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AcuteKidneyInjury:Drug-InducedUnlessProvenOtherwise

ElizaBorzadek,BSN,PharmD,BCPSAdvancedClinicalPharmacistEasternIdahoRegionalMedicalCenterSeptember28,2018

Disclosures•  IdonothaveanydisclosuresorconflictsofinterestinregardstomypresentaKon

•  Iwillnotdiscussoff-labelusesofanymedicaKons

LearningObjectives•  SummarizedefiniKonandstagingcriteriaforacutekidneyinjury(AKI)

•  OutlineeKologyanddiagnosisofacutekidneyinjury•  Reviewmanagementofacutekidneyinjury•  DiscussprevenKvestrategiesfordrug-inducedkidneyinjury

•  SummarizethejobdescripKonforaPharmacist-Ninja

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80y/ofemaleadmittedwithAMSand®footsurgicalwoundinfection•  PMH:s/precentCharcotfootrepair,anemia,HTN,T2DM,peripheralneuropathy,COPD,hypothyroidism,OA,depression

•  Drymucousmembranesnotedonphysicalexam•  VS:T98.6F,BP141/67,P84,T98.6F,RR20•  Height:5’1’’,weight105kg•  Labs:glucose113,Na135,K5.2,Cl98,Bicarb27,BUN53,SCr1.5(baseline0.9),eGFR33,CRP26,wbc8,200,Hgb9.5/Hct29,plt219

•  Woundculture:MRSA–sensiKvetoVancomycin(MICof1)•  Bloodculture–nogrowthx48hrs•  IsthispaKentexperiencingAKI?•  WhatisthemostlikelyunderlyingcauseforherAKI?

80y/ofemaleadmittedwithAMSand®footsurgicalwoundinfection•  Discharged5dayslatertoLTCFonVancomycin1.5gmIVevery24hrs,lasttroughpriorto3rddosewas15.2

•  SCr0.9atdischarge

•  WhatisyourassessmentofthispaKent’srenalfuncKon?•  ShouldthispaKentconKnueonvancomycintherapy?

8/21/18 8/22/18 8/23/18 8/24/18 8/25/18

SCr(mg/dL) 0.9 0.8 0.9 1.0 0.9

TotalIntake(ml) 2,319 2,773 3,610 3,003 1,356

TotalOutput(ml)

3,950 1,900 1,125 850 450

Acutekidneyinjury(AKI)increasestheriskofsubsequentAKI,theriskofprogressiontochronickidneydisease(CKD)andmortality

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Background•  Formerlyknownasacuterenalfailureoracuterenalinsufficiency

•  SyndromecharacterizedbyanabruptdeclineofrenalfuncKonmanifestedbyanaccumulaKonofcreaKnine,urea,andotherwasteproductswith/withoutreducedurineoutput

•  Globalpublichealthconcernassociatedwithhighmorbidity,mortalityandhealthcarecosts

•  AKIaffects~5-10%ofhospitalizedpaKents&upto60%ofpaKentsadmiledtoICU

•  AKIisassociatedwithhigherincidenceofCKD•  18-27%ofAKIinhospitalizedpaKentsisdrug-induced

PavkovME,HardingJL,BurrowsNR.TrendsinHospitalizaKonsforAcuteKidneyInjury—UnitedStates,2000–2014.MMWRMorbMortalWeeklyRep2018;67:289–293.

IncidenceofhospitalizationswithAKIamongmenandwomen≥20yearsofagewithandw/odiabetes:UnitedStates-2000-2014

PavkovMEetal.TrendsinHospitalizaKonsforAcuteKidneyInjury–UnitesStates,2000-2014.CentersforDiseaseControlandPrevenKon:MorbidityandMortalityWeeklyReports2018;67(10):289-293.

TrendsinHospitalizationforAKIAmongMenandWomenAged≥20YearswithandwithDiabetes

Characteris2c 2000 2006 2014 Absolutechange(95%CI)

Percentchange(95%

CI)

Allpersonswithdiagnoseddiabetes

WeightedNo. 11,863,011 17,109,522 21,871,994

AllAKINo. 364,527 666,060 1,571,265

HospitalizaKonRate(95%CI)

23.1(21.5–24.8)

28.5(27.0–29.9)

55.3(54.1-56.6)

32.2(30.1-34.3)

139.2(121.1-157.3)

Allpersonswithoutdiagnoseddiabetes

WeightedNo. 189,675,970 202,950,590 217,677095

AllAKINo. 589,399 1,156,994 2,388,295

HospitalizaKonRate(95%CI)

3.5(2.4-3.7)

6.5(6.3-6.7)

11.7(11.5-11.8)

8.1(7.9-8.3)

230.4(216.1-244.7)

PavkovMEetal.TrendsinHospitalizaKonsforAcuteKidneyInjury–UnitesStates,2000-2014.CentersforDiseaseControlandPrevenKon:MorbidityandMortalityWeeklyReports2018;67(10):289-293.

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AKIDeSinition• Accordingto2012KDIGOguidelines,AKIisdefinedbyanyofthefollowing:•  IncreaseinSCrby≥0.3mg/dLwithin48hrsOR•  SCrincreaseto≥1.5Kmesbaselinewhichisknownorpresumedtohaveoccurredwithintheprevious7daysOR

•  Urinevolume<0.5ml/kg/hrfor6hours

StagingofAKIRIFLECRITERIA COMMON

CRITERIAAKINCRITERIA

Classifica2on SCrorGFRCriteria UrineOutput Stage SCrorGFRCriteria

R RiskofrenaldysfuncKon

SCr↑1.5XbaselineORGFR↓>25%

<0.5ml/kg/hrfor6-12hrs

1 SCr↑≥0.3mg/dLOR1.5-1.9Xbaselinein48hrs

I Injurytokidney

SCr↑2XbaselineORGFR↓by>50%

<0.5ml/kg/hrfor≥12hrs

2 SCr↑to2-2.9Xbaseline

F FailureofkidneyfuncKon

SCr↑to3XbaselineORGFR↓by>75%ORSCr≥4mg/dLwithacute↑of≥0.5mg/dL

<0.3ml/kg/hrfor≥24hrsORanuriafor≥12hrs

3 SCr↑to≥3Xbaseline;ORSCr≥4mg/dLORiniKaKonofRRT

L LossofkidneyfuncKon

Completelossofkidneyfxnfor>4wks

E End-stagekidneydisease

Completelossoffxnfor>3mo

RiskFactorsforAKI•  Advancedage•  Sepsis•  DiabetesMellitus•  VolumedepleKon•  VomiKng,diarrhea,poorfluidintake,fever,diureKcuse•  Heartfailure,hepaKcfailurewithascites

•  Pre-exisKngCKD(GFR<60)•  Nephrotoxins•  Aminoglycosidesandamphotericin•  NSAIDs•  ACEIs/ARBs•  Cyclosporineandtacrolimus•  Iodinatedcontrastmedia•  CysplaKn•  Amphotericin

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46y/oMpresentstoEDwithgeneralizedweaknessx2wksandN/V•  HPI:Pt.alsoreportschronicblurredvisionandpolyuria,althoughhisUOhasbeenlowrecently

•  PMH:T2DM,dyslipidemia,hypertension,occasionalaches&pain(treatedwithibuprofen)

•  VS:T101.5F,BP66/42,HR140,RR32,95%onRA•  HomemedicaKons:•  Lisinopril20mgpodaily•  Ibuprofen200-400mgpoprnpain•  RosuvastaKn20mgpodaily

•  WhatarethispaKent’sriskfactorsforAKI?

ClassiSicationofAKIPrerenal/Func2onal Intrinsic(ATN&AIN) Postrenal

History&clinicalpresentaKon

VolumedepleKonRAS,HF,HypercalcemiaNSAID,ACEI/ARBuseCyclosporine

Long-standingrenalhypoperfusionNephrotoxins(contrast,anKbioKcs)VasculiKsGlomerulonephriKs

KidneystonesBPHCancers

Physicalexam HypotensionDehydraKon,AscitesPetechiaifthromboKc

Rash,fever(withAIN) DistendedbladderLargeprostate

SerumBUN/SCr >20:1 15:1 15:1

Urinesodium <20mEq/L >40mEq/L >40mEq/L

FENa <1% >2% >2%

Urineosmolality High Low Low

Urinesediment Normal Muddy,browngranularortubularepithelialcasts

Variable

UrineWBC NegaKve 2-4+ Variable

UrineRBC NegaKve 2-4+ 1+

Proteinuria NegaKve PosiKve NegaKve

FractionalExcretionofSodiumCalculation

FENa=(UrineNa/SerumNa)/(UrineCr/SerumCr)x100

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UrineOutputClassiSications• Anuric:<50ml/24hrs•  Associatedwithworseoutcomes

• Oliguric:50–500ml/24hrs• Nonoliguric:>500ml/24hrs•  AssociatedwithbelerpaKentoutcomes•  Easiertomanage–fewerproblemswithvolumeoverload

46y/omalepresentstoEDwithgeneralizedweaknessx2wksandintractableN/V•  CBC:wbc17,400,Hgb11.0,Hct33.5,plt298•  CMP:glucose566,Na130(corrected),K4.7,SCr5.4,BUN47,Alb1.6,Mag1.7,Phos0.7,lactate5.2,CRP21,procalcitonin28

•  UA:SG1.020,protein500mg/dL,glucose250mg/dL,nitrite(+),leukocyteesterase500/ul,rbc>100,wbc–packedfield,2-5granularcasts

•  Urine:randomNa91,randomcreaKnine25•  Urinaryoutput:iniKal150mlayer8Loffluids;400mlinthefirst24hrs•  Fourdayslater:SCr5.6•  Urineculture:>100,000CFU/mlofEnterobactercloacae•  Bloodculture:Enterobactercloacaein2of2bolles•  AccordingtoAKINcriteria,whichstageofAKIisthispaKentexperiencing?•  WhatisthispaKent’sAKIclassificaKonbasedonavailablelaboratorydata?

hlps://www.nursesKps.com/Kps-mnemonics/med-surg/causes-of-acute-renal-failure/

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EtiologyofAKI•  AmongthemostcommoncausesofAKIinhospitalizedpaKentsisexposuretonephrotoxins

•  Prerenal•  Characterizedbyrenalhypoperfusion

•  DecreaseineffecKveintravascularvolume(HF,cirrhosiswithascites)•  DehydraKon,hemorrhage•  MedicaKons(NSAIDs,ACEIs/ARBs)

•  Intrinsicrenal•  Mostcommoncauseisacutetubularnecrosis(ATN)•  Othercauses:acuteintersKKalnephriKs(AIN),acuteglomerulonephriKs,vasculiKs

•  Postrenal•  Inadequatedrainageofurinedistaltothekidneys•  BladderoutletobstrucKonisthemostcommoncause

Diagnosis•  EarlydiagnosisiscriKcalforimprovingoutcomes•  OnceAKIisrecognized,acriKcalnextstepispromptevaluaKonforthecauseofAKI

•  Carefulhistorytaking•  Exposuretonephrotoxins

•  Physicalexam&vitalsigns•  Carefulassessmentofhemodynamicandvolumestatus

•  Laboratorytests•  Urinalysis:granularcastsonmicroscopyindicateATN•  Renalpanel,CBC,uricacid•  Urinestudies:osmolality,sodium,creaKnine

•  Renalultrasound•  UsedtoruleoutobstrucKon

•  CTKUB(withoutiodinatedcontrast)•  Usedforsuspectedurolithiasis

•  Renalbiopsy•  DefinitewaytoestablishdiagnosisforAINandATN

MonitoringofRenalFunction•  InmostclinicalsezngsrenalfuncKonismonitoredviameasurementofserumcreaKnine•  NotasensiKvemarker

•  CreaKnineasaproductofmusclemetabolism•  ProporKonaltomusclemass

•  GlomerularfiltraKonrate(GFR)mustdeclineby~50%to60ml/minbeforeSCrrisesto1.5mg/dL•  BytheKmeSCrbecomesabnormal,significantrenaldysfuncKonmayalreadybepresent

•  GFRisanopKmalwaytomeasurekidneyfuncKon•  CreaKnineclearanceisacumbersometest(24-hoururinecollecKon)thusnotrouKnelyperformed

•  EsKmatedGFR(eGFR)–surrogatemarker•  CalculatedusingMDRD(ModificaKonofDietinRenalDisease)calculaKon(age,gender,SCr,race),Cockcroy-GaultorCKD-EPI

•  MoreaccuratepredictorofGFRthanserumcreaKninealone

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NovelBiomarkersforAKI•  BeingstudiesasmoresensiKvemarkersfordetecKonofAKI•  MaybeabletodetectpresentlyundetectablemildtomoderaterenaldysfuncKon

•  HavethepotenKaltodescribemechanismsandpredictanatomicalsitesofacutekidneyinjury

•  CysC(CystaKnC)hasbeenusedforGFResKmaKon•  ThoughttobemoreaccurateathigherGFRsandinthosewithreducedmusclemass

•  LimitaKons:notaccurateifnotatsteady-state,impactofvolumeofdistribuKonhasnotbeenstudied

•  Tubularinjurybiomarkers:NGAL(neutrophilgelaKnase-associatedlipocalin),KIM-1(kidneyinjurymolecule1),interleukin18(IL-18),liver-typefalyacidbindingprotein(L-FABP)

•  Biomarkersthatreflectkidneystress:TIMP-2,IGFBP-7•  RecentlyapprovedbyFDAtoIDpaKentsathighriskfordevelopingstage2and3AKIduringthenext12-24hrs

•  MarketedasNephroCheckTest

ManagementofAKI

ManagementofEstablishedAKI•  Generalmeasures•  FluidresuscitaKon(balancedcrystalloids)

•  Assessfluidresponsiveness•  DisconKnuaKonandfutureavoidanceofnephrotoxicmedicaKons•  AdjustmedicaKonsbasedonrenalfuncKon•  Avoidanceofcontrastmediaexposure•  CorrecKonofelectrolyteimbalance•  Renalreplacementtherapy(CRRT,IHD)

•  Prerenalazotemia:goalistocorrecthemodynamics•  FluidresuscitaKonifvolumedepleted(LRvs.NS)

•  Preferenceisforbalancedcrystalloids(LactatedRinger’ssoluKonorPlasma-LyteA)

•  Bloodpressuremanagement•  Bloodproductsifneeded•  HoldorD/CmedicaKonswhichaffectrenalhemodynamics

•  ACEIs/ARBs,NSAIDs

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ManagementofEstablishedAKI•  IntrinsicAKI•  NospecifictreatmentfoundtobeuniversallyeffecKve•  Eliminatethehemodynamicinstability•  DisconKnuethecausaKvetoxin•  AvoidaddiKonalinsults•  Managefluidandelectrolytes•  Avoid/treathyperglycemia

•  NICE-SUGAR:nodifferenceinratesofRRTbetweengroups,highermortalityinintensiveglycemiccontrolgroup

•  NutriKonsupport•  AKIisacatabolicstate;ptsmayneedenteral/parenteralnutriKon

•  MedicaKonmanagement•  LoopdiureKcs–lackofevidencefortheirbenefitinAKIexceptinthesezngofvolumeoverload

•  PostrenalAKI•  EarlyidenKficaKoniscriKcal•  RelievetheobstrucKon•  Consulturologyorradiology

MoorePKetal.ManagementofAcuteKidneyInjury:CoreCurriculum2018.AmJKidneyDis.72(1):136-148.

FluidResuscitationforAKI:AnEmptyPromise

•  MainstayofprevenKonandtreatmentofAKIhasbeenIVfluidtherapy•  RaKonale:augmentsCO,maintainsurinaryflow,dilutesnephrotoxins,thusminimizingischemicandtoxicinsultstothekidneys

•  IVfluidsarepotentdrugswithcomplexpharmacologicacKons•  Only~20%offluidsremainsinintravascularspaceayer90min

•  PosiKvefluidbalanceof5-10%ofbodyweighthasbeenassociatedwithorgandysfuncKonandpoorclinicaloutcomesincriKcallyillandayerrouKnesurgery•  FluidoverloadisassociatedwithAKI,prolongedICUstay,worseningorganfuncKonandexcessmortality

•  FluidoverloadappearstocauseendothelialdysfuncKon•  Benefitsoffluidsareshort-livedandlimitedonlytoearlystagesofselectdiseasestates

WatkinsSCandShawAD.FluidresuscitaKonforacutekidneyinjury:anemptypromise.CurrOpinCritCare2016;22:527-532.

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FluidResuscitationforAKI•  EvidencesuggeststhatavoidanceoffluidoverloadmaybeassociatedwithreducedneedforRRT,lowerincidenceofAKI,increasedsurvivalfromsepKcshock•  CertainfluidsimpairrenalfuncKonindependentofthequanKtyadministered•  Isotonicsaline(0.9%NaCl)hasbeenlinkedtogreaterriskofAKI,morbidityandmortalitywhencomparedwithotherbalancedelectrolytesoluKons•  Harmduetohyperchloremiaandmetabolicacidosis•  HighchloridecausesvasocontracKonoftheafferentarterioleleadingtodecreasesrenalcorKcalperfusion

•  ComposiKon,quanKtyandKmingoffluidsshouldbepersonalizedtoeachpaKentbasedonhis/herresponsetofluids

WatkinsSCandShawAD.FluidresuscitaKonforacutekidneyinjury:anemptypromise.CurrOpinCritCare2016;22:527-532.

46y/omalepresentstoEDwithgeneralizedweaknessx2wksandN/V

•  HowwouldyoumanageacutetubularnecrosisinthispaKent?•  WhatisyourplanregardinghishomemedicaKons?

IndicationsforRRT•  Life-threatening/refractoryhyperkalemia(K>6.5)•  BUN>100mg/dL•  Refractoryfluidoverload(pulmonaryedema)•  Signsofuremia:pericardiKs,pleuriKs,uremicencephalopathy•  Refractorymetabolicacidosis(pH<7.1)

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PreventiveStrategies•  PrevenKonisthekey:team-based,standardizedapproach•  AvoidanceofnephrotoxicmedicaKonswheneverpossible•  EnsuringadequatehydraKon•  PaKenteducaKon•  Useofdrugtherapiestodecreaseincidenceofcontrast-inducednephropathy

KDIGORecommendationsforPractice•  Low-dosedopamineisnotrecommendedfortheprevenKonortreatmentofAKI(LevelofEvidence1A)

•  DiureKcsdonotimprovemorbidity,mortalityorrenaloutcomesandshouldnotbeusedtopreventortreatAKIintheabsenceofvolumeoverload(2C)

•  KDIGOsuggestsnotusingaminoglycosidesfortreatmentofinfecKonsunlessnosuitable,lessnephrotoxictherapeuKcalternaKvesareavailable(2A)

•  AminoglycosidesaretobeadministeredassingledailydoseratherthanmulKple-dosedailyregimensinpaKentswithnormalrenalfuncKon(2B)

•  NACnotrecommendedfortheprevenKonofAKIincriKcally-illpaKentswithhypotension(2D)

•  NACnotrecommendedfortheprevenKonofpostsurgicalAKI(1A)

DRUG-INDUCEDACUTEKIDNEYINJURY(DI-AKI)

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BestReferenceforDrug-InducedDiseases

Background•  ExposuretonephrotoxinsrepresentsanearlyubiquitouseventinthecourseofhospitalizaKon

•  DI-AKIaccountsfor~7%ofalldrugtoxiciKes•  18-27%ofAKIcasesinhospitalizedpaKentsaredrug-induced•  TrueincidencehasnotbeenwellcharacterizedbecauseoflackofconsistencyindefiningthecondiKon

•  MostimplicatedmedicaKons:NSAIDs,ACEIs/ARBs,aminoglycosides,amphotericin,iodinatedcontrastmedia

•  Kidneysareatriskoftoxicinjury:•  Receive25%ofcardiacoutput•  ConcentraKonoftoxinsintubules•  Highintra-renaldrugmetabolism•  AutoregulaKon/specializedbloodflowthroughglomerulus

RiskFactorsforDI-AKI•  ConcomitantadministraKonofnephrotoxins•  Pre-exisKngCKD•  Advancedage•  Diabetes•  Dose/duraKonoftherapy•  Prolongedtreatmentwithnephrotoxins

•  Renin-dependentdiseasestates•  Cirrhosis•  Heartfailure•  Over-diuresis•  Hypovolemia

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Pseudonephrotoxicity•  MedicaKonsthatinhibittubularsecreKonofcreaKnine•  Trimethoprim,cimeKdine

•  MedicaKonsthatincreaseBUN•  Tetracyclines,corKcosteroids

•  MedicaKonsthatinterferewithserumcreaKnineassay•  CefoxiKnandothercephalosporins

AgentsImplicatedinDI-AKIHemodynamic-mediated•  DiureKcs•  ACEIs/ARBs•  Cyclosporine•  NSAIDs/COX-2inhibitorsGlomerulonephri2s•  Allopurinol•  Hydralazine•  Lithium•  NSAIDs•  Phenytoin•  PTU•  Rifampin

Nephrolithiasis•  Acyclovir•  Allopurinol•  Topiramate•  Zonisimide•  Sulfonamides•  Furosemide•  Indinavir•  Foscarnet

AcuteTubularNecrosis•  Aminoglycosides•  AmphotericinB•  Radiocontrastmedia•  CisplaKn•  Ifosfamide

AcuteInters22alNephri2s•  Allopurinol•  AnKbioKcs•  H2blockers/PPIs•  Phenytoin,valproicacid•  DiureKcs•  NSAIDs

Tisdaleetal.Drug-inducedDiseases,2ndediKon.

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ClinicalPresentationGeneralSignsandSymptoms•  CVAtenderness•  Edema•  ElevatedSCr•  Rapidweightgain•  Fever•  Malaise•  Hypertension

AcuteTubularNecrosis•  Oliguria•  MagnesiumwasKngNephrolithiasis•  Renalcolic•  Hematuria

AcuteInters22alNephri2s•  Eosinophilia•  Eosinophiluria•  Proteinuria•  Pyuria•  Skinrash•  Arthralgias

Glomerulonephri2s•  Foamyurine•  FacialandLEpizngedema•  Oliguria•  Proteinuria•  Skinrash

Tisdaleetal.Drug-inducedDiseases,2ndediKon.

Aminoglycosides:ATN•  Typicallycauseacutetubularnecrosis•  Incidenceofnephrotoxicity:1.7-58%ofpaKents•  PresentaKon•  GradualincreaseinSCrconcentraKonandadecreaseinGFR•  Onset:6-10days•  NonoliguricAKI•  Hypokalemiaandhypomagnesemia

•  Riskfactors•  LargetotalcumulaKvedose•  Prolongedtherapy•  TroughconcentraKons>2mg/L•  Recent,previousaminoglycosidetherapy•  Concurrentuseofnephrotoxins•  PaKent-related:CKD,advancedage,gram–bacteremia,liverdisease,hypoalbuminemia,dehydraKon,KandMagdeficiencies,shock,poornutriKon

Aminoglycosides:ATN• PrevenKon•  AvoidinhighriskpaKents•  MaintainadequatehydraKon•  Useonce-dailydosing•  Avoiduseofothernephrotoxins•  LimitthetotalcumulaKvedose

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IntravenousContrastMedia•  ThirdleadingcauseofAKIamonghospitalizedpaKents•  Incidence:2-50%ofpaKentsdependingonriskfactors•  Associatedwithhighin-hospitalmortalityrisk(34%)•  Iodine-containingcontrastmedia•  UsedforCT,angiography,coronaryangiography,arthrography,myelography,GIfluoroscopicstudies

•  CauseCI-AKI,specificallyATN•  Gadolinium-basedcontrastagents(GBCAs)•  UsedforMRIstudies•  Causenephrogenicsystemicfibrosis(NSF)

IntravenousContrastMedia:ATN•  Osmolalityofcontrastagents•  High-osmolarcontrastmedia(HOCM):~1500-2000mOsm/kg•  Oldestagents•  RelaKvelyinexpensive

•  Low-osmolarcontrastmedia(LOCM):500-800mOsm/kg•  Non-ionic→donotdissociateinwater→fewerparKclesinsoluKon

•  Examples:iohexanol240,iohexanol300(Omnipaque),iopamidol(Isovue-200,-300,-370)

•  Iso-osmolarcontrastmedia(IOCM):290mOsm/kg•  Non-ionicdimers•  Newestclassofagents•  Examples:iodixanol320(Visipaque)

Contrast-inducedAKI(CI-AKI)•  Asosmolalityofcontrastagentsapproachesthatofserum,thetoxicitydecreases•  Halflife:1-2hours,assumingnormalrenalfuncKon•  Pathogenesis•  ClearanceofcontractagentsisenKrelybyglomerularfiltraKon•  Renalischemia•  OsmoKcdiuresis–higherriskwithhigh-osmolarcontrastmedia•  SystemichypotensiononinjecKonandrenalvasoconstricKon

•  DirecttubulartoxicitycausedbyreacKveoxygenspecies•  DirectlyinfluencedbyduraKonofexposureoftubules

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Contrast-inducedAKI•  ClinicalpresentaKon•  IniKaltransientosmoKcdiuresis,thentubularproteinuria•  SCrrisewithin24hrswithapeak2-5daysayerprocedure•  50%ofpaKentsexperienceoliguriaandsomemayneeddialysis

•  Riskfactors•  CKD•  Diabetesmellitus•  Age≥75years•  Anemia•  VolumedepleKon/dehydraKon•  Hypotension•  Othernephrotoxins•  ConcomitantuseofdiureKcs•  Repeatedand/orlargevolumeofcontrast(>140ml)•  Hyperosmolarcontrastagents•  HF,liverfailure

Contrast-inducedAKI(CI-AKI)•  UncommoneventinpaKentswithnormalrenalfuncKonandnoaddiKonalriskfactors•  NosignificantadvantagewithregardtoAKIhasbeendemonstratedbyusingLOCMoverHOCM

•  ForpaKentswithrenalimpairment,severalstudieshavedemonstratedthatLOCMarelessnephrotoxic

•  AdverseeffectsofcontrastareintensifiedindehydratedpaKents

•  DiabetesincreasesCI-AKIevenwhenSCrisnormal•  Amongallpredisposingfactors,paKentswithdiabeteswithpreexisKngCKDareathighestriskforCI-AKI

Contrast-InducedAKI•  PrevenKon•  CINRiskCalculator•  VolumeexpansionwithIVNSat1ml/kg/hfor12hbeforeand12hayercontrastexposureor3ml/kg/hx1hourand1.5ml/kg/hx4-6h•  NobenefittousingbicarbonateinhighriskpaKentsundergoingangiographywithrespecttocompositeendpointofdeath,RRTand50%reducKoninGFRat90days

•  UsealternaKvenon-contrastimagingstudieswheneverpossible•  DisconKnuenephrotoxicagentsatleast24hrspriortoprocedure•  AvoidlaxaKvesanddiureKcs•  Uselow-osmolaroriso-osmolarcontrastagents•  UsethelowestnecessarydoseinpaKentswithrenalimpairment•  N-Acetylcysteine(NAC):anKoxidantandvasodilatoryeffects

•  Widelyused,conflicKngevidence,generallyconsideredsafe•  MayuseoralNACincombinaKonwithIVhydraKon(KDIGO,2D)

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Gadolinium-basedContrastAgents(GBCAs)•  UsedforMRIstudies•  Gadoliniumisretainedformonthstoyearsinbrain,bone,skin,kidney,liver,spleen

•  LinearGBCAs•  Examples:gadobenatedimeglumine,gadopentetatedimeglumine(Magnevist),gadoxetatedisodium

•  ResultingreaterretenKonofgadoliniumthanmacrocyclicGBCAs•  MacrocyclicGBCAs•  Examples:gadobutrol,gadoteratemeglumine,gadoteridol

•  Increaseriskofnephrogenicsystemicfibrosis(NSF)

NephrogenicSystemicFibrosis

•  Onset:2-18daysayerexposure•  PresentaKon:burning,itching,swelling,hardeningofskin,jointsKffness,muscleweakness

•  NSFmayresultinfatalordebilitaKngsystemicfibrosisaffecKngskin,muscleandinternalorgans

•  RiskofNSFishighestamongCKDstage4and5(GFR<30)andthosewithAKI•  UseofMagnevist(gadopentetatedimeglumine),Omniscan(gadodiamide),OpKMARK(gadoversetamide)isconsideredinappropriateforuseinpaKentswithCKDandAKI

Gadolinium-basedContrastAgents

•  PrevenKonofNSF•  ScreenallpaKentsforAKIorothercondiKonswhichmayreducerenalfuncKon

•  ObtainbaselineSCrandcalculateesKmatedGFRpriortocontrast-enhancedimaging

•  Donotexceedtherecommendeddose•  AllowsufficientperiodofKmeforeliminaKonofdrugfromthebodypriortore-administraKon

•  InhemodialysispaKents,considerpromptiniKaKonofhemodialysisfollowingadministraKon

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Cisplatin&Carboplatin:ATN•  Incidence:6-13%•  Directtubulartoxins•  PresentaKon•  SCrpeaks10-12daysayertherapyisiniKated•  RenalmagnesiumwasKngiscommon;maybeaccompaniedbyhypokalemiaandhypocalcemia

•  Maycauseirreversiblekidneydamage•  Riskfactors:mulKplecoursesofcisplaKn,advancedage,dehydraKon,concurrentnephrotoxins,alcoholabuse

•  PrevenKon•  Avoidconcurrentnephrotoxins•  Usesmallestdosepossible,decreasefrequencyofadministraKon•  AggressivehydraKon:1-4Lwithin24hrsofhigh-dosestomaintainUOof125ml/h

•  AmifosKne910mg/m2maybeadministered30minpriortocisplaKntoavoidnephrotoxicityinhighriskpaKents

AmphotericinB:ATN•  DrugofchoiceforiniKaltreatmentofMucormycosis•  IncidenceofAKIincreasesascumulaKvedoseincreases•  ~80%withcumulaKvedose≥4grams

•  CausesdirectproximalanddistaltubulartoxicityandafferentarteriolevasoconstricKon

•  PresentaKon•  Medianonsetis7days•  ManifestsayeradministraKonof2-3grams•  ElectrolytewasKng(K,Na,Mg)•  SCrincreasesandGFRdecreasesduetovasoconstricKonanddecreaseinkidneybloodflow

•  Riskfactors:exisKngCKD,highaveragedailydose,diureKcuse,concomitantnephrotoxins,rapidinfusion,dehydraKon

•  PrevenKon:avoidnephrotoxins,limittotalcumulaKvedose,IVhydraKonwith0.9%NaCl,useofliposomalproducts

Hemodynamically-mediatedAKI•  Mechanism:decreasedintraglomerularpressuresecondarytovasoconstricKonofafferentarteriolesorvasodilaKonofefferentarterioles

•  ACEIs/ARBs•  CausedecreaseinglomerularhydrostaKcpressureandadecreaseinGFR

•  SCristypicallyexpectedtoriseupto30%•  Onset:2-5days,shouldstabilizein2-3weeks•  Increases>30%maybedetrimental•  UsuallyreversibleupondisconKnuaKonofthedrug•  Riskfactors:bilateralRAS,decreasedeffecKvebloodflowtokidneys(HF,liverfailure),preexisKngCKD,dehydraKon

•  PrevenKon:startwithlowdoses,Ktrateslowly,switchtolong-acKngagents,monitorSCrdailyoninpaKentandweeklyforoutpaKents,avoidconcomitantdiureKcsandNSAIDs

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Hemodynamically-mediatedAKI•  NSAIDs•  Incidence:500,000–2.5millionpeopledevelopNSAID-inducednephrotoxicityinUSannually

•  CausevasoconstricKonofafferentarterioleandreducedglomerularbloodflow

•  PresentaKon:onsetwithindaysofstarKngtherapy;lowurinevolume,edema,weightgain;increaseinSCr,BUN,andserumK

•  Riskfactors:preexisKngCKD,highplasmareninacKvity,concomitantdiureKcs,advancedage

•  PrevenKon:avoidNSAIDs•  Treatment:DisconKnuedrug,providesupporKvecare,avoidconcomitantmedicaKonsaffecKngRAAS,recoveryistypicallyrapid

Hemodynamically-mediatedAKI

AcuteInterstitialNephritis•  AINisresponsibleforupto3%ofallAKIcases•  CausedbyallergichypersensiKvityreacKon•  Commonculprits:β-lactamanKbioKcsandNSAIDs•  PresentaKonforβ-lactamabx:•  Onset:1-2weeksayertherapyiniKaKon•  Fever,maculopapularrash,eosinophilia,pyuria,hematuria,proteinuria,eosinophiluria

•  PresentaKonforNSAIDs:•  Delayedonset:ayer6monthsoftherapy•  Nosystemicsymptoms

•  Kidneybiopsymaybeneededtoconfirmdiagnosis•  Treatment:disconKnuetheoffendingagent,considercorKcosteroids

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PostrenalAKI•  ObstrucKonofurineflowayerglomerularfiltraKon•  RenaltubularobstrucKon•  CausedbyintratubularprecipitaKonofKssuedegradaKonproducts•  UricacidprecipitaKonassociatedwithtumorlysissyndrome•  Drug-inducedrhabdomyolysis(precipitaKonofmyoglobin)•  RapiddeclineinrenalfuncKon•  OliguricoranuricAKI

•  CausedbyprecipitaKonofdrugs•  Sulfonamides,methotrexate,acyclovir,others•  Needle-likecrystalsseeninleukocytesonurinalysis

•  PrevenKon:pre-treatmenthydraKon,maintenanceofhighurinaryvolume,alkalinizaKonofurine

PostrenalAKI•  Extra-renalurinarytractobstrucKon•  BHP•  Tumors•  AnKcholinergicagents

•  Nephrolithiasis•  MedicaKonswhichcontributetoformaKonofkidneystones:triamterene,indinavir,sulfadiazine,others

Vancomycin-inducedAKI•  Nephrotoxicityassociatedwithvancomycinisalong-standing,yethighlydebatedadverseeffect

•  KnownasMississippimudin1950sduetobrowncolorofearlyformulaKons(70%pure)•  IncreasedincidenceofadversedrugreacKons•  In1985purityincreasedto95%

•  FrequencyofnephrotoxicityduetovancomycinmonotherapyfollowingpurificaKonwasconsideredinfrequentat5-7%

•  Mechanismofinjury•  Vancomycinisnotmetabolized;excretedunchangedintheurineviaglomerularfiltraKon

•  DecreasedGFRfromanycausewillresultinincreasedvancomycinconcentraKons

•  VancomycinhasoxidaKveeffectsoncellsoftheproximalrenaltubuleandcausesrenaltubularischemia

Elyasietal.Vancomycin-inducednephrotoxicity:mechanism,incidence,riskfactorsandspecialpopulaKons:Aliteraturereview.EurJClinPharmacol2012;68:1243-1255.

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Vancomycin-inducedAKI•  Guideline-drivenmoreintensevancomycindosingwithgoaltroughsbetween15-20hasbeenassociatedwithincreasingreportsofvancomycin-inducedAKI

•  Ratesreportedas5-43%inarecentmeta-analysisof15studies(1996-2012)–dependentonpopulaKon

•  OR=2.67fornephrotoxicityfortroughs≥15vstroughs<15•  Highestrateswithtroughs>20

•  OR=3.3forpaKentsreceivingconcomitantnephrotoxins•  Timeofonset:onaverage4-17daysayeriniKaKon•  Upto75%ofcasesresolvedwithin≤7days•  Short-termdialysisrequiredin3%ofpts•  Nonereportedtorequirelong-termdialysis

VanHal,SJetal.SystemicReviewandMeta-AnalysisofVancomycin-InducedNephrotoxicityAssociatedwithDosingSchedulesthatMaintainTroughsbetween15and20mg/L.AnKmicrobialAgentsandChemotherapy.2013;57(2):734-744.

Vancomycin-inducedAKI

•  Nephrotoxicityriskcorrelateswithtroughs>15andduraKonoftreatment>7-14days

•  Otherriskfactors:doses≥4gm/day,weight>100kg,criKcallyillinICU,concomitantnephrotoxicdrugs,preexisKngCKD

•  Concomitantnephrotoxinscanincreaseincidenceofvancomycin-inducedAKIbyupto35%•  Tobramycin,vasopressors,IVcontrastmedia,amphotericinB,loopdiureKcs,somecephalosporinsandPCNs

•  Althoughvancomycin-inducednephrotoxicityisusuallyreversible,itisassociatedwithpooreroutcomes•  Nephrotoxicityisassociatedwithincreasedoverallmortality,prolongedhospitalandICUlengthsofstay

Vancomycin-inducedAKI•  Avoidtotaldailydoses>4grams•  AvoidduraKonoftherapy>7days•  OrdernasalMRSAswabforpaKentsadmiledwithMDROpneumoniaandD/CMRSA-coverageifnegaKve•  95-98%negaKvepredicKvevalue

•  Limitexposuretoconcomitantnephrotoxins•  MonitorrenalfuncKonverycarefully•  BothurinaryoutputandSCr

•  ConsideralternaKveanK-MRSAagentsforpaKentswithriskfactorsfornephrotoxicityrequiringprolongedtreatmentwithvancomycin

•  ObtainathoroughallergyhistoryinpaKentsclaimingallergytopenicillininordertoavoidunnecessaryvancomycinprescribing

•  TreatpaKentswithMSSAinfecKonswithnafcillinorcefazolinovervancomycin(decreasedmortalityovervanco)

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Vancomycin+Piperacillin/TazobactamAKI

•  PackageinsertforPiperacillin/Tazobactamlistsincidenceofnephrotoxicityat<1%

•  RecentretrospecKvecohortstudycomparing99ptsonvancomycinalonewith92ptsoncombotherapyobservednephrotoxicityin8.1%and16.3%ofpts,respecKvely(p=0.041)

•  ConsideralternaKvestopiperacillin/tazobactam(e.g..cefepime)foranKpseudomalcoverageinpaKentsalreadyonvancomycin

BurgessLD,etal.ComparisonoftheIncidenceofVancomycin-InducedNephrotoxicityinHospitalizedPaKentswithandwithoutConcomitantPiperacillin-Tazobactam.Pharmacotherapy2014;34(7):670-676.

80y/ofemaleadmittedduetoincreasedconfusion•  Admissiondiagnosis:uremicencephalopathysecondarytoAKI•  VS:T36.6,BP161/79,P67,RR14•  Labs:wbc7,800,Hgb8.5/Hct27,platelets384,glucose170,Na135,K5.9,Cl105,Bicarb22,BUN28,SCr2.0,eGFR24,CRP16

•  HomemedicaKons:lisinopril20mgdaily,vancomycin1.5gmIVevery24hrs(heldx3days),aspirin81mgpoBID…

•  UA:SG1.011,protein30mg/dL,rbc>182/hpf,wbc71/hpf,glucose(-)

•  SCrondischarge:2.3(maxwhilehospitalized2.6)

•  WhatisthestageofherAKI?•  WhatistheunderlyingcauseofherAKI?

HelpPreventDI-AKI•  AvoiduseofmedicaKonsassociatedwithAKIinpaKentswithriskfactors

•  Avoidconcurrentuseofagentswhichaffectrenalhemodynamics•  Avoidover-diuresis•  Consideronce-dailydosingofaminoglycosides•  Avoidconcomitantexposuretonephrotoxins•  CounselpaKentsaboutrisksofvolumedepleKonandaneedtomaintainadequatefluidintake

•  PreferenKaluseofnon-ionic,iso-osmolarcontrastagents•  LimitduraKonoftherapywithmedicaKonsassociatedwithAKI•  Maintainadequatefluidstatus•  Startatlowestdoses(medicaKonswithhemodynamiceffects)•  PreferenKaluseoflipid-basedproducts

Tisdaleetal.Drug-inducedDiseases,2ndediKon.

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NINJAProject•  NINJA:NephrotoxicInjuryNegatedbyJust-in-TimeAcKon•  ProspecKvequality-improvementprojectuKlizingEHRscreeninganddecisionsupportprocessatCincinnaKChildren’sHospitalMedicalCenter

•  PopulaKon:•  ChildrenathighriskforDI-AKIadmiledtonon-criKcalcareunits•  PediatricpaKentsreceivingaminoglycosidesfor≥3daysor≥3nephrotoxinssimultaneously

•  IntervenKon:•  PharmacistsrecommendeddailySCrmonitoringinexposedpaKents

•  AKIwasdefinedbymodifiedcriteriaof≥25%decreaseinesKmatedcreaKnineclearance

GoldsteinSLetal.ElectronicHealthRecordIdenKficaKonofNephrotoxinExposureandAssociatedAcuteKidneyInjury.Pediatrics2013;132:e756-e767.

NINJAResults

•  Inthefirstyear,AKIoccurredin25%ofexposedpaKents•  In3years,EHR-driven,pharmacy-lednoKficaKonprocessresultedin38%decreaseintherateof3nephrotoxicmedicaKonexposureand64%decreaseinAKIrates

GoldsteinSLetal.ElectronicHealthRecordIdenKficaKonofNephrotoxinExposureandAssociatedAcuteKidneyInjury.Pediatrics2013;132:e756-e767.

HealthyPeople2020•  Oneofthegoalsfor2020focusesondecreasingtheburdenofChronicKidneyDisease(CKD)

•  ObjecKve#3forCKDgoalfocusesonAKIfollow-up•  PaKentshospitalizedforAKIshouldbeevaluated6monthsayerdischargetomonitorkidneyfuncKonandpreventordelayonsetofCKD•  PerKDIGOguidelines,allptswhoexperienceAKIshouldhavetheirkidneyfuncKonre-evaluated3monthsayerAKItoidenKfyneworworseningCKD

www.healthypeople.gov

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NewNomenclature•  TradiKonaltaxonomyofAKIbasedonanatomiclocaKons(pre,intra,andpost-renal)isoverlysimplisKc

•  NewspecificAKIsyndromes:•  Hepatorenal•  Cardiorenal•  Nephrotoxic•  Sepsis-associated

KellumJA.WhyarepaKentssKllgeznganddyingfromacutekidneyinjury?CurrOpinCritCare

2016;22:513-519.

References•  Barton-PaiAandMason,DL.AcuteKidneyInjury.In:Tisdaleetal.Drug-InducedDiseases,2ndEdiKon.2010;853-871.

•  Tisdaleetal.Drug-InducedDiseases:PrevenKon,DetecKon,andManagement.2ndEdiKon.

•  KIDGOAKIWorkgroup.KDIGOClinicalPracKceGuidelineforAcuteKidneyInjury.KidneyIntSuppl.2012;2(1):1-138.

•  MoorePK,HsuRK,andLiuKD.ManagementofAcuteKidneyInjury:CoreCurriculum2018.AmJKidneyDis.72(1):136-148.

•  BellomoR,KellumJA,andRoncoC.AcuteKidneyInjury.Lancet2012;380:756-66.

•  GoldsteinSL.MedicaKon-inducedacutekidneyinjury.CurrOpinCritCare2016;22:542-545.

•  GoldsteinSLetal.ElectronicHealthRecordIdenKficaKonofNephrotoxinExposureandAssociatedAcuteKidneyInjury.Pediatrics2013;132:e756-e767.

•  WatkinsSCandShawAD.FluidresuscitaKonforacutekidneyinjury:anemptypromise.CurrOpinCritCare2016;22:527-532.

•  RahmanM,ShadF,andSmithMC.AcuteKidneyInjury:AGuidetoDiagnosisandManagement.AmFamPhysician.2012;86(7):631-639.

AcuteKidneyInjury:Drug-InducedUnlessProvenOtherwiseElizaBorzadek,BSN,PharmD,BCPSAdvancedClinicalPharmacistEasternIdahoRegionalMedicalCentereliza@borzadek.com208.339.0604