringbloodlevelsofthedrugare important. These include gastrointestinal disorders and thrombocytopenia; the medicine doesnotappeartobenephrotoxic.

Mycophenolate mofetil (MMF)

Mycophenolatemofetil(MMF)isanantibioticthatishydrolyzedincellsinfreemyco-phenolic acid. This agent is a potent inhibitor of inosine monophosphate dehydrogenase and guanosinemonophosphatesynthase,ultimatelyinhibitingDNAsynthesis[14].

Corticosteroidsalsoexert immunosuppressiveeffectsoncell-mediatedimmunity,butthesearemuchlessspecificandaccompaniedbynumerousadversereactions.

8. Immunosuppressant Antibodies

Anti-thymocyte globulin

ThisisapolyclonalIgGantibodyfromhorsesorrabbitsimmunizedwithhumanthymo-cytes.Infusionsofanti-thymocyteglobulincauseprofoundT-celldepletionandthelymphope-niatypicallypersistsbeyondoneyear.Anunwantedeffectisthereleaseofcytokines.Thisisassociatedwiththe‘cytokinereleasesyndrome’characterizedbyfever,rigors,andhypoten-sion.

Antibodies against CD25

BasiliximabanddaclizumabaremonoclonalantibodiesagainstCD25.CD25isarecep-tor on the surface of T-lymphocytes.

Theseantibodiesarewelltoleratedandhypersensitivityreactionsareuncommon.So,theydon’tneedmonitoring[15].

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Muromonab-CD3

Thisisamouse-derivedmonoclonalantibodywhichbindstotheCD3componentoftheT-cellreceptorcomplexleadingtoT-celldepletion.Muromonabisalsoassociatedwiththecytokine release syndrome.

Alonger-termconcernistheincreasedincidenceoflymphoma[15].

9. Prophylactic Regimens for Renal Transplantation

Inanysolidorgantransplantation,preventionofpost-transplantinfectionisvital.

Bacterial infectionsusuallycomefromsurgicalwoundsand theurinary tract inkid-neytransplant.Hence,itisessentialtogiveperioperativeantibacterialprophylaxistopreventwoundinfectionsinkidneytransplantrecipients[16].

Many studies showed that prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX)orciprofloxacinafterkidneytransplantationareeffectiveinpreventingUTIsandbac-teremia[17].TMP-SMXprophylaxisalsoprotectsagainstP.carinii,L.monocytogenes,N.asteroides,andT.gondiiinfections[17].

IncaseofPurifiedProteinDerative(PPD)-positiverecipients,isoniazid(INH)prophy-laxisisrecommendedbytheAmericanLungAssociationbutwithsomeconcerns[18].De-spitebeingproveneffectiveinpreventingtuberculosis,INHcancausehepatotoxicityandalterthemetabolismofcyclosporineandtacrolimus[19].

Prophylaxiswithganciclovir,valganciclovirorfoscarnetiseffectiveforpreventingCy-tomegalovirus(CMV)infectioninsolidorgantransplantrecipientswithlatentCMV[20].

10. Induction Therapy in Adults

Thegoalistopreventacuterejection,optimizethefunctionofthetransplantedorganandminimizetheriskofinfectionsandcomplications.Inductiontherapycanbeusedforuptotwoweeksfollowingtransplantation.

The Immunosuppressive protocol includes induction therapy and long-termmainte-nance therapy.

Antibodyinductionisrecommendedinpatientswithimmunologicalrisk.IntheUS,ap-proximately60%ofrenaltransplantpatientsin2011receivedaninductionofT-cellantibod-ies,predominantlyanti-thymocyte(ATG).Another40%ofpatientsreceivedeitherantibodiesofIL-2receptor(IL-2RAB)ornoantibodyinduction[21].

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11. Induction Therapy in Children

ManyoftheinductionimmunosuppressiveagentscurrentlyusedintheUKarebiologi-calagentsincludingmonoclonalantibodies(suchasbasiliximab)andpolyclonalantibodies(such as rabbit anti-human thymocyte immunoglobulin).

12. Maintenance Immunosuppressive Therapy in Kidney Transplantation in Adults

Maintenanceimmunosuppressionisnecessaryaslongasallograftiswell-functioningtopreventrejectionofthetransplantedkidney[21].

Thereareseveralfactorstotakeinconsiderationwhenchoosingamaintenanceimmu-nosuppressiveregimenforaparticularpatientsuchasclinicalcharacteristics, immunologicrisk,comorbiditiesandthemedicationssideeffects[21].

Theriskofacuterejectionishighestinthefirstmonthsaftertransplantation.Infectionandothersideeffectscorrelatewithahighlevelofimmunosuppression.Malignancyisalatecomplication of immunosuppressive drugs.

Whenthereisnoepisodeofgraftrejection,immunosuppressionisusuallydecreasedslowlytoamaintenancelevelby6to12monthsfollowingtransplantation[22].

Inordertofindthebestregimensassociatedwithlessadversedrugsevents,researchersstudiedafewregimenswithandwithoutsteroids,CNIsandsirolimus.

The FREEDOMtrialincludedthreegroups:steroid-free,steroid-withdrawalandstan-dard-steroids.TheresultsofFreedomtrialandotherstudiesshowedthatsteroidsshouldbepartofthemaintenanceprotocolinsensitizedpatients[23,24].

The CAESARstudyprovedthatcyclosporinewithdrawallateraftertransplantwasas-sociatedwithhigherincidenceofacuterejectionthanthegroupwithcontinuedcyclosporine[25].

The SYMPHONYstudyconcludedthatthegrouptreatedwithdaclizumab/MMF/ste-roid/low-dosetacrolimushadthelowestrateofrejection,highergraftfunctionandbettergraftsurvivalthanothergroupstreatedwithstandard-dosecyclosporine/MMF/steroid,daclizumab/low-dosecyclosporine/MMFordaclizumab/MMF/steroid/sirolimus[26,27].

Inotherlong-termstudy,patientswithtacrolimus/MMFhadasignificantlylowerinci-dence of acute rejection and better renal function compared to other combinations of immuno-suppressivedrugs[28].

IntheUSA,combinationofmycophenolicacid(MFA),corticosteroidandtacrolimusis

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the most used maintenance both at beginning of transplant and later.

13. Maintenance Immunosuppressive Therapy in Kidney Transplantation in Children

Calcineurininhibitor(CNI;usuallytacrolimus)incombinationwithanantiproliferativeagent(e.g.,mycophenolatemofetilorazathioprine)andasteroid(e.g.,prednisolone),isusedin this population.

Long-termmaintenancetherapyisinalowerdosethantheinitialdoseastransplantedkidneybecomesmorestable[29].

Thistherapyiscontinuedthroughoutthegraftsurvival[30].

14. Barriers to Transplantation Tolerance

There are some barriers to transplantation tolerance. The optimal outcome for patients aftertransplantationwouldbeinductionofspecificimmunologicalunresponsivenessortoler-ance to the kidney allograft.

Bythistransplantedpatientscouldavoidtheadversesideeffectsassociatedwithcur-rent immunosuppressive regimens. To achieve tolerance is really problematic in the case of mismatched kidney allografts. The less mismatched HLA alleles the more acceptance of the kidneywithlessimmunosuppressivetherapycombinations.

Sincethefirstrenaltransplant,morethan55yearsago,onlysporadiccasesofclinicaloperationaltolerance(COT)havebeendocumentedafterrenaltransplantationintheabsencegeneticidentitybetweenadonorandrecipient.

MemoryTcellsarelesssensitivetoT-celldepletingantibodiesandcostimulatoryblock-ade and thus may be more resistant to some tolerance induction strategies.

KidneyrecipientsTreatedwithimmunodepletionantibodiescouldhaveanincreaseinthenaiveB-cellpopulation.

Thereisasignificantdevelopmentofalloantibodiesinkidneyrecipientstreatedwithdepleting antibodies therapy.

Lackoftolerancemeansepisodesofacuterejectionthatcanseverelyaffectthekidneyallograft survival. There is a lack of validated biomarkers of tolerance or predictors of rejec-tion.On thehorizon there are somepromising initiatives: -introductionof antigen-specificregulatory T cell therapy;

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-identificationofpredictorofregimenandtolerancesignatures;

-useofimmunomodulatorystemcellpopulation(i.e.,mesenchymalstromalcells).

Despiteprovidingthebestqualityoflifeandthemostcosteffectivetreatmentoptionfortreatmentofendstagerenaldisease,renaltransplantationremainsatthechallengingandexcitinginterfacebetweenclinicalresearchandlaboratoryscience.Itsdevelopmenthasalsobeenthecatalystfortransplantationofothersolidorgans,thepracticeofimmunosuppressionand much of clinical immunology.

Despiteallprogressesmoreworkneedstobedonetoachievelongtermimmunotoler-ance in kidney transplantation.

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