KDIGO CKD-MBD G U 2017...Karen A. Robinson Johns Hopkins University, BalKmore (USA) Kidney Disease: Improving Global Outcomes CHAPTER 3.2: TREATMENT OF CKD–MBD: BONE Kidney Disease:

KDIGOCKD-MBDGUIDELINEUPDATE2017:WHATISNEW?

PROF.MARKUSKETTELER,MD,FERADEPARTMENTOFMEDICINEIII:NEPHROLOGYKLINIKUMCOBURGGMBHCOBURG,GERMANY

Seoul–May20,201737thAnnualMeeKngoftheKoreanSocietyofNephrology

KidneyDisease:ImprovingGlobalOutcomes

KDIGOCONTROVERSIESCONFERENCEONCKD-MBD(MADRID,OCTOBER2013)

•  74aVendeesfrom5conKnentsand19countries•  Representedexpertsinadult,pediatric,andtransplant

nephrology;endocrinology,cardiology,bonehistomorphometry,andepidemiology

•  Dividedinto4BreakoutGroups–  VascularCalcificaKon

–  BoneQuality

–  CalciumandPhosphorus

–  VitaminDandPTH


KDIGOCONTROVERSIESCONFERENCEONCKD-MBD(MADRID,OCTOBER2013)


Conference recommendation…

Overviewofrecommendedchanges•  SelecKveUpdateinRed•  MinorAdaptaKoninGrey•  Nochangeslecuncoloured


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)

GuidelineChairsMarkusKeVeler(Germany)

MaryBLeonard(USA)

SupportedbyanEvidenceReviewTeamledbyKarenA.Robinson

JohnsHopkinsUniversity,BalKmore(USA)


CHAPTER3.2:TREATMENTOFCKD–MBD:BONE


ASSESSMENTOFPHOSPHORUSANDCALCIUM

3.2.1. InpaKentswithCKDStages3a-5DwithevidenceofCKD-MBD and/or risk factors for osteoporosis, we suggest BMDtesKng to assess fracture risk if results will impact treatmentdecisions.(2B)

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


RATIONALE

•  MulKplenewprospecKvestudieshavedocumentedthatlowerDXABMDdoespredictincidentfracturesinpaKentswithCKDStages3a-5D.


RATIONALE:MetaanalysisDEXAdeterminedfemoralBMD

BMDlowincaseoffracture

BMDhighincaseoffracture

DialysisPaKents

Non-DialysisPaKents


CHAPTER4.1:TREATMENTOFCKD–MBD:LOWERINGHIGHSERUMPHOSPHORUSANDMAINTAININGCALCIUM



4.1.1:InpaKentswithCKDStages3a-5D,treatmentsofCKD-MBDshouldbebasedonserialassessmentsofphosphorus,calciumandPTHlevels,consideredtogether.(NotGraded)

2009:Nocomparablestatement


RATIONALE

•  ThisnewrecommendaKonwasprovidedinordertoemphasizethecomplexityandinteracKonofCKD-MBDlaboratoryparameters.

•  Serumphosphorus,calciumandPTHconcentraKonsareallrouKnelymeasuredandclinicaldecisionsareocenmadebasedonthesevalues.Clinicaldecisionmakingshouldnotbebasedonasingleresult,butratheronthetrends.Recentpost-hocanalysesoflargedialysiscohortssuggestthattheprognosKcimplicaKonsofindividualbiochemicalcomponentsofCKD-MBDlargelydependontheircontextwithregardtoconstellaKonsofthefullarrayofMBDbiomarkers.


CKD-MBDPHENOTYPEANDADJUSTEDRISKOFDEATHORCVHOSPITALIZATION

Block,CJASN2013.

PTHhigh CalciumandPhosphatehigh

CalciumandPhosphatetarget


RATIONALE

•  Furthermore,therapeuKcmaneuversaimedatimprovingoneparameterocenhaveunintenKonaleffectsonotherparameters.Therefore,theWorkGroupconsidereditreasonabletotakethecontextoftherapeuKcintervenKonsintoaccountwhenassessingvaluesofphosphorus,calciumandPTH,andfeltthatitwasimportanttoemphasizetheinterdependencyofthesebiochemicalparametersforclinicaltherapeuKcdecisionmaking.



4.1.3:InadultpaKentswithCKDStages3a-5D,wesuggestavoidinghypercalcemia(2C).

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

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


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


RATIONALE

•  TheWorkGroupemphasizesanindividualizedapproachtothetreatmentofhypocalcemiaratherthanrecommendingthecorrecKonofhypocalcemiaforallpaKents.

•  MildandasymptomaKchypocalcemia(e.g.,inthecontextofcalcimimeKctreatment)canbetoleratedinordertoavoidinappropriatecalciumloadinginadults.


TREATMENT

4.1.5:InpaKentswithCKDStages3a-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).


RATIONALE

•  The2009KDIGOGuidelinecommentedthatavailablephosphatebindersarealleffecKveinthetreatmentofhyperphosphatemia,andthatthereisevidencethatcalcium-freebindersmayfavorhalKngprogressionofvascularcalcificaKonsvs.calcium-containingbinders

•  Butconcernsaboutcalciumbalance,uncertainKesaboutphosphateloweringinCKDpaKentsnotondialysis,addiKonalhardendpointRCTsandasystemaKcreview(effectsonmortalitycomparingcalcium-freevs.calciumcontainingphosphatebinders)promptedinthedecisiontore-evaluatethisrecommendaKon.


RATIONALE

PHOSPHATE

FGF23

CORONARYCALCIFICATION

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

ACTIVE PLACEBO

o  CKD3b–4o  Serumphosphateintheupper

normalrangeo  „AcKve“:Lanthanum–Sevelamer

–Caacetate


RATIONALE•  Blocketal.studiedsubjectswithessenKallynormal

phosphorusandassuch,normophosphatemiamaynotbeanindicaKontostartphosphate-loweringtreatments.Thissuggeststhatthatearly“prevenKve”treatmentofhyperphosphatemiaiscurrentlynotsupportedbydata(seeRec4.1.2)

•  TheWorkGroupfeltthattheupdatedguidelineshouldclarifythatphosphate-loweringtherapiesmayonlybeindicatedincaseof“progressiveorpersistenthyperphosphatemia”


RATIONALE•  Thebroaderterm“phosphate-loweringtherapies”is

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


TREATMENT

4.1.6:InadultpaKentswithCKDStages3a-5Dreceivingphosphate-loweringtreatment,wesuggestrestricKngthedoseofcalcium-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).


RATIONALE

•  NewevidencefromthreeRCTssupportsamoregeneralrecommendaKontorestrictcalcium-basedphosphatebindersinhyperphosphatemicpaKentsofallstagesofCKD.


PHOSPHATEBINDERSINMODERATECKD

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

ACTIVE PLACEBO PLACEBOLANTHANUM SEVELAMER CALCIUM


PHOSPHATEBINDERSANDMORTALITY(PREDIALYIS)

All-CauseMortality DialysisIncepKon

DiIorioBetal.ClinJAmSocNephrol2012;7:487-493

Calcium Sevelamer SevelamerCalcium


SEVELAMERVS.CALCIUM(DIALYSIS)

DiIorioBetal.AmJKidneyDis.2013;62:771-778

Arrythmias CVMortality


DIETARYPHOSPHATE

4.1.8:InpaKentswithCKDStages3a-5D,wesuggestlimiKngdietaryphosphateintakeinthetreatmentofhyperphosphatemiaaloneorincombinaKonwithothertreatments.(2D)

Itisreasonabletoconsiderphosphatesource(e.g.,animal,vegetable,addiKves)inmakingdietaryrecommendaKons.(NotGraded)

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


RATIONALE

•  TheprincipalrecommendaKonremainsthesameaspreviousbutWorkGroupaddedaqualifierstatementacknowledgingothersourcesforphosphorus:naturalphosphorus(ascellularandproteinconsKtuents)containedinraworunprocessedfoods;phosphorusaddedtofoodsduringprocessing;andphosphorusindietarysupplementsormedicaKons.


PHOSPHATEANDDIET

MoeSMetal.ClinAmJSocNephrol.2011;6:257-264


“HIDDEN”PHOSPHATE

ShermanRAetal.ClinJAmSocNephrol.2009;4:1370-1373


CLINICALKEYMESSAGES•  Itisimportanttoemphasizetheinterdependencyofserum

Ca,P,andPTHforclinicaltherapeuKcdecision-making.

•  Phosphate-loweringtherapiesmayonlybeindicatedinthecaseof“progressiveorpersistenthyperphosphatemia”.

•  NewevidencesuggeststhatexcessexposuretoexogenouscalciuminadultsmaybeharmfulinallstagesofCKD,regardlessofwhetherotherriskmarkersarepresent(e.g.,hypercalcemia,arterialcalcificaKon,adynamicbonediseaseorlowPTHlevels).


KEYMESSAGES

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

•  InCKD(includingpost-transplantaKon)DEXAisaspredicKveforfuturefractureriskasinthegeneralpopulaKon


CHAPTER4.2:TREATMENTOFABNORMALPTHLEVELSINCKD-MBD


VITAMIND

4.2.2:InadultpaKentswithCKDStages3a-5notondialysis,wesuggestcalcitriolandvitaminDanalogsnotberouKnelyused.(2C)ItisreasonabletoreservetheuseofcalcitriolandvitaminDanalogsforpaKentswithCKDStages4-5withsevereandprogressivehyperparathyroidism.(NotGraded)

Inchildren,calcitriolandvitaminDanalogsmaybeconsideredtomaintainserumcalciumlevelsintheage-appropriatenormalrange.(NotGraded)


RATIONALE

•  SuppressionofPTHviacalcitriolandothervitaminDanalogshavebeenthetherapeuKcmainstayforthetreatmentofSHPT.MulKpleRCTscitedinthe2009Guidelinereportedbenefitsoftheseagentsonimprovingbiochemicalendpointsandadverseeffectsofhypercalcemiawerealsonoted.

•  Twotrials,PRIMOandOPERA,demonstratedsignificantlyincreasedriskofhypercalcemiainpaKentstreatedwithparicalcitol,comparedwithplacebo,intheabsenceofbeneficialeffectsonsurrogatecardiacendpoints.


THEPRIMOTRIAL

ThadaniRetal.JAMA.2012;307:674-684


PARICALCITOLEFFECTONCALCIUMANDPHOSPHATE

•  Serumcalciumlevelsincreasedameanof0.32mg/dL(95%CI,0.19-0.45mg/dL)intheparicalcitolgroupanddecreased0.25mg/dL(95%CI,−0.37to−0.12mg/dL)intheplacebogroup(between-groupdifference,P<.001).

•  Serumphosphoruslevelsincreased0.23mg/dL(95%CI,0.07-0.39mg/dL)intheparicalcitolgroupandincreased0.04mg/dL(95%CI,−0.12to0.20mg/dL)intheplacebogroup(between-groupdifference,P=.05).

•  Hypercalcemia-paricalcitol22.6%versusplacebo0.9%,p


THEOPERATRIAL

WangAetal.JAmSocNephrol.2014;25:175-186

Hypercalcemia>2.55mmol/L:Paricalcitol43.3%Placebo3.3%NosignificanteffectonmeasuresofLVsizeorfuncKon


CONCLUSIONS•  RecentRCTsofvitaminDanalogsfailedtodemonstrate

improvementsinclinicallyrelevantoutcomesbutdiddemonstrateincreasedriskofhypercalcemia.Recentmeta-analyseswerelargelyconfirmatoryandsupportedthehypercalcemiariskassociaKonwithcalcitriolandvitaminDanalogs.

•  Theseresults,combinedwiththeopinionthatmoderatePTHelevaKonsmayrepresentanappropriateadapKveresponse,ledtheWorkGrouptoconcludethattherisk-benefitraKooftreaKngmoderatePTHelevaKonswasnolongerfavorableandthattheuseofcalcitriolorvitaminDanalogsshouldbereservedforonlysevereandprogressiveSHPT.


CONCLUSIONS•  TherearesKllnoRCTsdemonstraKngbeneficialeffectsof

calcitriolorvitaminDanalogsonpaKent-leveloutcomes,suchascardiaceventsormortality,andtheopKmallevelofPTHinCKDstages3a-5isnotknown.

•  TherapywiththeseagentsmayhaveaddiKonalharmfuleffectsrelatedtoincreasesinserumphosphateandFGF23levels.

•  IfiniKatedforsevereandprogressiveSHPT,calcitriolorvitaminDanalogsshouldbestartedwithlowdoses,independentoftheiniKalPTHconcentraKon,andthenKtratedbasedonthePTHresponse.

•  Hypercalcemiashouldbeavoided.


LOWERINGPTH

4.2.4:InpaKentswithCKDStage5DrequiringPTH-loweringtherapy,wesuggestcalcimimeKcs,calcitriol,orvitaminDanalogs,oracombinaKonofcalcimimeKcsandcalcitriol,orvitaminDanalogs.(2B)


RATIONALE

•  ThisrecommendaKonoriginallyhadnotbeenidenKfiedforanupdate.However,duetoasubsequentseriesofsecondaryandpost-hocpublicaKonsoftheEVOLVEtrial,theWorkGroupdecidedtore-evaluateRec.4.2.4aswell.


EVOLVESTUDY:CINACALCET

Chertow GM, et al. N Engl J Med. 2012;367:2482-2494

IntenKon-to-treatpopulaKon Lag-censoringpopulaKon


530475

489425

452374

415326

383293

345261

319239

291203

254182

233167

210155

194136

180119

11672

6746

1615

Age<65years

CinacalcetPlacebo

HazardraKo,0.99(95%CI,0.88,1.11)Log-rank,p=0.824

Prop

orKo

nEven

t-free

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time(months)0 4 8 12 1620 24 2832 364044 4852 5660

Subjectsatrisk:

0.2

0

0.3

TIMETOPRIMARYCOMPOSITEENDPOINT

CinacalcetPlacebo

HazardraKo,0.74(95%CI,0.63,0.86)Log-rank,p<0.001

Prop

orKo

nEven

t-free

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time(months)0 4 8 12 1620 24 2832 364044 4852 5660

Subjectsatrisk:

0.2

0

0.3

Age≥65years

14181460

13531379

12871319

12231253

11731183

11271123

10651073

10121021

976978

944942

905898

857860

809821

563578

332358

9799

Parfreyetal,CJASN,2015


TIMETOFIRSTEPISODEOFSEVEREUNREMITTINGHPT(INTENT-TO-TREATANALYSIS)

CinacalcetPlacebo

Prop

orKo

nEven

t-free

Time(months)

HazardraKo,0.43(95%CI,0.37,0.50)Log-rank,p1000pg/mL(106.0pmol/L)withserumcalcium>10.5mg/dL(2.6mmol/L)on2consecuKveoccasionsOR

–  PTH>1000pg/mLwithserumcalcium>10.5mg/dLonasingleoccasionandsubsequentcommercialcinacalcetusewithin2monthsofthelaboratoryassessmentOR

–  parathyroidectomy


RATIONALE•  AlthoughEVOLVEdidnotmeetitsprimaryendpoint,the

majorityoftheWorkGroupwerereluctanttoexcludepotenKalbenefitsofcalcimimeKcsforStage5DpaKents,basedonsubsequentprespecifiedanalyses.

•  NoPTH-loweringtreatmentwasprioriKzedatthisKme,sincecalcimimeKcs,calcitriol,orvitaminDanalogsareallacceptablefirst-lineopKonsinCKDStage5DpaKents.

•  TheWorkGroupexplicitlyendorsesthepresenceofclinicalequipoiseandtheneedtoconductplacebocontrolledtrialswithcalcimimeKcsversusstandardtherapyforthetreatmentofSHPTinpaKentswithCKDstage5Dwithemphasisonthoseatgreatestrisk(e.g.,older,presenceofcardiovasculardisease).


CONCLUSION

•  Noconsensuswasreachedtorecommendcinacalcetasfirst-linetherapyforloweringPTHinallpaKentswithSHPTandCKDStage5D.TheWorkGroupdecidedtomodifythe2009recommendaKontolistcalcimimeKctherapynowfirst,inalphabeKcalorder,amongacceptabletreatmentopKonswhilesKllrecognizingtheuKlityandefficacyofacKvevitaminDcompounds.

Documents

KDIGO CKD-MBD G U 2017...Karen A. Robinson Johns Hopkins University, BalKmore (USA) Kidney Disease: Improving Global Outcomes CHAPTER 3.2: TREATMENT OF CKD–MBD: BONE Kidney Disease: