CKD-RELATED ANEMIA KDIGO · Clinical Practice Guidelines on the Treatment of CKD-related Anemia...

CKD-RELATED ANEMIA CONCLUSION FROM KDIGO

CONTROVERSIES CONFERENCE Dr. Gregorio T. Obrador Vera, M.P.H.

Dean and Professor of Nephrology, Faculty of Health Sciences and School of Medicine, Universidad Panamericana (México, CDMX)

Adjunct Assistant Professor of Medicine, Tufts University School of Medicine & Tufts Medical Center (Boston, MA)

KDIGO

Clinical Practice Guidelines on the Treatment of CKD-related Anemia

1989 Introduction of EPO for clinical use

1997 KDOQI Guidelines on CKD-related anemia

2006 UPDATE à KDOQI Guidelines on CKD-related anemia

2007 UPDATE à KDOQI Guidelines on Hb target level

2010 REVISION à KDIGO Guidelines on CKD-related anemia

2012 PUBLICATION à KDIGO Guidelines on CKD-related anemia

2014 KDIGO Controversies Conference on the use of iron

2016 PUBLICATION à Article of the CC on the use of iron

KDIGO

KDIGO Controversies Conference

•  Ironoverload•  Oxida.vestress•  Infec.ons•  Anaphylactoidreac.ons

KDIGO

2012 KDIGO Guidelines Anemia in CKD

ü  Iden%fica%on,diagnosisandevalua%onofthecause

•  RoleofirontotreatCKD-relatedanemia

•  RoleofESAsandotherdrugstotreatCKD-relatedanemia

•  RoleofbloodtransfusionstotreatCKD-relatedanemia

KDIGO

Evaluation of Anemia FREQUENCY

PATIENTSWITHOUTANEMIAWhenitisclinicallyadvisedand

CKD3 Atleastannually

CKD4andCKD5ND Atleastonceevery6months

CKD5HDandCKD5PD Atleastonceevery3months

PATIENTSWITHANEMIA&WITHOUTTREATMENTWITHESAWhenitisclinicallyadvisedand

CKD3-5NDandCKD5PD Atleastonceevery3months

CKD5HD Atleastonceamonth

KDIGO

ANEMIA: Definition in Previous Guidelines

WHO 2001

●  Hb <13 g/dL à Men ●  Hb <12 g/dL à Women

KDOQI 2001

●  Hb <12.0 g/dL à Adult men and postmenopausal women ●  Hb <11 g/dL à Premenopausal and prepuberal women

EBPG 2004

●  Hb <13.0 g/dL à Adult men ●  Hb <12 g/dL à Men >70 years old ●  Hb <11.5 g/dL à Adult women

KDIGO

ANEMIA: Definition in 2006 KDOQI Guidelines

KDIGO

NHANES III (1988-1994) Distribution of Hb Levels

Hemoglobin(g/dl)

10

12

14

16

18

20

5th 50th 95th

15-19 20-29 30-39 40-49 50-59 60-69 > 69

Percentile

Females

Age group in years15-19 20-29 30-39 40-49 50-59 60-69 > 69

Number ofpersons

examined(x 1000) 0

1

2

Males

Vital Health Stat 11 (247), 2005 MMWR 47:1-36, 1998

KDIGO

ANEMIA: Definition in 2012 KDIGO Guidelines

KDIGO

ANEMIA: Definition - WHO 2008

KDIGO

ANEMIA: Definition - WHO 2001

KDIGO

ANEMIA: Definition

KDIGO

ANEMIA: Definition Challenges

•  WHO’sanemiadefini.onisques%onable;itcouldbeincludedasaresearchrecommenda.onintheguidelines

•  IdeallyaHbdistribu%onshouldbeobtainedtodefineappropriatecut-offlevelsforeachpopula.on

•  ItisnecessarytocorrecttheHblevelaccordingtoal%tude,smoking,andrace

KDIGO

Impact of Altitude on Hb Concentration

Altitude (meters)

Hb (g/dL) increase

<1000 0 1000 + 0.2 1500 + 0.5 2000 + 0.8 2500 + 1.3 3000 + 1.9 3500 + 2.7 4000 + 3.5 4500 + 4.5 WHO, 2001

KDIGO

Impact of Smoking on Hb Concentration

Smoker Status

Hb (g/dL) increase

Non smokers 0 Smokers (all) + 0.3 ●  ½-1 package/day + 0.3 ●  1–2 package/ day + 0.5 ●  >2 package/ day + 0.7

Am J Kidney Dis 41:S1-S135, 2005

KDIGO

Impact of Race on Hb Concentration

•  Hbconcetra.onlevelsvaryamongindividualsofdifferentraces

•  African-AmericanindividualshaveHblevelsthatare0.5-0.9g/dllowerthanthoseofnonAfrican-Americanindividuals

•  SincethecauseofthedifferenceinHblevelsamongracesisunknownandcouldreflectdifferentdegreesofcomorbidity,theguidelinedidnotincludespecificcut-offlevelsfordefininganemiaamongdifferentraces

KDIGO

Evaluation of the Causes of Anemia

KDIGO



ü  RoleofirontotreatCKD-relatedanemia

•  RoleofESAsandotherdrugstotreatCKD-relatedanemia


KDIGO

Treatment with Iron BENEFITS VS RISKS

Benefits Avoid or minimize •  Transfusions •  ESAs •  Symptoms

Risks •  Anaphylactoid and other acute reactions •  Unknown long-term risks

KDIGO Guidelines 2012

KDIGO

Treatment with Iron OBJECTIVES AND INDICATIONS

IVIron(ororalironx1-3monthsifCKD-ND)

↑ Hb without initiating ESA, and TSAT ≤30% and ferritin ≤500 ng/ml (2C)

NoIronorESA IVIron(ororal

ironx1-3monthsifCKD-ND)↑Hbor↓doseofESA,andTSAT≤30%yferri.n≤500ng/ml(2C)

ESA


KDIGO


Ini%a%ngTreatmentTSAT ≤20%

SerumFerri%n

≤100 ng/ml in CKD-ND and CKD-5PD

≤200 ng/ml in CKD-5HD

Do not exceed 500 ng/ml

KDOQI Guidelines 2006

KDIGO

Sensitivity and Specificity of TSAT and Serum Ferritin

KDIGO

TSAT≤30%

•  AlevelofTSAT<30%usuallyindicatesirondeficiency

•  Pa.entswithanemiaandTSAT>20%tendtorespondtotreatmentwithironeitherbyincreasingtheHblevelorbydecreasingtheESAdose

•  WithotherlevelsofTSAT,thesensi.vityandspecificityarelimitedtopredictirondeficiencyorHbincreasea`ertreatmentwithiron



KDIGO

•  134HDpa%entswithHb≤11g/dl,ferri.nof500-1200ng/ml,andTSAT≤25%

•  Randomizedtoreceive125mgofIVferricgluconatefor8consecu.vesessionsVSnoiron

•  BaselineEpodosewas↑25%inbothgroups•  Follow-upto6weeks


KDIGO


SerumFerri%n≤500ng/dl

•  Althoughmostpa.entswithserumferri.n>100ng/dlhavenormalironstoresinthebonemarrow,theytendtorespondtotreatmentwithironbyincreasingtheHbconcentra.onordecreasingtheESAdose

•  Thereisnotenoughevidencetodeterminethebenefitsandtherisksofadministeringaddi.onalirontopa.entswithserumferri.n>500ng/dlKDOQI2006andothersourcesrecommendNOTtoadministerirontopa.entswithserumferri.nlevelsbetween500-800ng/dl,becausetheincreaseinHblevelandthedecreaseinESAdoseislimitedandpoten.aladverseeffects


KDIGO


•  ItdoesnotdefinethelowerlimitofTSATandofferri.ndue

toinsufficientevidence

•  ItdefinestheupperlimitofTSATandferri.n

•  Itemphasizestheimportanceofindividualizingtreatment


KDIGO

European Renal Best Practice (ERBP) Recommendations for Iron Treatment

WithoutESAorFe WithESA Comments•  Ifthereisabsolutiron

deficiency,or

•  If↑HblevelwithoutrecurringtoESAisdesired,and

-TSAT<25%,and-Ferri.n<200ng/ml(CKDND)or<300ng/ml(CKD5D)

•  Donotinten.onallyexceedferri.n>500ng/mlorTSAT>30%

•  If↑inHblevelor↓inESAdoseisdesired,and

-TSAT<30%,and-Ferri.n<300ng/ml(evenhigherlevelsinpa.entsinHDwithaweakresponsetoESAsorunfavorablerisk/benefitwithESAs)

•  Donotinten.onallyexceedferri.n>500ng/mlorTSAT>30%

ItdefinesthelowerlimitofTSATandferri.ntostartirontreatmentbasedmoreonpragma.ccriteriathanonevidenceItdefinestheupperlimitofTSATandferri.nRiskofminimizingtheimportanceofindividualizingtreatmentwithiron

KDIGO

•  Inpa.entswithCKD-ND,selecttherouteofadministra%onbasedon

•  Severityofirondeficiency•  IVaccessavailability•  PreviousresponsetooralorIViron•  Treatmentcompliance•  Costs

Treatment with Iron ROUTE OF ADMINISTRATION


KDIGO

Treatment with Iron ROUTE OF ADMINISTRATION

Evidence

CKDNDNo clear evidence ofthebenefitsofIVvsPOiron(Hb ↑ 0.31 g/dl with IV versus PO iron)

CKD5HDIV iron ismoreeffec.vethanPOironanditiseasiertoadminister

CKD5PDLimited evidence thatIVironismoreeffec.vethanPOiron(KDOQICPG2006favoredPOironasini.altreatment)


KDIGO

Treatment with Iron ROUTE OF ADMINISTRATION AmJKidneyDis68:677-690,2016

KDIGO

•  Ini%alDose•  Administeredasasingledoseorasrepeatlowerdosesthataddupto

1gram

•  MaintenanceDose•  Periodicdoseswhenneeded•  Lowdosesatregularintervals

Treatment with Iron DOSAGE

KDIGO

KDIGO Controversies Conference

•  Ironoverload•  Oxida.vestress•  Infec.ons•  Anaphylactoidreac.ons

KDIGO

•  Anelevatedleveloftotalbodyironcouldbeassociatedwithagreaterriskoforgandamageover.me

•  Limleisknownaboutthecircumstancesinwhichtheexcessofironcausesdamagetotheorganswhereitaccumulatesandtheconsequencesoftheoverload

•  Inpa.entswithCKD,organdysfunc.oncausedbyironoverloadisrare;however,itcouldtakelongertoaccumulateforbeingclinicallyrelevant

Iron Overload

KDIGO

•  Administra.onofIVirontopa.entswithCKD•  Oxida%vedamagetoDNAandperipheralbloodlymphocytes•  Proteinoxida.onandlipidsperoxida.on•  Celularapoptosis,endothelialdysfunc.on,andmonocyteadhesion

•  Currentmethodstomeasureoxida.vestressandassessriskorprognosisareinconsistent

Oxidative Stress I

KDIGO

•  Evidencethattheadministra.onofironpromotesatherosclerosisandvascularremodelingisalsoinconsistent

•  Theeffectofan%oxidantsinpa.entswithCKDisunclear

Oxidative Stress II

KDIGO

•  Ironisimportantfor•  Prolifera.onandpathogenicityofmutlipleorganisms•  Regual.onoftheimmuneresponse(i.e.,modulatescellprolifera.onanddiferen.a.on,cytokineproduc.on,andotherac.onsoftheimmunesystemagainstinfec.ons)

•  Homeosta.cimbalanceofironcanaffectnotonlytheriskbutalsotheconsequencesofinfec.ons

Infections BASIC SCIENCE EVIDENCE

KDIGO

Clinicalevidenceisinsufficienttodetermineiftheadministra.onofironisassociatedwithanincreasedriskofinfec.on

•  Mostoftheevidencederivesfromobserva.onalstudiesinHDpa.ents•  Fewcontrolledclinicaltrialswithfewpa.entsandshortfollow-up•  VerylimitedevidenceinpredialysisandPDpa.ents•  Severalmeta-analysisandsystema.creviewshavebeeninconclusive

Infections CLINICAL EVIDENCE

KDIGO

Infections ELEMENTAL EVIDENCE

KDIGO

•  136pa.entswithCKD3-4andirondeficiencyanemia•  RandomizedtoreceiveIVironsucroseorPOiron•  Objec.ve:assessdifferencesinGFR


SeriousAdverseEvents AdjustedIncidenceRate

Global 1.60(1.28–2.00)

Cardiovascular 2.51(1.56–4.04)

Infec%ons 2.12(1.24–3.64)

KDIGO


KDIGO

•  Therearesignificantmethodologicaldifferencesbetweenthetwostudes(REVOKEandFIND-CKD),sotheyarenotfullycomparable

•  ThereisanurgentneedforacontrolledclinicaltrialtoassessthesafetyofthetreatmentwithIVironinpa.entswithCKD

•  KDIGO’srecommenda.ontoavoiduseofIVironinthepresenceofsystemicbacterialinfec.onsisreasonable(NotGraded)

Infections

KDIGO

•  IfhighMWirondextranisexcluded,thefrequencyofanaphylactoidreac.onsis<1:200,000administra%ons

•  TheFDArecommendstoslowtheinfusionofFerumoxytolduetosevereanaphylactoidreac.ons

Anaphylactoid Reactions FREQUENCY

11.3

3.3

0.9 0.6

0

2

4

6

8

10

12

HighMWDextran LowMWDextran Ferricgluconate FerricsaccharateKDIGO

•  Iftheini.aldoseofIVironisdextran(1B)ornotdextran(2C),werecommend/suggest

•  Tomonitorthepa.entfor60minutesa`ertheinfusion•  Havecardiopulmonaryresuscita%onequipmentathand

(includingdrugs)andtrainedpersonneltopoten.allytreatseriousadverseevents

KDIGO Recommendation


KDIGO




ü  RoleofESAsandotherdrugstotreatCKD-relatedanemia


KDIGO

KDIGO Recommendations Regarding ESA Use

Recommenda%ons3.1Iden.fyanytreatablecauseofanemia(e.g.irondeficiency,CKD-related)beforestar.ngtreatmentwithESAs(NotGraded)

3.2Forthedecisiontoini.ateandmaintaintreatmentwithESAs,itisrecommendedtobalancethebenefits(reduc.onoftherisksassociatedwithtransfusionsandsymptomsrelatedtoanemia)andtherisks(CVA,HTN,lossofvascularacces,malignancy)(1B)

3.3ItisrecommendednottouseESAsoronlywithextremecau%oninpa.entswith:•  Ac.vemalignancy(speciallyifcureisan.cipated)(1B)•  HistoryofCVA(1B)•  Historyofmalignancy(2C)

KDIGO

Benefits of ESA TREAT STUDY

Transfusions

Absoluteriskoftransfusions 15%inthehighHbgroup25%intheplacebogroup

QualityofLife

TREATStudy

Comparedwithplacebo,thetreatmentwithdarbepoe.ninthehighHbgroupresultedinamodestbutconsistentimprovementinfa.gueandglobalqualityoflife,butnotinenergyandfunc.onalcapacity

2recentsystema.creviews BothsuggestthethatthehighestimprovementinqualityoflifeiswithHblevelsbetween10-12g/dl

KDIGO

Risks of ESA I TREAT STUDY

CerebrovascularAccidentRela.veriskofCVA 1.92(95%CI,1.38–2.68)

AbsoluteriskofCVA 5%inthehighHbgroup2.6%intheplacebogroup

Absoluteriskinpa.entswithhistoryofCVA

12%inthehighHbgroup4%intheplacebogroup

AbsoluteriskofCVAamributabletoahighlevelofHb/darbepoei.n

8%inpa.entswithhistoryofCVA1%inpa.entswithouthistoryofCVA

VenousThrombosis

AbsoluteriskofVT 2%inthehighHbgroup1.1%intheplacebogroup

KDIGO

Risks of ESA II TREAT STUDY

MalignantNeoplasmInpa.entswithhistoryofmalignantneoplasmatthebegginingofthestudy

Mortalityof7.4%inthehighHbgroupMortalityof0.6%intheplacebogroupKDIGO

Recommendations for Starting Treatment with ESA

CKDND CKD5D

Donotini.atewhenHbis≥10g/dl(2D)WhenHb<10g/dl,itissuggestedtoindividualizethedecisiontostartdependingon(2C)•  Rateof↓oftheHblevel•  ResponsetopreviousRxwithiron•  Riskofrequiringtransfusion•  RisksassociatedwithESAuse•  Symptomsofanemia

StartwhenHbisbetween9-10g/dltopreventitfallingto<9g/dl(2B)

KDIGO

Recommendations for Maintaining Treatment with ESAs

CKDNDand5D

IngeneralitissuggestednottouseESAstomaintainHb>11.5g/dl(2C)Individualizetreatmentbecausesomepa.entscanhaveabemerqualityoflifewithHb>11.5g/dliftheyarewillingtoaccepttherisks(NotGraded)Donotinten.onallymaintainHb>13g/dl(1A)

KDIGO

Reasons for the Lower Limit of the Hb Target

•  IntheTREATstudy,pa.entsrandomizedtoplacebohadameanHblevelof10.6g/dldespitethattheydidnotreceiveoronlyreceivedsmalldosesofdarbepoie.niftheHbwas<9g/dl

•  Thereisnoevidencetosupportthatallpa.entswithHblevelsbetween9-10g/dlshouldreceivetreatmentwithESAs-INDIVIDUALIZE

•  Inpa.entswithCKD5HD,Hbtendstodropfasterandreachlevelsof8g/dl;riskoftransfusionissignificantlyreducedifHbdoesnotfallto<9g/dl

KDIGO

Canadian Erythropoietin Study Group

•  118pa.entswithCKD5HD•  EpowasadministeredifHb<9g/dlto↑to9.5–11g/dl(GroupI)or

>11g/dl(GroupII)versusplacebo

Placebo GroupI GroupII

Transfusions 58% 2.5% 2.6%

QOLImproved

comparedtoplacebo

ImprovementwassimilartoGroupI

NDT 7:811-16, 1992

KDIGO

Reasons for the Upper Limit of the Hb Target

•  Itisbasedupontheinterpreta.onthatthemaximumHblevelreachedinthecontrolgroupoftherecentECCswas<11.5g/dl

•  Thereisnoenoughevidenceregardingthepoten.albenefitofincreasingtheHblevelbetween11.5-13g/dl•  CREATEshowedbenefitsinqualityoflifebutCHOIRdidn’t

•  AHblevel>13g/dlisassociatedwithahigherriskofcomplica.ons

KDIGO

Reasons for the Upper Limit of the Hb Target

Besarab(98) Parfrey(05) CREATE(06) CHOIR(06) TREAT(09)

Pa%ents 1233HDwithCVD

596HDw/oCVD

603CKD3-4

1423CKD3-4

4038CKD3-4

AchievedHb(g/dl)

12.7-13.310.0

13.310.9

13.411.6

12.711.4

12.510.6

Mortality ↑IAM ↑CVA ND ↑CVevents ND

QOL ↑physicaldomain

↑vitalityscore ↑↑↑ ~ ↑

Transfusions ? ? 26vs33 ? ↓

KDIGO




ü  RoleofESAsandotherdrugstotreatCKD-relatedanemia

ü  RoleofbloodtransfusionstotreatCKD-relatedanemia

KDIGO

Role of Blood Transfusions to Treat Anemia

KDIGO

Risk of Transfusions IMMUNOLOGICAL MECHANISMS

KDIGO

KDIGO Recommendations I

KDIGO

KDIGO Recommendations II

KDIGO

New Therapies HIF STABILIZERS New Therapies

HIF STABILIZERS

KDIGO

New Therapies HIF STABILIZERS New Therapies

HIF-PH inhibitors under Development

AmJKidneyDis69:815-26,2017

KDIGO

Potential Advantages of HIF Stabilizers

•  Consistentalthoughnotcon.nuousandmorephysiologicaldosesofendogenousEpo

•  Increasedavailabilityofironforerythropoiesis

•  Oraladministra.on

KDIGO

Unanswered Questions

•  Effectoncardiovascularhealth

•  ImpactofnormalizingHbwiththeseagents

•  Risksassociatedwithac.va.onofVEGF(progressivere.nopathy,tumorgrowth…)

KDIGO

Conclusions

•  KDIGOguidelinerecommenda.onsforthemanagementofanemiaofCKDarebasedoncurrentlimitedevidence

•  Therearegapsofknowledgethatrequirefurtherinves.ga.on

•  CurrenttreatmentofanemiaofCKDisnotop.mal

•  NewtherapiessuchasHIFstabilizersarepromising

KDIGO

CKD-RELATED ANEMIA KDIGO · Clinical Practice Guidelines on the Treatment of CKD-related Anemia...

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Transcript of CKD-RELATED ANEMIA KDIGO · Clinical Practice Guidelines on the Treatment of CKD-related Anemia...