Strategies to halt the progression of CKD G4+: Evidence from

Randomized Trials NavdeepTangriMDPhDFRCP(C)

AssociateProfessor,DivisionofNephrologyDeptofMedicineandCommunityHealthSciences

UniversityofManitoba

KDIGO

Disclosures

• ResearchSupport•  AstraZenecaInc

• Honoraria•  OtsukaInc

• AdvisoryBoard•  ViewicsInc

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Outline

•  EvidencegapinCKDG4+

• AvailableevidenceforthefollowingintervenQons

•  Bicarbonate•  UricAcidReducQon•  ACE/ARB•  PhosphateBinders

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Evidence Gap

• PaQentswithCKDStagesG4-5areoUenexcludedfromrandomizedtrialsinthegeneralpopulaQon

• VeryfewposiQvetrialsexistinpaQentswithkidneyfailure

• DifficulttoextrapolatefindingsfromCKDStageG1-G3AandfrompaQentsondialysis

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Bicarbonate – Treatment of Met Acidosis

• MetabolicacidosisiscommoninpaQentswithadvancedCKD

• PaQentswithdiabetesmaybeataddiQonalrisk

• ProlongedmetabolicacidosiscanleadtobonelossandimpairedmusclefuncQon

• ClinicalpracQceguidelinesrecommendbicarbonatesupplementaQonatlevels<22mEq/l

SusanQtaphongetal.AJN2012

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Evidence for Alkali Therapy in CKD

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Evidence for Alkali Therapy

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Evidence for Alkali Therapy

•  Largesttrial–Debrito-Ashurstetal.

• MeaneGFR20ml/min,meanHCO3–20mEq/l

• Bicarbonatedose–22+/-10mEq/day

• PooledEsQmates•  SlightincreaseinDBP2.8mmHg•  IncreaseinsodiumexcreQon(24mEq/day)•  Decreaseinserumpotassium(0.7mEq/L)

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Uric Acid ReducJon

• UricacidlevelsarestronglyandconsistentlyassociatedwithCKDandCVDinobservaQonalstudies

• UricacidreducQoninpaQentswithnormalkidneyfuncQonmayleadtoimprovementsinbloodpressurecontrol

• RandomizedcontrolledtrialevidenceinpaQentswithadvancedCKDremainsscarce

Kanjietal.BMCNephrology2015

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Evidence for Uric Acid ReducJon

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Evidence for Uric Acid ReducJon

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Evidence for Uric Acid ReducJon

ForeGFR–Achangeof3ml/minoverfollowupwasdetected

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ACE/ARB in advanced CKD

• MainstayoftreatmenttopreventCKDprogression

•  LandmarkstudiesenrolledpaQentswithearlierstagesofCKD

•  Efficacymaybemodifiedbypresenceofproteinuria

•  Safetymaybemodifiedbyage

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Landmark Trials

• RENAAL•  MeaneGFR38ml/min,PaQentswithCr>3.0mg/dlexcluded

•  IDNT•  MeaneGFR43ml/min,PaQentswithCr>3.0mg/dlexcluded

• REINstudy•  NondiabeQckidneydisease,CrCl20-70,meaneGFR45ml/min•  Baselineproteinuria>3g/day

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Landmark Trials

• 

Jafaretal.JASN2007

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STOP ACEI Trial

• MoQvatedbyrecentfindingsfromONTARGETandTRANSCEND

•  Aimstoenroll410paQentswithCKDStagesG4-G5from15UKbasedPreDialysisClinics

•  3yearsoffollowup

•  StraQfiedenrollmenttoensurebalanceinproteinuriaandCKDStage

• Measurementofappropriateclinicalandsurrogateendpoints

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Phosphate Binders

• HyperphosphatemiaisassociatedwithearlymortalityinthegeneralpopulaQonandinpaQentsondialysis

• Highphosphorousandlowcalciumlevelsareassociatedwithprogressiontokidneyfailure

• PhosphateloadsinthepresenceofreducedkidneyfuncQoncanleadtoFGF23expression,whichmayhavedownstreamCVeffects

KDIGO

Evidence for phosphate binders

•  TworecentmetaanalysessuggesQngnon-calciumbindersmaybeassociatedwithimprovedsurvival

•  Evidenceislargelyfromdialysistrials

•  SmallertrialswithsurrogateoutcomeshavebeenperformedintheCKDpopulaQon

KDIGO

Evidence for phosphate binders

•  Blocketal.–JASN2012–Calciumandnon-calciumbindersvsPlacebo•  N=148•  NoeffectonFGF23,slightincreaseinCACwithbinders

•  IndependentStudy–DeIorioetal.CJASN2013–SevelamervsCalciumCarbonate•  N=212•  50%RelaQveriskreducQonindeathordialysis

•  Twosmallrecentstudiesonferriccitrate–shortfollowup(<12weeks)

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Summary

•  LimitedhighqualityevidenceexistsformedicalintervenQonstohalttheprogressionofCKDStage4+

• MostrandomizedtrialsfromthegeneralpopulaQondonotincludethesepaQents

• Dedicatedlargesimplerandomizedtrialsshouldbeperformedtoconfirmthesepreliminaryfindings

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