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PrintingDiuretics,ACEIs,ARBs,andNSAIDs:ANephrotoxicCombination

Diuretics,ACEIs,ARBs,andNSAIDs:A
NephrotoxicCombination
Author:JohnR.Horn,PharmD,FCCP,andPhilipD.Hansten,PharmD

Thistripletherapycanincreasetheriskofacuterenalfailure.
Diuretics,angiotensinconvertingenzymeinhibitors(ACEIs),andangiotensinreceptorblockers(ARBs)
represent3classesofdrugswidelyusedinthetreatmentofhypertensionandheartfailure,oftenin
combination.Wepreviouslyreviewedtheeffectofnonsteroidalantiinflammatorydrugs(NASIDs)on
thehypotensiveresponseofvariousantihypertensiveagents.1Inadditiontobluntingthehypotensive
effectsofdiuretics,ACEIs,andARBs,thereisanincreasedriskofpatientsdevelopingacuterenalfailure
whenanNSAIDiscoadministered.Ashypertension,heartfailure,andconditionscausingchronicpain
arecommonintheelderly,theriskofexposuretopotentialinteractionsbetweenthesedrugsincreases
overtime.
MechanismoftheInteraction
Diureticscanreduceplasmavolumeleadingtoreducedrenalbloodflow.Thismayleadtoincreased
serumcreatinineconcentrations.Thekidneycancompensateviathereninangiotensinsystemby
constrictingtheefferentrenalarterioletoincreaseglomerularfiltrationpressureandfavorwaterand
sodiumretention.ACEIsandARBsinhibitefferentrenalarteriolarvasoconstrictionthatlowers
glomerularfiltrationpressure.NSAIDs,byinhibitionofprostaglandinsandbradykinin,produce
vasoconstrictionoftheafferentrenalarterioleandreducetheabilityofthekidneytoregulate(increase)
glomerularbloodflow.TheadministrationofanNSAIDplusdiureticorACEIorARBmayreducethe
hypotensiveeffectoftheantihypertensiveagentbutdoesnotcommonlyleadtoacuterenalfailure.When
tripletherapywithanNSAIDplusdiureticandanACEIorARBisadministered,thekidneyisunableto
useitsnormalcompensatorymechanismsandmaysufferanacutereductioninglomerularfiltrationthat
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PrintingDiuretics,ACEIs,ARBs,andNSAIDs:ANephrotoxicCombination

ismarkedbyarisingserumcreatinine.
ClinicalOutcome
Severalstudieshavenotedthetendencyforpatientsreceivingtripletherapytohaveelevatedserum
creatines.2,3Recentlyalargecasecontrolstudyexaminedtheriskofacuterenaldiseaseinpatients
receivinga)doubletherapyconsistingofanNSAIDcombinedwithadiureticoranNSAIDwithan
ACEIorARB,orb)tripletherapywithbothadiureticandACEIorARBplusanNSAID.4Patientswere
includedonlyifkidneydiseasewastheirprimarydiagnosisuponadmissiontothehospital.The
investigatorswerecarefultocontrolforconfounderssuchasotherdiseasesanddrugusage.Thestudy
populationincludednearly500,000patientsfollowedforameanofabout6years.Acutekidneyinjury
wasidentifiedin2215patientswhowerecomparedwithabout22,000controlpatients.Theoverall
incidenceofacutekidneyinjurywas7per10,000personyears.Theriskofkidneydiseaseinthepatients
wascomparedwithmatchedcontrolpatientsnotexposedtothedoubleortripletherapy.Theuseof
doubletherapywasnotassociatedwithanincreasedriskofkidneyinjury.
Tripletherapywasassociatedwitha31%increaseinriskofinjury.Thegreatestriskwasnotedwithin
thefirst30daysofconcurrenttherapy,whenitwasnearlytwiceashighinpatientscomparedwiththe
controls.Duetothestudysconservativeentrycriteria,itispossiblethatthestudyactually
underestimatestherisk.Forexample,increasedserumcreatininelevelsmayhavecausedprescribersto
discontinuethecombinationtherapybeforekidneyinjurywassevereenoughtorequirehospitalization.
Management
PatientsreceivingNSAIDschronicallyincombinationwithdiuretics,ACEIs,orARB,areatriskfor
diminishedhypotensiveresponse,elevatedserumcreatinine,andacutekidneyinjury.Theyshouldbe
monitoredforalteredbloodpressureandserumcreatinine,particularlyduringthefirstfewmonthsof
combinationtherapy.Whileitappearsthatalternativehypotensiveagents(eg,calciumchannelblockers,
centrallyactingagents)arelessaffectedbyNSAIDs,similardataarenotavailablefortheriskofrenal
injury.

Drs.HornandHanstenarebothprofessorsofpharmacyattheUniversityofWashingtonSchoolof
Pharmacy.Foranelectronicversionofthisarticle,includingreferencesifany,visit
www.hanstenandhorn.com.

References:
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PrintingDiuretics,ACEIs,ARBs,andNSAIDs:ANephrotoxicCombination

1. HornJetal.CoadministrationofNSAIDsandantihypertensiveagents.PharmacyTimes.
20067254.
2. ThomasMC.Diuretics,ACEinhibitorsandNSAIDsthetriplewhammy.MedJAust.
2000172:184185.
3. LobozKK,ShenfieldGM.Drugcombinationsandimpairedrenalfunctionthetriplewhammy.
BrJClinPharmacol.200459:239243.
4. LapiF,AzoulayL,YinH,NessimSJ,SuissaS.Concurrentuseofdiuretics,angiotensin
convertingenzymeinhibitors,andangiotensinreceptorblockerswithnonsteroidalanti
inflammatorydrugsandriskofacutekidneyinjury:nestedcasecontrolstudy.BMJ.
2013346:e8525.

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