vetgirl - polzin - proteinuria 12-21-16 np · • positive leptospirosis test • physical evidence...

12/21/16

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ApproachtotheProteinuricCaninePatient

DavidJ.Polzin,DVM,PhD,DACVIMProfessor,UniversityofMinnesotaCVMChiefofSmallAnimalInternalMedicine

JustineA.Lee,DVM,DACVECC,DABTCEO,VETgirl

Introduction

GarretPachtinger,VMD,DACVECC

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DavidPolzin,DVM,PhD,DiplomateACVIM(SAIM)Professor,

UniversityofMinnesota

Introduction

• “Bubblesappearingonthesurfaceoftheurineindicatediseaseofthekidneysandaprolongedillness.”

• Nobody’sperfect!– Hippocratesconcludedthatthekidneyswerenotessentialtolife!

AphorismsofHippocratesHippocrates ofCos(460–377BCE)

CurrentMethods:Proteinuria 10y/oBlueHeeler,F/S

Concentration/Dilution&Proteinuria

• AtUSGof1.060,2+ondipstickproteincanbe~100mg/dl

• Diluteto1.030,samplehas50mg/dlandreads1+ondipstick

• Diluteto1.015,samplehas25mg/dl&readstraceondipstick

Urineconcentration/dilutionaltersthequantityofwaterextractedfromfiltrate,buthasnoeffecton

proteincontentofthefiltrate

ScreeningForProteinuria

• Urinedipsticks– Mostsensitivetoalbumin– Very AlkalinepH=falsepositive

• Precipitationmethods– Sulfosalicylic acid(SSA)– False+:radiocontrastagents,penicillins,sulfasoxazole,cephaloridine

– Inadditiontoalbumin,willdetectBence-Jonesproteinsandglobulins

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ScreeningForProteinuria

• Bothtestscanhavefalsepositive&negatives– Advantagewhenbotharereported– Causesforfalsepositive&negativefindingsdiffer

• Positivefindingsshouldbefollowed-upbyurineprotein:urine creatinine(UPC)

WhatDipstickLevelIndicatesThatAUPCShouldbePerformed?

• Generalization:1+atanyspecificgravity• Traceprotein

– Lookaturinespecificgravity– ThelowertheUSG,themoresignificantyoushouldconsideredthefindingofa“trace”protein

TheearlieryourecognizeandtreatGN– thebetterthechance

ofafavorableoutcome

UPC- Concept

• Creatininefilteredbutneitherabsorbednorsecreted

• Glomerularproteinuria– Exitsglomerularfilterwithcreatinine

– Somereabsorptionofsmallproteinmolecules&albumin

• Net:eliminatesimpactofurineconcentration&dilutionofurine

FatesofFilteredProteins

PathologicalRenalProteinuria• Glomerular

– Glomerularpermselectivitydefect(UPC>0.2up)– Smalltolargequantity– Albumin-sizedproteinsandlarger

• Tubular –– Failureoftubulestoreabsorbproteins– Smallquantity(UPClessthanabout2)– Smallproteinsuptoapproachingthesizeofalbumin

• Interstitial –– Trafficfromperitubularcapillaries– Usuallyofinflammatoryorigin– Smalltolargeamounts

WhyIsItImportanttoDifferentiatetheTypeofRenalProteinuria?

• UPCinaurinewithaquieturinarysediment=5.6&4.9.ThedoghasminimalclinicalsignsotherthanPU/PD.

• ShouldItreatthisdogwithbenazepril?• Notyet…needtoseekcausation:

– Leptospirosis– Cushing’ssyndrome– Others…

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QuantifyProteinuria– UPC

• Urineprotein:creatinine ratio• Calculation:Urineprotein(mg/dl)/Urinecreatinine(mg/dl)=unit-lessratioestimatingurinaryproteinloss

• Interpretation:

UPCConfounders

• Proteincouldenterurinethroughouttheurinarytract

• Inflammationintheurinarytract• Urinarytractinfection• Blood• [Serumcreatinine]• Math!

ConfirmingthatUPCisValid

• UPCRatioUninterpretable withGrossHematuria,Pyuria,orBacterialUTI

• Recommendurinalysis&urineculturebeforeUPC– Urinalysis

• Pyuria• Grosshematuria

–Urineculture

3-DayUrineCollections

• ImprovereliabilityofUPCvalues• Test-testvariabilitynotclearlyestablished• Method:

– Serialfor3dayscollect1st morningurinesamples– Combineequalvolumesfromeachsampleandmixwell(e.g.5mlfromeachcollectionà 15ml)

– SubmitforUPCdetermination

3y10mFChes. BayRetriever

Would“trace”proteinbeinterpreteddifferentlyiftheurinespecificgravitywerehigher(e.g.1.035)?

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ShouldanUPChavebeenperformed?


HowshouldyouproceedwithaUPCof0.9?

Repeattoconfirm!


HastheUPCincreased(clinicalinterpretation)?

No!

GuidelineforMonitoring• UrineP:Crratioshouldbereconfirmed– 3timesifUPC<3.0– 2timesifUPC>2.9– At2to4weekintervals

• ClinicallyimportantchangesinurineP:Crmayrequirea30%to50%change


What&whenshouldyoudonext?

Proteinuria!WhatNow?

• Detectproteinuria• Confirmproteinuria• Establishthemagnitudeofproteinuria• Determineorigin(intheurinarytract)oftheproteinuria

• Ifrenal…– Glomerularproteinuria– Tubular proteinuria– Interstitial proteinuria

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PathologicRenalInterstitialProteinuria…SomeCauses

• Inflammatorycells,hematuria,infection- ofrenalorigin(casts)

• Positiveleptospirosistest• Physicalevidenceofrenalorigin– enlarged,painfulkidney(s),etc.

• Biochemicalevidenceofkidneydisease?

SDSPageElectrophoresisofUrine• Canbeusedtoassesssizeofproteinsinurine

• Localizing– Small=tubular– Large=glomerular

MagnitudeofUPCandActionPlans

ACVIMProteinuriaConsensusStatement

GenerallyforUPCvalues>0.5– 1(± upto2.0?)

UPC> ~1.0– 2.0

UPC>0.5

Monitoring – What?Why?

• Magnitude• Pattern®

–Static–Progressive–Regressive

• Persistence

• Todetermineifinvestigationneeded

• Prognosis

Investigation ofProteinuricDogs• Medicalhistory:includefamilydetails,environment,travelhistory,drugexposure,andpriororconcurrentillnesses

• Physicalexam:Include:BCS,fundic exam,atleast2bloodpressuremeasurements

• Laboratorytests:– CBCincludingplatelets– Comprehensivechemistryprofile– Completeurinalysis(withsedimentexam)– UrineProtein:CreatinineRatio– (±)Urineculture

Hypertension!

• Recommendthatdogswithproteinuriahavebloodpressuremeasured

• Hypertensionis“common”indogsandcatswithkidneydiseases– Morefrequentinglomerulardiseases?– ~30-60%prevalenceoveralldogsglomerularDz

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WhiteCoatEffect

• SerialMeasurements• Techniques

BloodPressureRangesforDogs

PossibleAssociationswithRenalProteinuria

• AKI• CKD• Glomerulardisease• Acutepancreatitis• Viraldisease• Drugreactions• Systemichypertension• Diabetesmellitus(?)• Hyperadrenocorticism

• Immune-mediatedisease• Tick-bornedisease• Leptospirosis• Endocarditis• Heartwormdisease• Exogenoussteroiduse• Anysevereinflammation• Neoplasia

From:Harley&Langston,2012

8Year-OldFSGoldenRetriever

• Polyuria,Polydipsia,Panting• Laboratoryfindings:

– Serumcreatinine– 1.4mg/dl– Serumalbumin– 2.1mg/dl– SAP– 972U/dl– ALT– 211U/dl– Urinespecificgravity– 1.017/UPC– 10.1

• Diagnosis:Hyperadreocorticism

9Year-OldM/CLabradorRetriever

• Dry,dullhaircoat• Progressivelethargyoverpast3-4months• Laboratoryfindings:

– Hypoalbuminemia– 2.1mg/dl– UPC- 7.6– Serumcreatinine– 1.4mg/dl– Hypercholesterism – 1163

• Diagnosis:Hypothyroidism

TiersofCanineGlomerularDisease

• TierI: Persistentsubclinicalrenalproteinuria– Absentazotemia&hypoalbuminemia– Noapparentrenal-relatedclinicalsigns/sequellae– Non-hypertensive(A)orHypertensive(B)

• TierII:Renalproteinuriawithhypoalbuminemiabutnotazotemic– Clinicalsignstypicallyduetoedemaorthromboemboliccomplications

– Non-hypertensive(A)or Hypertensive(B)

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TiersofCanineGlomerularDisease

• TierIII:Renalproteinuriawithrenalazotemia– (A):Nohypertensionorhypoalbuminemia– (B):Withhypertension,nothypoalbuminemic– (C):Withhypoalbuminemia

• Withorwithoutclinicalsigns/sequellae ofhypoalbuminemia

• Oftenhypertensivebutnotconsistently

6yearoldLabradorRetriever

• “Jake”- medicalhistory– Losingweightlast~6weeks– Stilleating,butappetitehasbeendeclining

– Morelethargic• Physicalexamination

– Jakeisthin(bodyconditionscore3/9)andlethargic

– Otherwiseunremarkable

“Jake”- InitialEvaluation• CBC:Hematocrit=37%

...normalleukocytecount&differentialcount• Chemistryprofile:

Albumin 1.6g/dl Totalprotein 4.7g/dlALT 26U/L ALP 35U/L

BUN 11mg/dl Creatinine 1.4mg/dlCa+2 9.4mg/dl Phosphorus 5.4mg/dltCO2 20.1meq/L Na+ 148meq/L

K+ 4.8meq/L Cl- 116meq/LCholesterol 347mg/dl

“Jake”– Urinalysis,BP,US&Culture

• Urinalysis:– Specificgravity:1.034– Chemistries:

• 4+protein• Negativeforoccultblood

– Sediment:0-3RBC/0-1WBC

• Urineculture:Negative• Bloodpressure:systolicmean– 175/120

Goodurineconcentrating

Proteinuria

Hypertension

JakesTier?

• TierII:Renalproteinuriawithhypoalbuminemia,hypertension &non-azotemia

• KeyInitialGoals:– Diagnosticstofindcausation→ Specifictherapy?– Reduceproteinuria– Increaseserumalbuminconcentration– Normalizehypertension(HTmaypromoteproteinuria&cardiovascularcomplications)

Proteinuria:AdditionalStudies

• AdditionalStrategiestoidentifythecauseforproteinuria:– Serologyforpossibleinfectiousdiseases(local&travel)

• Borreliosis • Leishmaniasis• Ehrlichiosis • RMSF• Heartwormdisease • Otherregionalconsiderations• Leptospirosis(proteinuricearly)

– Imaging• Neoplasia• Inflammatorylesions

– Lipidprofile(especiallyhypertriglyceridemia)– Endocrinetests:Hyperadrenocorticism,hypothyroidism

• RenalBiopsy?

Ultrasound&AdvancedImaging

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“Jake”– FurtherEvaluation

• AbdominalUltrasound:NoAbnormalities• PositiveforBorrelia (LymeDiseaseagent)

WhatDoesAPositiveTestforLymeDzMeaninADogsWithGlomerularDz?

• PresumedthattheglomerulardiseaseisaconsequenceofBorreliosisinfection(butnot100%proof)

• AdministeringdoxycyclinetodogswithpresumedBorreliosis-associatedGNisveryunlikelytoimprovetheglomerulardisease– Butwestilltreatitthisway– Onemonth,sixmonths,untilthetiterdropsbyatleast50%- noconclusiveevidence

InMinnesota&NortheastUSA

• Borreliosisappearstohaveasignificantassociationwithproteinuria&glomerulardisease

• OfdogsthattestpositiveforBorreliosis,arelativelysmallnumberhaveorwilldevelopglomerulardisease

• Nonetheless– Earlyrecognitionofglomerulardiseaseimprovesprobabilityofbetteroutcomewithappropriatetreatment

Intervention

• Reducemagnitudeoftheproteinuria• Minimizecomplicationsofproteinuria

– Hypercoagulablecondition– Hypertension

• Treatinitiatingcausation(ifknown)• Treattheprimaryglomerulardisease

StandardTherapyofProtein-LosingNephropathy

ReducingtheMagnitudeofProteinuria

Event Times (nonproteinuric)

Cum. Survival (nonproteinuric)Event Times (proteinuric)

Cum. Survival (proteinuric)

0

.2

.4

.6

.8

1

0 5 10 15 20 25Time (months) Jacob, Polzin, Osborne, et al, 1999

P<0.02

Cumulative

Surviv

al

Time(Months)

EffectofProteinuriaonSurvival

DogswithCKD

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Goals

• Reducemagnitudeofproteinuria

• Secondary-- ↑ serumalbuminifhypoalbuminemiaispresent

• Therapyneedstocontinuesolongasproteinuriapersists

StandardTherapyofGlomerularDisease

LimitingProteinuria:InhibitionofRAAS&RenalDiet

EffectofACEIonGlomerularHemodynamics

ReductioninGFRCanLeadtoAzotemia

↓ AT1 DilatesPost-GlomerularArterial

Why Does Blocking the RAAS Decrease Glomerular Proteinuria?

• Decreased pressure in the glomerular capillaries– Higher pressure in glomerular

capillaries → increased production of glomerular filtrate

– Protein swept out through larger “holes” by solute drag

• Restore slit diaphragm integrity & increase negative charge on glomerular membrane

BenefitsofReducingProteinuria• Slowprogressionofglomerulardisease

– Thehigherbaselineproteinuria– greaterpotentialbenefit– Magnitudeofbenefitappearstoberelatedtomagnitudeofreduction inproteinuria(humans)

• EffectsonGFRandrenalpathologyindogs???• Todate,littleevidencethatstandardtherapyaloneislikelytoconsistentlyreverseorresolvelesionsofglomerulardiseaseindogs

DrugsReducingActivityoftheRAAS

• Angiotensinconvertingenzymeinhibitors– EnalaprilorBenazepril

• Angiotensinreceptorblockers– TelmisartanorLosartan(?)

• ACEI+ARBCombination

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ACEInhibitorsinDogs

Graueretal,2000

BaselineplaceboUPC:4.7BaselineenalaprilUPC:8.7

PlaceboEnalapril

EffectsofEnalaprilinSamoyedDogswithHereditaryNephritis

• Slowedtherateofincreaseofproteinuria(P<0.01)

• Delayedtheonsetofincreaseinserumcreatinineconcentration(P<0.05)

• Treateddogssurvived1.36timeslonger(P<0.05).

Grodecki etal,1997

UsingACEIinGlomerularDisease

• SideEffects:– Azotemia– ReducedBP– Hyperkalemia

• Starting ACEI:– Monitorserumcreatinine&K+ ,UPC,BP– Startingdose(~0.25-0.5mg/kg/day)

AdjustACEIDose“ToEffect”

• Goal:– Minimally:ReduceUPCby50%– Ideal® ReduceUPCto<0.5

• IfUPCnotattarget,increasedose(usually50-100%)totargetormaximumdose(~2mg/kg/day)

• Carefullymonitorrampuptoend-point

PotassiumManagement

• ManagingpotassiummayallowhigherdosagesofACEiandARB

• Options– Limitdietarypotassiumintake– Enhancedistaltubularflow:

• Avoiddehydration• Supplementfluids(Caution!)

ShouldYouStartwithACEiorARB?

• ACEiiscommonlyfirstchoice– Typicalpractice– morecomfortablewithdrugs?– Usuallywelltolerated(ifhydrated)– CommonlyneedtoincreaseACEidosages

• WhenmightyouuseARB– Nofirmguidelinesyet– ACEifailstoreduceproteinuriabyatleast50%– Patientishypertensive?

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ObservationalEvidence…

• OptionswhenACEihasnotachievedgoal– SwitchtoARB(Telmisartan)–AddARB(dualtherapy)

• Mayreduceproteinuria,but…• Increasedriskofadverseeffectsinpeople

Efficacy & Safety of Dual Blockade of the RAAS

• Potentialadverseeffects:– Impairedrenalfunction

– Hyperkalemia• Benefits:

– Reduceproteinuria

– Increasesurvival

Makani,(BMJ)2013

ObservationalEvidence…

• OptionswhenACEihasnotachievedgoal– SwitchtoARB(Telmisartan)– AddARB(dualtherapy)

• Mayreduceproteinuria,but…• Increasedriskofadverseeffectsinpeople

• Observations:– Inselectedcases,whereACEihavefailed,Telmisartanmayprofoundlyreduceproteinuria

– Sofar“better”drughasbeenunpredictable

3(Related)YorkshireTerriers

• 9yearold5lbYorkshireterrier– ACEi(Benazepril– 2mg/kg)+Losartan:UPC>7– ReplacedLosartanwithTelmisartan1mg/kgoncedaily.

– UPCdeclinedwithinfirstmonthfrom>7to<0.6• Previousdog’sbrotherUPC~2+onACEi

– ReplaceACEiwithTelmisartan® UPC~1• 3rd (unrelated)Yorkshireterrier– nochangeinUPConTelmisartan

KeytoSuccesswithACEI/ARB

• Drugmustreduceproteinuria!– Startingdose– ProgressiveACEIdosingto~2.0mg/kg/day– ARBdosing0.5-2mg/kg

• HowLongShouldYouTreat?– Atleastwhilethepatientisproteinuric– ProteinuricmeansUPC³ 0.5

• Howlongshouldyoukeepmonitoring?– Regularly~every3month(UPC,SCr,K,Albumin)

Goals:UPC<0.5,or

↓UPCby>50%

Burkholder,2004

Diet:LimitingProteinIntake• Limitingproteinintake

reducesproteinuria• Highproteinfeeding

increasesproteinuria(glomerularhyperfiltration)

• Inrats– highproteinfeedingactuallyimpairsproteinnutritionstatus

• Otherdietfactors:– Salt– n-6:n-3PUFAratio~5– Antioxidants

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StandardTherapyofProtein-LosingNephropathy

ManagementofHypertensionandThromboembolism

HypertensionandtheKidney• Nephronloss® impairedabilitytoadjustNaCl excretionrapidlyandquantitativelyasintakechanges– ECFV® increasingbloodpressure– Diureticsmainstayoftherapyinhumans

• Othermajorcontributors– ActivationofRAAS– IncreasedsympatheticNSactivity

WhatAreTheEffectsofHT?

• InKidneyPatients:Hypertensionpromotes…– Progressionofrenaldysfunction– Proteinuria– Polyuria

• Heart– Recent– Biomarkersindicatedassociationbetweenkidneydiseaseandcardiacdisease

– “Cardio-renalsyndrome”

WhatAreTheEffectsofHT?• Ophthalmological

– Retinaldetachment– Retinalhemorrhage– Hyphema– Vitreal hemorrhage– Retinaleffusion– Vasculartortuosity

• Neurological– Suddenchangeinmentation

– Seizures– Behavioral– Appetite

AntihypertensiveTherapyinCKD

• Goals:– Lowerbloodpressure(To<150/95???)– SlowprogressionofCKD– Prevent/treathypertensiveend-organinjuries– Reducecardiacimpact(cardiorenal axis)

• Consider:– Proteinuria– Coordinatewithothertherapies(e.g.ACEI)

DrugTherapyforHypertension

• Amlodipine– Dogs:0.1-0.6mg/kg/day– Cats:0.625-1.25mg/dayforcats<5kg

• ARB– Telmesartan– 0.5-2mg/kg/day– Protectsthekidneys

• ACEI(benazepril,enalapril)– 0.25-2.0mg/kgq12-24h– Protectsthekidneys

Treatmentis“toeffect”

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MultidrugApproachMayBeRequired

• Dogs– Amlodipine+ACEIè– Commonlyusedtogetherindogs– Protecttheglomeruli®Monitorproteinuria

• TelmisartanmaybegoodstartingchoicewhenhypertensionAND significantproteinuria

• Otheroptions(multi-drug):– Hydralazine(vasodilator) -b-blockers– Diuretics

GeneralPlanforHypertensionRx

• EstablishBPDxwithmultiplereadings• BeginRxbasedonBP&Creatinine• Goal:SystolicBP<150mmHg(ideal)• Monitorq1-3weeks,adjustdosageasindicated

• AtTargetBP® monitorq3months

ThrombosisProphylaxisinGN• Justification

– Thromboembolism– Fewerthromboembolicevents?

• Aspirindosage:1.0to5.0mg/kg/day– Efficacyunproven(dose?)– Appearstobesafe– Plavix(clopidogrel;1.1mg/kg/d)

• Indication?– Hypoalbuminemia– LowATIIIlevels?

ImmunotherapyofGlomerularDisease

ImmunomodulatoryTherapy

• Standardtherapydoesnot“cure”glomerulardisease!

• Immunomodulatorytherapy– justification?– Pathophysiologicreasoning– Thehumanexperiencewithglomerulardiseases– Preliminaryevidenceindogs

• ~50%ofdogswithglomerulardiseasehaveglomerularimmunecomplexes(50%donot!)

ProteinuricKidneyDisease↓

RenalBiopsySupportsAnImmunopathogenesis

↓ConsiderImmunotherapy

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“Firstdonoharm”&

Riskisatwo-waystreet!

Denialism,HowIrrationalThinkingHindersScientificProgress,HarmsthePlanet,andThreatensourLives, byMichaelSpecter

Immunotherapy

• Mycophenolate:– 5-10mg/kgPOq12- 24h– Usegeneric(works/lessexpensive)

• Glucocorticoids:– Immunosuppressivedose– Single“pulse”doseor<7daystherapy

– SoleTherapyorConcurrentTherapy

DoesMycophenolateWork?

• 10dogswithbiopsy-provenMPGN(proliferative)• Mycophenolate5-20mg/kg+StandardTherapy• Meanbaselinevalues(pre-treatment):

– Serumcreatinineconcentration:2.4mg/dl(range1.9to4.2)(normalvalue:≤1.4mg/dl)

– Serumalbuminconcentration:1.6g/dl(range1.1to1.9) (normalvalue:>2.5g/L)

– UPC:9.1 (range3.7to16.2)Fiveofthe10dogswereLymepositive(Borreliosis)

MycophenolateRxofMPGN- Survival

• StandardtherapymeansurvivaltimefordogswithMPGN:104.5days(Klosterman,2011)

• Of10dogs,9survivedbeyond104.5days

• Sixof10aliveandclinicallywellwithsurvivaltimesof4.5(135d),6,8.5,10,22.5 and48months

MycophenolateRxofMPGN- Survival

• Outcomeforthe7th dogunknown,butlastknowndata:– Serumcreatininehaddeclinedto0.7mg/dlfrom2.1

– Serumalbuminhadincreasedfrom1.6to3.2– UPCratiohaddeclinedfrom8.8to2.0

• Survivaltimesforthe3dogsknowntobedeadwere3,8,and39.6months.

MycophenolateTreatmentofMPGN

–Mean(median)changesfor10dogswithMPGNtreatedwithmycophenolate:• Reductioninserumcreatinineconcentration=0.9mg/dl(0.9)– meanwas2.4mg/dl

• Reductioninserumalbuminconcentrationwas1.1g/dL (0.6)– meanwas1.6g/dl

• ReductioninUPCratiowas6.0(6.7)• PercentreductioninUPCwas67%(75%).

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Summary

• Whatisknown:– About50%dogswithproteinurickidneydiseasehaveImmuneComplexGlomerulonephritis(ICGN)

– ManydogswithICGNrespondtoimmunotherapy– Mycophenolategenerallyappearstobesafe– Steroidsmaybeeffective,butneedfurtherstudy– AtleastsometreateddogsthatachievepartialorcompleteremissionwillrecrudescewithGN

• Needed:Appropriatetherapeuticclinicaltrials

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vetgirl - polzin - proteinuria 12-21-16 np · • positive leptospirosis test • physical evidence...

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