“this is too much pressure!” the use of ace...
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“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
1. McDonaldR.A.,NiaudetP,KimM.S.Generalprinciplesofrenaltransplantationinchildren.UpToDate.2018:1-11.
2. OrganProcurementandTransplantationNetwork.OPTN.https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/.AccessedMarch31,2019.
3. TheNewKidneyAllocationSystemFrequentlyAskedQuestions.OPTN.https://optn.tranplant.hrsa.gov/media/1235.pdf
4. Thefourthreportonthediagnosis,evaluation,andtreatmentofhighbloodpressureinchildrenandadolescents.Pediatrics.Aug2004,114:555-576.
5. VergoulasG.Antihypertensiveagentsandrenaltransplantation.Hippokratia.2007;11(1):3–12.6. RosnerB,CookNR,DanielsS,FalknerB.Childhoodbloodpressuretrendsandriskfactorsforhighblood
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.
https://www.cdc.gov/bloodpressure/youth.htm.AccessedMarch31,2019.9. UrbinaE,AlpertB,FlynnJ,etal.Ambulatorybloodpressuremonitoringinchildrenandadolescents:
recommendationsforstandardassessment:ascientificstatementfortheAmericanHeartAssociation.Hypertension.52:433-451.
10. HighBloodPressureDuringChildhoodandAdolescence.CentersforDiseaseControlandPrevention.https://www.cdc.gov/bloodpressure/youth.htm.AccessedMarch31,2019.
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11. KasiskeBL,AnjumS,ShahR,etal.Hypertensionafterkidneytransplant.AmJKidneyDisease.2004;43:1071.
12. PaolettiE,GherziM,AmidoneM,etal.Associationofarterialhypertensionwithrenaltargetorgandamageinkidneytransplantrecipients:thepredictiveroleofambulatorybloodpressuremonitoring.Transplantation2009;87:1864.
13. MangrayM,VellaJP.Hypertensionafterkidneytransplant.AmJKidneyDisease.2011;57:331.14. RossiAP,VellaJP.Hypertension,livingkidneydonors,andtransplantation:wherearewetoday?Adv.
ChronicKidneyDisease.2015;22:154.15. VergoulasG.Antihypertensiveagentsandrenaltransplantation.Hippokratia.2007;11(1):3–12.16. SeemanT,DusekJ,KreisingerJ,etal.Controlofhypertensioninchildrenafterrenaltransplantation.
PediatrTransplant.10:316-322.17. BaluarteHJ,GruskinAB,IngelfingerJR,etal.Analysisofhypertensioninchildrenpostrenal
transplantation-areportoftheNorthAmericanPediatricRenalTransplantCooperativeStudy(NAPRTCS).PediatrNephrol.8:570-573.
18. SorofJM,SullivanEK,TejaniA,etal.Antihypertensivemedicationandrenalallograftfailure:ANorthAmericanPediatricRenalTransplantCooperativeStudyreport.JAm.SocietyofNephrology.10:1324-1330.
19. LingensN,DobosE,WitteK,etal.Twenty-four-hourambulatorybloodpressureprofilesinpediatricpatientsafterrenaltransplantation.PediatrNephrol.11:23-26.
20. GiordanoU,MatteucciMC,CalzolariA,etal.Ambulatorybloodpressuremonitoringinchildrenwithaorticcoarctationandkidneytransplantation.JPediatr.136:520-523.
21. SorofJM,PoffenbargerT,PortmanR,etal.Abnormal24-hourbloodpressurepatternsinchildrenafterrenaltransplantation.AmJKidneyDisease.35:681-686.
22. MorganH,KhanI,HashmiA,etal.Ambulatorybloodpressuremonitoringafterrenaltransplantationinchildren.PediatrNephrol.16:843-847.
23. SerdarogluE,MirS,BerdelliA,etal.HypertensionandACEgeneinsertion/deletionpolymorphisminpediatricrenaltransplantpatients.PediatrTransplant.9:612-617.
24. SeemanT,DusekJ,KreisingerJ,etal.Controlofhypertensioninchildrenafterrenaltransplantation.PediatrTransplant.10:316-322.
25. PonticelliD,CucchiariD,etal.Hypertensioninkidneytransplantrecipients.TransplantInternational.24(2011);523-533.
26. CifkovaR.Cyclosporininducedhypertension.EuropeanSocofHypertension.2001:2(1);1-2.27. KDIGOSupplement.https://kdigo.org/wp-content/uploads/2017/02/KDIGO-2009-Transplant-Recipient-
Guideline-English.pdf.AccessedApril3,2019.28. Opelz,G.,Wujciak,T.,andRitz,E.Associationofchronickidneygraftfailurewithrecipientbloodpressure
(CollaborativeTransplantStudy).KidneyInt.1998;53:217–22229. ParekhRS,CarrollCE,WolfeRA,etal.Cardiovascularmortalityinchildrenandyoungadultswithend-
stagekidneydisease.JPediatr.141:1191-197.30. WeirMR,BurgessED,CooperJE,etal.Assessmentandmanagementofhypertensionintransplant
patients.JAmSocNephrol.2015;26(6):1248-60.31. Post-transplant(Tx)basalATPLevelsinTcellspredictriskforviralinfectionbutnotacuterejectionin
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transplantation:resultsofatwo-yrinterventionaltrial.PediatrTransplant.2007;11(5):491–49733. RosnerB,CookNR,DanielsS,FalknerB.Childhoodbloodpressuretrendsandriskfactorsforhighblood
pressure:theNHANESexperience1988-2008.Hypertension.2013;62(2):247–25434. TrachtmanH,FrymoyerA,LewandowskiA,etal.Pharmacokinetics,pharmacodynamics,andsafetyof
lisinoprilinpediatrickidneytransplantpatients:implicationsforstartingdoseselection.ClinPharmacolTher.2015;98(1):25-33
35. SuszynskiT,RizzariM,GillinghamK,etal.AntihypertensivePharmacotherapyandLong-TermOutcomesinPediatricKidneyTransplantation.ClinTransplant.2013May;27(3):472-480
36. Arbeiter,K.,Pichler,A.,Stemberger,R.etal.ACEinhibitioninthetreatmentofchildrenafterrenaltransplantation.PediatrNephrol(2004)19:222
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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