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DifferentiatingSIADHfromCerebral/RenalSaltWasting:FailureoftheVolumeApproachandNeedforaNewApproachtoHyponatremia

JClinMed.2014Dec3(4):13731385.

PMCID:PMC4470189

Publishedonline2014Dec8.doi:10.3390/jcm3041373

DifferentiatingSIADHfromCerebral/RenalSaltWasting:FailureoftheVolume
ApproachandNeedforaNewApproachtoHyponatremia
JohnK.Maesaka, 1,*LouisImbriano, 1,JosephMattana, 1,DympnaGallagher, 2,NaveenBade, 1,andSairahSharif 1,
1
DepartmentofMedicine,WinthropUniversityHospital,Mineola,NY11501,USAEMails:limbriano@winthrop.org(L.I.)Email:jmattana@winthrop.org
(J.M.)Email:nbade@winthrop.org(N.B.)Email:ssharif@winthrop.org(S.S.)
2
DepartmentofMedicine,ColumbiaUniversity,NewYork,NY10027,USAEMail:dg108@columbia.edu

Theseauthorscontributedequallytothiswork.
*
AuthortowhomcorrespondenceshouldbeaddressedEMail:jmaesaka@winthrop.orgTel.:+15166632169Fax:+15166632179.
Received2014Jul7Revised2014Aug26Accepted2014Sep9.
Copyright2014bytheauthorslicenseeMDPI,Basel,Switzerland.
ThisarticleisanopenaccessarticledistributedunderthetermsandconditionsoftheCreativeCommonsAttributionlicense
(http://creativecommons.org/licenses/by/4.0/).

Abstract

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Hyponatremiaisthemostcommonelectrolyteabnormality.Itsdiagnosticandtherapeuticapproachesareinastate
offlux.Itisevidentthathyponatremicpatientsaresymptomaticwithapotentialforseriousconsequencesatsodium
levelsthatwereonceconsideredtrivial.Therecommendationtotreatvirtuallyallhyponatremicsexposestheneed
toresolvethediagnosticandtherapeuticdilemmaofdecidingwhethertowaterrestrictapatientwiththesyndrome
ofinappropriateantidiuretichormonesecretion(SIADH)oradministersaltandwatertoarenalsaltwaster.Inthis
review,webrieflydiscussthepathophysiologyofSIADHandrenalsaltwasting(RSW),andthedifficultyin
differentiatingSIADHfromRSW,andreviewtheoriginoftheperceivedrarityofRSW,aswellasthevalueof
determiningfractionalexcretionofurate(FEurate)indifferentiatingbothsyndromes,thehighprevalenceofRSW
whichhighlightstheinadequacyofthevolumeapproachtohyponatremia,theimportanceofchangingcerebralsalt
wastingtoRSW,andtheproposaltoeliminateresetosmostatasasubtypeofSIADH,andfinallyproposeanew
algorithmtoreplacetheoutmodedvolumeapproachbyhighlightingFEurate.Thisalgorithmeliminatestheneedto
assessthevolumestatuswithlessrelianceondeterminingurinesodiumconcentration,plasmarenin,aldosterone
andatrial/brainnatriureticpeptideortheBUNtocreatinineratio.
Keywords:hyponatremia,renalsaltwasting,fractionalexcretionurate(FEurate),algorithm
1.Introduction

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Hyponatremia,definedasserumsodium<135mEq/L,isthemostcommonelectrolyteabnormalityencountered
worldwideandisanindependentriskfactorforhighermorbidityandmortalityrates[1,2].Symptomsrelatedto
hyponatremiahavebeentraditionallyassociatedwithseverehyponatremiaandacutereductionsinserumsodium,
butthereisagrowingawarenessthatevenmildhyponatremiaisassociatedwithmentaldysfunction,unsteadygait,
osteoporosis,increasedfallsandbonefractures[3,4,5,6,7,8,9].Basedonthisawareness,thereisanevolving
tendencytotreateverypatientwithhyponatremia.Thisrecommendationcreatesanurgentneedtoassesswith
assurancethecauseofthehyponatremiainagroupofpatientswithdiverseclinicalassociationsanddifferent
therapeuticgoals.Unfortunately,thepresentvolumeapproachtohyponatremia,whichhasbeeninexistencefor
decades,hasbeeninadequateandmisleading,inpartbecauseofmisconceptionsthatareunsubstantiatedby
supportivedata.Foremostamongthemisconceptionsisthecommonbutunprovenperceptionthatcerebralsalt
wasting(CSW)isarareclinicalentity.Clarificationofcerebral,orthemoreappropriateterm,renalsaltwasting
(RSW),videinfra,anditsdifferentiationfromSIADHbecomescriticalbecauseofopposingtherapeuticgoals,
whicharetoprovidesaltandwatertoavolumedepletedpatientwithRSWandwaterrestrictionforawaterloaded
patientwithSIADH.WeintendtobrieflydiscussthepathophysiologyofRSWandSIADH,currentmethodsof
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differentiatingSIADHfromRSW,thefailureofthevolumeapproachtoaddresshyponatremiawhichhasresulted
inmisconceptionsandmismanagementofmanyhyponatremicpatients,presentdatatosupportourproposalto
changeCSWtoRSW,andremovingresetosmostat(RO)asasubtypeofSIADH,andpresentanalgorithmwhich
eliminatestheneedtoassessvolume,determineurinesodiumconcentration(UNa),plasmarenin,aldosteroneor
atrial/brainnatriureticpeptide(A/BNP).
2.PathophysiologyofRSWandSIADHandEvolutionofControversyonRarityof
CerebralSaltWasting

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TheinitiationofRSWstartswiththestimulationofanatriureticfactorthatreducessodiumtransporttoinduce
RSWandextracellularvolume(ECV)depletion,whichinturnstimulatessecretionofantidiuretichormone(ADH),
reninandaldosteroneanddecreasesatrial/brainnatriureticpeptide(A/BNP).ThevolumestimulusforADH
secretioniscommontoanystatewherethereisineffectivecirculatoryvolumebeitheartfailureortruevolume
depletion.Thevolumestimulusismorepotentthantheosmolarstimulussoavolumedepletedpatientcontinuesto
secreteADHdespitebecomingprogressivelyhyponatremicaslongasthepatientcontinuestotakeinfreewater
[10].RemovalofthevolumestimulusallowsthecoexistenthypoosmolalitytoinhibitADHsecretion,remove
waterfromthebodybyexcretingdiluteurinesandcorrectingthehyponatremiatoillustrateappropriateADH
secretioninRSW[11,12].Aspreviouslyreviewed,thefirstdescriptionsofCSWfailedtoprovewithcertaintya
saltwastingsyndrome[13,14].RSWwaspossibleinonepatientwhowasdescribedasbeingdehydratedwitha
urinechlorideof61.6mEq/L[13].Previousstudieshavedemonstratedthatasodiumdepletedpatientwillvirtually
eliminatesodiumfromurineuntilthesodiumlosseshavebeenreplaced[15,16,17].Thehighurinechlorideand
presumablysodiumconcentrationinurinewould,thus,havebeenconsistentwithRSWandthetermCSWwas
thusderived.
SIADHevolvedasaclinicalentitybythedemonstrationofaclinicalcorrelatetotheseminalworkbyLeafetal.,
whodefinedtheconsequencesofadministeringvasopressintonormalhumansubjects[18].Theproposalofan
inappropriatesecretionofADHintheabsenceofmethodstodetermineplasmaADHlevelsepitomizedthe
applicationofbasicphysiologicprinciplestothebedside[19].Thishypothesiswaslaterprovenbydemonstrating
inappropriatelyhighADHlevelsthatdidnotrespondtotheusualvolumeandosmolarstimuli[19].Moreover,
ECVmeasuredbythesulfatemethodinthefirstreportedcaseofSIADHprovedthatitwaspossiblefora
euvolemic/hypervolemicpatienttohavehyponatremiawithhighUNawithoutimplicatingarenalsaltwasting
syndrome[19].Anincreaseinintravascularvolumebythegoldstandardradioisotopedilutionmethodhasbeen
demonstratedbyothersinSIADH[12,20,21].ItbecameevidentthattheoriginalcaseofCSWinadehydrated
patientwithhighUNacouldhavehadSIADHbecauseofthegeneralagreementthatonecannotaccuratelyassess
volumestatusbyusualclinicalcriteria.TheexistenceofCSW,therefore,wasseriouslyquestionedtothepointof
beingconsideredeithernonexistentorcertainlyrare.
3.DifferentiatingSIADHfromRSW

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DifferentiatingSIADHfromRSWhasbeenextremelydifficulttoaccomplish,inpartbecauseofsignificant
overlappingclinicalfindingsbetweenbothsyndromes.AsnotedinTable1,bothsyndromesareassociatedwith
intracranialdiseases,havenormalrenal,thyroidandadrenalfunction,arehyponatremicandhypouricemicandhave
concentratedurines,highUNaover40mEq/L,andhighfractionalexcretion(FE)ofurate.Theonlyclinical
differenceisthestateoftheirECV,beingeuvolemicorhypervolemicinSIADHandhypovolemicinRSW.The
overlappingofmajorclinicalcharacteristicsbetweenSIADHandRSWasnotedinTable1andtheperceptionthat
RSWisarareclinicalentityhavevirtuallyeliminatedRSWfromconsiderationatthebedside.Thisdiagnostic
dilemmaneedstobeurgentlyresolvedbecauseoftheevolvingawarenessthatevenmildlyhyponatremicpatients
aresymptomaticandshouldthereforebetreated[5,7].Theseperceptionsandrecommendationsareinlargepart
influencedbyreportsofunsteadygaitandafourfoldincreaseinfallrateswhichappearstobeconsistentfroma
serumsodiumof115132mEq/L.Inaddition,afourfoldincreaseinbonefracturesinelderlyhyponatremic
patientsandincreasedosteoporosiswithchronichyponatremiahasbeenreported[5,7,22].Theurgencyin
resolvingthediagnosticandtherapeuticdilemmabecomesmostevidentbythedivergenceintherapeuticgoalsof
waterrestrictingpatientswithSIADHandadministeringsaltandwaterinRSW.

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Table1
Listoffeaturescommontosyndromeofinappropriateantidiuretichormonesecretion(SIADH)
andrenalsaltwasting(RSW),exceptdivergentvolumestatus.
ThereisuniversalagreementthatwecannotassessECVwithanydegreeofaccuracybyusualclinicalcriteria,yet
theapproachtohyponatremiastartswithanassessmentofvolume.Theineffectivenessofthisvolumeapproachis
becomingevenmoreevidentbyanobjectivereviewoftheliteratureandrecentpublicationsofRSWoccurringin
patientswithoutclinicalcerebraldisease[11,12].Sinceanassessmentofvolumeisessentialindifferentiating
SIADHfromRSW,letusreviewstudiesthathavedeterminedvolumebycrediblemethods.AsnotedinTable2,
83%94%ofhyponatremicpatientswithdifferentformsofneurosurgicaldiseaseswerefoundtohavehypovolemia
withhighUNathatmetthecriteriaforRSWascomparedtohypervolemicpatientswithSIADH.Bloodvolume
wasdeterminedbygoldstandardradioisotopedilutionmethods,including51chromiumlabeledredcellsand/or
radioiodinatedserumalbumin(RISA)[20,21,23].ItisclearfromthesestudiesthatRSWismuchmorecommon
thanSIADH,yetitisstillperceivedasarareclinicalentity,whichhasbeenpropagatedformanyyearswithout
eithernegatingthesecompellingstudiesnorbyprovidingevidencetothecontrarybysuitablemethods.Moreover,
waterrestrictingthesepatientsforanerroneousdiagnosisofSIADHwheninfacttheyhaveRSWhasbeen
reportedtoincreasemorbidityandmortalityratesinpatientswithsubarachnoidhemorrhage[12,24,25].Thesedata
emphasizetheimportanceofdifferentiatingSIADHfromRSWinordertodevelopbettertargetedtherapeutic
strategies.
Table2
Summaryofvolumestudiesbygoldstandardradioisotopedilutionmethods
inhyponatremicneurosurgicalpatients.(Note:RSWismuchmorecommon
thanSIADH).
4.ValueofDeterminingFEurateinDifferentiatingSIADHfromRSWandChangingCSW Goto:
toRSW
Calculationoffractionalexcretion(FE)ofuratedeterminesthepercentexcretionofthefilteredloadofurateatthe
glomerulus.Itdeterminesthenettransportofuratewithoutdistinguishingwhatissecretedorreabsorbedandcanbe
readilydeterminedbycollectingbloodandspoturineatthesametime.FEurateinpercentageexcretionofthe
filteredloadofuratecanbedeterminedbydividingtheratioofurinetoplasmauratebytheratioofurinetoplasma
creatinineandmultiplyingby100.ItcanalsobederivedbydividingtheproductofUNa()serumuratebythe
productofserumsodium()urinecreatinineandmultiplyingby100.FEurate,normal4%11%,hasbeen
consistentlyincreasedto>11%inSIADHandRSWandhasauniquerelationshiptoserumsodiuminSIADHand
RSW.InSIADH,correctionofhyponatremiawillnormalizeFEurateto4%11%ascomparedtobeingpersistently
increasedto>11%inRSW,Figure1[26,27,28,29].TherelationshipbetweenFEurateandserumsodiumcannow
beutilizedtodifferentiateSIADHfromRSWbycorrectingthehyponatremiabyanymeans,beitbywater
restrictionorisotonic/hypertonicsalineandobservingwhetherFEuratenormalizesto4%11%asinSIADHor
remainsincreasedabove11%inRSW,Figure1[11,12,30,31,32,33].FEuratecanexceednormalvaluesinpatients
withreducedGFR,sothealgorithmisvalidinpatientswithserumcreatininelessthan1.5mg/dL.
Figure1
ChangesinFEurateinSIADHandRSWaftercorrectionofhyponatremia.
Shadedareasrepresentnormalranges.(MaesakaJ.K.,modifiedfrom[14]).
TwounequivocalcasesofRSWwithoutclinicalevidenceofcerebraldiseasenotonlyverifiedthepersistent
increaseinFEuratewithcorrectionofhyponatremia,butservedasthebasisforustomakeaclinicallyimportant
proposaltochangeCSWtoRSW[11,12,34].Onewasahyponatremicpatientwithasimplehipfracturewithno
clinicalevidenceofcerebraldiseasewhoexhibitedalloftheessentialfeaturesofRSW.Thehyponatremiawas
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associatedwitha7%reductioninbloodvolumeasdeterminedbythegoldstandardradioisotopedilutionmethod,
using51chromiumlabeledredbloodcellsandRISA,increasedbaselineplasmarenin,aldosterone,andADHand
lownormalatrialnatriureticpeptide.Shedilutedherurineto170mOsm/kg13hafterinitiationofsalinetherapy
whenherplasmaADHlevelwasnotdetectable.Herserumsodiumincreasedto138mEq/Lwithin48h(Figure2),
andtheincreasedFEuratepersistedwithnormalizationofserumsodium(Figure1)[12].AsimilarcaseofRSW
wasahyponatremicpatientwithapneumoniawithoutcerebraldisease,whodilutedhisurine20hafterinitiating
salinetherapy[11].Asinthehipfracturepatient,theincreasedFEuratepersistedaftervolumerepletionand
correctionofhyponatremia.Awaterloadingtestwasnormalaftervolumerepletionandcorrectionofhis
hyponatremia,suggestingthatlikethepatientwithahipfracture,therewasanappropriatehypovolemiainduced
increaseinADH.SalineinfusionseliminatedthevolumestimulusforADHsecretiontoallowthecoexistent
plasmahypoosmolalitytoinhibitADHsecretion,therebyexcretingdiluteurinesandcorrectingthehyponatremia
[11,12].IntwopatientswithSIADHandincreasedbloodvolumes,salineinfusionfailedtodilutetheirurineor
correcttheirhyponatremia[11].
Figure2
Correctionofserumsodiumandachievementofdiluteurineaftersaline
infusion(withpermission,KidneyInternational,MaesakaJ.K.[12]).
TherelationshipbetweenserumsodiumandFEurateasnotedinFigure1maybethebestavailablemethodto
differentiateSIADHfromRSW.Correctionofthehyponatremiacanbeaccomplishedbyanymethod,including
hypertonicsaline,todifferentiateSIADHfromRSW.Manyconsidertheadministrationofsalinetobeadetriment
totheevaluationofthehyponatremicpatientbecauseofitseffectonUNaandplasmarenin,aldosteroneand
A/BNP.Asextensivelyreviewedinourreviewofrenaluratetransport,wecitefourpapersthatdemonstratethe
meagereffectofsalineinfusionsonFEurate,Table3[35,36,37,38].ThemeagereffectofsalineonFEuratecanbe
illustratedinahyponatremicpatientwithhighFEuratewhoposedadiagnosticdilemmaofnotbeingableto
determinewhetherthepatienthadSIADHorRSW.ThediagnosisofSIADHwasmadebyincreasingserum
sodiumto138mEq/Lbyadministeringliberalamountsofisotonicandhypertonicsalineandobservingamarked
decreaseinFEuratefrom26%to8%[32].ThemarkedreductioninFEurateaftertheadministrationofisotonicand
hypertonicsalineiscontradictorytothecommonbeliefthatsalinereducesthenettransportofmanysolutes,
includingurate.ThereductioninFEurateaftercorrectionofhyponatremiabyisotonicandhypertonicsalineraises
anintriguingquestionastowhyFEuratewouldnormalizeinSIADHandremainincreasedinRSW.Aspreviously
reviewed,theincreaseinFEuratecannotbeexplainedbytheV1activityofADHorchronichyponatremiain
SIADHbutitisprobablethatthenatriureticfactordemonstratedinRSWmightreduceuratetransportinthe
proximaltubulewhereurateisexclusivelytransportedandisthemajorsiteofinhibitingsodiumtransportbythe
natriureticfactor[39,40,41].
Table3
Summaryofextracellularvolumeexpansionwithisotonic,hypotonicand
hypertonicsalineonfractionalexcretionofsodium[FEsodium]andurate
[FEurate]atcontrolandexperimental(Exp.)periodsaftersaline
administration.
5.NormalFEurateIdentifiesPatientswithResetOsmostat

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ThevalueofdeterminingFEurateinhyponatremicconditionshasbeenfurtheramplifiedbyanormalFEurate
beingobservedineveryhyponatremicpatientwithRO[42].ThenormalFEurateseeninpsychogenicpolydipsia
andpossiblyinbeerpotomaniacanbereadilyidentifiedbythehistoryofexcessintakeofwaterorbeer,
respectively[42,43].Basedonthesedata,weproposedeliminatingROastypeCSIADHbecauseofthenormal
FEurate,whichispathophysiologicallydifferentfromthehighFEurateseeninSIADH,andapredictableresponse
towaterloading[42].
6.ProposalofNewAlgorithm

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Basedonalargedatabase,wewouldliketointroduceanew,updatedalgorithmwhichcentersonthe
determinationofFEurateoutlinedinFigure3.Eachcitationcanbesupportedbycredibledata.Thisalgorithmhas
beenfoundtobesuperiortothetraditionalvolumeapproach,whichhasbeenusedfordecadesandisclearly
inadequate.Oncethepatienthasbeenidentifiedtohavehyponatremia,definedusuallytobeaserumsodium<135
mEq/L,wesuggestdeterminingFEuratebyobtainingaspotbloodandurinesampleandutilizingtheformula
providedabove.TheadministrationofsalineshouldnotaffecttheFEuratetoanysignificantdegree(Table3),and
drugssuchasatorvastatinandlosartanwhichareknowntoincreaseurateexcretionhavenotbeenshowntohavea
meaningfuleffectontheresults[44,45].IftheFEurateexceeds11%,itisconsistentwitheitherSIADHorRSW
butrepeatingFEurateaftercorrectionofhyponatremiabyanymethod,suchaswaterrestrictionoradministrationof
hypertonicsaline,willdifferentiateSIADHfromRSWitwillnormalizeto4%11%inSIADHandremain>11%
inRSW.IftheFEurateisnormal,between4%and11%,itismostconsistentwithRObutcanbeseenin
psychogenicpolydipsia[43,44,46,47],andpossiblyinbeerpotomania.Psychogenicpolydipsiacanbereadily
diagnosedbythehistoryofingestinglargevolumesofwater,havingpolyuriaandexcretionofdiluteurines,and
beerpotomaniabythehistoryofingestinglargeamountsofbeerwithlowsoluteintake[42,43].IftheFEurateis
<4%,itisconsistentwithprerenalconditionsincludingvolumedepletedstatesorinadequateperfusionwith
normalrenalfunctionasintruevolumedepletion,edematousstatessuchascongestiveheartfailure,cirrhosis,
nephrosisandpreeclampsia[48].ThelowFEurateinAddisonsdiseasecanbeexplainedbysaltwastingduetoa
distaldefectinsodiumtransportwheremineralocorticoidsexerttheireffect.Theintactproximaltubulewouldthus
increasethereabsorptionofurateandothersolutesasistypicalofprerenalazotemia,FEurate<4%[48].The
dottedlinesconnectingahighFEuratewithnormonatremiaandRSWcanbesupportedbyindirectdatabutitisour
beliefthatthiswilleventuallyturnouttobeapredictorofRSWwithoutgoingthroughaphaseofhyponatremia
becausethepatienthadverylittlewaterintake.Thispossibilityisevidentbytheneedtoingestwatertobecome
hyponatremic,sincetheinsensiblewaterlossesarelargelyhypotonictoinducehypernatremiawithoutsufficient
waterintake.Developinghyponatremiawithoutwaterintakeisextremelydifficultifnotimpossibletoachieve
exceptifUNaexceedsserumsodiumconcentrationintheabsenceofwaterintake.
Figure3
Algorithmfordeterminingcauseofhyponatremia,usingFEurate.

Thisalgorithmomitsarelianceonplasmarenin,aldosterone,A/BNP,UNaoreventheBUNtocreatinineratio.
Plasmarenin,aldosteroneandA/BNPhavenotbeenconsistentlyreliableindicesbecauseoftheeffectofsaline
infusionsthatareoftenutilizedinhyponatremicpatients,thepresenceofchronickidneydiseaseandfrequentuseof
ACEinhibitors,angiotensinreceptorblockers,diureticsandbetablockers.ThedeterminationofUNahasbeen
utilizedtoevaluatepatientswithhyponatremia,butUNa<20andeven<40mEq/Larebeingobservedwithgreater
frequencysothisparameterhasnotproventobeeffectiveintheevaluationofhyponatremicconditions.Thelow
UNainourexperiencehasbeenobservedmuchmorecommonlyinpatientswithRSWascomparedtopatients
withSIADHandRO.SinceUNareflectssaltintakeinconditionssuchasSIADH,ROandRSW,thelowUNa
suggeststhatthesesubjectshavereducedintakeofsalt,probablyreflectingtheseverityoftheircomorbid
condition.Insomecases,thereducedsaltintakecouldbeiatrogenic.Thishasbeenreportedwithincreased
morbiditywhenthepatientwithRSWwasfluidrestrictedforanerroneousdiagnosisofSIADH[12,24,25,30].
ThiswasthecaseinourRSWpatientwithahipfracturewhoseUNawas6mEq/Lafterbeingfluidrestrictedfor
10daysforanerroneousdiagnosisofSIADH[12,24,25].ThedeterminationofUNahasnotbeenusefulinthe
evaluationofpatientswithhyponatremia.
Thereismountingevidencetoprovetheineffectivenessofthevolumeapproachtohyponatremia.Surprisingly,
aboutathirdofhyponatremicpatientsoutsideoftheneurosurgicalintensivecareunithadRSWthemajority
demonstratingnoclinicalevidenceofcerebraldiseasethusprovidingadditionalsupportforourproposaltochange
CSWtoRSW[34,49].Asdiscussed,thisisanimportantchange,asRSWwouldotherwisenotbeconsideredin
theabsenceofclinicalcerebraldisease[34].ThehighprevalenceofRSWwasnotedinapopulationwherethe
clinicalvolumeapproachwouldhavebeenattributedtoSIADHbecauseoftheperceptionthatSIADHisthe
mostcommoncauseofhyponatremiainthisandallotherclinicalsettings.Thisraisesthepossibilitythatthehigh
morbidityandmortalityratesassociatedwithhyponatremiamayhaveasignificantiatrogeniccomponentsecondary
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toinappropriatewaterrestrictioninpatientswithRSWwhowerethoughttohaveSIADH.Thesedataprovide
furtherevidencefortheineffectivenessofthevolumeapproachtoevaluatingpatientswithhyponatremiaand
supportthecommonnotionthatwecannotassessthevolumestatusofpatientswithanydegreeofaccuracy.To
persistinthisoutmodedapproachwillleadtomisdiagnosisandmistreatmentofpatientswithhyponatremiathatwill
leadtoincreasedmorbidityandmortalityofagroupofpatientswithwhatappearstobemoreseriouscomorbid
conditions.Theproposedalgorithmhasbeenfoundtobesuperiortotheclinicalvolumeapproachandshouldbe
testedbyothergroupsforitsclinicaleffectivenessuntilneweralgorithmscanbedeveloped.
7.Conclusions

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ItisextremelydifficulttodifferentiateSIADHfromRSWlargelybecauseofsignificantoverlappingofclinicaland
laboratoryfindingsandtheperceptionthatRSWisarareclinicalentity.Thisdifferentiationisextremelyimportant
becauseofdivergenttherapeuticgoalsofappropriatelywaterrestrictingthosewithSIADHandincreasingsaltand
waterwithRSWtoavoidiatrogenicincreasesinmorbidityandmortality.Therecentrecommendationstotreatmost
orallpatientswithhyponatremiaintroduceanurgencytoresolvethisdiagnosticandtherapeuticdilemma.
ChangingCSWtoRSWisanimportantmodificationinnomenclaturethatwillexpandourconsiderationofalarge
numberofRSWpatientswithoutevidenceofclinicalcerebraldiseaseandtoavoidmismanagementandpossibly
reducemorbidityandmortality.ThevolumeapproachtohyponatremiaandperceptionthatRSWisarareclinical
entityshouldbeabandonedinfavorofamoreopenmindedapproachthatwillleadtobetterdiagnosisand
treatmentofhyponatremicconditions.Tothisend,weproposeanewalgorithmthatutilizesFEurateasapivotal
determination,(Figure3).DeterminingFEurateaftercorrectinghyponatremiabyjudicioususeofhypertonicsaline
mightbeaneffectivewayofdifferentiatingSIADHfromRSW(Figure1),beingmindfulofavoidingtoorapid
correctionofhyponatremiatoreducetheriskofdevelopingosmoticdemyelination,monitorthepatientforany
evidenceoffluidoverloadsuchasinductionofheartfailureandthatsalinehasameagereffectonFEurate.The
newalgorithmeliminatesthedeterminationofplasmarenin,aldosteroneandA/BNPandUNa,whichhavebeen
foundtobeineffectiveandoftenmisleading.
Acknowledgments

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PortionsoftheworkdiscussedinthismanuscriptweresupportedbyagrantfromOtsukaAmericaPharmaceutical,
Inc.ID156IST1107.TheauthorswishtothankMariaMarottaKollarus,RN,ClinicalResearchCoordinator,for
participatinginsomeoftheprojects.
AuthorContributions

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JohnK.Maesaka,LouisImbriano,JosephMattana,andDympnaGallagherhavecontributedtothedesign,
analysisandinterpretationoftheresults.NaveenBadeandSairahSharifcontributedtotheanalysisandthe
preparationofthismanuscript.
ConflictsofInterest

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Theauthorsdeclarenoconflictofinterest.
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