“ThisisTooMuchPressure!”TheUseofACEInhibitorsforHypertensionPost-RenalTransplantinthePediatricPopulation

KaylaM.Chambers,PharmDPGY1PharmacyResident

TheChildren’sHospitalofSanAntonioDivisionofPharmacotherapy,TheUniversityofTexasatAustinCollegeofPharmacy

UniversityofTexasHealthSanAntonioPharmacotherapyGrandRounds

April5,2019

LearningObjectives:1. Discussthesignificance,pathophysiology,andmanagementofhypertension(HTN)post-kidney

transplantinthepediatricpopulation.2. Reviewthepharmacokineticpropertiesofangiotensinconvertingenzyme(ACE)inhibitorsand

theirpotentiallybeneficialeffectsinpediatrickidneytransplantrecipients(KTRs).3. DiscusspotentialbarriersfortheuseofACE-Inhibitorspost-kidneytransplant.4. ReviewavailableliteratureregardingtheuseofACE-Inhibitorsforpost-renalhypertensive

managementinpediatricpatients.

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I.RenalTransplantinPediatricsA. EndStageRenalDisease(ESRD)1

1. ESRDisdefinedaschronickidneydisease(CKD)stage5definedasaglomerularfiltrationrate(GFR)<15mL/minper1.73m2

2. Theestimatedincidencevariesthroughouttheworlda. UnitedStates:14.8casespermillionchildren

3. RenaldiseasesresponsibleforCKDinchildrenaredifferentfromthoseobservedinadultpatients.

a. Renaldiseaseandfailurecanhaveanegativeimpactonachild’sgrowth,bonestrengthandneurologicfunction

4. RenaltransplantationisacceptedasthetreatmentofchoiceforchildrenwithESRD,asit:a. Providesbetterqualityoflifeb. Improveslong-termsurvivalthanincomparisontoothertypesofrenalreplacement

therapies

B. RenalTransplantation1. Epidemiology

a. IntheUnitedStates,approximately800renaltransplantsareperformedinchildrenbelow18yearsofageannually.2

i. 2018:755transplantswereperformedinpatients1-17yearsofage32. Etiology

a. Congenitalmalformationsofthekidneyandurinarytract(CAKUT),includingobstructiveuropathyandrenalaplasia,hypoplasia,ordysplasia

b. Hereditaryrenaldiseaseincludingpolycystickidneydisease,nephrolithiasis,congenitalnephroticsyndrome,andDrashsyndrome

c. Focalsegmentalglomerulosclerosis(FSGS)d. Othercausesofglomerulonephritise. Hemolyticuremicsyndrome(HUS)

3. Complicationspost-kidneytransplant

a. HTN(50-90%)b. Anemia(60-80%)c. Infection(20-30%)d. Malignancy(3-6%)e. Diabetesmellitus(1-7%)f. Mineralbonedisorders

II.PediatricHypertension

A. Background4-51. In2017,theAmericanAcademyofPediatrics(AAP)releasedthe“ClinicalPracticeGuideline

forScreeningandManagementofHighBloodPressureinChildrenandAdolescents”a. Providesupdatedrecommendationsfromthe2004“FourthReportontheDiagnosis,

Evaluation,andTreatmentofHighBloodPressureinChildrenandAdolescents”2. Prevalenceinthegeneralpediatricpopulation

a. NationalHealthandNutritionExaminationSurvey(NHANES)6-7i. MorethanoneinsevenU.S.youthaged12–19yearshadHTNor

elevatedbloodpressure(BP)in2013–2016

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3. BPshouldbe:a. Assessedinallchildren/adolescents(≥threeyearsofage)ateveryhealthcarevisit,

especiallyiftheyareobese,aretakingmedicationsknowntoincreaseBP,haverenaldisease,ahistoryofaorticarchobstruction,congenitalheartdisease,ordiabetes

4. ApproachtoBPMeasurementa. ThreemodalitiestomeasureBP:

i. CasualBPmonitoring:includesaseatedpatientwhohasrestedfor≥5minutes,duplicatemanualreadingsinanupperextremity,andtheappropriatecuffsize7

ii. 24-hourambulatorymonitoring(ABPM):includesadevicethatisprogrammedtorecordBPevery20-30minutesduringwakinghoursandevery30-60minutesduringsleephours9

iii. HomeBPmonitoring:moreaccurateandpredictiveoftarget-organdamagethancasualBPinchildrenandadolescents

b. TheinitialBPmeasurementmaybei. Oscillometric:performedusinganautomatedBPdevicethatanalyzes

pulsewavescollectedfromthecuffduringconstrictedbloodflowii. Auscultatory:performedmanuallyandallowsfortheaudibledetection

ofKorotkoffsoundsthatoccurduringconstrictedbloodflow

c. The2017UpdatedAAPGuidelinesincludeanewsimplifiedtableforinitialBPscreeningbasedonthe90thpercentileBPforageandsexforchildrenatthe5thpercentileofheight(seeAppendixA)

i. DesignedasascreeningtoolfortheidentificationofchildrenandadolescentswhoneedfurtherevaluationoftheirBP

d. IftheinitialBPiselevatedusingthesimplifiedtable,providersshouldperformtwoadditionalBPmeasurementsatthesamevisitandaveragethemtoclassifyBP(SeeAppendixB)

e. ClassificationofBPcanbeperformedonceaconfirmationofHTNhasbeendetermined

Table1.ClassificationofBloodPressureinchildren10

ChildrenAged1tolessthan13years ChildrenAged≥13yearsNormalBP:<90thpercentileElevatedBP:≥90thpercentileto<95thpercentileor120/80mmHgto<95thpercentile(whicheverislower)StageIHTN:≥95thpercentileto<95thpercentile+12mmHg,or130/80to139/89mmHg(whicheverislower)StageIIHTN:≥95thpercentile+12mmHg,or≥140/90mmHg(whicheverislower)

NormalBP:<120/80mmHgElevatedBP:120/80to129/<80mmHgStageIHTN:130/80to139/89mmHgStageIIHTN:≥140/90mmHg

II.Post-TransplantHypertensioninPediatrics

A. Background1. Poorlycontrolledbloodpressureiscommonamongkidneytransplantrecipients(KTRs);only

20-50%oftreatedchildrenreachnormalBP11-142. PrevalenceofHTNinchildrenafterrenaltransplantrangesfrom50-90%duringthefirst

monthfollowingtransplantation;incidencedecreasesovertime15

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Table2.PrevalenceofHTNinchildrenafterrenaltransplant16

PrevalenceofHTN

Studysize BPMethod DefinitionofHTN Author

59% 277 CasualBP UseofantihypertensivedrugsregardlessofBP Baluarteetal.1758% 5251 CasualBP UseofantihypertensivedrugsregardlessofBP Sorofetal.1870% 27 ABPM BP>95thcentileforclinicBPoruseofdrugs Lingensetal.1962% 37 ABPM BP>95thpercentile Giordanoetal.2083% 42 ABPM BPload>25%(95thcentileforclinicBP) Sorofetal.2162% 45 ABPM BP>95thcentileforBPload>30% Morganetal.2273% 26 ABPM BP>95thcentileforABPMandBPload>30% Serdarogletal.2389% 36 ABPM BP>95thcentileforABPMoruseofdrugs Seemanetal.24B. Etiology

1. Pre-transplantfactorsa. Pre-existingHTNandleftventricularhypertrophy(LVH)b. Bodymassindex

2. Donorrelateda. Livingordeceaseddonorb. Hypertensivedonor

3. Transplantationrelateda. Prolongedischemiatimeb. Delayedgraftfunction

4. Presenceofnativekidneyscausesunregulatedreninreleasethroughtheactivationoftherenin-angiotensinsystem(RAS)25

a. !Saltandwaterretentionb. !Extracellularvolumeandcardiacoutputc. !Peripheralvascularresistance

5. Renal-graftarterystenosisa. CorrectableformofHTNpost-transplant

6. Renaltransplantdysfunctiona. Chronicallograftnephropathy(CAN)

7. Immunosuppressivemedications

C. HypertensiveEffectsofImmunosuppressivemedications:Table3.SummaryofpathogenicmechanismsofHTNImmunosuppressiveAgent PathogenicMechanism SpecialNotesCorticosteroids !Sodiumretention

!Fluidretention!Responsivenesstovasoconstriction

Dose-dependenteffect

Cyclosporine(CsA) "Induciblenitricoxidelevelsandprostacyclin!Systemicvascularresistance!Endothelinandprostaglandins

CsA>TAC

Tacrolimus(TAC) "Induciblenitricoxidelevelsandprostacyclin!Systemicvascularresistance!Endothelinandprostaglandins

CsA>TAC

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1. CalcineurinInhibitors(CNIs)a. EvidenceofhypertensiveeffectsofTACandCsAafterrenaltransplantationwith

greatereffectsseenwithcyclosporine26,27b. ProposedmechanismofHTN

i. Impairedvasodilation,systemicandrenalvasoconstriction,andsodiumandfluidretention

2. Steroidsa. Steroidminimizationcanreducetheriskofpost-transplantHTNb. Causesodiumretentionresultingindose-relatedfluidretention

D. ComplicationsofHTNPost-RenalTransplant

1. AllograftFailurea. Definedasanacutedeteriorationinallograftfunctionassociatedwithspecific

pathologicchangesinthegraftb. Opetz,etal.:retrospectivecohortof1,666kidneytransplantrecipients

a. Forevery10mmHgincreaseofsystolicbloodpressure(SBP),therewas~5%increasedriskofgraftfailureanddeath28

b. Figure1showstheassociationofSBPatoneyearwithsubsequentgraftsurvivalinrecipientsofdeceaseddonorkidneytransplants

Figure1.AssociationofHTNat1yearwithtransplantsurvival28

2. LeftVentricularHypertrophy(LVH)a. Definedastheenlargementandthickeningofthewallsoftheheart’sleftventricle-

Anadaptiveresponsetovolumeandpressureoverloadb. PediatricKTRshavea10-to15-foldincreasedriskofcardiovasculardeathcompared

withthegeneralpopulationduetoLVH29

3. MorbidityandMortalitya. Each10-mmHgincrementofSBP>140mmHgisassociatedwithahazardratioof

deathof1.18(95%CI,1.12to1.2330

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E. Pathophysiology1. AcomplexinterplayexistsresultingfromdecreasedGFR,vasoconstriction,andsodium

retentionthatarethenadverselyaffectedbyimmunosuppressiveagents

Figure2.MechanismsbywhichHTNafterkidneytransplantismediated

F. Management

1. ThemanagementofHTNinthepediatrictransplantpatientcanbechallenginga. RatesofcontrolofHTNinrenaltransplantpatientsgenerallyrangefrom33-55%10b. Childrenwhoachievenormotensionhaveincreasedandprolongedgraftfunction

2. Goalsoftherapya. Prolonggraftsurvivalandminimizecardiovascularrisk

3. Non-pharmacologicmanagementa. Lifestylemodificationsshouldbeconsideredasthefirstlineapproach10

i. DietaryApproachestoStopHypertension(DASH)dietii. Mildtomoderatephysicalactivity3-5daysperweek

4. Pharmacologicmanagementa. 2017AmericanAcademyofPediatrics(AAP)“ClinicalPracticeGuidelinefor

ScreeningandManagementofHighBloodPressureinChildrenandAdolescents”i. Section11.3HTNandthePosttransplantPatient4ii. LimitedevidencethatACEinhibitorsandARBsmaybesuperiortoother

agentsinachievingBPcontroliii. DonotrecommendtheuseofACEinhibitorsorangiotensinreceptor

blockers(ARBs)asfirstlineinrenaltransplantiv. Nostep-wisetreatmentapproachforHTNmedicationmanagementin

pediatricsb. 2012KidneyDiseaseImprovingGlobalOutcomes(KDIGO)“ClinicalPractice

GuidelinefortheCareofKidneyTransplantRecipients”31i. Noantihypertensiveagentiscontraindicatedinkidneytransplant

recipientsii. ChooseaBP-loweringagentaftertakingintoaccountthetimeafter

transplantation,useofCNIs,presenceorabsenceofpersistentalbuminuria,andotherco-morbidconditions

iii. Nostep-wisetreatmentapproachforHTNmedicationmanagementinpediatrics

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c. Dihydropyridinecalciumchannelblockers(DHP-CCBs)32,33i. Moststudiedandroutinelyrecommendedasfirstlinetherapyii. Mosteffectiveantihypertensiveclasspost-transplantiii. Mitigatenephrotoxicitybycounteractingtheafferentarteriolar

vasoconstrictioncausedbyCNIsultimatelyreducingnephrotoxicityiv. Sideeffectprofileisnotassignificantasotheranti-hypertensiveagents

Table4.ClassesofAntihypertensivemedicationsusedaftertransplantinpediatrics11,31

DrugInteractionswithImmunotherapy

Beneficialeffectintransplantrecipients

Adverseeffects

DihydropyridineCCBs Positive MitigatesCNI-inducedHTNandnephrotoxicity

Edema

Non-dihydropyridineCCB Stronglypositive MitigatesCNI-inducedHTNandnephrotoxicity

Edema,CNItoxicity,bradycardia

ACEinhibitors

NodirectpharmacokineticinteractionsbutcautionwithCNIsduetoriskof

hyperkalemia

Mayreversepost-transplanterythrocytosis,mitigationofproteinuria,

maymitigateAMR-mediatedbyantibodyto

AT1receptor

HyperkalemiaAcutekidneyinjury

Anemia

ARBs

NodirectpharmacokineticinteractionsbutcautionwithCNIsduetoriskof

hyperkalemia

Maydecreaseuricacidlevels

HyperkalemiaAcutekidneyinjury

Anemia

Beta-blockers Negative MaydecreaserisksofperioperativeMI

HyperkalemiaAcutekidneyinjury

Anemia*CCB:calciumchannelblocker,ARB:angiotensinIIreceptorblockers,MI:myocardialinfarction

III.ACEInhibitorsinPediatricKidneyTransplantRecipients

A. UseofACEinhibitors/ARBsfortreatmentofHTNandforslowingtheprogressionofchronickidneydiseasehasbeenwelldefinedinthenon-transplantpediatricpopulation1. TheroleofACEinhibitorsinthepediatrictransplantpatientisincompletelydefined

Table5.AgentsandPediatricDoses

Benazepril(Lotensin®) Children≥6yearsandadolescents:Initial:0.2mg/kg/doseoncedaily(maxdose:10mg/day)Maintenance:0.1-0.6mg/kg/doseoncedaily(max:40mg/day)

Captopril(Capoten®) Infants:0.05mg/kg/doseQ6-24hours(max:6mg/kg/day)Childrenandadolescents:0.3-0.5mg/kg/doseQ8hours(max:6mg/kg/day)

Enalapril(Epaned®) Infants,children,andadolescents:0.08mg/kg/dose(max:5mg)

Fosinopril(Monopril®) Children≥6yearsandadolescents:≤50kg:Initial:0.1mg/kg/doseoncedaily(max:0.6mg/kg/day)>50kg:Initial:5mgoncedaily(max:40mg/day)

Lisinopril(Prinivil®,Zestril®) Children<6years:Limiteddataavailable;Initial:0.07mg/kg/doseoncedaily(max:0.6mg/kg/dayor40mg/day)Children≥6yearsandadolescents:Initial:0.07mg/kg/doseoncedaily(max:0.6mg/kg/dayor40mg/day)

Quinapril(Accupril®) Childrenandadolescents:Limiteddataavailable;Initial:5mgoncedaily(max:80mg/daily)

Ramipril(Altace®) Notspecifiedinthepediatricpopulation

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B. Proposedmechanismforbenefitpost-transplant:1. Vasodilation:dilatearteriesandveinsbyblockingangiotensinIIformationandinhibiting

bradykininmetabolism2. Regulation:downregulatesympatheticadrenergicactivityandreuptakeofnorepinephrine3. Promoterenalexcretionofsodiumandwater4. Inhibitionofcardiacandvascularremodeling

C. Assessmentofpotentialrisks:

1. GFRa. MaycauseorexacerbateadecreaseinGFRwhichmaymaskormimicearlysignsof

acutetransplantrejection2. Hyperkalemia

a. MayexacerbatethefrequencyandseverityofthiselectrolyteabnormalityespeciallywhengivenconcomitantlywithCNIs;canbelife-threatening

b. CNIstendtoraisetheplasmapotassiumconcentration,primarilybydecreasingurinarypotassiumexcretion

3. Anemiaa. Causestheinhibitionoferythropoiesisb. Candecreasethehematocritbyasmuchas5-10%

D. TherearesomepopulationswhomaybenefitfromanACEinhibitorpost-transplant:

1. Evidenceofproteinuria2. Presenceofchronickidneydisease(CKD)3. Presenceofcongestiveheartfailure(CHF)4. Highriskforcoronaryarterydisease(CAD)

IV.ClinicalQuestionandOverviewofLiterature

ClinicalQuestion:CanACEinhibitorsbeusedasfirstlinepharmacologictherapy,inpediatrics,forthetreatmentofHTNpost-renaltransplant?

Figure3.OverviewofLiterature34,35,36

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V.LiteratureReview

Table6.Pharmacokinetics,Pharmacodynamics,andSafetyofLisinoprilinPediatricKidneyTransplantPatients:ImplicationsforStartingDoseSelection(Trachtman,etal,2015)34

Objective Toevaluatethepharmacokinetics(PK),safety/tolerabilityprofile,andimpactonBPoflisinoprilinchildrenandadolescentswithHTNafterkidneytransplant

MethodsTrialDesign Prospective,open-label,multicentersafetyandpharmacokineticstudyParticipantsandSettings

InclusionCriteria ExclusionCriteria• Age7-17years• SBP≥75thpercentileforage,sex,andheight• AnestimatedGFR(eGFR)≥30ml/minper1.73m2

• Stableallograftfunction(<20%changeinserumcreatinineduringtheprior30days)

• Stableimmunosuppressiveregimen(<10%dosechangeduringtheprior14days)

• ReceivedanACEIotherthanlisinopril,anARB,orreninantagonistwithin30dayspriortoenrollment

• KnownallergyorhypersensitivitytoACEI,iohexol,oriodine

• Stage2HTN• Serumpotassium>6mEq/L• Ongoingplasmapharesistreatment• Historyofangioedema

Intervention • PatientswereassignedtoadoselevelbasedoffofeGFRinadoseescalationstrategy# LoweGFR(30-59ml/minper1.73m2)versushigheGFR(≥60ml/minper1.73m2)# EacheGFRgroup:thefirst3patientsreceivedlisinopril0.1mg/kgdaily,thenext4

patientsreceived0.2mg/kgdaily,andthefinal4patientsreceived0.4mg/kgdaily• Twostudypopulations:

# Population1:lisinopril-naïvepatients(n=12)- Receivedorallisinopriloncedailyatdosesat0.1mg/kg,0.2mg/kg,or0.4mg/kg

untilthePKvisit10-16daysafterthestartoflisinopriltreatment# Population2:lisinoprilstandardofcare(SoC)patients(n=10)

- Receivedlisinoprildosealreadyprescribedaspartoftheirongoingtherapy- PKvisit:11-41daysafterstudyenrollment- Foranalysis,patientswereassignedtoadose-levelgroup(0.1,0.2,or0.4mg/kg)

andeGFRgroup(loworhigh)asdefinedinpopulation1• Venousbloodsampleswerecollectedpre-doseandatvarioushourspost-lisinoprildose• 24-hourquantitativeurinecollectionwasperformedfollowinglisinoprildosing

• BP:measuredatthestartofthestudyandatpreselectedstudytimepointsatthePKvisit(pre-dose,10minutespost-iohexolinfusion,and4,8,12and24-hourspostlisinoprildose)

• Safety:monitoredforadverseeventsthroughstudyenrollmentandforatleast30daysfollowingthePKstudyday

Outcomes • Adverseeffectsandtolerabilityoflisinopriltherapy• ObservedchangesinBPwithinitiationoflisinopriltherapy

Pharmacokineticanalysis

• Non-compartmentalanalysisusingPhoenixWinNonlin:estimatedsteady-statePKparameters(CmaxandTmax)oflisinoprilfromplasmaandurineconcentrationdata

• Clast:definedasthelastobservedquantifiableconcentrationduringthedosageintervalandwasequivalenttoC24forpatientsononcedailydosingandC12forpatientsontwicedailydosing

• Cmax,Clast,andAUC0-24werealsodose-adjustedtoa0.1mg/kgdailydosefordoseandweight• Oralclearance(CL/F)wascalculatedandscaledforsizetoa70kgadult(CL/F/70kg)

StatisticalMethods

• PKparameterswerecomparedby0.1vs.0.2mg/kg/daydosegroupsandlowvs.higheGFRgroups(the0.4mg/kg/daydosegroupwasnotcomparedduetothelimitedsamplesize)

• Continuous:Student’st-testortheMann-WhitneyU-test;Categorical:Fischer’sexacttest

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ResultsBaselineData

Parameter LD:0.1mg/kg(n=12)

MD:0.2mg/kg(n=8)

HD:0.4mg/kg(n=2)

All(n=22)

Age(yrs.) 14.9±2.3 13±3 9.5±3.5 13.8±3.0Weight(kg) 56.8±19.4 50.2±28.7 23.1±3 51.3±23.8Female 4(42%) 2(25%) 1(50%) 7(32%)Race/ethnicity White 7(58%) 2(25%) 2(100%) 11(50%)Black 3(25%) 4(50%) 0 7(32%)Am.IndianorAlaskaNative

0 1(13%) 0 1(5%)

Hispanic/Latino 2(17%) 2(25%) 0 4(18%)eGFR-baseline(ml/min/1.73m2)

72.5±25.7(29.6,111.2)

62±16.7(29.2,79.8)

89.3±44.4(57.8,120.6)

70.2±24.4

eGFRatPKvisit(ml/min/1.73m2)

73.1±30.7(36.7,139.0)

63.2±18.4(30.3,86.0)

100.2±56.6(60,140.2)

72±29.4

*LD:lowdose,MD:middledose,HD:highdose

• Therewasatrendtoashortertimesincetransplantinthelisinopril-naïvevs.lisinoprilSoCpatients(3.1±3yearsvs.6.1±4.7years;p=0.08)

• Concomitantantihypertensivemedications:amlodipine(n=15),atenolol(n=2),clonidine(n=2),isradipine(n=2),andcarvedilol(n=1)

• Concomitantimmunosuppressivemedications:mycophenolate(n=19),prednisone(n=18),tacrolimus(n=16),sirolimus(n=7),andazathioprine(n=1)

Outcomes Pharmacokinetics:• LisinoprilPKexhibiteddoseproportionalitywithAUC0-242-foldhigherinthe0.2mg/kg

dosegroupcomparedwiththe0.1mg/kgdosegroup(p<0.001)• Oralclearance:

# Similarbetweenthe0.1mg/kgand0.2mg/kgdosegroups(p=0.84)# Clearancewasaffectedbyrenalfunction:11.9(95%CI8.4,7.0)L/h/70kginthelow

GFRgroupvs24(95%CI19.4,29.5)L/h/70kginthehighGFRgroup(p<0.001)BP:

BaselineBP(mmHg)

LisinoprilBP(mmHg)

Mean 95%CI

Systolic 0.1mg/kg(n=6) 121.2±3.9 115.3±7.6 -5.8 (-13.9,2.2)0.2mg/kg(n=5) 129.6±6.7 117.6±6.5 -12 (-19.6,-4.4)0.4mg/kg(n=2) 124.5±9.2 113.5±6.4 -11 N/ADiastolic 0.1mg/kg(n=6) 75.7±12.8 69.2±6.6 -6.5 (-21,8)0.2mg/kg(n=5) 73.8±7.5 68.2±11.8 -5.6 (-15,3.8)0.4mg/kg(n=2) 76.5±16.3 69.5±14.8 -7 N/A

*Dataaremean±SD.BP:bloodpressure;CI:confidenceinterval

• 5/9(56%)achievedasystolicBP<90thpercentileand3/5(60%)alsoachievedadiastolicBP<90thpercentileatthelisinoprilCmintimepoint

Safety:• Adverseevent(AE)ratesbydosegroup:2/6in0.1mg/kg/day,2/6in0.2mg/kg/day,and

2/3in0.4mg/kg/day(AEreported:dizziness,nausea,stomachache,andeGFRdecline)• ThemedianchangefrombaselineineGFRandserumpotassiumwas-2ml/minper

1.73m2and0.1mEq/Linlisinopril-naïvepatients

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DiscussionAuthors’Conclusions

• ThePKoflisinoprilinpatientswithakidneytransplantwascomparabletochildrenwhodidnothaveakidneytransplantandwhoweregiventhedrugforHTNmanagement

• GFRwasthemajordeterminantofdrugclearanceandconcomitantadministrationofimmunosuppressiveagentsdidnotappeartoaffectlisinoprilclearance

• Morethan75%ofpatientshadareductionof≥6mmHginsystolicand/ordiastolicpressureonlisinoprilafterkidneytransplant,whichprovesitsbenefitinreductionofBPinthispopulation

Reviewer’sInterpretation

Strengths Limitations

• ComprehensivePKevaluation• Assessmentofkidneyfunction• Correctedfortheimpactofpotential

covariates

• OnlyevaluatedonedrugintheACEinhibitorclass

• Concomitantanti-hypertensivemedicationuse

• Shortstudyduration• Promisingpharmacokineticandsafetydatabutsmallpopulationlimitstheutilityofthisdata• LisinoprilmaybeeffectiveatreducingHTNpost-renaltransplantandexhibitssimilarclearance

whencomparedtothenon-transplantpopulation

Table7.AntihypertensivePharmacotherapyandLong-TermOutcomesinPediatricKidneyTransplantation(Suszynski,etal,2013)35

Objective ToassesstheimpactofHTNandantihypertensivepharmacotherapyonpatientsurvival(PS),graftsurvival(GS),anddeathcensoredgraftsurvival(DCGS)inpediatrickidneytransplantrecipientswithgraftfunction

Methods TrialDesign Retrospective,single-centerchartreviewattheUniversityofMinnesotaParticipantsandSettings

• Inclusioncriteria:pediatric(≤18yearsold)transplantrecipientswithGSfor≥5years• Oftheserecipients:deceaseddonor(DD)$51;livingdonor(LD)$242• Norecipientswith≥5yearsGSwereexcluded

Intervention • Alldonorandrecipientdatawereretrospectivelyreviewed(February1984toAugust2005)usinganInstitutionalReviewBoard-approveddatabaseattheUniversityofMinnesota

• HTNwasdefinedasuseofantihypertensive(s)atthe5-yearpostkidneytransplantpoint• Antihypertensiveswereprescribedbytheattendingnephrologistbasedonstandardpediatric

definitionsofHTN• Medicationswerestratifiedbyclassandincludedthefollowingclasses:alpha-1antagonists,

alpha-2agonists,ACEIs,ARBs,beta-blockers,CCBs,anddirectvasodilators• GFRwascalculatedusingthemodifiedSchwartzformula• Immunosuppressiveprotocol:eachKTRreceivedquadrupletherapy,whichincluded:ATGAM

15mg/kgx14dosesorthymoglobulin1.5mg/kgx6-4doses,prednisone,azathioprineormycophenolatemofetil,andcyclosporine

• Rejectionprotocol:recipientswith≥25%increaseinserumcreatininelevelfrombaselineunderwentpercutaneousallograftbiopsy

Outcomes • PS,GS,orDCGS• ImprovedGSwithangiotensinblockadewithuseofACEIs

StatisticalMethods

• Categoricalvariables:Chi-squaretestandFisher’sexacttest• Continuousvariables:two-sidedstudent’st-test• PS,GS,andDCGSrateswerecalculatedusingKaplan-Meieranalyses• Statisticalsignificancecorrespondedtop-values<0.05usinga95%confidenceinterval• Logisticregressionanalysis:pre-andpost-kidneytransplantfactorsforpossibleassociations

withantihypertensivemedicationuseat5yearspost-transplant• Coxproportionalhazardsmodeling:pre-andpost-kidneytransplantfactorsforpossible

associationswithGSat5yearspost-kidneytransplant

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ResultsBaselineData

WithoutHTN(N=160) WithHTN(N=133)Age

<5years5-11years11-18years

86(53.8%)36(22.5%)38(23.7%)

39(29.3%)39(29.3%)55(41.4%)

GenderFemaleMale

54(33.7%)106(66.3%)

42(31.6%)91(68.4%)

RaceCaucasian

Non-Caucasian

153(95.6%)7(4.4%)

126(94.7%)7(5.3%)

Pre-transplantHTNNoYes

138(86.3%)22(13.7%)

72(54.1%)61(45.9%)

DonortypeDeceasedLiving

28(17.5%)132(82.5%)

23(17.3%)110(82.7%)

Outcomes Patientsurvival:• Didnotdifferbetweencohorts(p=0.8)

Graftsurvival:• WithoutHTN:10,15,and20-yearwas86%,68%,and53%• WithHTN:10,15,and20-yearwas78%,53%,and33%• LD:graftsurvivalwashigherinthosewithoutHTN(p=0.002)• DD:nodifferenceingraftsurvivalbetweenthecohorts(p=0.9)• Therewasadifferencebetweenthosetreatedwith0versus1antihypertensiveagent

(p=0.003)and1versus≥2antihypertensiveagents(p=0.002)ACEIuse:

• LD:# GSwassignificantlyhigherforrecipientsusinganACEIversusthoseusinganother

antihypertensive(p=0.04)# HTNtreatedwithnoACEIwasalsoasignificantriskfactorforgraftfailureat>5years

postkidneytransplant(p=0.02)butHTNtreatedwithanACEIwasnot(p=0.7)# ACEI/ARBusedidnotsignificantlyimpactPS(p=0.7)

• ACEI/ARBusesignificantlyimpactedGS(p=0.03)• NodifferenceinPSorGSwhencomparingtheuseofaCCBversusanother

antihypertensiveagent(p=0.7;p=0.7)• DD:Numbersweretoolowtoassessforeffectsofanyparticulardrugclass

DiscussionAuthor’sConclusion

• Thereisanassociationbetweenantihypertensivemedicationuseat5yearspost-kidneytransplantandincreasedlongtermGS

• Pediatricrecipientsaremorelikelytorequireantihypertensivepharmacotherapyat5yearspost-kidneytransplantiftheywereolder,hadanolderdonor,hadanacquiredcauseofend-stagerenaldisease,hadpre-transplantHTN,andweretransplantedinamorerecentera

• TheuseofanACEIexhibitedapositiveassociationwithpost-kidneytransplantGSandDCGSwhichmaybeduetorenoprotectionviaangiotensinblockade

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Reviewer’sInterpretation

Strengths Limitations

• Longpediatricrecipientfollow-up(>20years)

• Adjustedformultipleconfoundersnormallyrelatedtocomplicationsafterkidneytransplant

• AnalysiswasnotbasedonactualBPmeasurementsandonlyonuseofantihypertensivemedicationsatasinglepointintime

• Absenceofracialdiversity• Presenceofproteinuriaundetermined

• FuturestudiesareneededtoprospectivelyexaminetheimpactofBPcontrolandtheuseof

ACEinhibitorsonGSinchildrenafterkidneytransplant• ACEinhibitorsprovidesometypeofbenefitforlongtermGSandcanbeconsideredincertain

populations

Table8.ACEinhibitioninthetreatmentofchildrenafterrenaltransplantation(Arbeiter,etal,2004)36Objective ToreportontheefficacyandsafetyofACE-IinchildrenwithrefractoryHTNand/orchronicgraft

dysfunctionafterrenaltransplantationMethods TrialDesign Retrospective,single-centerchartreviewattheViennaGeneralHospital,UniversityofViennaParticipantsandSettings

• Inclusionandexclusioncriterianotreported• TherecordsofallchildrenundergoingrenaltransplantationbetweenJanuary1989and

December1998werereportedIntervention • DataofpatientsinwhomACE-Iwerestartedwithinthefirst6monthsaftertransplantation

(ACE-Igroup)werecomparedtodataofchildrenwhowerenottreatedwithACE-Iduringtheobservationperiod(non-ACE-Igroup)

• Datawerecollectedinbothgroupsimmediatelybeforeoratthetimeofdischargefromhospitalandatmonths6,12and24aftertransplantation.

• ToanalyzearenoprotectiveeffectofACE-I:asubgroupofchronicallograftdysfunction(CAD)wasclinicallydefinedaccordingtothefollowingcriteria:

# Abnormalgraftfunction:measuredusingtheSchwartzformula# Consistentlydecreasinggraftfunction(negativeslopeof>3estimationsofCrClbythe

SchwartzformulaforatleastthreemonthsbeforethestartofanACE-I• Antihypertensivetreatment:

# StandardprotocolwastostartwithaCCB(nifedipineornitrendipine).IfBPwasnotadequatelycontrolled,abeta-blocker(propranolol,metoprolol)orfurosemidewasadded.ACE-IwereaddedwhenBPwasrefractorytothismedication

# Captoprilwasstartedat0.15mg/kg/dayonthedaybeforethenextclinicvisit# Ifthecreatinineremainedstable,thedosewasslowlyelevateduntilBPwascontrolled

oradoseof2mg/kg/daywasreached.# Instablechildren,captoprilwasfrequentlyswitchedtoenalaprilatanequivalentdose

Outcomes • ChangesinBP• Numberofantihypertensivedrugs• Serumcreatininederivedclearance(Schwartzformula)• Proteinuria

StatisticalMethods

• Non-parametrictestswereperformedforstatisticalcomparisonbetweenthegroupsandinfluenceoftreatmentonthetimecourseofcontinuousvariables

• Qualitativevariables:Fisher’sexacttest

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ResultsBaselineData

ACEI(n=19) Non-ACEI(n=26) p-valueAge(years) 12(3.5-19) 10(1.5-15.5) n.s.Sex(M/F) 8/11 11/15 n.s.

PrimaryrenaldiseaseAcquiredrenaldiseaseCongenitalrenaldisease

Congenitalurologicdisease

4 4 n.s.6 11 n.s.9 11 n.s.

RenalreplacementtherapyNone/HD/PD

Duration(months)Re-transplants(2/>2)

Typeoftransplant(LD/DD)

5/7/7 5/9/12 n.s.8.3(3.5-37) 5(0.5-23) n.s.

5/1 3/1 n.s.3/16 4/22 n.s.

TherapyDual/triple/quadruple 0/17/2 3/19/4 n.s.

AcuterejectionepisodesTotalnumber

NumberofpatientsNumberperpatient

14 8 <0.058 7 n.s.

1.75 1.14 <0.05

Outcomes • Nosignificantdifferencesbetweenthetwogroups• ACE-Itreatment(captoprildose:median0.6,range0.2–4.9mg/kg;enalaprildose:median

0.15,range0.04–0.6mg/kg):BPrapidlydecreasedtonormalvaluesin94%within6monthsandin100%within12monthsafterinitiation(p<0.05)

• After24months,BPcontrolwasnolongerstatisticallydifferentbetweenthetwogroups(ACEIgroupversusNo-ACEIgroup)

• CrClandproteinuria:differencesbetweenandwithingroupsneverreachedstatisticalsignificance

• NodifferenceintheuseofanyotherantihypertensiveorimmunosuppressivedrugsthanACEinhibitors

• RenoprotectiveeffectsofACE-I:inthesubgroupofeightchildrenwithclinicalCAD,graftfunctionstabilizedinallchildrenandfourofthemexperiencedanimprovedcreatinineclearanceafterstartofACE-I(p<0.01)

• Sideeffects:# Serumpotassium:nosignificantchangesbeforethestartofACE-I(median4.6mmol/l)

andthecontrol2–4weekslater(median4.52mmol/l)# Proteinuria:datainconclusive# Nopatientdevelopedhyperkalemia# Hemoglobinremainedstableatamedianof11.3g/dl# Coughorangioedema:notreported

DiscussionAuthor’sConclusions

• ACE-IshouldbeconsideredasaneffectiveandsafetherapyinchildrenafterrenaltransplantationwithrefractoryHTNand/oraccelerateddeclineofgraftfunction

• AllograftfunctionandproteinuriademonstratedasimilarcourseinchildrentreatedwithorwithoutACE-Iduringa2-yearobservationperiodafterrenaltransplantation

Reviewer’sInterpretation

Strengths Limitations

• Strongpatientfollow-upperiod• Adjustedformultipleconfounders

normallyrelatedtocomplicationsafterkidneytransplant

• NoreportonthedefinitionofHTNandthecriteriaforstartingantihypertensives

• Assessmentofkidneyfunction

• ACEinhibitorsprovidesometypeofbenefitforlongtermGSandcanbeconsideredincertainpopulations

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VI.ConclusionsandRecommendationsA. Summary

a. PotentialeffectsofHTNpost-transplantincludeallograftfailure,LVH,andmortality.b. Lifestylemodificationsarethefirstlinetreatmentapproachbutareoftennotenoughto

adequatelycontrolBP.c. Thereisnoconsensusbetweentransplantandpediatricguidelinesforhowtoproperly

manageHTNpost-transplant.d. Thereareseveralsolidorgantransplantfactorsthatmustbetakenintoconsiderationwhen

choosinganantihypertensiveagent.

B. Recommendationsa. ACEinhibitorsshouldbeconsideredasfirstlineifthepatienthasconcomitantproteinuria,

anunderlyingcardiaccondition,orhigherbaselinekidneyfunctionb. Firstline:DHPCCBs

i. Welltoleratedandmostevidenceii. Proventoreducemeanarterialpressureandtotalrenalvascularresistanceiii. ProventoreduceCsAtoxicityandcombatthevasocontrictiveeffectofCNIs

c. DataevaluatingACEinhibitoruseforHTNaftertransplantislacking,butpractitionersmustcreateaconsensusonhowtoaddresspharmacologictreatmentoptions

i. MoredataisneededtodeterminewhichACEinhibitorismosteffectiveii. Medicationformulations(suspensions,tablet/capsulesize)mustbetakeninto

considerationforchildren

C. FutureDirectionsa. RandomizedcontrolledclinicaltrialsareneededtodeterminetheeffectsofACE

inhibitorsonpatientsurvivalandgraftsurvivalb. Moreantihypertensivemedicationclasscomparatorstudiesinpediatricsneedtobe

performedtohelpstandardizeHTNtreatmentafterkidneytransplantVII.References

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pressure:theNHANESexperience1988-2008.Hypertension.2013;62(2):247–2547. Din-DziethamR,LiuY,BieloMV,ShamsaF.Highbloodpressuretrendsinchildrenandadolescentsin

nationalsurveys,1963to2002.Circulation.2007;116(13):1488–14968. HighBloodPressureDuringChildhoodandAdolescence.CentersforDiseaseControlandPrevention.

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VII.AppendicesAppendixA4-5

ScreeningBPValuesRequiringFurtherEvaluationAge(years) BP(mmHg)

Boys Girls Systolic Diastolic Systolic Diastolic

1 98 52 98 542 100 55 101 583 101 58 102 604 102 60 103 625 103 63 104 646 105 66 105 677 106 68 106 688 107 69 107 699 107 70 108 7110 108 72 109 7211 110 74 111 7412 113 75 114 75≥13 120 80 120 80

AppendixB4

1. Creatinine-basedModified“BedsideSchwartz”Equation:a. eGFR(mL/min/1.73m2)=0.413x(height/SCr)b. Theformulawasupdatedin2009andiscurrentlyconsideredthebestmethodfor

estimatingGFRinchildren2. OriginalSchwartzEquation:

a. eGFR(mL/min/1.73m2)=k+L/SCrb. L:heightincentimeters;k:0.45(0mos.-1yearofage),0.55(childrenandadolescent

girls),0.7(adolescentboys)

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AppendixC4

SeatchildcorrectlyandmeasureBPbyauscultationorbyusingoscillometricdevice

Ispercentile≥90th?

RemeasureBPtwiceandthenaveragethesetwo

Isaverage≥90thpercentile?

Wasrepeatausculatory?

NormalBPNo

Yes

RemeasureBPbyusingausculatorytechnique;averagethesetwo

ClassifyBP Isaverage≥90thpercentile?

Yes

No

Yes

Figure4.ModifiedBPMeasurementAlgorithm