ckd: updates on diagnosis, treatment, and how to delay … · 2017-08-27 · 8/11/17 1 ckd: updates...
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CKD:UpdatesonDiagnosis,Treatment,andHowtoDelayProgression
MelissaTollett,DVM,DACVIMSpecializedVeterinaryServices
IRISStagingofChronicKidneyDisease(Dogs)
Stage Creatinine (mg/dl) Comments
AtRisk <1.4 Animalatincreasedrisk
1 <1.4 Nonazotemic. Someotherrenalabnormalitypresent.
2 1.4-2.0 Mildrenalazotemia. Clinicalsignsusuallymildorabsent.
3 2.0-5.0 Moderaterenalazotemia.Extrarenal clinicalsignsmaybepresent.
4 >5.0 Increasing riskofuremiccrisis
IRISStagingofChronicKidneyDisease(Cats)
Stage Creatinine(mg/dl) Comments
AtRisk <1.6 Animal atincreased risk.
1 <1.6 Nonazotemic.Someotherextrarenal abnormalitypresent.
2 1.6-2.8 Mildrenalazotemia.Clinical signsusuallymildorabsent.
3 2.9-5.0 Moderaterenalazotemia.Extrarenal clinicalsignsmaybepresent.
4 >5.0 Increasingriskofuremiccrisis.
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Symmetricdimethylarginine (SDMA)
•CreatinineismostcommonlyusedtoestimateGFR• SDMAalsousedtoevaluateGFR• Occursfrommethylationofarginine(allnucleatedcells)• Excretedexclusivelyintheurine• IncreaseswhenGFRincreases• Notinfluencedbyleanmusclemass• SDMAcanincreasewith25-40%lossofrenalmass
Substaging byProteinuriaUP/CValue Substage
Dogs Cats
<0.2<0.2 Non-proteinuric
0.2to0.50.2to0.4 Borderlineproteinuric
>0.5>0.4 Proteinuric
• Ruleoutpre-renal• Hemoglobin• Myoglobin• Immunoglobulins
• Ruleoutpost-renal• Goalistoidentifyrenalproteinuria• Tubular• Glomerular(>2.0)
Substaging byProteinuria
•UPCshouldbemeasuredinallcases• RuleouthemorrhageandUTI• Ifazotemic andUPC>1.0(greaterrisk)
•Needatleast2urinesamples2weeksapart• Ifborderlinere-evaluatein2months•Proteinuriamaydeclineasrenalfunctionworsens
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ResponsetoPersistentProteinuria
•Monitor• Detectworrisometrends• Stablepatients“atrisk”
• Investigate• Treatableinfections• Inflammation• Neoplasia
ResponsetoPersistentProteinuria
• Intervene• Slowtherateofprogression• Diet• Omega-3fattyacids• EvaluateOmega6:3ratio(5:1)• Dosage0.25-0.5g/kg(DHA&EPA)• Safeupperlimit140mg/kg0.75
• 1.1IUofVit E/kgoffishoil• NordicNaturals,Welactin,Nature’slogic
• RAASInhibition
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Substaging byBloodPressureSystolicBlood pressure(mmHg) BloodPressureSubstage RiskofOrganDamage
<150 Normotensive Minimal
150-159 BorderlineHypertensive Low
160-179 Hypertensive Moderate
>180 SeverelyHypertensive High
• Takemultiplebloodpressuremeasurements• Usebreedspecificreferenceranges• Sighthoundstendtohavehigherbloodpressure
• Targetorgandamage• Eyes• Brain• Kidneys• Cardiovascularsystem
InhibitionofRenin-Angiotensin-AldosteroneSystem(RAAS)
• RAAS=majortargetsystemtoreduceproteinuria• Angiotensin-convertingenzymeinhibitor(ACEi)• Enalapril andBenazepril• Proventoreduceproteinuria(Grauer etal,2000)
• Angiotensin-receptorblocker(ARB)• LosartanandTelmisartan
• Aldosterone-receptorblocker• Spironolactone
• ReninInhibitors• Aliskirine
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DosesofCommonInhibitorsofRAAS
InhibitionofRAAS• Angiotensin-convertingenzymeinhibitor(ACEis)• Decreaseefferentarteriolarresistance• SerumCreatinineshouldbemonitored
• Creatinine(>30%frombaseline)• Increasedriskwithdehydration• CautionwithStage4CKD
• Hyperkalemia• Enalapril
• Primarilyexcretedbykidney• Benazepril
• Mostlyeliminatedthroughliver• Notaffectedbyrenalfunction
InhibitionofRAAS• Angiotensin-receptorblockers(ARBs)• BlockAngiotensinIIreceptor
• Reduceproteinuria• Combinedtherapy(ACEi &ARB)• BlockadeofAgII receptor-increasedrenin• ACEi incompletelyblockformationofAngiotensinII• Monotherapy=incompleteblockofRAAS
• Aldosterone-receptorblockers• Adverseeffectsfromhyperaldosteronism• UsefulifpersistentproteinuriawithACEi &ARB
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MonitoringRAASInhibition
•Whenadjustingtherapy(doseordrug)• 1-2weeks• Creat,K,BP,UPC• Day-to-dayvariationinUPC• GreaterwhenUPC>4.0(Nabity MB.etal,2007)
• Use2-3collections• TargetUPC<0.5
MonitoringRAASInhibition
•Hyperkalemia• Commonindogswithrenaldisease• Potassium>6.0(monitor)• EvaluateECG
• Potassium>6.5(modify)
• Treatment• ReduceACEi orARB• StopSpironolactone• Potassium-reducedhomecook
diet(Segev G.etal,2010)• Potassiumbinder(kayexelate)
AntithromboticTherapy• Thromboembolism=complicationofproteinuria• Reportedrateupto25%(CookAK.etal,1996)
• ReducedlevelofAntithrombin III• Correlatewithalbumin• Increasedriskofthromboembolism
• HeparinandWarfarin• Currentrecommendations(ConsensusStatement)• Lowdoseaspirin(0.5-5.0mg/kgdaily)• <1mg/kgdaymaynotbeeffective(HohCM.etal,2011)
• Clopidogrel 1.1mg/kgq24
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Hypertension
•Oftensilentandslowlyprogressive•Becertainofdiagnosis• White-coateffect• Evaluate• Cuffsize• Site• Position
• Whentotreat• Systolic>160mmHg• Diastolic>100mmHg
• Goalsoftreatment• Systolic<150mmHg• Diastolic<95mmHg
ManagementofHypertension
• RAASInhibitors• ReduceBP10-15%• Antiproteinuric• ACEi isappropriate1st step• ARBifneeded
• Calciumchannelblocker(Amlodipine)• 0.1-0.75mg/kgPOq24
• BetaBlocker(Atenolol)• 0.25-1.0mg/kgPOq12
• DirectVasodilator(Hydralazine)• 0.5-2mg/kgPOq12
RenalSecondaryHyperparathyroidism
•ReducedGFR• Promotesphosphorusretention• Inhibitionof1a-hydroxylase• Decreasecalcium
• IncreasedPTHproduction• Increasephosphaturia• Maintainnormalphosphate(initially)
• Calcitrioldeficiency• Parathyroidglandhyperplasia=PTH
•WanttominimizeCa&Pdisturbances
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DietaryIntervention• FeedaRenalDiet• 1st stepintreatmentofCKD
• IRISStage2-4
• Recentstudiesshowbenefit-IRISStage1• Geriatricdogs(HallJAetal,2016)• Geriatriccats(HallJAetal,2016)
• Controversialincats• Modestproteinrestriction
• Dietmodifications• Reducedprotein,phosphorusandsodium
• IncreasedB-vitamins,caloricdensityandsolublefiber
• Supplementedomega-3andantioxidants
• Majorbenefit• DecreaseprogressionofCKD• Increasesurvival
Phosphorus• Negativeeffectsofphosphorus• Renalsecondaryhyperparathyroidism• IncreasedlevelsofFGF-23(FinchNC etal,2013)• Reducedlevelsofcalcitriol• IncreasedCaxPproduct=mineralization• Riskofdeath4.2xhigherwhenCaxPproduct>70(BraffJetal,2014)
• ProgressionofCKD• PhosphorusGoal• 2.7-4.5g/dl• Optimalgoal-lowerhalfofRR
PhosphorusBinders•AluminumSalts• Mostcommonlyused• Inexpensive• Goodphosphorusbinding• Noknownsafedoseinhumans• 30-100mg/kg/day-dividedwithmeals• GIVEWITHFOOD!• Monitorq10-14days,then4-6weeks
• Sideeffects• Constipation• Hypophosphatemia• Reduceddrugabsorption• Fluorquinolones,Tetracyclines,Steroids,Thyroidhormones,H-2antagonists
• Aluminumtoxicity(chronicuse)• Neuromusculareffects,Microcytosis
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CalciumSalts• CalciumAcetate(PhosLo,Calphron)
• Goodphosphorusbinder• 2xmorethanCalciumCarbonate
• LessHypercalcemia• CautionwithCalcitriol• DONOTUSEifhypercalcemic• DrugInteractions
• Fluoroquinolones,Tetracyclines,Levothyroxine,Calcitriol• Dose20-40mg/kgeachmeal
• CalciumCarbonate(Epakitin/Tums)• Oralphosphorusbinder,antacid• Dose90-150mg/kg/day
• Dividedandgivenwithmeals
AlternatePhosphorusBinders• Sevelamer (Renagel)• NoCalcium/Aluminum• Expensive• Mayreduceabsorptionofvitamins• Dose200-1600mg/doseq8-12
• LanthanumCarbonate(Lantharenol/Renalzin)• Excellentphosphorusbinder• Noknowntoxicities• ReallyExpensive!• Dose30-60mg/kg/day
AlternatePhosphorusBinders• Lenziaren (SBR759)• Neworalphosphorusbinder• Insolublecomplexofironoxide/hydroxide• Increasedbindingofirontophosphate
• Notyetcommerciallyavailable• Dose0.125-1.0g/day
• Niacinamide• Safeandfairlyeffective• Contraindicatedwithliverdz,ulcers• Dose125-500mg/day
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Calcitriol•WhyuseCalcitriolwithCKD?• DecreasedPTH• MinimalincreaseiniCa• Correctabsolute/relativedeficiency• OccupyVitaminDreceptors
• Intra-renaleffects• Anti-inflammatory• Anti-fibrotic• ReduceRAAS
• Increasedsurvivalforazotemic dogs(Polzin Detal,2005)• IRISStage3-4• MeanCreatinine4.0• MST365daysvs250days
• CaandPlevelsshouldbenormal• Priortotreatment(<6.0mg/dl)
• Donotuseifhyperphosphatemic• Increasedriskfortissuemineralization
• CautionifsusceptibletoCaOxuroliths• Promoteshypercalciuria
Calcitriol
• Ifhypercalcemiadevelops• Discontinueuse(atleast1week)• Therapymaybeabletobe
reinstituted• Lowerdose,altereddosing
• MonitorCa,P,PTH• Assessafter1-2weeks,thenq6months
• PTHalsomeasureafter4-6weeks• Increasedoseifstillelevated
Calcitriol-EmergingProtocol
•HighDoseTwiceWeekly• 9-12ng/kgq3.5days• 2.5-3.5ng/kgq3.5days• TuesdayPM,SaturdayAM• WednesdayAM,SaturdayPM• StillControlsPTH• LessensConcernforHypercalcemia
• DailyDosing• 2-2.5ng/kgPOSID(initially)• Donotexceed5ng/kg/day• Preferablyinevening/emptystomach
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VitaminDandD-metaboliteOptions• Vit D2-Ergocalciferol• Initial:4,000-6,000U/kg/day• Maintenance1,000-2,000U/kgdaily-weekly• Onset5-21days
• 25(OH)Vit D-Calcidiol• 1,25(OH)2VitD-Calcitriol• Initial20-30ng/kg/day(3-4days)• Maintenance5-15ng/kg/day• Rapidonset(~1-4days)• Shortduration(2-3days)
Hypokalemia
• Potassiumdepletion• Uncommonindogs• CommonincatsIRISstage2-3
•Negativeeffects• Reducedrenalbloodflow• Promotespolyuria• Hypokalemicpolymyopathy• Muscleweakness,Cervicalventroflexion
• Oralsupplementation• Potassiumgluconate(2-6mEq/cat/d)
• Potassiumcitrate(40-60mg/kg/d)• Alkalinization therapy
MetabolicAcidosis•Whentosupplement• HCO3<15mmol/L
• Treatmentoptions• Renaldiet
• Firststep• Sodiumbicarbonate
• 8-12mg/kgq8-12hrs• Potassiumcitrate
• Hypokalemia+Metabolicacidosis• 40-60mg/kgq8-12hrs• Riskforexcessivealkalinization
• ParenteralNaHCO3• pH<7.10
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Anemia
•Multifactorial• Latrogenic• Bloodloss• Reducedlifespan• Poornutrition/Fedeficiency• DecreasedEPO
• Treatment• H-2blockers/Protonpumpinhibitors+Sucralfate
• IronDextran• 10-20mg/kgIM
• Ferroussulfate• 100-300mgperdogPOSID
Anemia(cont.)
• Erythropoietin• Erythropoietic agent• 100units/kgSQ3xweekly• Adverseeffects
• Autoantibodies• Hypertension• Seizures• Irondepletion
• MonitorPCV/Bloodpressure
• Darbepoietin (Chalhoub etal,2012)• Recombinanthumananalog• Lessimmunogenic• Administerlessfrequently• Moreexpensive• Whentostart?
• PCV<20%• 0.25-1.0mcg/kgSQweekly
OtherManagement
• DrugTherapy• Usecautionwithrenalmetabolism• Antibiotics• Penicillins,cephalosporins,fluoroquinolones,aminoglycosides
• AmphotericinB• Chemotherapy• Cisplatin,Carboplatin,Doxorubicin
• Atenolol• Gabapentin• Other
• Subcutaneousfluids• Asneededtomaintainhydration
• IRISStage3-4
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SummaryCKDTreatment
•Diet•Greatphosphoruscontrol•Greatproteinuriacontrol•Greatbloodpressurecontrol•RAASInactivation•Calcitriol•Othermanagement
References• BraffJ,Obare E,Yerramilli M,ElliotJ.Relationshipbetweenserumsymmetricdimethylarginineconcentrationandglomerularfiltrationrateincats.JVIM.2014;28:1699-1701.
• BrownS,ElliotJ,Francey T,Polzin D,Vaden S.Consensusrecommendationsforstandardtherapyofglomerulardiseaseindogs.JVIM2013;27:S27-S43.
• Chalhoub S,LangstonCE,Farrelly J.TheuseofDarbepoetin tostimulateerythropoiesisinanemiaofchronickidneydiseaseincats:25cases.JVIM2012;26(2):363-369.
• CookAK,CowgillLD.Clinicalandpathologicalfeaturesofprotein-losingglomerulardiseaseinthedog:Areviewof137cases(1985-1992).JAAHA1996;32:313-322.
• FinchNC,GeddesRF,Syme HM,ElliotJ.Fibroblastgrowthfactor23concentrationsincatswithearlynonazotemic chronickidneydiseaseandinhealthygeriatriccats.JVIM2013;27(2):227-233
• Grauer GF,GrecoDS,Getzy DM,etal.Effectofenalapril vsplaceboasatreatmentforcanineidiopathicglomerulonephritis.JVIM2000;14:526-533.
• HallJAetal.Plos One.2016;11:e0153654• HallJAetal.Plos One.2016;11:e0153653
References• HohCM,SmithSA,McMichaelM,ByronJK.Urinarythromboxanemetabolitesareinconsistentlyaffectedbylowdoseaspirinadministrationtohealthydogs.AJVR2011;72:1038.
• IRISStagingofCKD.http//iris-kidneycom/pdf/staging-of-ckdpdf.2015• LeesGE,ElliotJ,Grauer GF,Vaden SL.Assessmentandmanagementofproteinuriaindogsandcats:2004ACVIMForumConsensusStatement.JVIM2005;19:377-385
• Nabity MB,Boggess MM,Kashtan CE,LeesGE.Day-to-dayvariationintheurineprotein:creatinineratioinfemaledogswithstableglomerularproteinuriacausedbyX-linkedhereditarynephropathy.JVIM2007;21:425-430.
• Polzin D,RossS,OsborneC,Lulich J,SwansonL.Clinicalbenefitofcalcitriolincaninechronickidneydisease.JVIM.2005;19:433.
• Segev G,Fascetti AJ,Weeth LP,CowgillLD.Correctionofhyperkalemiaindogswithchronickidneydiseaseconsumingcommercialrenaltherapeuticdietbyapotassium-reducedhome-cookeddiet.JVIM2010;24:546-550.
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Questions?