ACSAP 2018 Book 3 • Nephrologic/Geriatric Care 7 Acute Kidney Injury

Acute Kidney Injury

1. Evaluateapatientusingdiagnosticandphysiologicclassificationsandriskfactorsforacutekidneyinjury(AKI).

2. Assessapatientforthepresenceofdrug-relatedriskfactorsforAKI.

3. DesignaplantopreventormanageAKIinapatient.

4. Justifythepharmacist’sroleinpreventingandmanagingAKI.

INTRODUCTIONEpidemiologic studies documenting the incidence and prevalenceof acute kidney injury (AKI) in the community setting are sparse.ThisislargelybecauseofthelackofacommonAKIdefinition,mak-ing generalization and evaluation of outcome measures difficult.OurcurrentunderstandingoftheepidemiologyofAKIanditsmor-bidity,mortality,andassociationwithchronickidneydisease(CKD)isalmostexclusivelybasedonstudiesthatevaluatedpatientswhodevelopedAKIwhile hospitalized. In these settings,AKI hasbeenreported to be responsible for hospitalmortality rates of 8%–26%(Hoste2006).Amorerecentretrospectiveanalysisofalargedata-base from a single U.S. Veterans Affairs hospital showed thatcommunity-acquiredAKIwasmorecommonthanhospital-acquiredAKI,accountingforabout80%ofthepatientswithadischargediag-nosisofAKI(Schissler2013).

DefinitionUnderstanding the epidemiology of AKI has been limited by theabsenceofabroadlyaccepteddefinitionofAKI.Recently,theimpor-tanceofconsideringAKImorebroadlyasaclinicalsyndromehasbeenemphasized.Thissyndromeencompassesseveraletiologiesofrenaldiseaseaswellasextra-renalpathologyinvolvingfunctionalchangesandcellulardamage.UnlikeCKD,whichhasawell-establishedmodelfordiagnosis,AKIdefinitionandstagingreliesonlaboratoryvaluessuchasSCr,urinaryoutputand imagingsuchas renalultrasonog-raphy.Althoughmoresensitiveandspecificbiomarkersareneeded,changes inSCr and/or urinary output form thebasis of all currentdiagnosticcriteriaforAKI.

Diagnostic ClassificationThe standard options for calculating the CrCl with either theCockcroft-Gault equation or the 4-variable Modification of Diet inRenalDisease(MDRD)equationareinappropriateforthissyndrome

ReviewedbyAmyBartonPai,Pharm.D.,MHI,FASN,FCCP,FNKF;AliceGahbauer,Pharm.D.,BCACP; andWilliamDarrylMeyers,Pharm.D.,BCACP

By Nicole M. Sifontis, Pharm.D., FCCP, BCPS; and Margaret A. Miklich, Pharm.D., BCACP

LEARNING OBJECTIVES

ABBREVIATIONS IN THIS CHAPTERAIN AcuteinterstitialnephritisAKI AcutekidneyinjuryCIN Contrast-inducednephropathyCKD ChronickidneydiseaseCNI CalcineurininhibitorESRD End-stagerenaldiseaseMI MyocardialinfarctionPPI ProtonpumpinhibitorRAS Renin-angiotensinsystemSGLT-2 Sodium-dependentglucose

transporter-2

Table of common abbreviations.

ACSAP 2018 Book 3 • Nephrologic/Geriatric Care 8 Acute Kidney Injury

becausetheseequationsassumeastableSCr.Increasingly,the CKD Epidemiology Collaboration (CKD-EPI) equationis being reported by laboratories. The CKD-EPI equation ismore accurate than theMDRD study equation for estimat-ing theglomerularfiltration rate (GFR)athigherGFR levelsand allows for estimated GFR (eGFR) reporting throughoutthe GFR range (Stevens 2010). An evaluation of baselineSCr,whichisnotalwaysknowninthecommunitysetting,isneeded to further estimate changes in kidney function. Nostandardapproach todeterminingbaselinekidney functionexists, and ultimately, clinical judgment is necessary. Alsoof importance,SCr lagsbehindGFRandmay thereforenotprovide an exact real-time assessment of kidney function,whichhelpsexplaintheoften-latediagnosisofAKI.AsGFRdecreases, the creatinine half-life increases from 4 hoursto 24–72 hours, resulting in an SCr increase at least 24– 36hoursaftertheinitialinsult(Ostermann2016).

Consensus criteria that provide amethod of diagnosinganddescribingAKIseverity includetheAcuteKidney InjuryNetwork(AKIN)diagnosticcriteriaandtherisk,injury,failure,

loss,andend-stagerenaldisease(ESRD)(RIFLE)classifica-tion(Table1).

According to the Kidney Disease: Improving GlobalOutcomesguidelines,AKIisanincreaseinSCrby0.3mg/dLormorewithin48hours;oran increase inSCr to1.5 timesbaseline or more, which is known or presumed to haveoccurredwithintheprior7days;orurinaryoutputlessthan0.5mL/kg/hourfor6hours.

Physiologic ClassificationThecausesofAKIcanbedividedintothreecategories:pre-renal,intrinsic,andpostrenalAKI(Box1).Themostcommonclassification in community-acquired cases is prerenal,whichiscausedbydecreasedrenalperfusionthatistypicallyvolume related. Intrinsic AKI is characterized according tothestructuralcomponentofthekidneythatisaffectedbythehistologic injury.Acute interstitialnephritis (AIN),a formofintrinsicAKI,resultsfromlymphocyticinfiltrationoftheinter-stitium. The classic triad of fever, rash, and eosinophilia isoftenpresentinadiagnosisofAINandmayhelpdistinguishAINfromacutetubularnecrosis,whichisthemostcommoncauseofintrinsicAKI.PostrenalAKIresultsfromobstructionoftheurinarycollectingsystem.

Pseudo AKIPseudo AKI is characterized by an acute increase in SCrindependent of change in GFR. The most common mech-anism for this phenomenon involves medications thatdecreasethetubularsecretionofcreatininebyinhibitingcer-tain drug transporters required for its elimination. Notableexamplesofmedications thatdecreasecreatininesecretionincludecimetidine,trimethoprim,dronedarone,andcobicistat(Duncker 2013; German 2012). Historically, certain medica-tions such as cephalosporins and substances like bilirubinhavebeenshowntointerferewithcreatinineassays,resultinginfalseelevationsinSCr.However,thisislessofaconcerntoday becausemost clinical laboratories use assays trace-able to these substances, which minimizes the impact ofcross-sensitivity.Conversely,cliniciansshouldpayattentiontoconditionsinwhichSCrisfalselylowered,inwhichcaseanormalvaluemaynotruleoutAKI.

Diagnosticworkupshouldincludeurinalysiswithmicros-copy,serialmonitoringofbloodandurinaryindices(Table2),andimagingsuchasrenalultrasonography.Inpatientswitholiguria,thefractionalexcretionofsodiumhelpsdistinguishprerenal from intrinsic causes of AKI. Concomitant use ofdiureticsmaydecreasetheusefulnessofurinesodiummea-surements, thusmasking a prerenal diagnosis. As a result,itismoreappropriatetousethefractionalexcretionofurea(FEUrea)asadiagnosticmeasureinthissetting.LowFEUreacanoccurintheclassicvolume-depletedstate,aswellasinthe volume-overloaded state that has decreased effectivearterialbloodvolumesuchascongestiveheartfailure,cirrho-sis,andsepsis.

BASELINE KNOWLEDGE STATEMENTS

Readers of this chapter are presumed to be familiarwiththefollowing:

• Generalknowledgeofrenalanatomyandrenalpathophysiology

• Conceptsbehindandinterpretationofcommonmeasuresofrenalfunction:CrCl,eGFR,anuria,oliguria,non-oliguria,urinalysisfindings

• Drugknowledgeofpharmacologicagentscom-monlyimplicatedinacutekidneyinjury

• Generalknowledgeofdiseasestatescommonlyencounteredintheambulatorycaresetting

Table of common laboratory reference values.

ADDITIONAL READINGS

The following free resources have additional back-groundinformationonthistopic:

• KidneyDisease:ImprovingGlobalOutcomes(KDIGO).AcuteKidneyInjuryWorkGroup.KDIGOclinicalpracticeguidelineforacutekidneyinjury. KidneyIntSuppl2012;2:1-138.

• PalevskyPM,LiuKD,BrophyPD,etal.KDOQIUSCommentaryonthe2012KDIGOclinicalpracticeguidelineforacutekidneyinjury.AmJKidneyDis2013;61:649-72.

• ChawlaLS,BellomoR,BihoracA,etal.Acutekidneydiseaseandrenalrecovery:consensusreportoftheAcuteDiseaseQualityInitiative(ADQI)16workgroup.NatRevNephrol2017;13:241-57.

ACSAP 2018 Book 3 • Nephrologic/Geriatric Care 9 Acute Kidney Injury

Table 1.ComparisonofRIFLEandAKINCriteriaforDiagnosingandClassifyingAKI

RIFLE ClassificationUrinary Output (common to both) AKIN Criteria

Classification SCr or GFR Criteria Urinary Output Stage SCr Criteria

Risk IncreaseinSCrto1.5timesbaselineorGFRdecrease>25%

<0.5mL/kg/hr for>6hr

1 SCrincrease1.5–2timesbaselineOR≥0.3mg/dLincreaseabovebaseline

Injury IncreaseinSCrto2timesbaselineorGFRdecrease>50%

Lessthan0.5mL/kg/hrfor>12hr

2 SCrincrease≥2.0–3timesbaseline

Failure IncreaseinSCrto3timesbaseline,orSCr>4mg/dLwithanacuterise>0.5mg/dLorGFRdecrease>75%

<0.3mL/kg/hrfor 24hroranuriafor 12hr

3 SCrincrease>3timesbaselineORIncreaseinSCr≥4.0mg/dLwithanacuteincreaseofatleast0.5mg/dLORInitiationofrenalreplacementtherapy

Loss Needforrenalreplacementtherapyfor>4wk

ESRD Needforrenalreplacementtherapyfor>3mo

DiagnosticandStagingTimeIntervalforEachCriterion

Within7days Within48hr

AKI=acutekidneyinjury;ESRD=end-stagerenaldisease.Informationfrom:UchinoS,BellomoR,GoldsmithD,etal.AnassessmentoftheRIFLEcriteriaforacuterenalfailureinhospitalizedpatients.CritCareMed2006;34:1913-7;MehtaRL,KellumJA,ShahSVetal.Acutekidneyinjurynetwork:reportofaninitiativetoimproveoutcomesinacutekidneyinjury.CritCare2007;11:R31.

Box 1. Common Causes Associated with AKIPrerenal AKI (hemodynamically mediated AKI)Decreasedeffectivebloodvolume

• Cirrhosis• Congestiveheartfailure

Intrarenalvasoconstriction• Cardiorenalsyndrome• Druginduced:NSAIDs,ACEIs,ARBs,CNIs• Hepatorenalsyndrome

Truehypovolemia• GIloss(diarrhea,vomiting)• Hemorrhage• Renalloss(diureticoveruse)

Intrinsic AKIAcuteglomerulonephritis

• Poststreptococcalglomerulonephritis• Thromboticthrombocytopenicglomerulonephritis

Acuteinterstitialnephritis(AIN)• Druginduced:Penicillins,cephalosporins,sulfonamides,protonpumpinhibitors,NSAIDs

• Malignancy• Systemicdisease:Sarcoidosis,lupus

Acutetubularnecrosis• Cardiopulmonaryarrest• Druginduced:Aminoglycosides,cisplatin,amphotericin,methotrexate

• Hypovolemicshock• Prolongedhypotension• Radiocontrastmedia• Sepsis

Acutevascularsyndromes• Renalarterythromboembolism• Renalveinthrombosis

Postrenal AKI• Malignancy• Nephrolithiasis• Urethralstricture

ACEI=angiotensin-convertingenzymeinhibitor;AKI=acutekidneyinjury;ARB=angiotensinreceptorblocker;CNI=calcineurininhibitor.Informationfrom:KhalilP,MurtyP,PalevskyP.Thepatientwithacutekidneyinjury.PrimCareClinOfficePract2008;35:239-64;RahmanM,ShadF,SmithMC.Acutekidneyinjury:aguidetodiagnosisandmanagement.AmFamPhysician2012;86:631-9.

ACSAP 2018 Book 3 • Nephrologic/Geriatric Care 10 Acute Kidney Injury

hasbeenreportedtobeashighas66%(Naughton2008).Thekidneys are at elevated risk of drug toxicity because theyreceivealargeamountofcirculatedblood(25%ofthecardiacoutput)andareinvolvedindrugmetabolismandelimination.

Nonsteroidal Anti-Inflammatory DrugsNonsteroidal anti-inflammatory drugs are among the mostcommonprescriptionandOTCmedicationsusedintheUnitedStates. Although patients may reach for NSAIDs becausetheyareeffectiveandseeminglybenign,theirusecomeswithrisks.SomedatasuggestthatNSAIDuseincreasestheoddsofAKIinthegeneralpublicbyabout50%andincreasestheriskinolderadultsby2-to3-fold(Zhang2017).

The mechanisms by which NSAIDs induce AKI are var-ied.Themostcommonmechanismofinjuryisbyalterationof renalhemodynamics,but thisdrugclasscanalsocauseacuteorchronicinterstitialnephritisaswellasglomerulone-phritis.Arecentpooledmeta-analysisshowedthattheoddsof thegeneralpopulation, thosewithCKD,andolderadultsdevelopingAKI fromNSAIDswere increasedby1.73-,1.63-,and2.01-fold,respectively(Zhang2017).Thedegreeofcyclo-oxygenase-2(COX-2)selectivityofNSAIDsdidnotaffecttheoddsofdevelopingAKI(Zhang2017).

PreventionofNSAID-inducedAKIshouldbemultifaceted.An accurate medication history including OTC NSAID useshouldbeobtainedbecausepatientsmayunderreportuseofthesemedications.TheclinicianshouldaccountforseveralsourcesofNSAIDs, includingOTC,prescription,andcombi-nation products (e.g., cough/cold, sleep aids) and educatepatientsonthepresenceofNSAIDsinproductsandtheirkid-ney-relatedrisks.ThoseusingNSAIDsshouldbeinstructedtousethematthelowestdoseandfortheshortestdurationpos-sible.Alternative therapiessuchasacetaminophen, topicalanalgesic agents, adjuvant therapy, and nonpharmacologic

RISK FACTORS ASSOCIATED WITH AKIPatient-Related Risk FactorsLargeepidemiologicstudieshaveidentifiedseveralriskfac-tors associated with developing AKI. These predisposingfactors include age older than 75, diabetes, heart failure,liverfailure,andchronickidneydisease(Chawla2014;Ishani2011). The 2017 U.S. Renal Data System (USRDS) annualreportunderscoredageasamajorriskfactorfordevelopingAKI.Theanalysisshowedthatinthoseolderthan60,theinci-denceofAKIwas46.6%–82%.

Comorbid conditions are important risk factors associ-atedwithAKI.A longitudinal follow-upofa largesampleofpatients with diabetes with an eGFR greater than 30 mL/minute/1.73m2inaVeteransAffairshealthcaresystemover10yearsshowedthateachAKIepisodewasassociatedwithdoublingtheriskofprogressiontostage4CKD(Thakar2011).Othervariablessuchasraceandsexseemedtobelesswellestablished as independent risk factors associated withdevelopingAKI(Leblanc2005).

Inaddition,therelationshipbetweenAKIandCKDseemstobebidirectionalbecauseAKIisamajorriskfactorfordevel-oping CKD. Data analyses involving hospitalized Medicarebeneficiaries have shown that AKI was associated with a13 times higher risk of ESRD than in patients without AKI(Ishani 2009). This link between AKI and CKD needs to bemoreaggressivelyembracedinthecommunitysettingtocor-rectitstrendanddecreasethehigheconomic,societal,andpersonalburdenassociatedwithAKI.

Drug-Related Risk FactorsMedicationsaccountforabout20%ofcommunity-andhospi-tal-acquiredepisodesofAKI,andtheincidenceinolderadults

Table 2.BloodandUrinaryIndicesforDifferentialDiagnosisinAKI

Prerenal AKI Intrinsic AKI Postrenal AKI

BUN/SCrratio >20:1 10–15:1 10–15:1

FENa(%) < 1 > 2 Variable

FEUrea(%) <35 <60

Urineosmolality(mOsm/kg) >500 <350

Urinesodium,mmol/L <20 >40 >40

Urinesediment SG>1.018,normal orhyalinecasts

SG<1.012,granularcasts, cellulardebris

Cellulardebris

UrinaryRBC Negative 2–4+ 1+

UrinaryWBC Negative 2–4+ Variable

FENa=fractionalexcretionofsodium=(urinesodium×SCr)/(serumsodium×UCr)×100;FEUrea=fractionalexcretionofurea=(UUN×SCr)/(BUN×UCr)×100;SG=specificgravity;UCr=urinecreatinine;UUN=urineureanitrogen.

ACSAP 2018 Book 3 • Nephrologic/Geriatric Care 11 Acute Kidney Injury

patientsafterinitiationordoseincrease.Concomitantuseofagentsaffectingrenalhemodynamicsalsoplacespatientsatrisk(e.g.,concomitantuseof loopdiureticswasassociatedwitha4-foldincreaseintheriskofSCrelevationof30%abovebaseline) (Schmidt2017a).Propermonitoringof renal func-tionandaction in response tochange in renal functionareoftenoverlooked.Inoneretrospectivestudyofover200,000patients,lessthan50%ofpatientshadbaselineandfollow-upmonitoringofSCr,and10%ofpatientshadnomonitoringatall(Schmidt2017b).Inaddition,inthosewhohadanSCrele-vationofover30%ofbaseline,only20%hadtheACEIorARBdiscontinued(Schmidt2017b).ItisimportanttomonitortheSCrbefore initiatingRAS-blockingagentsaswell aswithin1weekofinitiationordoseincrease.IfRAS-blockingagentsaredeemednecessaryinhigh-riskpatients,initiationofalowdoseofashort-actingagentwithsubsequenttitrationshouldbeconsidered.AnACEI-orARB-inducedAKIisusuallyman-agedbydiscontinuingtheoffendingagent;resolutionofAKIoccurswithinseveraldays,butitslong-termimpactrequiresadditional study.

Loop DiureticsLoopdiuretics can induceAKI throughprerenal or intrinsiccauses.Twosmallstudiesfoundthatpatientswithheartfail-ureusingloopdiureticshadagreaterriskofAKIiftheywereusinghigherdosesofdiuretics,haddiabetes,wereolder,hadnegativefluidbalance,hadlowerbaselinekidneyfunction,orhadhyponatremia(Ricci2013;Sun2006).Althoughnoguide-linesexist,specialcareshouldbegiventobalancetheneedtomaintaineuvolemiawiththeriskofAKIintheambulatorysetting,especiallyinat-riskpopulations.Rarely,sulfonamideloop diuretics can causeAIN. Preventivemeasures are notpossiblebecauseoftheidiosyncraticnatureofthisreaction.However, AKI resolution typically occurs rapidly (days) onremovaloftheoffendingagent(Krishnan2015).

Combination of NSAIDs, ACEIs/ARBs, and Diuretics – The "Triple Whammy"AlthoughAKIcanbepotentiatedbyNSAIDs,ACEIs/ARBs,anddiuretics on their own, a special discussion of the risks ofcombineduseiswarranted.Eachmedicationaffectskidneyfunctiondifferently–diureticscan lead todecreased renalperfusion through hypovolemia, NSAIDs do so by constric-tionofafferentarterioles,andACEIs/ARBsdosobydilationofefferentarterioles.Controllingthetoneoftherenalaffer-entandefferentarteriolesisnecessarytomaintainperfusionpressure,especiallyduringreducedrenalbloodflow.SeveralstudieshaveidentifiedanincreasedriskofAKIwiththeuseofthiscombinationofdrugs.Oneretrospectivecohortstudyofalmost500,000subjectsfollowedforalmost6yearsiden-tifieda31%higher rateofAKIwith triple therapy thanwithtreatmentwithonlyoneagent(Lapi2013).Thesubgroupanal-ysisshowedthattheAKIriskdoubledwithinthefirst30daysof triple therapy. A smaller prospective cross-sectionalstudyalsofoundanincreasedriskofAKIinfemalestaking

therapycanbeconsideredforcertainindications(e.g.,head-ache, muscle ache, arthritis pain) and patient populations(e.g.,thoseatincreasedriskofprerenalAKI,thoseatriskofcardiovascular-orGI-relatedadverseeffectsofNSAIDs,thosewithoutcontraindications toalternative therapies).Outrightavoidance ofNSAIDsmay bewarranted in patients at highrisk of developing prerenal AKI such as thosewith hepaticfailure, heart failure, or preexisting renal impairment; thoseusingagentsaffecting renalhemodynamics (e.g., diuretics,ACEIs, ARBs); and those at risk of volume depletion (e.g.,olderadults,acuteillness,diarrhea,vomiting).

Patients with NSAID-induced AKI and intravascular vol-umedepletionshould receivevolume repletionasclinicallywarranted(e.g.,weightheappropriatenessoffluidresuscita-tioninheartfailure).PrerenalAKIusuallyresolvespromptlyafterdiscontinuingtheNSAID.

AlesscommonetiologyofNSAID-inducedAKIisAIN,anidiosyncratic immune-mediated hypersensitivity response.With NSAIDs, this reaction occurs an average of 6monthsafterinitiation(Perazella2010).Becausethereactionisidio-syncratic and not dose-dependent, there are no preventivemeasures,andmanagementinitiallyconsistsofdiscontinu-ingtheNSAID.

RAS InhibitorsPrescription claims data show that ACEIs and ARBs areamong themost commonly prescribed drug classes in theUnitedStates; in 2017, therewere 106million prescriptionsforlisinoprilalone(Aitken2018).

Similar to NSAIDs, renin-angiotensin system (RAS) inhi-bition can induceAKI by altering renal hemodynamics andreducingglomerularcapillarypressure.Becauseofthisphar-macologic mechanism of action, an increase in SCr and adecreaseinGFRarecommonwithin3–5daysofinitiatinganACEIorARB.Typically,thisRASinhibitionbyACEIsandARBsiswell tolerated in low-risk patients, but some recommendthatACEIsorARBsbediscontinued if theSCr increasesby30%ormoreabovebaselineafterinitiationordoseincrease(Bakris2000).However,onestudyargues that the30%cut-offisbasedonweakevidenceandsuggeststhatcontinuingACEIs or ARBs aftermoremodest rises in SCr also carriesrisks(Schmidt2017a).Thiscohortstudyofover100,000pri-mary care patients showed statistically significant – andgraduated – increases in ESRD,myocardial infarction (MI),heartfailure,andall-causemortalityatallconcentrationsofincreasedSCrabove10%oninitiationofanACEIorARB.Forexample,comparedwiththereferencegroupwith lessthana10% increase inSCr, the incidencerateratioofESRDwas1.73forthe10%–19%increasegroup,2.58forthe20%–29%increase group, 3.80 for the 30%–39% increase group, and4.04forthe40%andgreaterincreasegroup.

Prevention of RAS inhibitor–induced AKI can be under-takenthroughscreeningforsusceptiblepatients,minimizinguse of concomitant nephrotoxic agents, andmonitoring all

ACSAP 2018 Book 3 • Nephrologic/Geriatric Care 12 Acute Kidney Injury

fluoroquinolones were implicated in 14% of drug-relatedcauses (Muriithi 2014). In crystal nephropathy, fluoroquino-lonecrystalsprecipitateinalkalineurine,leadingtoobstructedurineflowandan interstitial reaction.Preventivemeasuresincludeensuringadequatehydrationandusingappropriatedosesonthebasisofrenalfunction.

Sulfonamide AntibioticsMechanisms by which trimethoprim/sulfamethoxazole(co-trimoxazole)causesAKIincludeAIN,acutetubularnecro-sis, and crystal nephropathy. Like with NSAIDs, AIN withco-trimoxazole is caused by an idiosyncratic cell-mediatedimmune reaction. As with other drug-induced AIN, thereis no dose relationship. Unlike with NSAIDs, AIN second-ary to co-trimoxazole typically occurs more rapidly, within7–10days,ofexposureandismanagedbydiscontinuingtheagent(Perazella2010).

TenofovirTenofovir is a nucleoside reverse transcriptase inhibitormostcommonlyusedincombinationwithotherantiretrovi-rals for the treatmentofHIV.Tenofovirdisoproxil fumaratewas approved in 2001 and is co-formulated with severalotherantiretrovirals.Long-termrenalandbonedamagearewell-knownadverseeffectsofthistenofovirformulation,butthemedicationisalsoimplicatedinAKIthroughacutetubu-lar necrosis, proximal tubulopathy, and Fanconi syndrome(Pazhayattil 2014; Pannu 2008). It is estimated that 20%of patients treatedwith tenofovir disoproxil fumarate havetubular dysfunction (Fernandez-Fernandez 2011). Althoughtenofovirdisoproxilfumarateismetabolizedtotenofovirandthentotheactivemetabolitetenofovir-diphosphate,highcir-culating concentrations of tenofovir are responsible for itsadverseeffects(Sax2015).Typically, tubulardamagepres-ents after 20 or more weeks of therapy (Izzedine 2005).Preventive measures such as renally dose-adjusting teno-fovir disoproxil fumarate can be used. Once kidney injuryoccurs,ittakesanaverageof5weeksafterdiscontinuationfor kidney function to return (Izzedine 2005). Another pre-ventionandmanagementstrategy is touse thenewerandless toxic formulation of tenofovir, tenofovir alafenamide.Tenofoviralafenamidewasapprovedin2015andiscurrentlypartoffourdifferentco-formulations;itisnotavailableonitsown.Asanovelprodrugoftenofovir,tenofoviralafenamiderequiresamuchlowerdosethantenofovirdisoproxilfuma-rate to achievehigher concentrationsof activemetabolite;this mechanism is hypothesized to contribute to reducedrenal adverse events because of the reduced exposure tonephrotoxictenofovir(Sax2015).Manystudieshaveshownareductioninadverserenalevents,andnationalguidelinesrecommendsubstituting tenofovirdisoproxil fumaratewithtenofoviralafenamidetomitigatetheriskof renaldysfunc-tion and improve proteinuria and renal biomarkers (Wang2016;Sax2015,2014).

atwo-or three-drugcombinationandmalestakingathree-drugcombinationcomparedwithnoNSAID,diuretic,orACEI/ARB(Loboz2005).

Calcineurin InhibitorsCalcineurininhibitors(CNIs),namelycyclosporineandtacroli-mus,haverevolutionizedthepracticeoftransplantpharmacyandareessentialcomponentsinmanyposttransplantmain-tenance immunosuppressive protocols. According to thelatest Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients report, around96% of adult kidney transplant recipients were dischargedafter transplantation on a CNI-based regimen (Hart 2017).Oneofthemostcommondose-limitingtoxicitiesassociatedwith cyclosporine and tacrolimus is nephrotoxicity. AcuteCNI toxicity is describedas renal dysfunctionmediatedbyhemodynamicchangesthatisreversibleandtypicallyclas-sifiedasprerenalAKI.Thereversiblefunctionalimpairmentassociated with CNI use is caused by vasoconstriction oftheafferentarterioles,resultinginreducedrenalbloodflow(Naesens 2009). Long-termCNI use can also contribute toan irreversible and progressive tubulointerstitial injury andglomerulosclerosis labeled as chronic CNI nephrotoxicity(Naesens2009).

RiskfactorsforCNInephrotoxicityincludesystemicover-exposuretocyclosporineortacrolimus,concomitantNSAIDuse,anddiureticuse(Naesens2009).Strategiesforprevent-ingCNInephrotoxicityshouldbeaimedatloweringtotaldrugexposurebytherapeuticdrugmonitoring.Alternatively,dihy-dropyridinecalciumchannelblockersplayaprotective roleinminimizingCNInephrotoxicitybecauseoftheir intrarenalvasodilatoryeffectsoffsettingthevasoconstrictiveeffectsoftheCNIsattheafferentarteriole(Naesens2009;deMattos2000).Intherenaltransplantpopulationwhenhypertensionisachronicissue,useofcalciumchannelblockersmayofferabenefit, but careshouldbe taken toassess foranydrug-druginteractionswiththeCNIusedinthispopulation.

Oral Antimicrobialsβ-LactamsPenicillins and cephalosporins are among the most com-monantimicrobialsimplicatedinAIN.Inacaseseriesof133patients with biopsy-proven AIN, penicillins caused 20% ofdrug-related AIN, whereas cephalosporins were implicatedin 5% (Muriithi 2014). Acute interstitial nephritis caused byβ-lactamsoftenpresentswiththe“classic”triadofsymptoms– eosinophilia,rash,andfever(Pannu2008).Asdiscussedpre-viously,becauseAINisidiosyncratic,therearenopreventivemeasures.Atrialofglucocorticoidsmaybewarranted.

QuinolonesCiprofloxacinisthemostcommonlyimplicatedfluoroquino-lone in AIN aswell as crystal nephropathy (Khan 2015). Inone case series of 133 patients with biopsy-proven AIN,

ACSAP 2018 Book 3 • Nephrologic/Geriatric Care 13 Acute Kidney Injury

concentrations within 24–48 hours, often peaking at 3– 5 days. If renal function returns to normal, it usually doessowithin 7–10days (Kitajima2011). For patients undergo-ingcontrast-enhancedimagingprocedures,patient-specificrisk factors for developingAKI shouldbe evaluated. In theambulatory care setting, this can be performed by patientquestionnaires. Historically, these questionnaires captureage,historyofrenaldisease,priorkidneysurgery,hyperten-sion,diabetes,historyofcongestiveheartfailure,historyofcontrastmediaexposure,medicationuse(specificallymet-formin), and concomitant nephrotoxic medications. TheincidenceofCINinsuchpatientshasbeenreportedas12%–50%(Brueck2013).

The only intervention that has consistently decreasedthe risk of contrast-induced AKI is periprocedural intrave-nous isotonic crystalloids (Pavlesky 2013). Since the firstrandomizedtrialtestingacetylcysteineforthepreventionofCIN almost 2 decades ago, several subsequent trials havereached inconsistent results. Many of these studies havebeen limited by low statistical power and lack of blinding.Systematicreviewshaveyieldedhighheterogeneityacrossstudies, precluding definitive conclusions regarding theefficacyof acetylcysteine. To this end, a largemulticenter,randomized clinical trial called the Acetylcysteine forContrast-Induced Nephropathy Trial (ACT) with over 2300patients evaluated the incidence of CIN 48–96 hours afterangiographyinpatientsreceiving1200mgofacetylcysteineevery 12 hours (two doses before and two doses after theprocedure)comparedwithplacebo(ACTInvestigators2011).Subjectswith at least one risk factor for CIN such as ageolderthan70,SCrgreaterthan1.5mg/dL,diabetesmellitus,congestiveheartfailure,leftventricularejectionfractionlessthan45%,orhypotensionwereincluded,representinghigher- risk subgroups than in previous studies. The incidence ofCINwasidenticalintheacetylcysteineandplacebogroups,12.7% (p=0.97). Acetylcysteine had no statistically signifi-cantbenefitinanysubgroup,includingthosewithabaselineSCrgreaterthan1.5mg/dL,whichconsistedofaround16%ofthestudypopulation(ACTInvestigators2011).

Ascorbicacid’sability tooffernephroprotectionbecauseofitsantioxidantpropertieshasbeenstudiedinrandomizedclinicaltrialswithconflictingresults.Onesingle-center,ran-domizedtrialsuggestedascorbicacid’sbenefitinpreventingCIN (Spargias 2004). However, a second, large, two-center,randomized,double-blindstudycomparingintravenoussalineplus acetylcysteine administration or intravenous sodiumbicarbonate plus acetylcysteine or intravenous saline plusintravenous ascorbic acid plus acetylcysteine found thatascorbic acid provided no added benefit in reducing CIN(Briguori2007).

Metformin should be held before contrastmedia admin-istrationandupto48hourspost-administration.NostrongdatasupportdiscontinuingACEIs,ARBs,ordiuretics inthissetting(Pavlesky2013).

Proton Pump InhibitorsProtonpumpinhibitors(PPIs)areoneofthemostcommonlyprescribedmedicationclassesintheUnitedStates.SeveralPPIsarealsoavailableOTC.DocumentedPPIuseoccurredin9.2%ofallambulatoryvisitsin2009(Rotman2013).Arecentmeta-analysis includingover2millionpatientsshowedthatPPI use was associated with a 61% increased risk of AKI(Yang2017).On average,AIN took11weeks fromPPI initi-ation todevelopanddidnot presentwith the “classic”AINsymptoms of eosinophilia, rash, and fever. This adverseeffectappearstobeaclasseffectbecauseallPPIshavebeenimplicated in AIN (Brewster 2007). Beyond AKI, long-termPPIusehasbeenassociatedwithCKD,increasedbonefrac-tures, increased infections such asClostridium difficile and community-acquired pneumonia, and electrolyte abnormal-ities such as hypomagnesemia. Because of emerging dataonadverseeffects,severalinitiativestodeprescribePPIsareongoing (Farrell 2017). One way to prevent PPI-associatedAKIistodeprescribePPIsinpatientswhonolongerhaveanindicationforaPPIorchangetoalternativeacid-suppressivetherapy(e.g.,histamine-2receptorantagonists).

Sodium-Dependent Glucose Transporter-2 InhibitorsSodium-dependent glucose transporter-2 (SGLT-2) inhibi-torsarearelativelynewclassofantidiabeticagents.TheseagentsinhibittheSGLT-2receptorintheproximaltubuletoblockglucosereabsorption,therebyloweringbloodglucoseconcentrations.Althoughsomemembersoftheclassslowtheprogressionofkidneydiseaseinpatientswithdiabetes,over100AKIcaseshavebeenreportedtotheFDAinvolvingcanagliflozin and dapagliflozin (Wanner 2016). Themech-anism bywhich SGLT-2 inhibitors cause AKI is uncertain,but some theorize that it is because of dehydration fromosmoticdiuresisand/ortubular injuryfromincreaseduricacidproduction(Hahn2016).PostmarketingreportsofAKIpromptedtheFDAtoreviseandintensifythewarningofAKIfor these medications. Before initiating an SGLT-2 inhibi-tor, risk factors forAKIsuchasdehydration,heart failure,CKD,anduseofconcomitantnephrotoxicagentsshouldbeconsideredandaddressed, if possible.Most reportedAKIcasesoccurredwithin1monthofinitiationandresolvedondiscontinuation, according to FDA reports. The FDA alsorecommends preemptive discontinuation of SGLT-2 inhib-itors in the presence of reduced fluid intake or increasedfluidlosses.

Radiographic Contrast MediaContrast-inducednephropathy(CIN)isacommoniatrogeniccomplicationassociatedwith radiographiccontrastmedia.Contrast-inducednephropathy is definedas an increase inSCrbygreaterthan25%or0.5mg/dLoccurringwithin3daysafter intravascular administration of radiographic contrastmedia in the absence of an alternative etiology (Kitajima2011). Typically, CIN is associated with an increase in SCr

ACSAP 2018 Book 3 • Nephrologic/Geriatric Care 14 Acute Kidney Injury

co-trimoxazoleduringperiodsofvomiting,diarrhea,orfever.Thispracticeisbasedonexpertopinionandlacksevidencein the primary and secondary care settings (Whiting 2017;Griffith2015).Inaddition,thispracticecanplacepatientsatrisk of harm if inappropriate self-management occurs (e.g.,worsening control of hypertension, heart failure, or diabe-tes; inadvertent long-term discontinuation of maintenancemedications).Educatingat-riskpatientsisparamountinpre-ventingAKIintheambulatorycaresettingandisdiscussedinasubsequentsection,OpportunitiesforthePharmacist.

ManagementPatientswithAKIgenerallyshouldbehospitalizedunlessthecondition ismild and clearly results from an easily revers-ible cause. The focus on managing AKI in the ambulatorycaresettingistorestorerenalbloodflowanddiscontinueoradjustmedicationsassociatedwithnephrotoxicity.

Acutekidney injurycausedbyvolumedepletion requiresvolumeresuscitationwithisotoniccrystalloidsandacorrec-tionofthecauseofvolumelosstoreverseorameliorateAKI.Patientswithcongestiveheartfailureorcirrhosismaydevelopprerenal AKI because of reduced intravascular volume or

GENERAL PREVENTION AND MANAGEMENTPreventionThe fundamental principle of preventing AKI is to treatthe underlying cause or trigger. Primary prevention strate-gies involve identifyingpatientsathigh riskofAKIsuchasolderadults, thosewithheart failure,andthosewithunder-lying kidney disease and avoiding exogenous renal insults,when possible. Clinicians should be cognizant of commonnephrotoxins and their potential effects on kidney functiontoappropriatelydose reduceor avoid thesemedications inpatientsathighriskofdevelopingAKI.Cliniciansshouldalsoconsider correcting modifiable risk factors such as hypo-volemia before initiating new therapy. Some organizationsrecommend discontinuing potentially harmful medicationsduring periods of intercurrent illness, otherwise known as“sickdayrules.”Patientsmaybeeducatedonsickdayrulesorprovidedwitha “sickday rulescard” instructing themtostopmedicationstemporarilyuntiltheyareeatingordrinkingnormallyfor24–48hours.ThisincludesmedicationssuchasNSAIDs,ACEIs,ARBs,diuretics,metformin,sulfonylureas,and

Patient Care ScenarioA 75-year-old man is brought to the urgent care clinic by his daughter with nausea, vomiting, and diarrhea occur-ring over the past 3 days. He has been unable to keep any food down, only liquids. The patient reports a decrease in urinary output and darker urine. Associated symptoms over the past few days include increased pain caused by osteoarthritis, for which he has been taking naproxen 200 mg by mouth three times daily. Home medications include enalapril 5 mg by mouth daily, atorvastatin 10 mg by mouth daily, pantoprazole 40 mg by mouth daily, docu-sate 100 mg by mouth twice daily, insulin glargine 20 units

subcutaneously at bedtime, insulin lispro 5 units subcuta-neously three times daily with meals, and aspirin 81 mg by mouth daily. On examination, the patient appears frail with dry mucous membranes. Blood pressure is 105/60 mm Hg with heart rate of 80 beats/minute when sitting and 80/ 55 mm Hg with heart rate of 100 beats/minute on standing. Laboratory tests consist of Na 137 mEq/L, K 4.1 mEq/L, Cl 101 mEq/L, HCO3 21 mEq/L, BUN 52 mg/dL, SCr 2.3 mg/ dL, and glucose 98 mg/dL. Baseline renal function is unknown. What is the most likely etiology of this patient’s AKI and what is the best recommendation for him?

ANSWERThe patient’s history of decreased oral intake, vomiting, and diarrhea suggest volume depletion. The patient has also been taking an NSAID as well as an ACEI concomi-tantly, both of which can increase the risk of AKI, especially in a volume-depleted state. Physical findings of dry mucous membranes, orthostatic hypotension, and tachy-cardia further support a diagnosis of volume depletion. It is important to try to obtain this patient’s historical laboratory information to determine the degree of change in kidney function and confirm the diagnosis of AKI. However, the patient reported a change in urinary output, and the change in color strongly suggests AKI. A urine sample should also be obtained to screen for urinary electrolytes and the pres-ence/absence of urine sediments. Given the information provided, the most likely etiology for AKI in this patient

would be altered renal hemodynamics secondary to volume depletion. This would likely lead to a diagnosis of prerenal AKI. Together with the patient’s advanced age and diabe-tes, these events likely occurred because of his naproxen use in combination with enalapril while the patient was vol-ume depleted because of a 3-day history of vomiting and diarrhea. Acute kidney injury secondary to PPI use cannot be ruled out, underscoring the need for a complete medi-cation history. The patient may require hospital admission for intravenous fluid replacement and hydration, given that the oral route is not an option. Close monitoring of his renal function and electrolytes is necessary. The patient must avoid all NSAIDs, and enalapril should be held until blood pressure and renal function improve. Urinary output should be monitored closely.

1. Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Lancet 2012;380:756-66.2. Chawla L, Eggers PW, Star RA, et al. Acute kidney injury and chronic kidney disease as interconnected syndromes. N Engl J Med

2014;371:58-66.3. Rahman M, Shad F, Smith MC. Acute kidney injury: a guide to diagnosis and management. Am Fam Physician 2012;86:631-9.

ACSAP 2018 Book 3 • Nephrologic/Geriatric Care 15 Acute Kidney Injury

PrognosisCommunity-acquiredAKIhasbeenassociatedwithsignificantadverselong-termoutcomes,includingnew-onsetorprogres-sionofCKDsimilar tohospital-acquiredAKI (DerMesropian2014;Wonnacott2014).Ameta-analysisof13cohortstudiesshowedthatcomparedwithpatientswithoutAKI, thosewhorecovered fromAKIhadalmosta10-foldhigher riskofCKD,3-foldhigherriskofESRD,anddoubletheriskofdeath(Coca2012).Anotherstudyshoweda67%increasedriskofcoronaryevents inpatientswhodevelopedAKI requiringdialysis (Wu2014).The2017USRDSreportedthatin2013,oftheMedicarepatientsolderthan66whowerehospitalizedforAKI,28%weregivenan initialdiagnosisofCKDintheyearafterthathospi-talizationandhada35%cumulativeprobabilityofarecurrentAKIhospitalization.Thesestudiesandothersreportthatmostpost-AKI adverse events occur in the first 3–6months afteran acute episode (Silver 2015; Bucaloiu 2012). Recent dataanalysessuggestthatonly40%ofpatientswithAKIrequiringdialysisreceiveanephrologyreferralwithin90daysofhospitaldischarge(Harel2013),andaseparatestudyofpatientswhodid not require dialysis post-discharge reported a follow-uprate of 11%within 30 days,with only 19% referred at 1 year(Siew2012).Thesedatarepresentanimportantcaregap.

Evidenceislackingtoguidethetiming,frequency,andmeth-odstoevaluatekidneyfunctioninpatientsafteranepisodeofAKI.TheAcuteDiseaseQualityInitiativeworkgrouprecommendsthattheintensityofsurveillancebeproportionatetotheriskoffutureoutcomes.ThosewithcomorbidconditionsthatincreasetheriskoffutureCKDprogressionmayhavegreaterbenefitfromearlierormorefrequentsurveillancethanpatientswithalowerriskoffutureCKD(Siew2016;Hickson2015).Onestudyprospec-tively evaluated over 35,000 patients with diabetes from over100VeteranAffairsmedicalcentersintheUnitedStateswhohadtheirfirstnoncardiacsurgery.Inthisstudy,AKIwasstratifiedbymagnitudeaccordingtoAKINstageandduration–specifically,shortdurationwasdefinedby lessthan2days,mediumdura-tionwasdefinedby3–6days,andlongdurationwasdefinedas7daysormore(Coca2010).MortalityratesinthisanalysisweregreaterforthosewiththelowestAKINstageandwithmedium(3–6days)or long (7daysormore)durationofAKI (21.5and29.3deathsper100person-years, respectively) than for thosewiththemostsevereAKINstagebutshort(2daysorless)dura-tionofAKI(12.8deathsper100person-years).

OPPORTUNITIES FOR THE PHARMACISTPharmacistscanplayaroleinidentifyingpatientsatriskofAKI;providingearlydetectionofAKI;optimizingmedicationsforpreventingandtreatingAKI;providingpatienteducation,including providing sick day rules, maintaining hydration,andavoidinginappropriateuseofOTCNSAIDs;andpromot-ing adequate referral and follow-up. Quality improvementinitiativesandotherscholarlyactivitiescanhelpimprovepre-ventionandtreatmentofAKI.

aggressivediuresis. In thesesituationsofdecreasedeffec-tivearterialbloodvolume,themanagementstrategyinvolvestreatingtheprimaryorganfailure.

Management of drug-induced AIN involves removingthe suspected causative agent and providing supportivetherapy. Inmost cases, AIN is self-limiting and reversible;however,recoverymaytakeweekstomonths(Pannu2008).Use of corticosteroids in the treatment of drug-inducedAIN is controversial. In a multicenter, retrospective studyin Spain, researchers evaluated the influence of cortico-steroids in 61 patients with biopsy-proven AIN (González2008). Most patients (85%) who received corticosteroids(methylprednisolone 250–500 mg for 3–4 days followedbyoralprednisone1mg/kg/day taperedover8–12weeks)had a significantly lower SCr at the end of follow-up (SCr2.1mg/dL vs. SCr 3.7mg/dL in thosewhodid not receivecorticosteroids).Amongtreatedpatients,thosewhostartedcorticosteroidswithin7daysofwithdrawingtheoffendingdrugweresignificantlymorelikelytorecoverrenalfunctionthan those who received corticosteroids after this period(OR 6.6; 95% CI, 1.3–33.6) (González 2008). Conversely, aretrospective single-center analysis in the United Statesamong 95 patients with biopsy-proven drug-induced AINsecondarytoantibiotics(49%),PPIs(14%),andNSAIDs(11%)foundthatcorticosteroidtreatment(prednisone40–60mgdaily) did not significantly affect recovery of kidney func-tion at 6 months (Muriithi 2014). Factors correlated withpoorrecoveryincludedlongerdrugexposure(15vs.30vs.130 days for complete, partial, and no recovery, respec-tively;p=0.04)and longerdelay instartingsteroid therapy(8vs.11vs.35days, respectively;p=0.05).LowerbaselineSCrconcentrationcorrelatedwithpartialrecoveryversusnorecovery(p=0.006)(Muriithi2014).

Intheambulatorycaresetting,mildelectrolyteabnormali-tiesmayaccompanyAKI.Ingeneral,attentionshouldbepaidtocorrectinghypo-orhyperkalemia,hypomagnesemia,andhyperphosphatemia.

Indicationsforrenalreplacementtherapyincludelife-threat-eningelectrolyteabnormalities–specifically, hyperkalemia,refractorymetabolicacidosis,volumeoverload,diureticresis-tance,uremia(definedasaBUNgreaterthan100mg/dL),orencephalopathy. The absolute number of patients with AKIrequiringdialysismorethandoubledfrom63,000in2000to164,000 in2009,andaboutone-thirdof thosewhosurvivedremaineddialysis-dependentonhospitaldischarge(Gautam2015;Hsu2013).Thiscreatesascenarioformanypatientstobetreatedinoutpatientdialysissettingswhentheirindicationfordialysis isadiagnosisofAKI.Around20%–60%ofthosewhoremaineddialysis-dependentpost-dischargewereabletosuccessfullycomeoffdialysis(Cerda2015).OnerecentMayoClinic analysis showed thatmost (73%) of these recoveriesoccurredwithin the first 3months post-discharge (Hickson2015).Ofnote,renalrecoveryisstronglyinfluencedbyindivid-ualpatientcomorbidities.

ACSAP 2018 Book 3 • Nephrologic/Geriatric Care 16 Acute Kidney Injury

The International Society of Nephrology developed the0by25campaign to reduceAKImortalityworldwidebypro-moting awareness to the public, health care professionals,and policy-makers (Mehta 2015). Five core elements havebeendevelopedtoaidintheseefforts:riskassessment,rec-ognition,response,renalsupport,andrehabilitation.

ThinkKidneysisaUK-basedcampaignfundedthroughtheNationalHealthServiceandtheUKRenalRegistrytoimprovecareforthoseaffectedbyoratriskofAKI.Thewebsite(think-kidneys.nhs.uk) is a repository for completed and ongoingAKIresearch,news,andeducationalresourcesforphysicians,pharmacists,nurses,communityorganizations,andthepub-lic.Specifically,thereisguidanceforpharmacistsinoptimizingmedicationsduringAKIandfreepatienteducationmaterials.

AlthoughtheNationalKidneyFoundation and the NationalKidney Disease Education Program largely focus on CKD,otherresourcesalsotargetAKI.TheChoosingWisely initia-tive’smissionistodecreasewastefulorunnecessarymedicalcare–oneinitiativethisinitiativehaschampionediseducat-ing patients on the risks ofNSAID use, forwhich a patienteducationhandouthasbeencreated.Althoughaframeworkexaminestheeffectofeducationalinterventionsonprevent-ingAKI,moreresearchisneeded(Byrne2015;Pai2015).

CONCLUSIONAcute kidney injury is common in the community settingand is associated with high morbidity, high mortality, andincreased health care costs. Early recognition and preven-tion are paramount to achieving good patient outcomes.Heightened screening and preventive management shouldoccurforthoseathighrisk,whichincludesadultsolderthan60,individualswithdiabetesorpreexistingCKD,andindivid-ualswithchronicmedicalproblemssuchasheartfailureorcirrhosis.Pharmacistsintheambulatorycaresettingareonthefrontlinesofeducatingpatientsontheirriskandevaluat-ingmedicationsthatcanposeariskofAKI.

Transitions of CareIn general, few patients with AKI have adequate follow-upafteranepisodeofAKI (Siew2012).Becauseof the lackofrecognitionofpriorAKIandlackoffollow-up,someauthorsadvocatethatamedicalhistoryof“episodeofAKI”bedoc-umentedinAKIsurvivors’medicalrecords(Goldstein2013).ThiscouldprovideamethodbywhichpatientswithahistoryofAKIaresystematicallyidentified.Inaddition,descriptionsofAKI follow-upclinicsexist; todate,nodatasupport theirimpactonAKImorbidityormortality(Silver2015).

For patients who become dialysis-dependent after AKI,carecoordinationfromtheinpatienttotheoutpatientsettingis critical. Before January 1, 2017, Medicare only providedpayment to hospital-based dialysis units for patients withAKI requiringdialysis,which limitedaccessandavailabilitytotheseservices.Addingcommunity-baseddialysiscentersserves as a much-needed expansion of care. Pharmacistscanplayacrucialroleinmedicationreconciliationandclin-ical follow-up as it relates to clinical laboratory results inthese patients. Practical strategies to promote and moni-torrenalrecoveryinthisuniquepopulationincludeavoidinghypotension during dialysis, minimizing nephrotoxins, hav-ingaregularclinicalfollow-up,andhavingregularlaboratoryevaluation.

Pharmacists in the ambulatory setting also play a rolein medication optimization and patient education bothduring transitions of care and routine follow-up (Shaw2015).Many patients with AKImay need referral for hos-pitalization and/or alterations in medications to preventfurtherinsult.ThosewhoarerecoveringfromAKImayneedreferral to a nephrologist. According to the 2017 USRDSannual report,only16%ofMedicarepatientssurvivinganAKIhospitalizationhadanoutpatientnephrologyfollow-upwithin6monthspost-hospitalization,underscoringthelackof timely follow-up. Pharmacists can help bridge the gapregardingfollow-up.Periodicassessmentofrenalfunctiontoassessprognosisisparamountinminimizinglong-termriskandcanbecompletedinpharmacist-runclinics.OnceAKIhasresolved,heldmedications(e.g.,antihypertensives,antihyperglycemics) should be evaluated for reinitiation,when appropriate. Patients should be educated on theirrisks and advised on strategies they can use tominimizethe risk, including sick day rules, hydration (if clinicallyappropriate),andgeneralprescriptionandnonprescriptionmedicationeducation.

Initiatives and ResourcesGlobally, research and resources allocated to developingevidence-based, standardized approaches to preventing,diagnosing, and treating AKI are lacking. Similarly, limitedeffortsareinplacetopromotehealthprofessionalandpub-licawarenessofAKI.Asvaluablemembersofthehealthcareteam,pharmacistsshould jointhemovementtoreduceAKImorbidityandmortality.

Practice Points• AKI is characterized by many inciting causes that can

complicate coexisting illnesses. AKI is common in the ambulatory care setting and is associated with high morbidity, high mortality, and increased health care costs.

• Risk factors for AKI include older age, preexisting CKD, heart failure, and liver failure.

• Main prevention strategies include avoiding or dose-reducing nephrotoxic agents, correcting for modifiable risk factors, and educating patients on agents that can negatively affect renal function.

• Management relies largely on treating the underlying cause and/or discontinuing the offending agent.

• Patients with a diagnosis of AKI should be evaluated within 3 months after resolution of renal injury and should have continued surveillance over 2–3 years to monitor for worsening of renal function or development of CKD.

ACSAP 2018 Book 3 • Nephrologic/Geriatric Care 17 Acute Kidney Injury

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ACSAP 2018 Book 3 • Nephrologic/Geriatric Care 18 Acute Kidney Injury

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NaesensM,KuypersD,SarwalM.Calcineurininhibitorneph-rotoxicity.ClinJAmSocNephrol2009;4:481-508.

NaughtonCA.Drug-inducednephrotoxicity.AmFamPhysician2008;78:743-50.

OstermannM,JoannidisM.Acutekidneyinjury2016;diag-nosisanddiagnosticworkup.CritCare2016;20:299.

PaiAB.Keepingkidneyssafe:thepharmacist’sroleinNSAIDavoidanceinhigh-riskpatients.JAmPharmAssoc(2003)2015;55:e15-23.

PannuN,NadimMK.Anoverviewofdrug-inducedacutekidneyinjury.CritCareMed2008;36:S216-23.

PazhayattilGS,ShiraliAC.Drug-inducedimpairmentofrenalfunction.IntJNephrolRenovascDis2014;7:457-68.

PerazellaMA,MarkowitzGS.Drug-inducedacuteinterstitialnephritis.NatRevNephrol2010;6:461-70.

RicciF,RamirezT,MarmoratoR,etal.PredisposingfactorsforacutekidneyinjuryinHispanicpatientstreatedwithdiureticsfordecompensatedheartfailure.PRHealthSciJ2013;2:63-7.

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ACSAP 2018 Book 3 • Nephrologic/Geriatric Care 19 Acute Kidney Injury

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ACSAP 2018 Book 3 • Nephrologic/Geriatric Care 20 Acute Kidney Injury

5. A41-year-oldmanpresentswithuncontrolledhyperten-sion.Hismedicalhistoryissignificantfortype2diabetes,hyperlipidemia, and renal transplantation (1 year ago).His current drugs include tacrolimus 3 mg by mouthevery12hours,mycophenolate1000mgbymouthevery12 hours, prednisone 5mg bymouth daily,metoprolol 50mgbymouthtwicedaily,clonidine0.2mgbymouthtwicedaily,atorvastatin10mgbymouthdaily,andaspi-rin81mgbymouthdaily thepast3days.HisbaselineSCris1.4mg/dL(stable).Vitalsignstodayincludebloodpressure 158/88 mm Hg, heart rate 62 beats/minute,respiratory rate 18 breaths/minute, and temperature98.6°F. Tacrolimus trough concentration is 9.3 ng/mL(goal8–10ng/mL).Whichoneofthefollowingisbesttorecommend tomanage thispatient’shypertensionandreducehisriskoftacrolimus-relatednephrotoxicity?

A. Initiateenalapril2.5mgbymouthdaily.B. Increasemetoprololto100mgbymouthtwicedaily.C. InitiatediltiazemCD180mgbymouthdaily.D. Initiateamlodipine5mgbymouthdaily.

6. A67-year-oldwomanwithamedicalhistoryofhyperten-sionanddiabetesisseenintheambulatorycarecenterforaworkupofhematocheziaandchangeinbowelhab-its.ACTscanofherabdomenandpelvisisscheduledfornextweekatoneofyouraffiliatedoutpatient facilities.Herhomedrugsincludeenalapril20mgbymouthdaily,metformin850mgbymouth twicedaily,aspirin81mgbymouthdaily,andatorvastatin40mgbymouthdaily.Thebasicmetabolicpanelobtainedtodayisasfollows: Na138mEq/L,K4.1mEq/L,Cl101mEq/L,HCO324mEq/L,BUN14mg/dL,SCr1.6mg/dL,andglucose105mg/dL.As part of the coordinating care team preparing thispatientforheroutpatientprocedure,youarediscussingthe role of oral acetylcysteine in preventing contrast- inducednephropathy(CIN)accordingtotheACTclinicaltrial.Whichoneofthefollowingbestdescribestheappli-cationofthoseclinicaltrialresultstothispatientcase?

A. AcetylcysteinewasassociatedwithalowerincidenceofCINthanintravenousisotoniccrystalloidsandmaybebeneficialinthispatient.

B. Acetylcysteinewasstudiedinpatientsundergoingintravascularangiography;therefore,thispatientmayhavenoclinicalbenefit.

C. AcetylcysteinehadastatisticallysimilarincidenceofCINinpatientswithworseningdegreesofkidneyfunctionandmayaddnobenefitinthispatient.

D. AcetylcysteinedidnotreducetheriskofCINstatisticallyinthestudypopulation,buttheclinicalbenefitsmayoutweightheriskinthispatient.

Questions 1–3 pertain to the following case.

Z.K. isa50-year-oldmanwithamedicalhistoryof chronickidneydisease(CKD),diabetes,hypertension,andheartfail-ure. Last week, he was discharged from the hospital aftermanagementandtreatmentofamyocardial infarction(MI).Z.K.’sBUNandSCrvaluesondischargewere26mg/dLand1.8mg/dL,respectively(baseline).Today,hisBUNis32mg/dL,SCris2.4g/dL,serumsodiumis134mEq/L,urineosmo-lality is290mOsm/kg,urinesodiumis40mEq/L,andurinecreatinineis14.3mg/dL,andtherearegranularcastsintheurine.Renalultrasonographyisnegative.

1. AccordingtotheAKINclassificationscheme,whichoneofthefollowingbestassessesZ.K.’sstageofacutekid-neyinjury(AKI)?

A. 1B. 2C. 3D. 4

2. Given thepatient’s laboratory values,whichoneof thefollowing best estimates Z.K.’s fractional excretion ofsodium(FENa)?

A. 0.8%B. 1.3%C. 2.3%D. 5.0%

3. Givenhislaboratoryfindings,whichoneofthefollowingmostlikelycausedZ.K.’sAKI?

A. PostrenalAKIB. PrerenalAKIC. Acuteinterstitialnephritis(AIN).D. Acutetubularnecrosis

4. WhichoneofthefollowingpatientshasthehighestriskofdevelopingAKIfromanacuteillnessresultinginvol-umedepletion?

A. 83-year-oldmanwithdiabetesprescribedlosartan50mgbymouthoncedaily

B. 77-year-oldwomanwithdiabetesandcongestiveheartfailureprescribedlosartan50mgbymouthonce daily

C. 65-year-oldwomanwithdiabetesandCKDprescribedlosartan50mgbymouthoncedailyandfurosemide40mgbymouthtwicedaily

D. 56-year-oldmanwithdiabetesandcongestiveheartfailureprescribedlosartan50mgbymouthoncedailyandfurosemide40mgbymouthtwicedaily

Self-Assessment Questions

ACSAP 2018 Book 3 • Nephrologic/Geriatric Care 21 Acute Kidney Injury

Questions 10 and 11 pertain to the following case.

R.D.,a54-year-oldmaninyourinternalmedicineclinic,wasinitiatedonfosinopril20mgbymouthdailyforhypertensionlastweek.R.D.’sSCrwas0.9mg/dLbefore initiationand is1.1mg/dLtoday.

10. TheresidentcaringforR.D.asksyouaboutthecardio-renalrisksofRASinhibitors.WhichoneofthefollowingbestinterpretsrecentdataforR.D.’smedicalresident?

A. AnincreaseinSCrbymorethan30%abovebaselineledtoastatisticallysignificantincreaseintheriskofMIandCKDbutnotinmortalitycomparedwiththereferencegroup.

B. AnincreaseinSCrbymorethan20%abovebaselineledtoanonstatisticallysignificantincreaseintheriskofMI,CKD,andmortalitycomparedwiththereferencegroup.

C. AnincreaseinSCrbymorethan40%abovebaselineledtoastatisticallysignificantincreaseintheriskofCKDbutnotinMIormortalitycomparedwiththereferencegroup.

D. AnincreaseinSCrbymorethan10%abovebaselineledtoastatisticallysignificantincreaseintheriskofMI,CKD,andmortalitycomparedwiththereferencegroup.

11. Whichoneofthefollowingisbesttorecommendtopre-ventfutureadverseeffectsfromR.D.’sepisodeofAKI?

A. Referhimtoanephrologist.B. Document“historyofAKI”asaprobleminthe

electronicmedicalrecord.C. Documentadrugallergytofosinoprilinthe

electronicmedicalrecord.D. Developapharmacist-ledpost-AKIclinic.

12. A74-year-oldwomanhasamedicalhistoryofdiabetes(A1C8.7%),hypertension(bloodpressure128/74mmHg),andhyperlipidemia.HereGFRis68mL/minute/1.73m2. Herhomedrugs includemetformin1000mgbymouthdaily,sitagliptin100mgbymouthdaily,hydrochlorothi-azide25mgbymouthdaily,androsuvastatin20mgbymouthdaily.Herendocrinologistwantstoinitiatecana-gliflozin100mgbymouthdailyforfurtherA1Clowering.Whichoneofthefollowingisbesttorecommendtopre-ventAKIinthispatient?

A. Counselhertomaintainadequatehydration.B. MonitorSCrwithin1weekofinitiation.C. Provideaprescriptionforfluconazoleintheevent

ofagenitalmycoticinfection.D. Avoidinitiationofcanagliflozininreducedkidney

function.

7. A 47-year-old man presents to the clinic with a 2-dayhistory of fever and rash.Hismedical history includeshypertension, type2diabetes, gastroesophageal refluxdisease (GERD), and low back pain. His home drugsincludeenalapril10mgbymouthdaily(×8years),panto-prazole20mgbymouthdaily(×8years),metformin1000mgbymouthtwicedaily(×7years),glyburide5mgdaily(×5years),ibuprofen600mgbymouthevery6hours(×6months),andoxycodone5mgbymouthevery6hoursasneededforbreakthroughpain(×3months).ThepatientreceivesadiagnosisofAIN.Whichoneofthefollowingmostlikelycausedthispatient’sAIN?

A. PantoprazoleB. IbuprofenC. GlyburideD. Enalapril

8. A58-year-oldwomanhasamedicalhistoryofintravenousdrugabuse,alcoholabuse,hepatitisCvirusinfection,cir-rhosis,andpoororalintake.PertinentlaboratoryvaluesincludeeGFR72mL/minute/1.73m2andalbumin2.9g/dL.Herhomedrugsincludefurosemide40mgbymouthdaily,spironolactone100mgbymouthdaily,propranolol20mgbymouthtwicedaily,thiamine100mgbymouthdaily,lactulose20gbymouthtwicedaily,andelbasvir50mg/grazoprevir100mgbymouthoncedaily.Whichoneofthefollowingposesthispatient’sgreatestriskofAKI?

A. AgeB. LiverfailureC. PoororalintakeD. Spironolactoneuse

9. A 66-year-old woman presents for a routine follow-up.Shehasamedicalhistoryofosteoarthritis,heartfailure,andchronicobstructivepulmonarydisease(COPD).Herhome drugs include acetaminophen 650mg bymouthevery 8 hours as needed for pain, lisinopril 20 mg bymouthdaily,carvedilol12.5mgbymouthevery12hours,bumetanide1mgbymouth twicedaily,and tiotropiuminhaledone18-mcgcapsulebymouthdaily.Areviewofsystems and physical examination finds the patient inmoderatepain,bloodpressure122/72mmHg,heartrate64beats/minute,lungscleartoauscultationandpercus-sion,andpositivehepatojugularreflex.Whichoneofthefollowing is best to recommend to prevent AKI in thispatient?

A. DiscontinueacetaminophenandinitiateaCOX-2inhibitor.

B. Discontinuebumetanide.C. CounselthepatienttoavoidNSAIDuse.D. Counselthepatienttoincreasefluidintake.

ACSAP 2018 Book 3 • Nephrologic/Geriatric Care 22 Acute Kidney Injury

15. A27-year-oldmanpresentstoyourclinicwithconcernsof low urinary output and peripheral edema. He has ahistory of hypertension (blood pressure 126/74 mmHg), intravenous drug abuse (last use 1 year ago),HIV(initiatedtherapy6monthsago;viralloadundetectable3 months ago), and GERD (asymptomatic today). Hishomedrugsincludevalsartan80mgbymouthdaily(×6months),elvitegravir150mg/cobicistat150mg/emtric-itabine200mg/tenofovirdisoproxilfumarate300mgbymouthdaily (×6months),omeprazole20mgbymouthdaily (×4years),andnaproxen500mgbymouthevery12hoursasneededforpain(×4years).HisFENais3%;urinalysis+granularcasts,3+RBC,3+WBC.Whichoneofthefollowingisbesttorecommendforthispatient’sAKI?

A. Discontinuevalsartanandchangetohydrochlorothiazide25mgbymouthdaily.

B. Discontinueelvitegravir/cobicistat/emtricitabine/tenofovirdisoproxilfumarateandchangetoelvitegravir/cobicistat/emtricitabine/tenofoviralafenamidebymouthdaily.

C. Discontinueomeprazoleandinitiatecalciumcarbonate500mgbymouthevery4hoursasneededforGERD.

D. Discontinuenaproxenandinitiateacetaminophen500mgbymouthevery6hoursasneededforpain.

13. A79-year-oldHispanicwomanpresentstoyourinternalmedicineclinicwithachiefconcernofachesandpains.Shehasamedicalhistoryofheartfailurewithreducedejectionfraction(ejectionfraction15%),MI(6yearsago),andCOPD.HerhomedrugsincludemetoprololXL50mgbymouthdaily, lisinopril20mgbymouthdaily, furose-mide 40mg bymouth twice daily, atorvastatin 40mgby mouth daily, and umeclidinium 62.5 mcg/vilanterol25 mcg 1 inhalation daily. Which one of the followingwouldbestpreventAKIinthispatient?

A. PerformamedicationhistoryandaskabouthomeNSAIDuse.

B. Referthepatienttonephrology.C. Educatethepatienton“sickdayrules.”D. Developaqualityimprovementinitiativetoreduce

inappropriatemedicationuseinolderadults.

14. Whichoneofthefollowingbestexemplifiesthepracticeofsickdayrules?

A. Patientwhostopsaloopdiureticwhileimmobileafterspinalsurgery

B. PatientwhostopsanACEIwhilerecoveringfromgastroenteritis

C. Patientwhostopsmetforminbeforereceivingradiographiccontrastmedia

D. Patientwhostopsinsulinaspartwhilefastingfora colonoscopy