Ø marc vervloet is associate professor at the kdigo · 3/3/2017 · kidney disease: improving...

KidneyDisease:ImprovingGlobalOutcomes

Marc G Vervloet MD, PhD

Ø  MarcVervloetisassociateprofessoratthedepartmentofNephrologyoftheVUuniversitymedicalcenter.

Ø  HeisprojectleaderattheIns=tuteofCardiovascularResearchVU(ICaR-VU).

Ø  Heco-chairedthena=onalcommiCeedeveloping

DutchguidelinesonCKD-MBD,boardmemberofthescien=ficcommiCeeoftheDutchkidneyFounda=on,andisco-founderandsecretaryoftheERA-EDTAworkinggrouponCKD-MBD.

Ø  Hehaspublishedseveraloriginalstudiesonseveraltopics,mainlyfocusedonCKD-MBD,ismemberofERA-EDTAandtheASN.

KDIGO

UPDATEONTHEMANAGEMENTOFCALCIUM&PHOSPHATEINCKD

MARCG.VERVLOET,MD,PHD,FERAVUUNIVERSITYMEDICALCENTERAMSTERDAMAMSTERDAM,THENETHERLANDS

KDIGO2016ClinicalPracCceGuidelineUpdate

KDIGO


DisclosureofInterests

Ø Employer: VU University Medical Center

Ø Research funding Ø  Dutch Kidney Foundation, European Committee, FMC, Pfizer,

Sanofi, Shire, AbbVie, Amgen

Ø Consultant, lecture fees, other Ø  AbbVie, Alexion, Amgen, Astellas, Baxter, FMC

Ø Membership/Advisor Ø  Secretary ERA-EDTA working group on CKD-MBD Ø  KDIGO committee working group on CKD-MBD

KDIGO


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)

GuidelineChairsMarkusKe[eler(Germany)

MaryBLeonard(USA)

KDIGO


EVIDENCEREVIEWTEAMLeader

KarenA.RobinsonDirector,JohnsHopkinsUniversity

AHRQEvidence-BasedPracCceCenter

EvidenceReviewTeamCaseyM.Rebholz,PhD,MPHMS

LisaM.Wilson,ScMErmiasJirru,MD,MPHMarisaChiLiu,MD,MPH

JessicaGayleard,BSAllenZhang,BS

KDIGO


KDIGOCONTROVERSIESCONFERENCEONCKD-MBD(MADRID,OCTOBER2013)

•  74a[endeesfrom5conCnentsand19countries

•  Representedexpertsinadult,pediatric,andtransplantnephrology;endocrinology,cardiology,bonehistomorphometry,andepidemiology

•  Dividedinto4BreakoutGroups–  VascularCalcificaCon

–  BoneQuality

–  CalciumandPhosphorus

–  VitaminDandPTH

KDIGO


Conference recommendation…

Overviewofrecommendedchanges•  SelecCveUpdateinRed•  MinorAdaptaConinGrey•  Nochangeslehuncoloured

KDIGO


KDIGO


CHAPTER4.1:TREATMENTOFCKD–MBD:LOWERINGHIGHSERUMPHOSPHORUSANDMAINTAININGCALCIUM

KDIGO


ASSESSMENTOFPHOSPHORUSANDCALCIUM

4.1.1:InpaCentswithCKDStages3a-5D,treatmentsofCKD-MBDshouldbebasedonserialassessmentsofphosphorus,calciumandPTHlevels,consideredtogether.(NotGraded)

2009:Nocomparablestatement

KDIGO


RATIONALE

•  ThisnewrecommendaConwasprovidedinordertoemphasizethecomplexityandinteracConofCKD-MBDlaboratoryparameters.

•  Serumphosphorus,calciumandPTHconcentraConsareallrouCnelymeasuredandclinicaldecisionsareohenmadebasedonthesevalues.Clinicaldecisionmakingshouldnotbebasedonasingleresult,butratheronthetrends.Recentpost-hocanalysesoflargedialysiscohortssuggestthattheprognosCcimplicaConsofindividualbiochemicalcomponentsofCKD-MBDlargelydependontheircontextwithregardtoconstellaConsofthefullarrayofMBDbiomarkers.

KDIGO


CKD-MBDPHENOTYPEANDADJUSTEDRISKOFDEATHORCVHOSPITALIZATION

Block,CJASN2013.

PTHhigh CalciumandPhosphatehigh

CalciumandPhosphatetarget

KDIGO


RATIONALE

•  Furthermore,therapeuCcmaneuversaimedatimprovingoneparameterohenhaveunintenConaleffectsonotherparameters.Therefore,theWorkGroupconsidereditreasonabletotakethecontextoftherapeuCcintervenConsintoaccountwhenassessingvaluesofphosphorus,calciumandPTH,andfeltthatitwasimportanttoemphasizetheinterdependencyofthesebiochemicalparametersforclinicaltherapeuCcdecisionmaking.KDIGO



4.1.2:InpaCentswithCKDStages3a-5D,wesuggestloweringelevatedphosphoruslevelstowardsthenormalrange.(2C)

2009:In pa;ents with CKD stages 3–5, we suggest maintaining serumphosphorus in the normal range (2C). In pa;entswith CKD stage 5D,wesuggestloweringelevatedphosphoruslevelstowardthenormalrange(2C).

KDIGO


RATIONALE

•  ThereisanabsenceofdatathateffortstomaintainphosphorusinthenormalrangeareofbenefittoCKDStage3a-4paCents,includingsomesafetyconcerns.Therefore,treatmentshouldaimatoverthyperphosphatemia.

KDIGO


P-BINDERSINPREDIALYSIS

PHOSPHATE

FGF23

CORONARYCALCIFICATION

BlockGetal.JAmSocNephrol.2012;23:1407-1415.

ACTIVE PLACEBOKDIGO



4.1.3:InadultpaCentswithCKDStages3a-5D,wesuggestavoidinghypercalcemia(2C).

InchildrenwithCKDStages3a-5D,wesuggestmaintainingserumcalciumintheage-appropriatenormalrange.(2C)

2009:Inpa;entswithCKDstages3–5D,wesuggestmaintainingserumcalciuminthenormalrange(2D).

KDIGO


EVOLVETRIAL:LONGITUDINALLABVALUESiP

TH (p

mol

/L)

0

42.4 63.6 84.8

127.2 148.4 169.6 190.8

Time (months) 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60

21.2

100.6

P (m

mol

/L)

1.12

1.44 1.60 1.76

2.08 2.24 2.40 2.56

Time (months) 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60

1.28

1.92 C

a (m

mol

/L)

2.05

2.20 2.28 2.35

2.50 2.58 2.65 2.73

Time (months) 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60

2.13

2.43

Ca

x P

(mm

ol2/L2

)

2.72

3.36 3.68 4.00

4.64 4.96 5.28

5.92

Time (months) 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60

3.04

4.32

5.60

MedianiPTH MedianSerumCalcium

MedianSerumPhosphorus MedianCaxPProduct

CinacalcetPlacebo

KDIGO


RATIONALE

•  TheWorkGroupemphasizesanindividualizedapproachtothetreatmentofhypocalcemiaratherthanrecommendingthecorrecConofhypocalcemiaforallpaCents.

•  MildandasymptomaCchypocalcemia(e.g.,inthecontextofcalcimimeCctreatment)canbetoleratedinordertoavoidinappropriatecalciumloadinginadults.KDIGO


PEDIATRICPERSPECTIVE

•  ChildhoodandadolescencearecriCcalperiodsforbonemassaccrual.AprospecCvepediatriccohortstudyshowedlowerserumcalciumlevelswereindependentlyassociatedwithlowercorCcalvolumetricBMDZ-scores,whichpredictedfuturefractures.TheWorkGrouprecognizesthehighercalciumrequirementsofthegrowingskeletonandsuggeststhatserumcalciumlevelsaremaintainedintheage-appropriatenormalrange.KDIGO


DIALYSATECALCIUM

4.1.4:InpaCentswithCKDStage5D,wesuggestusingadialysatecalciumconcentraConbetween1.25and1.50mmol/l(2.5and3.0mEq/l).(2C)

2009:In pa;ents with CKD stage 5D, we suggest using a dialysate calciumconcentra;onbetween1.25and1.50mmol/l(2.5and3.0mEq/l)(2D).

KDIGO


RATIONALE

•  TwoaddiConalstudiesofbe[erqualityareavailable;however,theydonotallowdiscriminaConofbenefitsandharmbetweencalciumdialysateconcentraConsof1.25and1.50mmol/l(2.5and3.0mEq/l).Hence,thewordingisunchangedbutevidencegradeisupgradedfrom2Dto2C.

KDIGO


TREATMENT

4.1.5:InpaCentswithCKDStages3a-5D,decisionsaboutphosphate-loweringtreatmentshouldbebasedonprogressivelyorpersistentlyelevatedserumphosphorus.(NotGraded)

2009:In pa;entswith CKD stages 3–5 (2D) and 5D (2B),we suggest using phosphate-binding agents in the treatment of hyperphosphatemia. It is reasonable that thechoice of phosphate binder takes into account CKD stage, presence of othercomponents of CKD–MBD, concomitant therapies, and side-effect profile (notgraded).

KDIGO


RATIONALE

•  The2009KDIGOGuidelinecommentedthatavailablephosphatebindersarealleffecCveinthetreatmentofhyperphosphatemia,andthatthereisevidencethatcalcium-freebindersmayfavorhalCngprogressionofvascularcalcificaConsvs.calcium-containingbinders

•  Butconcernsaboutcalciumbalance,uncertainCesaboutphosphateloweringinCKDpaCentsnotondialysis,addiConalhardendpointRCTsandasystemaCcreview(effectsonmortalitycomparingcalcium-freevs.calciumcontainingphosphatebinders)promptedinthedecisiontore-evaluatethisrecommendaCon.

KDIGO


RATIONALE

PHOSPHATE

FGF23

CORONARYCALCIFICATION


ACTIVE PLACEBOKDIGO


RATIONALE•  Blocketal.studiedsubjectswithessenCallynormal

phosphorusandassuch,normophosphatemiamaynotbeanindicaContostartphosphate-loweringtreatments.Thissuggeststhatthatearly“prevenCve”treatmentofhyperphosphatemiaiscurrentlynotsupportedbydata(seeRec4.1.2)

•  TheWorkGroupfeltthattheupdatedguidelineshouldclarifythatphosphate-loweringtherapiesmayonlybeindicatedincaseof“progressiveorpersistenthyperphosphatemia”

KDIGO


RATIONALE•  Thebroaderterm“phosphate-loweringtherapies”is

preferredovertheterm“phosphate-bindingagents”introducedin2009Guidelinebecauseitappearslikelythatallpossibleapproaches(i.e.,binders,diet,dialysis)canbeeffecCve

KDIGO


TREATMENT

4.1.6:InadultpaCentswithCKDStages3a-5Dreceivingphosphate-loweringtreatment,wesuggestrestricCngthedoseofcalcium-basedphosphatebinders.(2B)

InchildrenwithCKDStages3a-5D,itisreasonabletobasethechoiceofphosphate-loweringtreatmentonserumcalciumlevels.(NotGraded)

2009:In pa;ents with CKD stages 3–5D and hyperphosphatemia, we recommendrestric;ng the dose of calcium-based phosphate binders…..in the presence ofpersistentorrecurrenthypercalcemia(1B).Inpa;entswithCKDstages3–5Dandhyperphosphatemia,wesuggest restric;ngthedoseofcalcium-basedphosphatebindersinthepresenceofarterialcalcifica;on(2C)and/oradynamicbonedisease(2C)and/orifserumPTHlevelsarepersistentlylow(2C).

KDIGO


RATIONALE

•  NewevidencefromthreeRCTssupportsamoregeneralrecommendaContorestrictcalcium-basedphosphatebindersinhyperphosphatemicpaCentsofallstagesofCKD.

KDIGO


PHOSPHATEBINDERSINMODERATECKD


ACTIVE PLACEBO PLACEBOLANTHANUM SEVELAMER CALCIUM

KDIGO


PHOSPHATEBINDERSANDMORTALITY(PREDIALYIS)

All-CauseMortality DialysisIncepCon

DiIorioBetal.ClinJAmSocNephrol2012;7:487-493

Calcium Sevelamer SevelamerCalcium

KDIGO


SEVELAMERVS.CALCIUM(DIALYSIS)

DiIorioBetal.AmJKidneyDis.2013;62:771-778

Arrythmias CVMortality

KDIGO



•  Concernsregardingtheadverseeffectsofexogenouscalciummaynotbegeneralizabletochildren.

•  Studiesofcalcium-andnon-calcium-containingbindersandothertherapiesthatimpactcalciumbalanceshouldconsidertheneedsofthedevelopingskeleton.TheobservaConthatserumcalciumlevelswereposiCvelyassociatedwithincreasesinBMDinchildrenwithCKD,andthisassociaConwassignificantlymorepronouncedwithgreaterlineargrowthvelocity,illustratestheuniqueneedsofthegrowingskeleton.

KDIGO



•  InlightofthelackofdatasuggesCngadverseeffectsofexogenouscalciuminchildren,theWorkGroupconcludedthattherewasinsufficientevidencetochangethisrecommendaConinchildren,whomaybeuniquelyvulnerabletocalciumrestricCon.

KDIGO


DIETARYPHOSPHATE

4.1.8:InpaCentswithCKDStages3a-5D,wesuggestlimiCngdietaryphosphateintakeinthetreatmentofhyperphosphatemiaaloneorincombinaConwithothertreatments.(2D)

Itisreasonabletoconsiderphosphatesource(e.g.,animal,vegetable,addiCves)inmakingdietaryrecommendaCons.(NotGraded)

2009:Inpa;entswithCKDstages3–5D,wesuggestlimi;ngdietaryphosphateintakeinthe treatment of hyperphosphatemia alone or in combina;on with othertreatments(2D).

KDIGO


RATIONALE

•  TheprincipalrecommendaConremainsthesameaspreviousbutWorkGroupaddedaqualifierstatementacknowledgingothersourcesforphosphorus:naturalphosphorus(ascellularandproteinconsCtuents)containedinraworunprocessedfoods;phosphorusaddedtofoodsduringprocessing;andphosphorusindietarysupplementsormedicaCons.

KDIGO


PHOSPHATEANDDIET

MoeSMetal.ClinAmJSocNephrol.2011;6:257-264

KDIGO


“HIDDEN”PHOSPHATE

ShermanRAetal.ClinJAmSocNephrol.2009;4:1370-1373

KDIGO


CHAPTER3.2:TREATMENTOFCKD–MBD:BONE

KDIGO



3.2.1. InpaCentswithCKDStages3a-5DwithevidenceofCKD-MBD and/or risk factors for osteoporosis, we suggest BMDtesCng to assess fracture risk if results will impact treatmentdecisions.(2B)

2009:Inpa;entswithCKDstages3–5DwithevidenceofCKD–MBD,we suggestthat BMD tes;ng not be performed rou;nely, because BMD does notpredictfractureriskasitdoesinthegeneralpopula;on,andBMDdoesnotpredictthetypeofrenalosteodystrophy(2B).

KDIGO


RATIONALE

•  MulCplenewprospecCvestudieshavedocumentedthatlowerDXABMDdoespredictincidentfracturesinpaCentswithCKDStages3a-5D.

KDIGO


RATIONALE:MetaanalysisDEXAdeterminedfemoralBMD

BMDlowincaseoffracture

BMDhighincaseoffracture

DialysisPaCents

Non-DialysisPaCents KDIGO


KEYMESSAGES•  Itisimportanttoemphasizetheinterdependencyofserum

Ca,P,andPTHforclinicaltherapeuCcdecision-making.

•  Phosphate-loweringtherapiesmayonlybeindicatedinthecaseof“progressiveorpersistenthyperphosphatemia”.

•  NewevidencesuggeststhatexcessexposuretoexogenouscalciuminadultsmaybeharmfulinallstagesofCKD,regardlessofwhetherotherriskmarkersarepresent(e.g.,hypercalcemia,arterialcalcificaCon,adynamicbonediseaseorlowPTHlevels).KDIGO


KEYMESSAGES

•  Itisreasonabletolimitdietaryphosphorusintake,whenconsideringallsourcesofdietaryphosphorus(including“hidden”sources).

•  InCKD(includingpost-transplantaCon)DEXAisaspredicCveforfuturefractureriskasinthegeneralpopulaCon

KDIGO


THANKYOU

TotheKDIGOstaffforallofthemeCculoushelptheyhaveprovidedincreaCngthedrahGuidelinesandwiththedisseminaConofknowledge

MichaelCheung

DanielleGreen

TanyaGreen

KDIGO


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Ø marc vervloet is associate professor at the kdigo · 3/3/2017 · kidney disease: improving...

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