Optimal use and interpretation of the aldosterone renin ratio to ...

In healthy volunteers, the range of the ARR (ng/dl per μg/l/h) is 2–17 with a mean of 5.5 (50–470, mean 150 when aldosterone is expressed as ... Skiptomaincontent Thankyouforvisitingnature.com.YouareusingabrowserversionwithlimitedsupportforCSS.Toobtain thebestexperience,werecommendyouuseamoreuptodatebrowser(orturnoffcompatibilitymodein InternetExplorer).Inthemeantime,toensurecontinuedsupport,wearedisplayingthesitewithoutstyles andJavaScript. Advertisement nature journalofhumanhypertension review article Optimaluseandinterpretationofthealdosteronereninratiotodetectaldosteroneexcessinhypertension DownloadPDF AbstractWiththeintroductionofthealdosterone/reninratioasascreeningtest,thedetectionrateofprimaryaldosteronismhasincreasedconsiderably.Nevertheless,noconsensushassofarbeenreachedregardingthecutoffpoints,operatingcharacteristicsorindeedeventhereferencevaluesforreportingthealdosterone/reninratiousingplasmaactiverenin(ng/lormU/l)measuredbyimmunoradiometricassay.Wereviewthecharacteristicsofthisratioinnormalindividuals,essentialhypertensionandprimaryhyperaldosteronisminanattempttoreachanagreementregardingitsoptimumuseandinterpretation–bothusingthereninactivityorconcentration.Itseemsthattheoptimalcutoffforpatientswithprimaryaldosteronismisabove30 ng/dlperμg/l/hor800 pmol/lperμg/l/hor130 pmol/ngor80 pmol/mU.Weexploreenhancingmeasuressuchascaptoprilloadingorusewithaplasmaaldosteronecutoffaswellaspitfallswiththetestsuchasconfoundingmedicationsortheneedforconfirmatorytesting.Forthelatter,demonstrationofautonomousaldosteroneproductionviasaltloadingiswidelyused,butmaynotbemostadvantageousandmayevenbecontraindicatedinpatientswithseverehypertension.Thereninstimulationtestmaybeanalternativebeingsafe,welltolerated,andcosteffective. 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IntroductionIthasgenerallybeenrecommended1,2,3thatscreeningforhyperaldosteronismbeconsideredforatleasthypertensivepatientswithspontaneoushypokalaemia(K<3.5 mmol/l),hypertensivepatientswithmarkeddiuretic-inducedhypokalaemia(K<3.0mmol/l),patientswithhypertensionrefractorytotreatmentwiththreeormoredrugsorhypertensivepatientsfoundtohaveanincidentaladrenaladenoma.Althoughprimaryhyperaldosteronismwaspreviouslybelievedtoaccountforlessthan1%ofhypertensivepatientsandhypokalaemiawasconsideredaprerequisiteforpursuingdiagnostictests,3recentstudiespursuingscreeningofbothhypokalaemicandnormokalaemichypertensiveshavereportedamuchhigherprevalenceofthisdisease,withprimaryhyperaldosteronismaccountingforupto12%ofhypertensivepatientsandmostpatientsbeingnormokalaemic.4,5,6,7,8Therefore,primaryhyperaldosteronismcouldbethemostcommonidentifiable,specificallytreatableandpotentiallycurableformofhypertension.Itwaspreviouslythoughtthatitwasonlyworthwhiletoperformdiagnosticworkupforprimaryhyperaldosteronisminhypokalaemicpatientsinthebeliefthatthegreatmajorityofpatientswithnormokalaemicprimaryhyperaldosteronismhavebilateraladrenalhyperplasiaratherthanaldosterone-producingadenomaandarethereforerarelysurgicallycurable.9However,retrospectiveevaluationofthediagnosisofprimaryhyperaldosteronismfromclinicalcentersinfivecontinentssuggestthattheapplicationofawidespreadscreeningstrategytoagreaternumberofhypertensiveswillleadtoa5-to15-foldincreaseintheidentificationofpatientsaffectedbyprimaryhyperaldosteronism.10Onlyasmallproportionofpatients(between9and37%)arehypokalaemicandtheannualdetectionrateofaldosterone-producingadenoma(APA)increasedinallcentersbyuptosixtimesafterthewidespreadapplicationofscreening.10Overall,itseemsthereforethatthewidespreadscreeningofallhypertensivepatientswillleadtoamarkedincreaseinthedetectionrateofprimaryhyperaldosteronism.Indeed,thedecisiontakenbytheBrisbanegrouptoscreenall(andnotjusthypokalemicorresistant)hypertensivesledtoa10-foldincreaseindetectionrateofprimaryhyperaldosteronismandfour-foldincreaseinremovalrateofAPAs.11Increaseddetectionnotonlyallowsincreaseddiagnosisofprimaryhyperaldosteronismbutcanhelptowardoptimizingantihypertensivetherapyinindividualpatientswithhypertensionandtherebypotentiallyreducecostsbydecreasingthenumberofdrugsrequired.Theprescriptionofantihypertensivetherapybasedonthereninprofileofthepatienthasresultedinameanreductionof0.6drugs(from2.1to1.5)perpatient,comparedwitharandomprescription,12whichisinturnassociatedwithreductionsincost(−20%)andsideeffects.Furthermore,suchastrategyallowsadiagnosisofsecondaryhypertensioninafifthofsuchpatients,halfofwhomareindeedpatientswithprimaryhyperaldosteronism.12Owingtopoorsensitivityandspecificity,(upto60%ofpatientswithprimaryaldosteronismmayhavenormalplasmaaldosteroneconcentrations13),measuresofreninandaldosteronebythemselvesareconsideredtohavelimitedvalueinscreeningforprimaryaldosteronism.Hiramatsuetal.14firstproposedthecomputationoftheplasmaaldosteroneconcentration(PA)toplasmareninactivity(PRA)ratio(ARR)forevaluationofprimaryhyperaldosteronismin1981.Today,calculationofthisratio,whichreducesthesemeasurestoasinglenumber,iswidelyadvocatedasausefulscreeningmethod15,16becauseitpresentslessday-to-dayfluctuationthaneitherplasmaaldosteroneorplasmareninactivity.17However,itisdifficulttomakeoutfromtheliteraturewhataretheoperatingcharacteristicsoroptimumthresholdlevelsfortheARR.AreviewoftheliteratureuptoOctober2001thatincluded16studieswith3136participantsdemonstratedARRcutoffvaluesthatrangedwidelyfrom200to2774 pmol/lperμg/l/h.18AsthepredictivevalueoftheARRisdependentonthethresholdusedwithahigherARRmakingthediagnosisofprimaryaldosteronismmorelikely,19thehigherthethreshold,themorespecifictheARRwithaconcomitantlossinsensitivity.Wethereforedecidedtoextractrelevantinformationfromtheliteratureonthistopicandmakerecommendationsforclinicaluse.Toestablishthemostinclusionaryliteraturesetpossible,extensivesystematicsearcheswereconductedofPubMed,startingwiththeMeSHterm‘Hyperaldosteronism/diagnosis’followedbyhandsearchesofselectedjournals,authorsearches,andsearchesofselectedreferencelists,especiallyofreviewarticles.OperatingcharacteristicsandthresholdvalueTocomputethisratio,bloodisdrawnforPA&PRAafter2 hofambulation,butpreferablyat0800 h,sinceatthattimeplasmaaldosteroneisnormallyatitshighestlevel.Inhealthyvolunteers,therangeoftheARR(ng/dlperμg/l/h)is2–17withameanof5.5(50–470,mean150whenaldosteroneisexpressedaspmol/l).20OthersreporthighervaluesinhealthyvolunteersbutusuallyARRnotexceeding21–34(amountingtoaratioof580–940whenplasmaaldosteroneisexpressedaspmol/l).13,21Inessentialhypertensivestoo,theARRisusuallylessthanthisandremainswithinthisrangeduringantihypertensivetreatment.14,17ArecentstudyconcludedthatiftheARRvalueislessthan23.6 ng/dlperμg/l/h(<650ifPAinpmol/l),clinicianscanbeassuredthatthelikelihoodofprimaryhyperaldosteronismisextremelylow17sowecanbeconfidentthatpatientswithlaterprovenAPAoridiopathichyperaldosteronism(IHA)usuallywillhaveanARRabove25–34(690–940ifplasmaaldosteroneisexpressedinpmol/l)(Table1).13,17,21Table1OperatingcharacteristicsandthresholdvaluesofhormoneassaysFullsizetableIthasbeenshownthattheARRhasgreaterthan90%sensitivity22aroundathresholdoftheratioof30(830ifplasmaaldosteroneisexpressedinpmol/l),15andanegativepredictivevalueof93–99%.23Thismakesitpossibletoconfirmadefinitivediagnosisofprimaryaldosteronisminasignificantproportionofsuchnormokalaemichypertensivepatients,leadingtoaremarkableincreaseintherateofdiagnosis.24Usingthissensitivetestthresholdtoscreenunselectedhypertensivepatients,theprevalenceofprimaryaldosteronisminthisgroupisover10%.4Asthecutoffisincreasedto50(1380ifPAinpmol/l)fortheARR,thereisasignificantlylowernegativepredictivevalue(dropsbyathirdfromthecutoffof30)butfarlessfalse-positivediagnosesaremade.8,25Above66.9 ng/dlperng/ml/h(>1850ifPAinpmol/l),thediagnosisofprimaryhyperaldosteronismcanpracticallybeconsideredestablished17althoughnowthenegativepredictivevalueispoor.QuantitativestudiesusingROCanalysisoftheARRsuggestthatcombiningthisratiowithaPAthresholdmightimprovediagnosticdiscriminationofAPAandIHAfromlow-reninessentialhypertension(LREH)25andovercomerenindependencyoftheratiobecausewhenplasmareninlevelsareverylow,plasmaaldosteronelevelsaslowas114 pmol/lmightresultinapositiveARR.26,27UsingthecombinedROC-definedcutoffpointsof27–30fortheARR(750ifPAinpmol/l)and12 ng/dl(330 pmol/l)foraldosterone,thereporteddiscriminationofpatientswithprimaryaldosteronism(APAandIHA)fromthosewithlow-reninessentialhypertensionwaswithgreaterthan90%sensitivityandspecificity.25Weinberger,alsohassuggestedthatanARR>30(830ifPAisexpressedinpmol/l)withanabsolutePA>420 pmol/l(15 ng/dl)mightnotneedaconfirmatorystudy.15Cautionisadvisedhere,however,sincealthoughsuchastrategyincreasesthespecificityofthetest(i.e.,decreasesthenumberoffalsepositives),italsomarkedlydecreasessensitivity(i.e.,increasesthenumberoffalsenegatives).Forexample,ithasbeenshownthatimpositionofathresholdvalueofaldosteroneof420 nmol/l(15 ng/dl),assuggestedbytheauthorsintheabove-citedstudies,totheoptimumARRthresholdincreasedthespecificityoftheARRfrom74to97%butmarkedlydecreasedthesensitivityfrom73to33%.22Thus,basedonthisfinding,suchastrategymaybeilladvisedinscreeningforprimaryaldosteronism.22IthasbeensuggestedthatsincepatientswithanAPAarethesoleoneswhowillbenefitfromsurgery,theycanbeidentified(positivepredictivevalueof90%)andseparatedfromothercauses(IHAandLREH)ofthelow-reninhypertensionsyndromeusingahighercombinedcutoffvaluesfortheARR>100(>2760ifPAinpmol/l)andPAC(>20 ng/dl;>550 pmol/l)whichhasapositivepredictivevalueof89.5%indiscriminatingAPAfromIHA(with84%sensitivityand82.6%specificity).25Itisunlikely,however,thatAPAcanbedistinguishedfromIHAbasedsolelyonahighARR.AlthoughahighratioislikelyveryspecificforAPA,itsnegativepredictivevalueremainsquestionable.Also,thelatterstudywasaretrospectiveanalysisofdatacollectedovera15-yearperiod.Althoughadenomaswereconfirmedbysurgicalexcision,theabsenceofanadenomawaspresumedbasedonnegativeCTfindingsasopposedtoadrenalveinsampling.MorerecentstudiesindicatethatCTimagingisnotaveryreliablemethodofexcludingAPAandthereforeAVSisprobablynecessarytoexcludeAPA.CaptoprilenhancementMeasurementoftheARR60–120 minafterasingledoseof25–50 mgofcaptoprilmightenhancediagnosticdiscrimination28byincreasingspecificityanddecreasingthenumberoffalsepositives.28,29,30TheuseofcaptoprilthereforeincreasestheutilityoftheARRbyincreasingspecificityandthusdecreasingtheneedforconfirmatorytesting.In1983,Lyonsetal.30comparedtheuseoftheARRobtained2 hafteradoseofcaptoprilwithresultsobtainedusingthe‘goldstandard’salineinfusion.TheyfoundthattheacutesuppressionofaldosteroneandremovalofanynegativefeedbackoncirculatinglevelsofreninusingthepostcaptoprilARRwereasefficaciousasthemorecumbersomeinfusionofsalineovera4 hperiod.Theyalsofoundthattheplasmaaldosteroneisusuallylessthan15 ng/dl(415 pmol/l)inallnormotensivesubjectsandin9of10essentialhypertensives,whileitremainedabovethisthresholdinall6patientswithAPAandin4of5withIHA.Morerecently,Agharaziietal.31publishedadetailedcomparisonofthecaptopriltestand3daysofhigh-saltloadingin49patientswithapresumeddiagnosisofprimaryaldosteronism.Theseinvestigatorsdemonstratedthatthecaptopriltestisasefficaciousinconfirmingthediagnosisasisthe‘goldstandard’testof3daysoforalsaltloading.Thus,thecaptopril-stimulatedARRseemstohavenowbeenconfirmedusingtwodifferent‘gold-standard’salt-loadingtests.30,31Thesimpleadditionof25 mgoralcaptopril2 hbeforeobtainingasecondsetofbloodsamplesfortheARR,therefore,notonlyservesasascreeningtestbutalsomightestablishadefinitivediagnosisofprimaryaldosteronism.32ThespecificityoftheARRtestismoredependentondemonstratingthatthepost-captoprilARRremainsabove12(330ifPAinpmol/l),despitethelossoftheinhibitorylevelsofangiotensinII,andthePAfailstobesuppressedtolessthanadefinablelevel(<240–330 pmol/l).31,32Thistestsavestimeandmoneyandcouldleaddirectlytodefinitivestudieslocalizingthelesion(Figure1).Figure1Summaryofthediagnosticpathwayforprimaryhyperaldosteronism.FullsizeimagePlasmareninconcentrationTheplasmareninconcentration(PRC)isreplacingthePRAasameasureofrenininclinicalpractice.ItseemsthatthelowerlimitofthePRCassayincreasesinnumericalvalueandthismaynecessitatealowercutofffortheARR.AlthoughonestudywithafullyautomatedsystemandtwostudieswithmanualPRCassaysforscreeningforprimaryhyperaldosteronismhavebeenpublished,33,34,35thecomparisonwithdatafromtheliteratureislimited.Trenkeletal.33suggestedacutoffvalueof50(aldosteronemeasuredinserumbyRIA,expressedinng/l;PRCmeasuredbyIRMA,expressedinng/l),whichcorrespondsto83 pmol/mU(forPRC,1 mU/l=0.6 ng/l34).Ferrarietal.35andRacineetal.36recommendedacutoffof140–150(PAinpmol/landPRCinng/l)correspondingto84–90 pmol/mU.Perscheletal.34producedatentativelyproposedcutoffvalueof71 pmol/mU.Subsequentstudiesincludingessentialhypertensivecohortsmaynecessitatereadjustment,althoughthereisgoodconcordancewiththerecommendationsmadebyTrenkeletal.33,Ferrarietal.34andPerscheletal.35TheequivalentcutofffortheratiousingPRCinmU/l(>80)isthereforeapproximatelyone-tenthoftheratioderivedusingPRAinμg/l/h(>800).PitfallsSubjectsingestinglargeamountsofsodium,patientswithrenalimpairmentorthosetakingbeta-adrenoceptorblockerscanhavefalse-positiveresults.37Saltrestriction,ingestionofspironolactoneandotherdiuretics,especiallypotassium-wastingdiureticscanleadtofalse-negativeresults.Optimalperformanceofthistestconsistsofeliminatingotherfactorsthatcanaffectreninandaldosteronesuchascorrectionofhypokalaemiawithpotassiumchloridesupplements,cessationofdiureticsandbetablockers.Itwasinitiallyrecommendedtoavoidorstopallantihypertensivetreatmentsforatleast2weeks,especiallybeta-blockersandACEIwhichcouldgivefalse-positiveorfalse-negativevalues,respectively.However,theratioismoresensitivethanscreeningbyeitherdeterminationconsideredsinglyandappearstobelessaffectedbydrugadministration,day-to-dayanddiurnalvariationandbythepositionofthesubjects,thusallowingitsuseunderrandomconditions.13Cautionshouldbeexercisedinrecognizingfalselyelevatedvaluesinpatientswithrenalfailure(5of17patientswithrenalfailurepresentedwitharatioabovethelimitof34);13furthermore,thereisthepossibilityoffalse-positivevaluesundertreatmentwithbeta-blockingagentsordiureticsorwhenaldosteroneisabruptlystimulatedbypotassiumadministrationresultinginastimulationofaldosteronebiosynthesisandaloweringofPRA,38andfalse-negativevaluesundertreatmentwithACEIandperhapscalciumantagonists,althoughinthelongterm,incontrasttotheiracuteeffect,theseagentsappeartoaffectneitherreninnoraldosterone.39Workershaveinvestigatedtheeffectsoftherapywithatenolol,amlodipine,doxazosin,fosinopril,andirbesartanonthealdosteronereninratioinagroupof230patientswithsuspectedprimaryaldosteronism.8ThepercentchangefromcontrolofARRinpatientstakingamlodipinewas−17%±32;atenolol,62%±82;doxazosin,−5%±26;fosinopril,−30%±24;andirbesartan,−43%±27.TheARRchangeinducedbyatenololwassignificantlyhighercomparedwiththatinducedbyallotherdrugs,andtheARRchangeinducedbyirbesartanwassignificantlylowerthanthatinducedbydoxazosin.Oneof55patientsfromthegrouptakingamlodipine(1.8%)and4/17ofthepatientstakingirbesartan(23.5%)gaveafalse-negativeARR(<50).Noneofthepatientsofthegroupstakingfosinopril,doxazosin,andatenololdisplayedafalse-negativeARR.Itseemsthatalpha-blockers(doxazosin)andcalciumchannelblockers(amlodipine)canbeusedinhypertensivepatientswhoneedtoundergoaldosteroneandPRAmeasurementforthediagnosisofprimaryaldosteronism.Beta-Blockerscanberesponsibleforanincreasedrateoffalse-positivealdosteronereninratio'sandACEI/ARBforincreasedfalsenegativeratios.Beta-blockersandaldosteroneantagonistshavethestrongestimpactontherenin–angiotensinsystem(Table2).40Table2ReportedeffectofdrugsontheARRFullsizetableConfirmatorytestingUsuallytheARRratioisrepeatedatleastthrice41asprimaryhyperaldosteronismmayoccurinhypertensivepatientsdespiteanormalrenin/aldosteroneprofileonlimitedoccasions.Ifpositive(ARR>800(pmol/l)/(μg/l/h)orPA/PRC>80 pmol/mUorPA/PRC>130 pmol/ng)thisisfollowedbyaconfirmatorysuppressionorstimulationtest.3,42ThisisbecausewiththeARRuptoaquarterofsubjectsmayhavefalse-positiveresults22withacorrespondingpositivepredictivevalueof33–56%(butanegativepredictivevalueof93–99%).22,23EvenamongAfrican-Americansubjects,wheretheARRislesssensitivethaninwhitesubjects(75vs80%),itstillhadahighnegativepredictivevalue(92vs94%)23suggestingthatwhiletheARRisvalidasascreeningtestforprimaryhyperaldosteronisminAfricanAmericanandwhitepatientsonstableantihypertensivetreatments,therewillbesignificantfalse-positivityandahighratiowhilesuggestiveofprimaryhyperaldosteronism,mustbeconfirmed(Table3).43Table3ConfirmatorytestsFullsizetableThesuppressiontypeofconfirmatorytestingisaimedatdemonstratingautonomyofaldosteronesecretionandiscommonlyutilizedandcomprisebasicallyofsodiumloading(andmeasurementofserumorurinaryaldosterone)orfludrocortisonesuppressionofPA.However,false-negativeresultsarelikelytooccurincasesofoverproductionofaldosteronewhichisresponsivetoangiotensinII(IHAandangiotensinII-responsiveAPA).Furthermore,inelderlypatientsandpatientswithseverehypertension,sodiumloadingisnotwithoutrisk.Analternativetherefore,istheuseofcaptoprilloadingaspreviouslydiscussedanddemonstratingfailuretodecreasetheARRratiobelow12 ng/dl/μg/l/h(330 pmol/lperμg/l/hor33 pmol/mU)incombinationwithafailuretodecreasePAbelow240–330 pmol/l.AnotheralternativeisthestimulationofPRAorPRC.44,45,46,47,48Thisisdoneusingfurosemide40 mggivenorallyeighthourlytheprecedingdayandinthemorningfollowedafter2 hofuprightambulationbybloodsamplingforPRAat0800 hours.Aftersuchahypovolaemicstimulation,PRAremainssuppressed.Itiseasilyperformedwiththesubjectambulatory,requiresonlyonebloodsample,anditisnotnecessarytostopantihypertensivetreatmentexceptforbeta-blockingagents.Itofferstheadvantageofasimpleandsafeconfirmatorytest,notjustforprimaryaldosteronism,butalsoforthesyndromeofapparentmineralocorticoidexcess,DOC-producingadenoma,andeveninLiddle'ssyndrome.Morerecently,44reninstimulationhasbeenassessedbymeasurementofPRAafterpatientshavebeensupinefor30 min,andagainafterani.v.bolusof40 mgfurosemidefollowedby1 hor2 hinanuprightposture.TheseauthorsfoundthatreninstimulationbythefrusemideanduprightposturemaynotbeasaccurateoreffectiveastheARRindistinguishingAPAvsnon-APAinlow-reninhypertensives44althoughitisnotclearfromthestudywhetherthenon-APAgroupincludedonlyIHAorsomelow-reninessentialhypertensives.Itislikely,basedonthedatatheypresented,thatthesewereallmainlypatientswithprimaryhyperaldosteronismandtheirdata44suggestsapoststimulationcutoffforlow-reninhypertensionbeplacedat0.5 ng/l/swhichis1.7 ng/ml/handequivalenttoaPRCof14 mU/lor8 ng/l.ConclusionAltogetherthecomputationoftheARR,particularlywhencorrelatedtothePAvalue,30appearsthemostrobustscreeningtestforprimaryaldosteronism.24Nowthatplasmaaldosteroneandreninassessmentsarereadilyavailableinmostcommerciallaboratoriesandmajorhospitalsatareasonablecost,measurementoftheseparametersinsimultaneouslydrawnbloodsamplesisrecommended,followedbycomputationoftheARR(Figure1).UsuallytheARRratioisrepeatedatleastonceandifpositive(ARR>800(pmol/l)/(μg/l/h)or>80 pmol/mUor>130 pmol/ng)isfollowedbyaconfirmatorysuppressionorstimulationtest.Above66.9 ng/dlperμg/l/h(>1850ifPAinpmol/l),thediagnosisofprimaryhyperaldosteronismcanpracticallybeconsideredestablished17andnoconfirmatorytestingisrequired(Figure1). 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PubMed GoogleScholarMMAl-QudhaibyViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarKAl-HumoodViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarMFHafezViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarKASAl-ShoumerViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarCorrespondingauthorCorrespondenceto SARDoi.RightsandpermissionsReprintsandPermissionsAboutthisarticleCitethisarticleDoi,S.,Abalkhail,S.,Al-Qudhaiby,M.etal.Optimaluseandinterpretationofthealdosteronereninratiotodetectaldosteroneexcessinhypertension. JHumHypertens20,482–489(2006).https://doi.org/10.1038/sj.jhh.1002024DownloadcitationReceived:11October2005Revised:02March2006Accepted:02March2006Published:13April2006IssueDate:01July2006DOI:https://doi.org/10.1038/sj.jhh.1002024SharethisarticleAnyoneyousharethefollowinglinkwithwillbeabletoreadthiscontent:GetshareablelinkSorry,ashareablelinkisnotcurrentlyavailableforthisarticle.Copytoclipboard ProvidedbytheSpringerNatureSharedItcontent-sharinginitiative Keywordsprimaryhyperaldosteronismhypertensionaldosterone-reninratio Furtherreading Indicatorsofmineralocorticoidexcessintheevaluationofprimaryaldosteronism MelaniaBalaş IoanaZosin HolgerSWillenberg HypertensionResearch(2010) DownloadPDF Advertisement Explorecontent Researcharticles Reviews&Analysis News&Comment Currentissue Collections FollowusonTwitter Signupforalerts RSSfeed Aboutthejournal Announcements JournalInformation AbouttheEditors AboutthePartners Contact ForAdvertisers Subscribe Publishwithus ForAuthors&Referees Submitmanuscript Search Searcharticlesbysubject,keywordorauthor Showresultsfrom Alljournals Thisjournal Search Advancedsearch Quicklinks Explorearticlesbysubject Findajob Guidetoauthors Editorialpolicies