8/11/17

1

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.

8/11/17

2

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

8/11/17

3

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

8/11/17

4

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

8/11/17

5

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

8/11/17

6

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

8/11/17

7

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

8/11/17

8

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

8/11/17

9

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

8/11/17

10

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

8/11/17

11

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

8/11/17

12

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

8/11/17

13

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.

8/11/17

14

Questions?