1

KDIGO Controversies Conference on Blood Pressure & Volume Management in Dialysis

- Public Review Comments -

As of January 7, 2019

Industry comments are highlighted in blue

LauraSola(CASMU,Montevideo,Uruguay) Itisaverycomprehensivescopeofcoveragethatyouhadprepared.Ihave2comments:Forworkinggroup1,includedinthepharmaceuticalapproach,whendiscussinganti-hypertensiveagentstobeused,shouldwediscuss:shoulddiureticsbeusedforbloodpressureorvolumecontrol,ifyes,whichonesanddoses.Forworkinggroup2,whendiscussingthebeststrategiestolowerUFratesandRKF,Shouldweincludeinthediscussion:WhatmethodformeasuringRKFshouldweuse,withurinecollectionoronlyserummeasuresasbetatraceprotein?MartinWilkie(SheffieldTeachingHospitals,UK)Iwouldsuggestthatrelevanttothesediscussionsarethefollowingpoints:1)therelationshipbetweenco-morbidity(specificco-morbidities)andextracellularfluid(Inoteco-morbidityisnotmentionedinthescope,althoughfrailtyis).Thishasbeenraisedinseveralfora-seeMaria-EleniRoumeliotietal.Fluidbalanceconceptsinmedicine:principlesandpractice.WorldJournalofNephrology2018Jan6;7(1):1-282)thatincident(baseline)measuresofextracellularvolumerepresentthepatient'sclinicalconditionratherthantheimpactofthedialysisitselfegasobservedinthebaselineIPODstudypaper-RoncoCetalNDT201530:849-58.

2

3)thattheuseofmeasureslongitudinallyforindividualpatientsprovidesdifferentandtheoreticallymorerelevantdatathantheplacementofanindividual'smeasurementwithinacross-sectionalpopulationofmeasures.AndrewDavenport(UniversityCollegeLondon,UK)IthinkoneareanotcoveredistheroleofpreservingresidualrenalfunctionAnthonyBleyer(WakeForestSchoolofMedicine,USA)Ithinkthisisareallygreatidea,andIlookforwardtohearingtheoutcomes.HidekiKawanishi(TsuchiyaGeneralHospital,Japan)IbelievethatthisKDIGOControversiesConferencedrawsimportantconclusionsandcandoCVDpreventionfordialysispatients.Mypersonalopinionsandinterestarerelatedtothedialysismodalityselections.Peritonealdialysis(PD)iswellknowntomaintaintheeventsofCVDsandBPdrop.Moreover,thepreservationofRKFbyPDwasbelievedtomaintainoffluidbalanceandmortalityforpatients(1).However,theseveralevidencesshowedthatthePDpatientswasmaintainedontheoverhydrationconditionandLVHduetothepurposeofpreservationofRKF(2,3).TheNECOSADstudyshowedtheRKFwasnotrelatedthehydrationcondition(4).TheBIAinPDwasshowedthefluidoverloadwasnotrelatedtheRKFmaintained(5).ThesedatadoubttheusefulnessofRKFforCVDsmanagementinPD.TheISPDAdHocCommitteeonUltrafiltrationManagementinPeritonealDialysiswasemphasesthepointandrecommendedthedefine“DryWeight”forPDpatient(6).Althoughthisindicationwaspresentedin2000,ithasnotbeenwidelyacceptedeven18yearslater.ThecauseisthatitisdifficulttocontroltheUFinthePD,butnowitispossibletosettheDWbyusingtheIcodextrin-PDForHybridPD+onceHD/wk(7).Ihopetodiscusstheimportanceof“DryWeight”settinginPDpatientsagain.1)BargmanJM,ThorpeKE,ChurchillDN.Relativecontributionofresidualrenalfunctionandperitonealclearancetoadequacyofdialysis:areanalysisoftheCANUSAstudy.JAmSocNephrol.2001Oct;12(10):2158-62

3

2)NakayamaM,KawaguchiY.MulticentersurveyonhydrationstatusandcontrolofbloodpressureinJapaneseCAPDpatients.PeritDialInt.2002May-Jun;22(3):411-4.3)EniaG,MallamaciF,BenedettoFA,PanuccioV,ParlongoS,CutrupiS,GiaconeG,CottiniE,TripepiG,MalatinoLS,ZoccaliC.Long-termCAPDpatientsarevolumeexpandedanddisplaymoresevereleftventricularhypertrophythanhaemodialysispatients.NephrolDialTransplant.2001Jul;16(7):1459-64.4)JansenMA,HartAA,KorevaarJC,DekkerFW,BoeschotenEW,KredietRT.Predictorsoftherateofdeclineofresidualrenalfunctioninincidentdialysispatients.KidneyInt.2002Sep;62(3):1046-53.5)McCaffertyK,FanS,DavenportA.Extracellularvolumeexpansion,measuredbymultifrequencybioimpedance,doesnothelppreserveresidualrenalfunctioninperitonealdialysispatients.KidneyInt.2014Jan;85(1):151-7.6)MujaisS,NolphK,GokalR,BlakeP,BurkartJ,ColesG,KawaguchiY,KawanishiH,KorbetS,KredietR,LindholmB,OreopoulosD,RippeB,SelgasR.Evaluationandmanagementofultrafiltrationproblemsinperitonealdialysis.InternationalSocietyforPeritonealDialysisAdHocCommitteeonUltrafiltrationManagementinPeritonealDialysis.PeritDialInt.2000;20Suppl4:S5-21.7)KawanishiH,McIntyre,Complementaryuseofperitonealandhemodialysis:Therapeuticsynergiesinthetreatmentofend-stagerenalfailurepatients.KidneyIntern2008;73:S63-S67Hemodiafiltration(HDF)iscontroversialforthemaintaintheDialysis-RelatedHypotension(DRH).AlthoughtheseveralmechanismsuchastheGibbs-Donnan,andlow-temperaturedialysiseffectswerediscussed(1),theseeffectofHDFwasdeniedbyRCT(2).However,intermittentinfusionHDF(IHDF)hasbeenproposedasanewmodalityforpreventtheDRH.ThebasicprincipalofIHDFisintermittentinfusionusedbyback-filtrations,andthesmallsizestudyshowedthateffects(3,4).Itismeaningfultodiscussthesenewtherapies.1)KawanishiH.IsThereEnoughEvidencetoProveThatHemodiafiltrationIsSuperior?BloodPurif.2018;46(1):3-6.2)SmithJR,ZimmerN,BellE,FrancqBG,Mc-ConnachieA,MactierR:Arandomized,single-blind,crossovertrialofrecoverytimeinhigh-fluxhemodialysisandhemodiafiltration.AmJKidneyDis2017;69:762–770.3)KodaY,AoikeI,HasegawaS,OsawaY,NakagawaY,IwabuchiF,IwahashiC,SugimotoT,KikutaniT.Feasibilityofintermittentback-filtrateinfusionhemodiafiltrationtoreduceintradialytichypotensioninpatientswithcardiovascularinstability:apilotstudy.ClinExpNephrol.2017Apr;21(2):324-332.4)MineshimaM,EguchiK,ShishidoK,TakahashiS,KuboT,KawaguchiH,ShitomiK,ShibagakiK,SugaK,NagaoH,TakadaM,TaokaM,SatoT.ClinicalEffectivenessofIntermittentInfusion

4

HemodiafiltrationUsingBackfiltrationofUltrapureDialysisFluidComparedwithPredilutionOn-LineHemodiafiltration.ContribNephrol.2017;189:24-29TheeffectivenessoffrequentHDhasbeenproveninmanystudies,buttheadaptationatthecenterisnotclear.Althoughthequasi-intensivecenterHDwasintroducedintheANZDATA(1),thereactive(rescue)indicationofintensivecenterHDisnotyetclearevidence(2).Howevertheeffectivenessofthistherapyisinferredandneededthefurtherdiscussions.1)MarshallMR,PolkinghorneKR,KerrPG,HawleyCM,AgarJW,McDonaldSP:IntensivehemodialysisandmortalityriskinAustralianandNewZealandpopulations.AmJKidneyDis2016;67:617–6282)BanshodaniM,KawanishiH,MoriishiM,ShintakuS,TsuchiyaS.IncreasedFrequencyofIn-CenterHemodialysisasRescueTherapy:ImpactonHospitalizationforAcuteCardiovascularEvents.BloodPurif.2018Nov22:1-8.Finally,IhopethatthediscussionatKDIGOwillcontributetotheimprovementofthelifeprognosis/QOLofdialysispatientsFanFanHou(NanfangHospital,SouthernMedicalUniversity,China)Thescopeofcoverageisverycomprehensive,includingalmostallcrucialissuesaboutdialysis.Iwouldliketosuggesttwomorequestionsbeingconsidered.1.Howmightlifestylemodificationsbebeneficialforhypertensionmanagementindialysispatients?Ifyes,whichstrategyshouldberecommended?(dietarypattern,exercises,body-weight,etc.)2.WhatistheoptimalBPtargetforpediatricdialysispatients?Doesthedefinitionapplyacrossallpatients?Ifnot,howshouldtargetsbeindividualized?GeoffreyBlock(ReataPharmaceuticals)Iapplaudtheconferenceagenda!Ihavejustafewthoughts/commentsforconsideration.

5

-in-centerHDpatientsget48BPmeasurements/month(sitting/standing,pre-post12sessions/month)-itisreallyunclearIFtheseshouldbeusedandIfso,howdoestheclinicianintegratethemultitudeofmeasurementsinhis/herheadwhilerounding?-Ididn'tseeanythingabouttheTREATMENTofintradialytichypertension-shoulditbetreated?ignored?shouldEPObegiventopatientswhodevelopintradialytichypertension?-Ididn'tseeanythingontheverycommonproblemofdiabeticautonomicneuropathyresultinginprofoundorthostatichypotensionBUTseverepre-dialyticHTN-itistotallyunclearhowtoRxtheseindividuals-regardingdialysisRx-howshould(orshouldit)bemodifiedforintradialytichypERtension?-ishypotensioninPDpatientsreallyaproblemthatneedstobeaddressedatthisconference?doesn'tseemlikeatremendous(orcomplicated)issueclinically-theconferenceshouldaddresssomewheretheconceptofa'MaxUFR'strategy-shouldclinicsenforceamaximumUFRinml/kg/hrgiventheriskabove10andifso,shouldthisbesubjecttoarandomizedtrial(pragmaticwouldworkwell)versusStandardTherapy?Thisrelatestotheclinicalmanifestations/outcomes-thosequestionsshouldconsiderhowthesecouldbeimplementedinaclinicaltrialwhichrandomizestoaMaxUFRstrategyvs.standard-ofcoursehospitalizationwouldbemeasuredandpresumablysomeobjectivemeasureofstunning/cognition-Ididn'tseeanythingabouttheimplementationissueswithadialysatetemp(0.5belowcoretemp)strategyandhowitcanbedone/assessed-shouldweuseserialimagingtodocumenttheadverseeffectsofpoorBPmanagment?shouldwegetserialLVassessments,testsofcognition/executivefunction?-I'msureitisinherebutshouldweusetheNON-dialysisdayBPself-assessedbypatientover2daysasthestandard?ifso,howdoestheclinicianhandletheCQIaspectofBPcontrol?HowshouldBPcontrolbeassessedinaCQIprogram?It'snotcurrently-onlyUFRMona Alrukhaimi (DubaiMedicalCollege,UAE)Iagreewiththescopeofworkandhavenothingtoadd

6

MichaelGermain (Baystate-UMassMedSchool,USA)1)MoredetailontherelativelyrareintradialyticHTN.Causesandtreatment2)discussthechangesinBPonthedifferentdaysoftheweek3)morediscussiononhowoverlikel1/3ofptshaveatoohighDW,1/3toolowDWandhowwecanbetterdeterminecorrectDW4)perhapsthebiggestgapintheSOWIScardiacandvascularissuesWHICHareintimatelyinwinedwithvolumestatus,physiologicalresponsetoUF,BPandcardiacissues,useofmedsforHTNoncardiacissuesMarianoArriola(HospitalCullen,Argentina)Veryinterestingmeeting.Iamwaitingtheresults.ThomasGolper(VanderbiltUniversityMedicalCenter,USA)Thephysiologicsideisveryimportant,butpleasediscussstrategiesforamoreholisticapproachaswell.Aseparatecomponentisthebehavioral/psychologicalaspecttovolumemanagementvisavisNaandfluidintake.Obviously,partofthatisculturalandeducational.EduardoAguilera(InstitutoMexicanodelSeguroSocial,Mexico)InregardtomanagementofBPandvolumecontrolindialysispatients,itshouldbeanindividualizedapproachgiventhefactthatalmosteverypatientisdifferentandthereshouldbeconsideredcomorbiditiesotherthantherenaldiseasetomakeasatisfactorytreatmentsuchasconcomitantatrialfibrillation,LVH,CHFasthesearemodifierstotheliquidoverloadordifficultcontrolhypertension.Otherfactorsincludetheweight,ageandsexofthepatient,itshouldbeconsiderdthe“dialysabilty”ofantihypertensiveagentandifthehypertensionisvolumedependentorotherfactorsareintervening.Thankyou

7

RolandoClaure-DelGranado(UniversidadMayordeSanSimon,Bolivia)Howtoutilizeteamcare?Thisisaquestionthatshouldbeaddressedduringtheconferenceinordertooptimallytreathypertensionandfluidoverloadindialysispatients:theteamofnephrologist,nursesandrenaldietitianneedtoapplyamultidisciplinaryapproachtooptimizedialysisprescriptionanddetermineappropriateuseofanti-hypertensiveregimensaswellastoadviseandempowerpatientstotheappropriateindividualizeddietaryfluidandsaltintaketooptimizebalance.ClarissaHavel(RPh-on-the-go,USA)Goodreviewandseminar,symposiumtopicsofbloodpressureandvolumemanagement.MirrorstheACCPPSAPforpharmacistBoardRe-certification.MegJardine(TheGeorgeInstituteforGlobalHealth,Australia)Thankyoufortheopportunitytocommentonthisimportantarea.Fortunatelyweareatlastseeingariseinrandomisedtrialsbeingplannedandundertakenintheseareaswhichwillhelpaddressknowledgedeficits.TheKDIGOconferenceshavetheopportunitytoinformnewandongoingtrialsbydefiningcurrentknowledgebut,moreimportantly,definingknowledgegapsandpriorityresearchareas.Itwillbeimportantinthisconferenceasinallofthem,todistinguishbetweenthecurrentstateofknowledgeandthesignificanceofanygivenarea.Forexample,timetorecoverypostdialysisisahighsignificancetopicbutonewherethereisstillanevidencegapforinterventions.TheconsideredstatementsbyKDIGOCCsareveryvaluableinfundingandIRBapplicationsastheyprovideaconsensus,independentviewfromanaugustbody.Byarticulatingareasofevidencegap,theConferencestatementwillassistresearchprioritisationandfundingapplicationsuccessforissuesofimportancetothenephrologycommunity.InmyownareasofresearchactivityIwouldnominate3priorityareas.1)Dialysatesodium.Thecurrentevidence(smalltolargeobservationalandsmallrandomisedstudies)forbenefitisconflicting.Thereissmallandindirectevidenceonthepatientexperience(intradialytichypotension)whichsuggestsharm.Thereisevidencethatindividualisationincreasesprescribingmistakes.Theareaisripeforaconsideredandthoughtfulsummaryofthecurrentevidenceand,importantly,theevidencegaps.TheRESOLVEtrialIleadhascommencedwhichwillprovidedefinitiveevidence.

8

2)Haemodialysishours.Idon’tthinkIsawthisonthepreliminarystatementandIthinkitisimportanttoinclude.Extended/nocturnal/frequentdialysisisapotentialmeanstoenablehaemodynamicstabilityduringandbetweendialysissessions.Surprisinglylittleoftheobservationaldatareportsonhaemodynamicstabilityorthepatientexperienceofintradialytichypotension.WehavecompletedtheACTIVEDialysisstudywhichisthelargestRCTgloballyofextendeddialysishourswith200patientsinwhichweassessedmultiplefactorsincludingBloodpressure,intradialyticweightgain,bloodpressureloweringmedications.Importantly,wealsoincludedthemostcomprehensiveassessmentofpatientreportedoutcomemeasuresofthesetrials,includingEQ5d,SF-6D,SF36MCS,SF36PCS,KDCSanditscomponents(articlesinpress/presentedatconferencepresentations).ThecombinedevidencefromtheACTIVE,FHNandAlbertatrialsnowprovidesatleastsomeevidencetoprovideguidanceinthisareaforhaemodynamicmanagementandthepatientexperience.3)Haemodiafiltration.Theevaluationoftheimpactofhaemodiafiltrationrequiresacarefulevaluationandanuancedstatement.Wehavethebenefitofsomelargecompletedtrialsandtherehavebeenusefulpublicationsarising.Therewerealsosomeparticularcharacteristicsofreportinginsomethathavebeendescribedinsystematicreviewsfrommygroup(Wangetal)andothers(Nistoretal).Therearefurthertrialstoreportincludingourowncompletedtrialwhichwillreportin2019.Moreimportantly,alargeRCTisongoingintheUKwhichrepresentsavitalopportunitytoaddresssomeoftheuncertaintiesthatremain.GuillenMiguel-Ange(PrivateNephrology&Epicura,Belgium)1/bloodvolumemonitoring:recommandationtominimaluse?,minimalcomposantofmonitor.?2/bloodvolumemonitoring:nurseeducation?3/Ultrafiltrationrateanddurationofhemodialysis?4/bloodpressuremonitoringinlegs:value/comment?5/biofeedbackwithmultiplecessionanalysisdata:researchtofutureapproachofbloodpressurestability...

9

ClaireGardiner(BritishDieteticAssociation,UK)IamrespondingonbehalfoftheBritishDieteticAssociationRenalNutritionGroup.Ihavehadareadthroughthedocumentanditisverycomprehensive.AlotofthequestionsshoulddirectdiscussionsaroundthefactorswehavediscussedwhendevelopingthefluidmanagementdocumentonbehalfoftheRenalAssociation.Group4willfocusonQOLandtheroleofsaltandfluidmanagement,althoughitismoredirectedatevidencerelatingtocounselling,educationandhowweempowerthepatient.Whatisnotclearfromthequestionsishowthedecisionismadeaboutindividualisingtotalfluidintake(basedonbodysizeandgender)andwhatsaltrecommendationsarereferredto.TherearenoquestionsthatIcanseethatwoulddirectthatconversationandadviseforfurtherresearchinthisarea.Ibelievethatthereisinconsistenciesinfluidmanagementandalthoughthereisanotonesizefitsallapproachthereshouldbesomeagreementinhowandwhenthedecisionismaderegardingfluidallowance(ratherthanreducingsaltintakefirst),especiallyintheinterestofprotectingRRFinthisgroup.Thequestionsaskedwillhopefullydirectdiscussionsaroundresourcesthatmaybeusedtoeducateandempowerthepatientwhichisparamounttothemanagementofvolumeindialysispatients.PhilipZager(DialysisClinicInc.,USA)CurrentrecomendationsonBPguidelinesinHDpatientshavebeenlargelyextrapolatedfromthegeneralpopulation.WerecentlypublishedtheresultsofasuccessfulpilotRCTcomparingususalvs.intensivecontrolofBP.AlthoughweobtainedseparationinSBPthiswaslargelyaccomplishedwithmedicationsratherthanvolumecontrol.Sincethepilotdemonstratedfeasibilityandsafetyitseemstimeforanadequatelypowered,full-scale,RCT.Itwouldrequirecloseattentiontovolume.Possiblestepstocontrolvolumeinclude,lowsaltdiet,individualizeddialysatesodiumconcentrations,longerormorefrequenttreatments.Giventhehighmortalityonthedayafterthelongintervalapilotofeveryotherdaydialysisseemswarranted.MariaFernandaSlonRoblero(ComplejoHospitalariodeNavarra,Spain)IbelievevolumecontrolisaveryimportantissueinthefieldofdialysisandIamgladtoknowthatwewillhaveveryvaluableinformationonitattheendofthismeeting!Itisincreasinglyevidentthatvolumecontrolmustbeafundamentalaspectindialysisadequacyanddirectlyrelatedtothesurvivalofourpatients;sothiscontroversywillhelptoimprovetheknowledgeofNephrologists,updatingandreinforcingknowledgerelatedtothistopic.Ihavereviewedthe

10

differentaspectstodealwithduringthecontroversyanditseemstomethatitisverybroadandcomplete.ThankyouforyourworkandIhopetohavetheinformationavailablesoon.PatriciaFerreiraAbreu(UniversidadeFederaldeSãoPaulo,Brazil)Dearcolleagues,Congratulationsforthistopic;itisfundamentalindailyclinicalpracticeIwouldliketosuggesttheroleofspirolactonetotreathighbloodpressureandheartfailureAspectsaboutDrugandremovalduringdialysisCorrelationbetweenfluidwithdrawalandonlinehematocritBestregardsAlvaroGarcia(ColombiaGroup1:BloodPressure(BP)MeasurementandTargetsandPharmacologicApproachestoBPManagementamongIndividualsReceivingMaintenanceDialysisBPMeasurement1.HowandwhenshouldBPbemeasuredamongindividualsreceivingdialysis?a.Whatapproach,ifany,isconsideredthegoldstandardtomeasureBPamongindividualsreceivingdialysis?Doestheapproachdifferbydialysis?Modality?AtypicaldialysistherapyforpatientsinG5is:hemodialysis3timesaweekinthedialysisunit;withfrequentmeasurementsofbloodpressure(BP),ateachvisit;thisperi-dialysismeasurementofBPisusedbymostofthenephrologistasadiagnosisandtreatmentofBP,afrequentcomplicationofCKD(ChronicKidneydisease).RecentdatashowthatBPmeasurementsinsitesotherthanthedialysisunitsaresuperiorinthediagnosisandtreatmentoftheBPofthepatientinRRT.TheGoldstandardtomeasureBPindialysispatients,isanextrapolationofthemethodsusedforthediagnosisofBPinthegeneralpopulation(HomeBPandAmbulatoryBPmonitoring[ABPM]),notonlymakesthediagnosismoreaccuratebutalsocorrelatesinahigh%ofaccuracywithcardiovascularadverseevents,whichcause60%ofthedeathsofpatientsondialysisb.Whengoldstandardmeasurementsarenotavailable,whatalternativeBPmeasurementsshouldbeusedtodiagnosehypertension?Itisdifficulttoapplyin100%theGoldstandardmeasuretheBPfor(expensiveinfrastructures,patientdisplacements,comfort,etc.),thatiswhyotheralternativeshavearisen:likethehomeBP,whichisbasedonaself-serialmonitoringofBPmeasurementsbythepatientathome:on7daysaweek,itismeasuredtwiceaday(inthemorningbeforebreakfastandintheafternoon

11

beforethemealandthesupplyofthehypotensors);itissuggestedtomaintaintheSBPbetween120-135andonlyusetheABPM,inthosepatientswithpre-dialysishypotension-post-dialysishypertension,andwithuseofmorethan3hypotensors,alltoestablishaprofileofBPbehaviorin24hours.c.Shouldin-centerBPmeasurementseverbeusedtomanage?Hypertension?HavinganOut-of-ClinicBPinthemanagementofhemodialysispatients,isstrikingtowhichpatientscouldattendintheinterdialyticperiods,andtobeabletoapplypreviouslyestablishedprotocols,forastandarddiagnosisandtreatmentwouldbethestandardGold;butanAnalysisPerformedbytheU.S.AgencyforHealthCareResearchandQuality,determinedthattomeasureandcompareitwithothermodalitiesofstudyandtreatmentofBPandcardiovascularrisk,thestatisticallysignificantsampleforthiswouldbeaprospectivestudywith59,000patientsina10-yearfollow-upperiod,inordertoobtainconclusivedataandstatisticalweight.TheBloodPressure(BP)targetsinhemodialysispatients:•K-DOQI-2005:Predialysis<140/90mmHg,postdialysis<of130/80mmHg•ProposedApproach:•HomeBP(BPmeasurementtwicedailyfor7days):TargetSBP120-135mmHg,andTargetDBP60-80mmHg•StandardizedclinicBPonnon-dialysis(alternativewhenBPisnotavailable):TargetSBP<140,TargetDBP60-80mmHg•StandardizeddialysisunitBP:TargetpredialysisSBP130-159mmHgyDBP60-99mmHg;Targetpostdialysis:SBP120-139mmHgyDBP70-89mmHgDefinitionsofHypertension,IntradialyticHypotensionandHypertension2.Whatistheoptimaldefinitionofintradialytichypotension?BasedonwhatEvidence?Intradialytichypotension(IDH)isamedicalcomplicationwithahighmorbidityandmortalityrate;itscausesaremultiple,itmaybeassociatedwithsubsequentvascularaccessthrombosis,inadequatedialysisdose,andmortality.Generallyitisreportedinaverywiderange15to50%ofambulatoryHDsession.Thiswiderangeimpliesthedifferentcriteriaforitsdefinition.The(KDOQI)GuidelinesdefineHDI,asasuddendecreaseinsystolicpressure(SBP)of≥20mmhgor≥10mmhg(SBP),withsymptomsattributedtoit(Cramping,dizziness,headache).TherearemultiplestudiesanddefinitionsregardingthepercentageofPBdrop,accompaniedbysymptomsornotandthatrespondtosalinebolusadministration,ultrafiltration(UF)reduction,orbloodflowreduction.SomedefinitionsarebasedonthereductionofSBPduringdialysistreatment(20,30,40mmHg),ordropsoftheSBP,topointslowerthanthelowerlimitofthenormalacceptedSBP(90,95,100),withsymptomsofIDH,whicharerecoveredwithspecific

12

measuresalreadynoted.ASecondaryanalysisoftheHEMOstudy,referringtoIDHaccordingtothedropofSBPanditssymptomatologywasassociatedwithahighriskofmortality.a.Doesthisdefinitionappliesacrossdialysismodalities?Thispathologyisfullydefinedandstudiedinpatientsonhemodialysis(butitcanoccurinanydialysismodality);thebasiccauseistheincreaseofultrafiltration(UF),inapatientwithwateroverload,inwhichlargeamountsoffluidareremovedfromthevascularandinterstitialspace,causingcardiovascular,electrolyte,neurologicalalterations,deatharrest,whentryingtoleadthepatienttohisdryweightinashorttime.b.Shouldthedefinitionvarydependingonitsplanneduse(identificationofPhenotype/patternvs.anepisode)?ToavoidIDHepisodes,andcardiovasculardecompensating,thereareseveralstudies,inwhichtheallowedvolumeofUFperminuteisshownaccordingtothepatient'sdryweight10-12ml/Kgofweight/hour,duringthetimescheduled(average4hours).Thecentralpointoftheproblemisthecontrolofthedryweightofthepatientindialysis,especiallyinthosewhodonothaveresidualrenalreserveandareauric.Interdialyticgaincannotbemorethan2%ofitsdryweight;acontinuoushydrationofthepatientinachronicform(2.5to3litersmore),leadstothepresenceofSBPanddevelopcardiovasculardisease,withahighriskofdeathat2years.3.Whatistheoptimaldefinitionofintradialytichypertension?BasedonwhatEvidence?ThecontrolofbloodpressureisaconditionthatcannotbeexcludedaspartofthetreatmentofpatientswithCKDandESKDondialysis.Thehighprevalenceoffluidoverload(FO)inchronicform,inthispopulation,isoneofthemostimportantcausesoftheincreaseinSBPandtheriskofdeath.ThroughtheWhole-BodyBioimpedanceSpectroscopy(BCM),ithasbeenpossibletocorrelatethatachronicoverhydration≥15%inmenand13%inwomen,thatistosaymorethan2.5liters,representriskandincreasethelevelsofSBPandtheinherentrisksthereto.Theoptimalbloodpressurevaluesinpredialysisaredeterminedbetween130-160mmHg;theriskofsecondarymortalityis6%withlowBPto26%inthosewithhighBP;aswecansee,diastolicpressure(DBP)ispracticallynottakenintoaccountforthisdecision,itsrangevariesbetween60to90mmHg.a.Doesthisdefinitionapplyacrossdialysismodalities?HighlevelsofBP,atherosclerosis,endothelialdysfunction,arterialstiffness,structuralchangesintheheartandbrainincreasetheriskofdeathinhypertensivepatients.ThemechanismsresponsibleforendothelialdysfunctioninthepatientwithCKDandESKD,Dialysisisdifferentfromthatofthegeneralhypertensivepopulation;inthemareincreasedthelevelsof:AsymmetricDimethylarginine,fibroblastgrowthfactor23,increasedarterialstiffnessowingto

13

procalcifyingpathways,andimpairedbonemineralmetabolism.Inaddition,apatternofdiffusemyocardialfibrosissecondarytouremictoxins,hasbeenfoundindialysispatients.Thus,hypertensionisnotpartofthedialysismodalitythatistypicalofCKD,butmaybemorefrequentinadialysismodalityduetothewateroverloadandtheUFlevelsobtained.b.Shouldthedefinitionvarydependingonitsplanneduse(identificationofPhenotype/patternvs.anepisode)?Basedonadjustedpatient'smodelsindialysisandstudyandmonitoringpatterns,wecanconceptualizethatthetargetoftheBPpre-dialysisis130to159/60to99mmHgandBPpost-dialysisof120/70to89mmHgPatientswhopresentpre-dialysishypotensionpatterns-postdialysishypertension,orwhoneedmorethan3hypotensors,itismandatorytoevaluateotherdiagnosticformsandapressurepatternin24hours,includingsleep.4.WhatistheoptimalBPtargetfordialysispatients?Itisnotclearlydefinedbutarangebetween130-160mmHg(SBP)andaDBPbetween90-60,hasshownlesscomorbiditiesandgoodtoleranceforpatientsa-Doesthisdefinitionapplyacrossdialysismodalities?Acrossallpatients?Ifnot,howshouldtargetsbeindividualized?-Itistoocomplicatedtohavereferencevaluesofarterialhypertension,accordingtothetherapeuticmodalityapplied(HD,PD)-theintimatemechanismofBPisthevasculopathycharacteristicofthepatientwithCKD,butBPlevelsaregreatlyinfluencedbythedryweight,wateroverload,UF,theirrangesgraphicallyformaU,andtheriskofmortalityincreasesattheextremes.PharmacologicApproachestoBPAbnormalities5.Whenshouldanti-hypertensiveagentsbeused?OncethepatientcomplieswiththeOptimalDialysisParametersandcontrolstheestablisheddryweightcontinuously;also,iftheBPlevelsarepersistentlyoutsidetheestablishedranges;thiswouldbethetimetostartthehypotensivemedicines.6.Howshouldanti-hypertensiveagentsbeselected?Thereareseveralparameterstotakeintoaccount.•Theyaredialyzable•Actiontime,longorshort•Hypotensorefficacy•Comorbidityofthepatienttobetreated,heartdisease,wateroverloadetc.•Monotherapyoraccompaniedbyothers,(adverseeffectsuseofβblockers+calciumantagonists=riskofAVblock,increaseKlevels,hirsutism),itisimportanttokeepinmind.

14

•ResidualKidneyFunctionRKF•Hepaticorkidneydisposalroutea.Comparativeeffectivenessofanti-hypertensiveagents?Theperipheralvasodilatorsarepowerfulhypotensors,suchashydralazineandMinoxidil-theyactdirectlyproducingarterialdilation,withoutvenouscompromise-theproblemisthatthetimeofactionofthefirstoneisshortandrequiresseveraldosesduring24h;Minoxidilisapowerfulvasodilatorbutproducesfluidretention,edema,maypresentpericardialeffusion,andhirsutism,amongothers,itsactiontimeis24h.2.TheAngiotensin-convertingenzymeinhibitors(ACEis),andangiotensinIIreceptorblockers(ARBs),theyareexcellenthypotensors,buttheiruseismoretargetedinthetreatmentofthepatientswithCKD(predialysis)withdepurationsbetween60a30ml/min71.73m2andsignificantproteinuria;theyaredialyzable,theiruseinhemodialysisisgood,theyarepowerfulhypotensive,thereareseveraljobswiththeuseofLisinopril,Trandolopil,3timesaweek,postdialysis,withexcellentresults;oneoftheproblemstoconsiderishyperkalemia.3.Theβ-adrenergicBlockingagents(BABAs)originallywererelatedtothetreatmentofheartdisease(cardiopathy)andHF(cardiacfailurewhenmodifyingcardiacoutput).TheHypertensioninhemodialysispatient’streatmentwithAtenololorLisinopril(HDPAL)trial,showeditshypotensiveeffectinpatientsindialysis,andleftventricularhypertrophy(LVH).TherearemanyjobswhereitisusedasthefirstlineoftreatmentforBPindialysistotheBABA,3timesaweek.4.Calciumantagonistsareexcellenthypotensive,onalllong-actingdehydroperidinessuchasnefidipine,felodipine;theirproblemliesinthepresenceofedema.Theyareofhepaticmetabolism.Thenon-dehydroperidinestypeVerapamil/Diltiazem,inmanygroupsitsprescriptionisabolished,duetotheriskofAVblock,whenusedinconjunctionwiththeBBAs,theyalsodecreasecardiacoutput,edema,constipation,etc.5.Diuretics,(ThiazideandLoopDiuretics)andtheiruseashypotensors.TheThiazidetype,whichblockstheco-transporterofNa-Clinthedistalconvolutedtubule,responsiblefor5%oftheabsorbedsodiumandtheloopdiureticswhichinhibittheNa-K-Clco-transporter,presentintheThickascendinglimboftheloopofHenle,responsiblefor25%oftotalNaabsorption,havenohypotensiveeffectinpatientswithdialysis.

15

6.MineralocorticoidReceptorBrooches.ThealdosteroneblockerstypeSpironolactone/Eplerenone,areexcellentantihypertensive,cardioprotective,antiproteinuric;itsuseinhemodialysisisconditionedbysecondaryhyperkalemia.7.CentrallyActingα-AgonistsTheyarepowerfulperipheralvasodilators(Clonidine/Guanfacine)andfrequentlyusedinthecontrolofBPinhemodialysis;buttheyhavemanysideeffects:drymouth,sedation,bradycardia,andreboundhypertensionwhenstoppedabruptly.b.Howdoesdialysismodalityfactorintoanti-hypertensiveagentselection?Ingeneralterms,itisLittlewhatinfluencestheanti-hypertensiveagentandthedialecticmethodtochoose,thisismorerelatedtothecomorbiditiesofthepatient,displacementtothedialysisunit,dialyticaccess,andadherence,amongothers.Itisrecommendedtohaveadefinedplanofantihypertensivestratifiedasfollows:InthefirstlineBABAs,Atenololtypeforitslongactionandhypotensivepower.Insecondline,calciumantagonists(DHP-CCBs).Thirdlineisnotestablishedtheroleofdiureticsinhemodialysis,theACEIs/ARBscouldbeevaluated.Inthefourthline,theperipheralvasodilatorsarepowerfulhypotensive.c.Howcananti-hypertensivetherapystrategiesbeindividualized?Itisimportanttodeterminethecomorbiditiesofthepatient,totakeintoaccount,inordertoavoidfurtherdeteriorationofthem;forexample,toprefertheuseofBABAs,ACEIsorARBs,inpatientswithCVD,duetoitsbeneficialeffectandtoavoidtheuseofcalciumantagonists.Inpatientswithdifficultymaintainingtheirweight,donotuse-CentrallyActingα-Agonists,duetoitsdrymoutheffect,whichforcesthepatienttoconstantlyconsumewaterandthusitisnotpossibletocontrolhisdryweight.ToavoidusingACEIsoARBs,inthosewithtendencytohyperkalemia,etc.7.Whatistheoptimaltimingofanti-hypertensiveadministration?Whenareusedanti-hypertensivedialyzabletypeBABAs,ACEIsorARBs,itisrecommendedtosupplythem3timesaweekafterthedialysis.a.Howdoesdialysismodalityfactorintotimingofanti-hypertensiveagentAdministration?ThebloodbioavailabilityofthehypotensiveagentisimportantinthecontrolofBS,during24hours;itisimportanttotakeintoaccountitsexcretionvia(hepatic,kidney,other),proteinbinding90a100%,ifitisdialyzableornot,residualkidneyfunction,etc.Thiswillallowusnotonlytoselectthetypeofmedicine,takingtime(postdialysis),andtimeintervals.

16

8.WhatgapsremaininourunderstandingofantihypertensivemedicationsinDialysisandwhattype(s)ofresearchis(are)neededtofillthesegaps?Thepatientindialysisispolymedicated,inmostofthetimeshetakes>of3hypotensorstocontrolBP,withfrequentsideeffects;itwouldbeimportantthecombinationofpotent,non-dialyzablehypotensiveagents,whichcanbedeliveredperiodicallywithoutconsideringthedialysisday,thisaddedtoarationalUF,wouldallowthepatientstomaintainBPinacceptablerangesandinthiswaydecreasetheriskofacutemorbidityordeathduetoCVD.9.ShouldpharmacologicagentsbeusedtoraiseBP?TherearenosystematicreviewsorRCTsthatevaluatethistopic;thefewreportsareanecdotalintheirmajority.Onlyinspecificpathologiessuchashyporeninemichypoaldosteronism,hasaspecifictherapyevenindialysispatients;dailydosesofFludrocortisone(0.025to0.05mgs/day),withcontrolsofNa,K,anddryweight,arerecommended.a.If,yes,inwhatclinicalsituationsandwhatagents?If,no,why,andwhatarealternativemanagementstrategies?ItisfullydemonstratedthattheperiodicsupplyoffluodrohydrocortizonenotonlycorrectsthedefectofNa/K,butalsoincreasestheBPaverages,byexpandingtheintravascularandinterstitialspaceinpatientswithhyporeninemichypoaldosteronism.Itseffectismorepotentthanthesupplyofsaltcapsuleoruseofothermineralocorticoids.Thehypotensivepatientdeservesanextensivenutritionalevaluationtodeterminealbumin/totalproteinlevels,acontroloftheirdryweight,andmoderateUFpreviouslyestablished,accordingtotheirBCM.b.ComparativeeffectivenessofBP-raisingagents?Ourexperiencewiththeuseofhypertensioninchronicformisnull,wedonotuseanymedication;inourhypotensivepatientswemakeanevaluationoftheirpharmaceuticalpolypharmacyandtheirmedicalinteractions,oftheirnutritionalstatus,andoftheuseofawellprogrammedUF,insomeoccasionswetransferthemfromHDtoaDP.BIBLIOGRAFIA1-FlytheJE.Associationofmortalityriskwithvariousdefinitionsofintradialytichypotension.JAmSocNephrol26:724-734,20152-ZoccaliC.ChronicfluidoverloadandmortalityinESRD.JAmSocNephrol28:2491-2497,20173-Bansaln.Studyinvestigators:Bloodpressureandriskofall-causemortalityinadvancedchronickidneydiseaseandhemodialysis:Thechronicrenalinsufficiencycohortstudy.Hypertension65:93-100,201454-JeffreyM.Bloodpressuretargetsforhemodialysispatients.Kidneyinternational82017)92:816-823

17

5-ArjunD.ClinicalPharmacologyofAntihypertensiveTherapyfortheTreatmentofhypertensioninChronicKidneyDisease.ClinJAmSocNephrol14,2019.6-AgarwalR.hypertensioninhemodialysispatienttreatedwithAtenololorlisinopril:Randomizedcontroltrial.Nephroldialtransplant29:672-681,20147-RobinsonBM.BloodPressurelevelsandmortalityriskamonghemodialysispatientsinthedialysisoutcomesandpracticepatternsstudy.KidneyInt.2012,82.570-5808-BogerRH.Anovelriskfactorthatexplainsexcesscardiovasculareventrateinpatientswithend-stagerenaldisease.AtherosclerSuppl.2003;4:23-289-HeineGH.FGF-23:theriseofnovelcardiovascularriskmarkerinCKD.NephrolDialTransplant2012;3:3072-308110-RaggiP,Contributionofboneandmineralabnormalitiestocardiovasculardiseaseinpatientswithchronickidneydisease.ClinJAmSocNephrol.2008,3:836-843EugenMota(UniversityofMedicineandPharmacyCraiova,Romania)Routinedialysisunitsystolicbloodpressuremeasurementshavesignificantlimitations.ThevastmajorityofdialysisclinicsdonotadheretotheAmericanHeartAssociation(AHA)guidelines.Moreover,largeinterandintra-patientvariabilityhasbeenreported,usingroutinedialysisunitbloodpressuremeasurements."Outofdialysisunit"bloodpressuremeasures;eg,homebloodpressuremonitoring(HBPM)andambulatorybloodmonitoring(ABPM)maybemorestronglyassociatedtoclinicaloutcomes.However,adherencetoHBPMandABPMscheduleshasbeennotedtobepoor.Furthermore,whetherABPMarethemostreflectivemeasuresofapatient’struebloodpressureremainscontroversial.Finally,currentclinicalguidelinesforthediagnosisandtreatmentofhypertensioninhemodialysispatientsarebasedonroutinepre-dialysissystolicbloodpressure.Severalbiomarkershavebeenadvocatedaspotentialindicatorsofvolumeoverload(atrialnatriureticpeptide[ANP],brainnatriureticpeptide[BNP]andcylicguanosinemonophosphate[cGMP]).However,allarefraughtwithexcessivevariabilityandpoorcorrelationwithvolumestatus.Sinceestimateddryweight(EDW)isdifficulttoassessbyphysicalexam,othermethodshavebeenusedtoguideultrafiltration;e.g.,extracellularfluidvolume(ECFV)measurementbybioelectricalimpedance,ultrasonicmeasurementoftheinferiorvenacavadiameterandcollapsibilityuponinspiration,ultrasoundmeasurementoflungwater,andcontinuousintra-dialyticbloodvolumemonitoring.Thesemeasuressufferfromoperatordependence,lowaccuracyand/orprecision,andimpracticality.Furthermore,noneissufficientlyreliabletojustifyroutineuseinclinicalpractice.Whetherthebloodpressuretargetidentifiedbycurrentclinicalguidelinesactuallycontributestoimprovedsurvivalofhemodialysispatientsremainscontroversial.Arecentmeta-analysisconcludedthatdecreasingSBPinHDpatientsloweredthenumberofCVDevents,aswellasallcause-andCVD-mortality.

18

ARCTcomparingintensivevs.standardhypertensioncontrolinHDpatientsisneededtoassessthesafetyandefficacyoftheKDOQIguidelines.TheavailableevidenceindicatesthatmanyHDpatientswithelevatedBPmayexperiencehigherratesofcardiovasculareventsandmortality.TheexceptionmaybeinHDpatientspronetointradialytichypotension(whichmaybefromcardiomyopathy,slow’vascularrefilling’,autonomicdysfunction,othercauses)orthosewithrecurrentvascularaccessthrombosis/limitedvascularaccessoptions.However,poorvolumecontrolcanexacerbatehypertensionanditsmyriadofdetrimentaleffectsonthecardiovascularsystem.Severalstudiessupporttheassociationbetweenfluidoverloadandall-causeandcardiovascularmortality.Fluidoverloadhasalsobeenassociatedwithmyocardialstunning,leftventricularhypertrophyanddeath.Perhapsinpatientsnotatriskofacutehypertensivecomplications,itisprudenttoinitiallydetermineandachievetheappropriatedryweightandfluidbalance,beforepharmacologicanti-hypertensivetherapyisinitiatedorintensified.Inordertooptimallytreathypertensionandfluidoverloadindialysispatients,thenephrologist,nurseandrenaldietitianwillapplyamultidisciplinaryapproachtooptimizedialysisprescriptionanddetermineappropriateuseofanti-hypertensiveregimensaswellastoadviseandempowerpatientstotheappropriateindividualizeddietaryfluidandsaltintaketooptimizebalanceIndranilDasgupta(UniversityHospitalBirminghamandRenalAssociation,UK)Firstofall,Iwouldliketocongratulatethechairsfordrawingupaverycomprehensivescopeofwork.IhaveafewcommentswhichIhavelistedbelow:1.BPmeasurement-interdialyticambulatoryBPmonitoringisconsideredgoldstandardbutisnotwidelyavailableandpatientsdonotalwaysagreetohavingthisdone.InterdialyticHomeBPmonitoringisconsideredsecondbestbutthattooisnotwidelyavailableespeciallyinresource-constrainedhealthsystems,andalsothereareconcernsabouttheaccuracyofpatientreportedBPreadings.Ontheotherhand,preandpostHD(andsometimesintradialytic)BPmeasurementsarerecordedroutinely.IfeeladiscussionneedstobehadastohoweffectivelytheseroutinelycollectedBPreadingsbeusedtomanagehypertensioninHDpatients.2.BPtarget-BPtargetwillvarydependingonthemethodofmeasurement(ABP/HBP/OBP)andtimingofmeasurement(interdialytic/pre/post/intra).Observationaldatasuggestpre-dialysisSBP130-160/170mmHgisassociatedwithlowestratesofCVeventsandmortality(Robinson2012,Bansal2017).Ideally,anadequatelypoweredRCTusinginterdialyticBPreadingswillinformtheidealtargetBPinHDpatientsbutthismaynotbepossibleintheforeseeablefuturegiventhecomplexityandcostofsuchatrial.TheBIDpilotstudy(MisculinJASN2017)tookalongtimetorecruit126patientstoatrialcomparingintensive(preHDSBP

19

110-140mmHg)vsstandard(preHDSBP155-165)targets.ThereweresafetysignalsintheintensiveBPgroupwithhigherhospitalisation,intra-dialyticsymptomsandvascularaccessthrombosis.Thismayaddtothelackofequipoiseamongnephrologiststoenroltoasubstantivetrialinthefuture.Therefore,wemayhavetogowiththecurrentlyavailableobservationaldata.Abestpracticeguidelineinthisregardwillbeextremelyuseful.3.PharmacologicalapproachinBPmanagement-thereisnoheadtoheadcomparativetrialavailableyettoinformwhatthebestagenttotreatBPinHDpatientsis.Afewsmalltrialssuggestbeta-blockersmaybemostbeneficial.ArecentlargeDOPPSstudyshowsallcommonlyusedagentsareassociatedwithlowermortalitybutARBsmayhaveaslightedgeovertheothers(Karaboyas,KI2018).4.Theotherissuethatmustbeconsideredisnon-adherencetoantihypertensivetreatmentwhichisverycommon(around50%)amonggeneralhypertensives.WithpolypharmacyinHDpatients,thismaybeevencommoner.ItisdifficulttoproveinHDpatientsasurineLCMS/MSassaysarenotpossibleandserumassaysarecostlyandnotwidelyavailable.Shouldweberecommendingin-centresupervisedadministrationofbeta-blockerspostHD(givenwhatweknowabouttheirpharmacokinesisinHDpatients)asfirstlinetherapyorwherethereisdoubtaboutpatient'scompliance?5.Managementofintradialytichypotension-thereisgrowingevidencefortheuseoflowertemperaturedialysateinHD.Studieshaveshownit'sbenefitinreducingmyocardialandcerebralstunning(BurtonCJASN2009,OduduCJASN2015,EldehniCJASN2015).Cognitiveimpairmentisnowawell-recognisedcomplicationofHDandrecentevidencesuggestsitisassociatedwithlowerintradialyticcerebralbloodflow(Findlayetal,JASN2018).OurownworkfromDOPPS(Dasguptaetal,CJASNinpress)showsthattheroutineuseoflowtempdialysatetopreventIDHisassociatedwitha24%lowerriskofCVmortality.Ontheotherhand,theuseofsodiumprofilingwasassociatedwithhigherall-causemortality(36%),CVmortality(34%)andCVevents(21%).Theseevidencesneedtobeconsideredindevelopingaconsensusstatementinthisregardandprovideguidancetotheclinicianintheuseoflowtemperaturedialysateandtoolstoprevent/mitigateIDH.6.ExtracellularVolumeManagement-ourworkmentionedaboveshowsthevariabilityinpracticeacrosstheworld;andtheimportanceofregularandcarefulclinicalassessmentoftargetweightandfluidbalance.Protocolthatspecifiedhowoftentoassessdryweight(50%of279centresacrosstheworld)wasassociatedwith22%lowerall-causeand28%lowerCVmortalities.Moreover,thecentresthatuseorthostaticBPmeasurementtoassesstargetweight

20

havelowerall-causehospitalisation(14%)andCVevents(15%).Ibelievetheimportanceofcarefulclinicalassessmentforfluidstatusneedstobeemphasisedintheconsensusstatement.7.Technology-BasedConsiderationsRelevanttoVolumeManagement-bioimpedancespectroscopyseemstohavethebestevidencewithanumberofobservationalstudiesand2smallRCTsdemonstratingbetterpatientoutcomesassociatedwithitsusetoassessfluidvolumeinHDpatients(HuretalAJKD2013,OnofrescuetalAJKD2014).AlargeRCTisunderwayintheUK(BISTRO,DaviesetalBMCnephrol2017)assessingtheimportanceofBISguidedfluidmanagementinHDinprotectingresidualrenalfunctionwithmortalityandCVeventsamongsecondaryendpoints.AsforHDF,thedataavailablearecontradictory;alargeadequatelypoweredstudyisunderwayintheUKcomparingHDFwithHD(H4H)whichisexpectedtoaddresstheissueconvincinglyinthenearfuture.Untilthenitmaynotbewisetorecommenditsuse.Asforon-linebloodvolumemonitoring,thereareafewrecentstudiesthatsuggestitsuseisassociatedwithworsepatientoutcomes(LeungCJASN2017).Ourowndata(DasguptaCJASNinpress)shows19%higherall-causemortalityassociatedwiththeuseofon-linevolumemonitoring.Intheabsenceoftechnologies(orevidenceoftheirbenefit)toassistfluidvolumemanagement,especiallyinresourceconstrained-healthsystems,Istronglyfeelthattheimportanceofregularandcarefulclinicalassessmentforfluidvolumeneedstobeemphasisedintheconsensusdocument.Thanksforgivingmetheopportunitytofeedbackonthescope.Kindregards,IndranilDasguptaRommelBataclan(UniversityoftheEastRamonMagsaysayMedicalCenter,Philippines)Ithinkit'simportantalsotodiscussifthetreatmentforhypertensiveemergenciesissimilartoCKD5Dpatients.Thescopeiscomprehensiveandalotofissuesthoughmaybeunresolved.Formulationofresearchgapswillhelpoptimizetreatmentofhypertensionamongthesepatients.AnsgarConrad(Relypsa)ThankyouforprovidingusanopportunitytocommentontheScopeofWorkfortheKDIGOControversiesConferenceonBloodPressureandVolumeManagementinDialysis.Wehavereviewedtheselectedtopicsthatwillbecoveredduringthemeetingandwouldliketo

21

recommendthatthefollowingclinicallyrelevantquestionsbeaddedandaddressedduringthecontroversiesconference.Group1Topics5to9intheproposedScopeofWorkcommentonpharmacologicapproachestobloodpressure(BP)abnormalitiesinCKDpatientsreceivingdialysis.Apartofthisdiscussionmayfocusontheemergingevidenceofrenin-angiotensin-aldosterone-system(RAAS)inhibitors,includingangiotensin-converting-enzyme(ACE)inhibitors,angiotensin-receptor-blockers(ARBs),andmineralocorticoid-receptor-antagonists(MRAs)indialysisandtheneedforfurtherstudies.Hyperkalemia(HK)hasbeenreportedinclinicaltrialswithRAASinhibitorsinbothpatientswithnon-dialysisCKDandpatientsondialysisandmaylimittheuseofthesemedications.Forthesereasons,wesuggestthatthefollowingquestionsbeaddressedwithintheproposedScopeofWork:-TowhatextentmayhyperkalemiamaylimittheuseofRAASinhibitorsindialysispatients?-When(days,weeks),andhowoftenshouldserumpotassiumbemonitoredincaseanACEinhibitor,ARB,orMRAisprescribedforthetreatmentofhypertensioninpatientsondialysis?-HoweffectivearecurrentstrategiesfortreatmentofhyperkalemiainpatientsondialysisreceivingRAASi?-IncasehyperkalemiaoccurswhileonRAASinhibitors,whattreatmentsshouldbeprescribedtocontrolBPindialysis?-WhatistheroleforpotassiumbindersinthemanagementofRAASinhibitor-associatedhyperkalemiainpatientsondialysis?Inarelateddiscussion,Group4Topic4focusesonfluidandsaltrestrictionsinBPandvolumemanagement.Partofthediscussionmayfocusonsalt-containingmedications.Wesuggestthatthefollowingquestionsbeaddressed:-Shouldsodium-containingmedicationsbeavoidedinhypertensivepatientsreceivingdialysis? Rationale:Hypertensionandvolumeoverloadarecommonclinicalconditionsamongpatientsondialysisandareofteninadequatelydiagnosedandpoorlycontrolled.StrategiestocontrolvolumeandlowerBPintheseindividualsmayincludenonpharmacologicalstrategiessuchascontrollingsodiumbyrestrictingdietarysodiumintake,individualizeddialysatesodiumprescriptionandoptimizeddurationofdialysisarefirst-linetreatment,and,ifBPremainsuncontrolled,antihypertensivetherapy(Georgianos&Agarwal,2018).TheassociationofRAASinhibitorswithimprovementinclinicaloutcomesamongthoseonhemodialysisisnotclearlyunderstood(Georgianos&Agarwal,2016,2018)andasubjectofthepresentmeeting.ThereissomeevidencefortheefficacyofARBs(Takahashietal.,2006,Zuzukietal.,2008)andthecombinationofACEiandARBs(Ciceetal.,2010)indialysiswhileotherstudieshavenotdemonstratedabenefit(Zannadetal.,2006,Isekietal.,2013,Petersetal.,2014).Similarly,thesafetyandefficacyofMRAsinthetreatmentofdialysispatientsisnotwelldefined.Panagiotis

22

etal.(2017)conductedasystematicliteraturesearchofMEDLINE/PubMedandidentified11randomizedcontrolledclinicaltrialsevaluatingtheefficacyandsafetyofMRAsindialysispatients.TheauthorsconcludedthattheMRAsspironolactoneandeplerenonemaybebeneficialinimprovingseveralsurrogatecardiovascularendpointsamongdialysispatients.Properlydesigned,largerstudiesareneededtoconfirmtheeffects,includingtheongoingPhaseIIIALdosteroneAntagonistChronicHEModialysisInterventionalSurvivalTrial(ALCHEMIST)(UniversityHospital,Brest,2018).Hyperkalemiaisacommonelectrolytedisorderamongdialysispatientsandisassociatedwithincreasedriskofcardiovascularandarrhythmogenicdeath(Sanghavietal.,2013).Giventhehighvulnerabilityofdialysispatientsindevelopinghyperkalemiaandthecloseassociationofthiselectrolytedisorderwithadverseevents,thepotentialcardioprotectivepropertiesofMRAsinthedialysissettingmaybecompromisedbyMRA-inducedhyperkalemia(Panagiotisetal.,2017).Forexample,inthePHASEstudy(Walshetal.,2015),154prevalenthemodialysispatientswererandomlyallocatedtoeplerenone(titratedupto50mgdaily)orplacebofor13weeks.Theincidenceofhyperkalemia(definedaspre-dialysisserumpotassium>6.5mEq/L)was4.5-foldhigherineplerenone-treatedparticipantsthaninplacebo-treatedparticipants[RelativeRisk(RR):4.5;95%CI:1.0-20.2].ThereisnoconsensusonhowoftenserumpotassiumshouldbemonitoredincaseanACEinhibitor,ARB,orMRAisutilizedforthetreatmentofhypertensioninpatientsondialysis.Inaddition,discussioncouldbewarrantedonhoweffectivecurrentstrategiesfortreatmentofhyperkalemiainpatientsondialysisreceivingRAASiare,includingiftherecouldbearoleforpotassiumbinders.AnotherapproachtocontrollingvolumeandBPofpatientswithCKDisreducedsodiumintake.Infact,BPofpatientswithCKDismoresensitivetohighsodiumintakethanpersonswithnormalkidneyfunctionduetoadiminishedcapacitytoexcretesodium(Johnsonetal.,2002).Millsetal.(2016)followed3757patientsintheChronicRenalInsufficiencyCohort(CRIC)Studyforamedianof6.8yearsandfoundthatamongpatientswithCKD,higherurinarysodiumexcretionwasassociatedwithincreasedriskofCVD.KDIGOguidelines(2013)recommendthatCKDpatientsconsume<2g(<90mmol)perdayofsodium(~5gofsalt),unlesscontraindicated.Thus,adiscussionmaybewarrantedifhighsodium-containingmedicationsshouldbeavoidedinpatientsreceivingdialysistohelpcontrolinterdialyticweightgainandimprovebloodpressurecontrol.References:CiceG,DiBA,D'IsaS,etal.Effectsoftelmisartanaddedtoangiotensin-convertingenzymeinhibitorsonmortalityandmorbidityinhemodialysispatientswithchronicheartfailureadouble-blind,placebo-controlledtrial.JAmCollCardiol.2010;56(21):1701-1708.GeorgianosP&AgarwalR.Bloodpressurecontrolinconventionalhemodialysis.SeminarsinDialysis.2018;1–6.

23

GeorgianosP&AgarwalR.PharmacotherapyofHypertensioninChronicDialysisPatients.ClinJAmSocNephrol.2016,11(11):2062-2075.GeorgianosP,VaiosV,EleftheriadisT,etal.MineralocorticoidAntagonistsinESRD:AnOverviewoftheirEfficacyandSafety.CurrentVascularPharmacology,2017,15,1-8.IsekiK,ArimaH,KohaguraK,etal.Effectsofangiotensinreceptorblockade(ARB)onmortalityandcardiovascularoutcomesinpatientswithlong-termhaemodialysis:arandomizedcontrolledtrial.NephrolDialTransplant.2013;28(6):1579-1589.JohnsonRJ,Herrera-AcostaJ,SchreinerGF,Rodríguez-IturbeB.Subtleacquiredrenalinjuryasamechanismofsalt-sensitivehypertension.NEnglJMed.2002;346(12):913-923.KidneyDisease:ImprovingGlobalOutcomes.KDIGO2012ClinicalPracticeGuidelinesfortheevaluationandmanagementofchronickidneydisease.KidneyIntSuppl.2013;3(1):1-150.MillsKT,ChenJ,YangW,etal.SodiumExcretionandtheRiskofCardiovascularDiseaseinPatientsWithChronicKidneyDisease.JAMA.2016;315(20):2200-10.PetersCD,KjaergaardKD,JensenJD,etal.NosignificanteffectofangiotensinIIreceptorblockadeonintermediatecardiovascularendpointsinhemodialysispatients.KidneyInt.2014;86(3):625-637.SanghaviS,WhitingS,UribarriJ.Potassiumbalanceindialysispatients.SeminDial2013;26(5):597-603.SuzukiH,KannoY,SugaharaS,etal.Effectofangiotensinreceptorblockersoncardiovasculareventsinpatientsundergoinghemodialysis:anopen-labelrandomizedcontrolledtrial.AmJKidneyDis.2008;52(3):501-506.TakahashiA,TakaseH,ToriyamaT,etal.Candesartan,anangiotensinIItype-1receptorblocker,reducescardiovasculareventsinpatientsonchronichaemodialysis–arandomizedstudy.NephrolDialTransplant.2006;21(9):2507-2512.UniversityHospital,Brest:NCT01848639:ALdosteroneAntagonistChronicHEModialysisInterventionalSurvivalTrial(ALCHEMIST).ClinicalTrials.gov,U.S.NationalInstitutesofHealth,2013.2018.WalshM,MannsB,GargAX,etal.TheSafetyofEplerenoneinHemodialysisPatients:ANoninferiorityRandomizedControlledTrial.ClinJAmSocNephrol2015;10(9):1602-8.ZannadF,KesslerM,LehertP,etal.Preventionofcardiovasculareventsinend-stagerenaldisease:resultsofarandomizedtrialoffosinoprilandimplicationsforfuturestudies.KidneyInt.2006;70(7):1318-1324.YusukeTsukamoto(ItabashiChuoMedicalCenter,Japan)Effectofdialysis,comorbiditiesbyBPderangementanditsmanagementaresomuchdifferentbetweenhemoandperitoneal.IwouldsuggestseparategroupdiscussiontodiscusshemoandPD.

24

AxelDessal(TrioxBio,Inc.)Asdevelopersofadrugtotreatandpreventintra-hemodialytichypotension,includinghypotensionintheimmediatepost-hemodialyticperiod,weareparticularlyinterestedingroups1and2,moreespecially,ineverythingrelatedtothedefinitionofintra-hemodialytichypotensionandtoitspharmacologicprevention.IthinkthatgivenourongoingdiscussionswiththeFDA,theEMA,clinicalresearchorganizations,dialysisorganizationsandpotentialinvestors,wecouldcontributetotheconferencewithveryvaluableknowledge.Basedonourdiscussionswithpotentialinvestors,IthinkthatitisveryimportantthatKDIGO,asitintends,providesanewdefinitionofintra-hemodialytichypotensionwhich“officially”replacestheonethatKDOQIpresentedin2005.Wehaveadopted,andwecontinuouslydefend,thenadir-SBP-baseddefinitionproposedbyJenniferFlythe,StevenBrunelliandothersin2015,andthepotentialinvestorsalwaysaskwhetherthisdefinitionhasalreadybeenacceptedbytheFDA,EMA,etc.Wehavedesignedaphase2clinicaltrialwhichwillindeedusenadirSBPasitsprimaryendpoint,andwewillevenexplorethepracticalityofotherendpoints,forinstance,theareaabovetheSBPcurveandbelowtheIDHdefinitionthreshold(AACBDT),whichmightbettercorrelatewithmortality,asittakesintoaccounthowoften,howdeeplyandforhowlongthepatientshavebeenhypotensiveduringthehemodialysissession.ThebeautyaboutthisendpointisthatFlytheandBrunellicouldcomputeitwiththesamedatapointsthattheyusedtocomputenadirSBPintheirwork.

Inourphase2clinicaltrial,wewillalsoexploretheabilityofourdrugtopreventorthostatichypotensionimmediatelyfollowingthehemodialysissession.Ithinkthatthistopiccouldalso

25

beincludedinyourprogram.Althoughorthostatichypotensionimmediatelyfollowingthehemodialysissessionissometimesmentionedtogetherwithintra-hemodialytichypotensionas“hemodialysis-associatedhypotension”,thetruthisthatthereisnotmuchinformationaboutitsimportanceanditsincidence.Ingeneral,IthinkthattheScopeofWorklooksverygoodandthatthetimingfortheconferenceisgreat!Bestregards,AxelEzioMovilli(UniversityofBrescia,Italy)Iwouldsuggesttoincludeinthe“Ultrafiltrationrateandtreatmenttime“sectionadiscussionpointontheroleof“end-dialysisoverweight”or“end-dialysisHyperorhypohidrationon”onmorbidityandmortality.TherearesomeinterestingobservationssuggestinganindependentroleofresidualhyperorhypohydrationonallcauseandcardiovascularmortalityinpatientsonchronicHDtreatment.(MovilliE,CameriniC,GaggiaP,etal.AmJNephrol.2013;37(4):370-7;FlytheJE,KshirsagarAV,FalkRJ,BrunelliSM:ClinJAmSocNephrol10:808–816,2015;AssimonMM,WangL,FlytheJE.JAmSocNephrol29:2178–2188,2018.)