vetgirl - polzin - proteinuria 12-21-16 np · • positive leptospirosis test • physical evidence...
TRANSCRIPT
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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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3y10mFChes. BayRetriever
ShouldanUPChavebeenperformed?
3y10mFChes. BayRetriever
HowshouldyouproceedwithaUPCof0.9?
Repeattoconfirm!
3y10mFChes. BayRetriever
HastheUPCincreased(clinicalinterpretation)?
No!
GuidelineforMonitoring• UrineP:Crratioshouldbereconfirmed– 3timesifUPC<3.0– 2timesifUPC>2.9– At2to4weekintervals
• ClinicallyimportantchangesinurineP:Crmayrequirea30%to50%change
3y10mFChes. BayRetriever
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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