Strategies to halt the progression of CKD G4+: Evidence from Randomized Trials Navdeep Tangri MD PhD FRCP(C) Associate Professor, Division of Nephrology Dept of Medicine and Community Health Sciences University of Manitoba KDIGO
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
KDIGO
Outline
• EvidencegapinCKDG4+
• AvailableevidenceforthefollowingintervenQons
• Bicarbonate• UricAcidReducQon• ACE/ARB• PhosphateBinders
KDIGO
Evidence Gap
• PaQentswithCKDStagesG4-5areoUenexcludedfromrandomizedtrialsinthegeneralpopulaQon
• VeryfewposiQvetrialsexistinpaQentswithkidneyfailure
• DifficulttoextrapolatefindingsfromCKDStageG1-G3AandfrompaQentsondialysis
KDIGO
Bicarbonate – Treatment of Met Acidosis
• MetabolicacidosisiscommoninpaQentswithadvancedCKD
• PaQentswithdiabetesmaybeataddiQonalrisk
• ProlongedmetabolicacidosiscanleadtobonelossandimpairedmusclefuncQon
• ClinicalpracQceguidelinesrecommendbicarbonatesupplementaQonatlevels<22mEq/l
SusanQtaphongetal.AJN2012
KDIGO
Evidence for Alkali Therapy in CKD
KDIGO
Evidence for Alkali Therapy
KDIGO
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)
KDIGO
Uric Acid ReducJon
• UricacidlevelsarestronglyandconsistentlyassociatedwithCKDandCVDinobservaQonalstudies
• UricacidreducQoninpaQentswithnormalkidneyfuncQonmayleadtoimprovementsinbloodpressurecontrol
• RandomizedcontrolledtrialevidenceinpaQentswithadvancedCKDremainsscarce
Kanjietal.BMCNephrology2015
KDIGO
Evidence for Uric Acid ReducJon
KDIGO
Evidence for Uric Acid ReducJon
KDIGO
Evidence for Uric Acid ReducJon
ForeGFR–Achangeof3ml/minoverfollowupwasdetected
KDIGO
ACE/ARB in advanced CKD
• MainstayoftreatmenttopreventCKDprogression
• LandmarkstudiesenrolledpaQentswithearlierstagesofCKD
• Efficacymaybemodifiedbypresenceofproteinuria
• Safetymaybemodifiedbyage
KDIGO
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
KDIGO
Landmark Trials
•
Jafaretal.JASN2007
KDIGO
STOP ACEI Trial
• MoQvatedbyrecentfindingsfromONTARGETandTRANSCEND
• Aimstoenroll410paQentswithCKDStagesG4-G5from15UKbasedPreDialysisClinics
• 3yearsoffollowup
• StraQfiedenrollmenttoensurebalanceinproteinuriaandCKDStage
• Measurementofappropriateclinicalandsurrogateendpoints
KDIGO
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)
KDIGO
Summary
• LimitedhighqualityevidenceexistsformedicalintervenQonstohalttheprogressionofCKDStage4+
• MostrandomizedtrialsfromthegeneralpopulaQondonotincludethesepaQents
• Dedicatedlargesimplerandomizedtrialsshouldbeperformedtoconfirmthesepreliminaryfindings
KDIGO