KidneyDisease:ImprovingGlobalOutcomes
David C Wheeler
Ø David’scurrentposi1onsincludeProfessorofKidneyMedicineatUniversityCollegeLondon,UKandHonoraryConsultantNephrologistattheRoyalFreeLondonNHSFounda1onTrust.
Ø HeisClinicalLeadforDivision2oftheNorthThamesClinicalResearchNetworkandheadsa
teamofeightclinicaltrialsnurses/prac11onersattheCentreforNephrology,RoyalFreeHospitalinLondon.Hehasbeeninvolvedinclinicalprac1ceguidelinedevelopmentforseveralorganisa1ons,
mostrecentlyforKDIGO,ofwhichheiscurrentlyCo-Chair.
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GUIDELINEOVERVIEWANDOBJECTIVES
KDIGO2016ClinicalPrac?ceGuidelineUpdate
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KidneyDisease:ImprovingGlobalOutcomes
WHYUPDATE?
ClinicalPrac?ceGuidelinesshouldbeupdatedif:
• newevidenceshowsthatarecommendedinterven?oncausespreviouslyunknownsubstan?alharm;
• anewinterven?onissignificantlysuperiortoapreviouslyrecommendedinterven?onfromanefficacyorharmsperspec?ve;or
• arecommenda?oncanbeappliedtonewpopula?ons.
Ins?tuteofMedicine,2011ClinicalPrac*ceGuidelinesWeCanTrust
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WHYUPDATE?Addi?onalconsidera?onsforupda?ng:
• Changesintherelevanceofaclinicalques?ontotheprac?ceofmedicine
• Changesinavailableinterven?ons(e.g.newdrugsordevices)• Changesinevidenceontheexis?ngbenefitsandharmsof
interven?ons
• Changesinoutcomesconsideredimportant
• Changesinvaluesplacesonoutcomes
• Changesinevidencethatcurrentprac?ceisop?mal
• Changesinresourcesavailableforhealthcare
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HOWLONGDOESITTAKEUNTILCLINICALPRACTICEGUIDELINESAREOUTOFDATE?
ShojaniaKGetal.AnnInternMed2007
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KDIGO2009CKD-MBDGUIDELINE
ShojaniaKGetal.AnnInternMed2007
ThefirstKDIGOclinicalprac?ceguidelineonCKD-MBDwaspublished
inAugust2009.KDIGO
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KDIGOCONTROVERSIESCONFERENCEONCKD-MBD,2013(MADRID,SPAIN)
• 74aQendeesfrom5con1nentsand19countries
• Representedexpertsinadult,pediatricandtransplantnephrology,endocrinology,cardiology,bonehistomorphometry,andepidemiology
• Dividedinto4BreakoutGroups– BoneQuality
– CalciumandPhosphate
– VitaminDandPTH
– VascularCalcifica?on
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CONTROVERSIESCONFERENCEOBJECTIVE
Theoverallgoalwastoprovideasuggestedroadmapforthenextguidelineupdategroupbyiden?fyingwhichrecommenda?onspoten?allywarrantrevisions(ordele?ons)andwhatnewscopetopicsorrecommenda?onscouldbeconsideredinafuturesystema?creview.
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CONTROVERSIESCONFERENCEOBJECTIVEQues?onstobeaddressedforallguidelinerecommenda?onsunderreviewbytopicgroups:•Hastherebeennewevidencesincetheoriginalreportthatbegersubstan?atesorconflictswithcurrentrecommenda?ons?Aretherelarge-scalestudiesthatmaysignificantlyimprovethecertaintyormagnitudeofnetbenefit/harm?•Shouldanyoftheguidelinestatementsbemodified/createdorremovedbecauseofnewdataornewinterven?ons,strategiesortechniquesnotpreviouslyconsidered?•Shouldanyoftheguidelinestatementsbemodified/createdtoaddressspecificCKDpopula?onsbylevelsofseverityorCKDpopula?onsnotpreviouslycovered(e.g.,elderly,pediatric,transplantrecipients)?
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CONTROVERSIESCONFERENCEPUBLICATION
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GUIDELINERECOMMENDATIONSTOREVISITBoneQuality3.2.1 Inpa?entswithCKDstages3–5D,itisreasonabletoperformabonebiopsyinvariousselngsincluding,butnotlimitedto:unexplainedfractures,persistentbonepain,unexplainedhypercalcemia,unexplainedhypophosphatemia,possiblealuminumtoxicity,andpriortotherapywithbisphosphonatesinpa?entswithCKD-MBD(NotGraded).3.2.2 Inpa?entswithCKDstages3–5DwithevidenceofCKD–MBD,wesuggestthatBMDtes?ngnotbeperformedrou?nely,becauseBMDdoesnotpredictfractureriskasitdoesinthegeneralpopula?on,andBMDdoesnotpredictthetypeofrenalosteodystrophy(2B).
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GUIDELINERECOMMENDATIONSTOREVISITBoneQuality4.3.4 Inpa?entswithCKDstages4–5Dhavingbiochemicalabnormali?esofCKD–MBD,andlowBMDand/orfragilityfractures,wesuggestaddi?onalinves?ga?onwithbonebiopsypriortotherapywithan?resorp?veagents(2C).5.5 Inpa?entswithanes?matedglomerularfiltra?onrategreaterthanapproximately30ml/min/1.73m2,wesuggestmeasuringBMDinthefirst3monthsamerkidneytransplantiftheyreceivecor?costeroids,orhaveriskfactorsforosteoporosisasinthegeneralpopula?on(2D).5.7 Inpa?entswithCKDstages4–5T,wesuggestthatBMDtes?ngnotbeperformedrou?nely,becauseBMDdoesnotpredictfractureriskasitdoesinthegeneralpopula?onandBMDdoesnotpredictthetypeofkidneytransplantbonedisease(2B).
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GUIDELINERECOMMENDATIONSTOREVISITBoneQuality4.3.4Inpa?entswithCKDstages4–5Dhavingbiochemicalabnormali?esofCKD–MBD,andlowBMDand/orfragilityfractures,wesuggestaddi?onalinves?ga?onwithbonebiopsypriortotherapywithan?resorp?veagents(2C).5.5Inpa?entswithanes?matedglomerularfiltra?onrategreaterthanapproximately30ml/min/1.73m2,wesuggestmeasuringBMDinthefirst3monthsamerkidneytransplantiftheyreceivecor?costeroids,orhaveriskfactorsforosteoporosisasinthegeneralpopula?on(2D).5.7Inpa?entswithCKDstages4–5T,wesuggestthatBMDtes?ngnotbeperformedrou?nely,becauseBMDdoesnotpredictfractureriskasitdoesinthegeneralpopula?onandBMDdoesnotpredictthetypeofkidneytransplantbonedisease(2B).
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BONEQUALITY:WHYUPDATING?• 2009Guidelinewaslargelylimitedtobisphosphonates
• Clinicaltrialdataarenowavailablefordenosumabandteripara?de
• Therearerecentdatafromatleasttwostudiessugges?ngthatlowBMDisassociatedwithhigherriskoffractures;whetherthisisapplicabletotransplantrecipientsisunknownandawaitsformalsystema?creviewbytheEvidenceReviewTeam(ERT)
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GUIDELINERECOMMENDATIONSTOREVISITCalciumandPhosphate4.1.1 Inpa?entswithCKDstages3–5,wesuggestmaintainingserumphosphorusinthenormalrange(2C).Inpa?entswithCKDstage5D,wesuggestloweringelevatedphosphoruslevelstowardthenormalrange(2C).4.1.2 Inpa?entswithCKDstages3–5D,wesuggestmaintainingserumcalciuminthenormalrange(2D).4.1.3 Inpa?entswithCKDstage5D,wesuggestusingadialysatecalciumconcentra?onbetween1.25and1.50mmol/l(2.5and3.0mEq/l)(2D).
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GUIDELINERECOMMENDATIONSTOREVISITCalciumandPhosphate4.1.4 Inpa?entswithCKDstages3–5(2D)and5D(2B),wesuggestusingphosphate-bindingagentsinthetreatmentofhyperphosphatemia.ItisreasonablethatthechoiceofphosphatebindertakesintoaccountCKDstage,presenceofothercomponentsofCKD–MBD,concomitanttherapies,andside-effectprofile(notgraded).4.1.7 Inpa?entswithCKDstages3–5D,wesuggestlimi?ngdietaryphosphateintakeinthetreatmentofhyperphosphatemiaaloneorincombina?onwithothertreatments(2D).
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CALCIUMANDPHOSPHATE:WHYUPDATING?• Renewedsafetyconcernsconcerningliberalexposureto
calciuminbothpredialysisanddialysispa?ents
• Effectofcalciumbalanceonendpointssuchasvascularcalcifica?on,mortality,andprogressiontoESRD
• Poten?alnewdataondialysiscalciummasstransferduringhemodiafiltra?on/nocturnalhemodialysis.Anybenefitsforuseoflowcalciumdialysate?
• Newevidencesugges?ngthatcalcimime?csmayalterclinicalsignificanceoflowcalcium
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CALCIUMANDPHOSPHATE:WHYUPDATING?• Relevanceofaboveissuesforthepediatricpopula?onsascalcium
balanceisexpectedtobemoredynamicforthisgroup?
• Relevanceofaboveissuesforthetransplantrecipients?Anydataonmanagementofhypercalcemiaforthispa?entgroup?
• Datatosupportseparaterecommenda?onsonuseofphosphatebindersformanagementofhyperphosphatemiainpredialysisanddialysispa?ents?
• Datatoprovidemoreguidanceonlimi?ngdietaryphosphateintakebytarge?ngspecificphosphoproteinsources?
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GUIDELINERECOMMENDATIONSTOREVISITVitaminDandPTH4.2.1 Inpa?entswithCKDstages3–5notondialysis,theop?malPTHlevelisnotknown.However,wesuggestthatpa?entswithlevelsofintactPTH(iPTH)abovetheuppernormallimitoftheassayarefirstevaluatedforhyperphosphatemia,hypocalcemia,andvitaminDdeficiency(2C).Itisreasonabletocorrecttheseabnormali?eswithanyorallofthefollowing:reducingdietaryphosphateintakeandadministeringphosphatebinders,calciumsupplements,and/orna?vevitaminD(notgraded).4.2.2 Inpa?entswithCKDstages3–5notondialysis,inwhomserumPTHisprogressivelyrisingandremainspersistentlyabovetheupperlimitofnormalfortheassaydespitecorrec?onofmodifiablefactors,wesuggesttreatmentwithcalcitriolorvitaminDanalogs(2C).
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VITAMINDANDPTH:WHYUPDATING?• BothPRIMOandOPERAfailedtoshowabeneficialeffectoflowering
PTHwithparicalcitoloncardiacstructureandfunc?on,butdiddemonstrateanincreasedriskofhypercalcemia.
• TherearealsoconcernsabouttreatmenttolowerPTHvaluestowithinthenormalrangeinCKDstages3to5,whilemoderatePTHeleva?onsmayserveasabeneficialadap?veresponse(e.g.,phosphaturia,boneturnover).Forthisreason,alongwithissuesmen?onedpreviouslyrela?ngtoappropriatecalciumbalanceandload,supportedrevisi?ngthesetworecommenda?ons
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WHATABOUTVASCULARCALCIFICATION?3.3.1 Inpa?entswithCKDstages3–5D,wesuggestthatalateralabdominalradiographcanbeusedtodetectthepresenceorabsenceofvascularcalcifica?on,andanechocardiogramcanbeusedtodetectthepresenceorabsenceofvalvularcalcifica?on,asreasonablealterna?vestocomputedtomography-basedimaging(2C).3.3.2 Wesuggestthatpa?entswithCKDstages3–5Dwithknownvascular/valvularcalcifica?onbeconsideredathighestcardiovascularrisk(2A).Itisreasonabletousethisinforma?ontoguidethemanagementofCKD–MBD(notgraded).
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WHATABOUTVASCULARCALCIFICATION?3.3.1 Inpa?entswithCKDstages3–5D,wesuggestthatalateralabdominalradiographcanbeusedtodetectthepresenceorabsenceofvascularcalcifica?on,andanechocardiogramcanbeusedtodetectthepresenceorabsenceofvalvularcalcifica?on,asreasonablealterna?vestocomputedtomography-basedimaging(2C).3.3.2 Wesuggestthatpa?entswithCKDstages3–5Dwithknownvascular/valvularcalcifica?onbeconsideredathighestcardiovascularrisk(2A).Itisreasonabletousethisinforma?ontoguidethemanagementofCKD–MBD(notgraded).
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WHATNOUPDATEFORVASCULARCALCIFICATION?
• Nohighqualitydatatojus?fyrou?nescreeningforcardiovascularcalcifica?oninCKD
• Nonewdatacomparingdifferentimagingmethodshaveemerged
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CONFERENCERECOMMENDATIONS
• Selec?veupdateofthe2009CKD-MBDGuideline.
• Mostofthe2009guidelinerecommenda?onswereunchanged.
• 12recommenda?onswereiden?fiedforre-evalua?on.
• Addi?onalrecommenda?onswereproposedforrevisi?ngsincecompletetrialdataanalyses(e.g.,EVOLVE)werepublishedamertheMadridconferenceandarenowavailableforformalsystema?creview.
• Largegapsofknowledges?llpersist,despitethecomple?onofseveralRCTssince2009.
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CKD-MBDGUIDELINEUPDATE2016
WorkGroup
• GeoffreyBlock(USA)• PieterEvenepoel(Belgium)• MasafumiFukagawa(Japan)• CharlesA.Herzog(USA)• LindaMcCann(USA)
• SharonM.Moe(USA)• RukshanaShroff(UK)• MarcelloA.Tonelli(Canada)• NigelD.Toussaint(Australia)• MarcG.Vervloet(TheNetherlands)
GuidelineChairsMarkusKegeler(Germany)
MaryBLeonard(USA)
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EVIDENCEREVIEWTEAMLeader
KarenA.RobinsonDirector,JohnsHopkinsUniversity
AHRQEvidence-BasedPrac?ceCenter
EvidenceReviewTeamCaseyM.Rebholz,PhD,MPHMS
LisaM.Wilson,ScMErmiasJirru,MD,MPHMarisaChiLiu,MD,MPH
JessicaGayleard,BSAllenZhang,BS
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METHODOLOGY
• Refineandupdateguidelineclinicalques?ons
• Reviewpriorsearchstrategy,inclusion/exclusioncriteria,andamendifnecessary
• Performdataextrac?ononstudiesfulfillinginclusioncriteria
• RelevantoutcomesandevidenceappraisalaresummarizedintheformofEvidenceMatricesandEvidenceProfiles
• WorkGroupreviewedERTdataandrevisedrelevantguidelinerecommenda?ons
• WorkGrouprevisitedthestrengthoftherecommenda?on
• ERTassistedwiththeevidencegradingoftheindividualrecommenda?ons
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GRADINGRECOMMENDATIONS
Ungradedrecommenda?onsarealsoissuedtoprovideguidancebasedoncommonsenseorwherethetopicdoesnotlenditselfforsystema?creview.Themostcommonexamplesincluderecommenda?onsregardingmonitoringintervals,counseling,andreferraltootherclinicalspecialists.recommenda?ons.
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THEGRADESYSTEM
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FINALGRADEFOROVERALLEVIDENCEQUALITY
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SUMMARYOFERTSEARCHYIELD
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SIGNUPTOREVIEWCKD-MBDGUIDELINEUPDATEDRAFT
http://kdigo.org/home/kdigoreviewer/
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