ARTICLE IN PRESS

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www.elsevier.pt/ge

ORIGINAL ARTICLE

Comparative study of spot urine Na/K ratio and 24-hour urine sodium in natriuresis evaluation of cirrhotic patients with ascites

Otávio Marcos da Silva, Gabriela Bicca Thiele, Leonardo Fayad, César Lazzarotto, Esther Buzaglo Dantas-Corrêa, Leonardo de Lucca Schiavon,

Janaína Luz Narciso-Schiavon

^∗

NúcleodeEstudosemGastroenterologiaeHepatologia(NEGH),FederalUniversityofSantaCatarina(UFSC), Florianópolis,SC,Brazil

Received7February2013;accepted29April2013

KEYWORDS Livercirrhosis;

Ascites;

Sodium;

Urine;

Endstageliver disease

Abstract

Introduction:The‘‘spot’’urinesodium/potassium(Na/Ku)ratioisaconvenienttooltoidentify sodiumexcretion<78mequiv./d.Ithasbeenestablishedthatthisratioisasusefulandaccurate as24-hurinesodium(Nau24h),butnoLatinAmericanstudyhasevaluatedthisissue.Theaimof thisstudyistoevaluatetheaccuracyoftheNa/KuratioandtocompareittoNau24h.

Materialsandmethods: Thiscross-sectional study included20 patients withdecompensated livercirrhosisandascites.

Results:Mean age was 56.1±11.8 years old, 70% were men and 60% presented Nau24h<78mequiv./d.Poorsodium excretiongrouppresented higherMELDscore(P=0.002), creatinine(P=0.029),AST(P=0.027)andbilirubin(P=0.013) levels,andalso lowermedian spotsodiumurine(P=0.001).TherewasahighpositivecorrelationbetweenNa/Kuratioand Nau24h(r=0.857;P<0.001)andnegativecorrelationwithMELD(r=−0.498;P=0.025)andserum creatinine(r=−0.498;P=0.025).TheAUROCofNa/KuinpredictingNau24h<78mequiv./dwas 0.948±0.046andtheclassicalNa/Kuratiocut-off(≤1.0)showedPPV=70%,NPV=90%,accuracy=80%,sensitivity=88%andspeciﬁcity=75%.

Conclusion: Na/Ku≤1issensitiveandspeciﬁc,andsubstantiallycorrelateswithNau24h,which enablestheuseofthistestintheroutineevaluationofpatientswithlivercirrhosisdecompen- satedinascites.

∗Correspondingauthor.

E-mailaddress:janaina.narciso@uol.com.br(J.LuzNarciso-Schiavon).

http://dx.doi.org/10.1016/j.jpg.2013.04.006

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PALAVRASCHAVE Cirrosehepática;

Ascite;

Sódio;

Urina;

Doenc¸ahepática terminal

AnálisecomparativadarazãoNa/Kemamostraisoladadeurinacomsódionaurinade 24horasnaavaliac¸ãodanatriuresedecirróticoscomascite

Resumo

Introdução:A razão sódio/potássio em amostraisoladade urina (Na/Ku)éuma ferramenta apropriadaparaidentificaraexcreçãourináriadesódio<78mEq/d.Foiestabelecidoqueessa razãoétãoútileacuradaquantoadosagemdesódionaurinade24horas(Nau24h),contudo nenhumestudoLatinoAmericanoavaliouessaquestão.Oobjetivodesseestudofoiavaliara razãoNa/Kuecompará-laadosagemdeNau24h.

Materialemétodos:Estudotransversalqueincluiu20pacientescomcirrosehepáticadescom- pensadaemascite.

Resultados: Aidade médiafoi de56,1±11,8anos, 70%eramhomens e60% apresentaram Nau24h<78mEq/d.OgrupomauexcretordesódioapresentoumaiorescoreMELD(P=0,002), creatinina(P=0,029),AST (P=0,027),bilirrubinas (P=0,013),e tambémmenormediana de sódio em amostraisoladadeurina(P=0.001).Houvecorrelac¸ão positivaentrerazão Na/Ku

e Nau24h (r=0,857;P<0,001) e correlac¸ão negativa com MELD (r=0,498; P=0.025) e crea- tininasérica(r=−0,498;P=0,025).AAUROCdarazãoNa/Kuem predizerNau24h<78mEq/d foide0,948±0,046 eocut-offclássicodarazãoNa/Ku(≤1.0)exibiuVPP=70%,VPN=90%, acurácia=80%,sensibilidade=88%eespeciﬁcidade=75%.

Conclusão:Na/Ku≤1ésensíveleespecíﬁcoesecorrelacionasubstancialmentecomNau24h,o quepermiteousodessetestenaavaliac¸ãorotineiradepacientescomcirrosedescompensada emascite.

Introduction

Ascitesisdefinedasthepathologicalaccumulationoffluid intheperitonealcavity.¹Therearethreetheoriestoexplain thedevelopmentofascitesinindividualswithlivercirrho- sis:underfill,overflowandvasodilatation.Themodernview suggeststhatthethreestatesareingreaterorlesserextent, present in the same patientwith cirrhosis.² The underfill theoryproposesthatthetwomostimportantfactorsinthe developmentofascitesareportalvenoushypertensionand failureofthelivertosynthesizeofalbumin,whichresultsin areductioninplasmaosmoticpressure.Thesefactorslead toreductionineffectivecirculatingvolume,whichactivates the renin---angiotensin---aldosterone system and promotes theabsorptionofsodiumandwater.Ascitesmaybeformed partlyfromthehepaticlymphandthoracicductwouldbe responsibleforremovingit.Bythesevariouscompensatory mechanisms, body fluids are depleted, more ascites is formedandthecyclerestarts.³Theoverflowtheorystates that,initially,therewouldbeincreasedsodiumretentionby thekidneyswhichwouldincreasetheeffectivecirculating volume. Peripheral vascular resistance would decrease to accommodate hypervolemia. The encounter between hypervolemia and increased portal pressure would result inoverflowthatwouldformtheascites.⁴The vasodilation theoryexplainsthattheascitesformationwouldstartwith arterialvasodilationinthesplanchniccirculationsecondary to portal hypertension. Then a hyperdynamic circulation would occur to maintain homeostasis. This compensatory mechanism, with the progress of the disease would be insufficient tosupport homeostasis.Blood pressurewould decrease which would stimulate the baroreceptors and leadtoincreasedhomeostaticactivity ofthe sympathetic

nervoussystem,therenin---angiotensin---aldosteronesystem, circulation levels of antidiuretic hormone, and retention of sodium and water. The activation of these systems associated withdecreased lymphatic returnby splanchnic congestionwouldformtheascites.⁴Thevasodilationtheory wouldbepresentinpre-asciticphaseanditwouldbeimpor- tantinanysubsequentdevelopments.Theoverflowtheory wouldbethemostimportantaetiologyinthefirstmonths ofthedevelopmentofascitesinindividualswithcirrhosis, and the underfill theory explains most of the findings of ascitesinpatientswithchronicdecompensation.²

Ascitesisconsideredthemostcommonofthethreemajor complicationsofcirrhosis.Othercomplicationsarehepatic encephalopathyand oesophagealvariceal bleeding.About 50%ofpatientswithcompensatedcirrhosisdevelopascites over10yearsoffollow-up.⁵In1yearwithascites,approxi- mately15%ofpatientswilldie,and44%willdiein5years.⁶ The mainstay treatments of patients with cirrhosis and ascites are: a low sodium diet (2000mg/day=88mequiv./day) and diuretics.⁷ The mea- surement of urinary sodium excretion has been used for manyyearstoidentifythepatientundersodiumrestrictive dietanddistinguishhimfromthosewhorequirediuretics.

AlthoughspoturineNameasurementcouldbeusefulinthis setting,thesodiumexcretionisnotuniformduringtheday, which complicates the interpretation of results. For that reason, the most used method to estimate natriuresis is themeasurement of24-h urinesodiumexcretion(Nau24h).

Patientswitharestricteddietof2000mgofsaltthatdoes notloseweightandhave Nau24h excretion≥78mequiv.per day are usually labelled as noncompliant diet.⁸ Although widely requestedin evaluatingthisgroup ofpatients, the collection of Nau24h can be cumbersome to the patient,

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nursing and physician. The patient may have difﬁculty storing urinary content (e.g., hepatic encephalopathy, management of the collector, embarrassment in front of otherpatientsandvisitors).Nursingmaypresent difﬁculty in monitoring the urine collection and checking whether the collected volume actually corresponds to 24-h urine.

The physician,when requesting the test makes urges for theresult,whichusuallyexceedsthe24hofcollection.

TheNa/Kratioin‘‘spot’’urinesample(Na/Ku)isaprac- ticalwaytoidentifyNau24h dosage lowerthan78mequiv..

Someevidenceshowsthatthisratiois asusefulandaccu- rateasthecollectionNau24h,butnoLatin Americanstudy hasevaluatedthisissue.^9---15Thisstudyaimstoevaluatethe accuracyoftheNa/KuratioandcompareittoNau24hinthe evaluation of natriuresis in patients with decompensated livercirrhosisascites.

Methods

Thiscross-sectionalstudyassessedindividualswithdecom- pensatedlivercirrhosisandascitesadmittedtothehospital ortreated intheoutpatientclinicsofGastroenterologyat University Hospital PolydoroErnani deSãoThiago of Fed- eralUniversityofSantaCatarina.BetweenAugust2010and January2012,42patientsadmittedinthegastroenterology wardorintheoutpatientgastroenterologyclinic.Thestudy protocolcomplieswiththeethicalprinciplesoftheDecla- rationof Helsinki andwasapprovedbythe localresearch ethicscommitteeundernumber322597.

Clinical variables of all individuals included in the study were collected in interview and conﬁrmed in medical records. Laboratory parameters were extracted frommedical records.The following variableswere stud- ied: age, gender, race, being a carrier of hepatitis B or C, alcohol consumption >40g/day, diabetes mellitus, hypertension, liver cancer, history of upper gastrointestinal bleeding, spontaneous bacterial peritonitis, use of diuretics;serumcreatinine,haemoglobin,platelets,serum sodium, serum potassium, aspartate aminotransferase (AST),alanineaminotransferase(ALT),alkalinephosphatase (ALP),gamma-glutamyltransferase (GGT),bilirubin,serum albumin, international normalized ratio (INR), activated prothrombintime(APT);Nau24h dosage,sodiumandpotas- siuminurinesample.BiochemicallivertestsAST,ALT,ALP andGGT wereexpressed astimesthe upperlimit of nor- mal(xULN).Theotherlaboratoryvariableswereexpressed asabsolutevalues.Examinationofbilirubin,INRandcreat- ininevalueswereusedintheMELDcalculation (Modelfor End-stageLiverDisease).¹⁶TheNa/Kuratioiscalculatedon thevaluesof sodiumandpotassium in‘‘spot’’ urinesample.Urine wascollected withinless thanor equal to48h fromadmission.Collectionof24-hurinesample forcalcu- lationof sodiumwas done insterile plasticcontainersby recordingthevolumein24h;startingat8:00a.m.Instruc- tionswere giventoassurecompletenessof collection. All sampleswereprocessedonthedayof collection.Inorder toobtainthewhole24-hurinarysodium,sodiumconcentra- tionwasmultipliedbythevolumeinlitters.Randomurine sampleswereobtainedbeforeor aftercompletionof24-h collectionformeasurementof‘spot’Na/Kratio.Anykidney

diseasewasexcludedbymedicalhistory, urinalysis,serum creatinineandultrasoundexaminationofthekidneys.

Numerical variables were expressed as mean and standard deviation, whereas categorical variables were described in absolute numbers and proportions. Continu- ousvariableswerecomparedusing eitherStudent’s ttest or Mann---Whitneywhen appropriate,categorical variables wereanalysedusingeitherChi-squaredtestorFisher’sexact test. A P-value<0.050 wasconsidered statistically signiﬁ- cant.The correlation between theNau24h andNa/Ku ratio wasevaluated by the Spearman’s correlation coefﬁcient.

DiagnosticaccuracyoftheNa/Kuratiowasanalysedbyesti- matingtheareaunderthereceiveroperatingcharacteristics curve(AUROC)andbycalculatingsensitivity,speciﬁcity,pos- itiveandnegativepredictivevalue.Alltestswereperformed bythestatisticssoftwareSPSS,version17.0(SPSS,Chicago, IL,USA).

Results

Sampleanalysis

BetweenAugust2010andJanuary2012,42patientsadmit- ted in the gastroenterology ward were evaluated for inclusionastheypresent livercirrhosis decompensatedin ascites.Twenty-twopatientswithouturinarysodiumdosage wereexcluded. Twentypatientswithdecompensatedliver cirrhosisandasciteswereincluded.Amongthem,60%pre- sentedpoorurinarysodiumexcretion(Nau24hdosagelower than78mequiv.).

Among the 20 included individuals, the mean age, standard deviation and median were 56.1±11.8 (54.5) years,70.0%weremen,66.7%wereCaucasian.Regardtothe aetiologyofcirrhosis:33.3%hadalcoholabuseandhepatitis Cvirus,27.8%hadalcoholonly(Table1).Threepatientshad hepatocellularcarcinoma.

Evaluationofincludedpatientsaccordingtothe abilitytoexcretesodium(Na_u24h)

When individuals with poor urinary sodium excretion were compared to those with Nau24h ≥ 78mequiv.

(Tables 1 and 2), they exhibited a higher proportion of malesex (91.7% vs. 37.5%; P=0.018); higher mean MELD scores (16.3±9.3 vs. 5.0±3.5; P=0.002), higher mean creatinine(1.1±0.4mg/dLvs.0.8±0.2mg/dL;P=0.029), higherASTmeans (3.1±1.7vs.xULN1.6±0.7;P=0.027), higher median bilirubin (1.1g/dL vs. 0.3g/dL; P=0.013) andlower median spot urine sodium (21.5mequiv./L 222 vs. 137.0 mequiv./L; P = 0.001); P = no. No differences wereobserved withrespecttoage,race,aetiologyof cirrhosis, diabetes, hypertension, hepatocellular carcinoma, prior upper gastrointestinal bleeding, spontaneousbacte- rialperitonitis,currentuseofdiuretics,urea,haemoglobin, platelets,serumsodium,serumpotassium,spoturinepotas- sium,ALT,ALP,GGT,albumin,andINRwhenindividualwith poorurinarysodiumexcretionwerecomparedtothosewith Nau24h≥78mequiv.

There was a strong positive correlation between the Na/Ku and Nau24h (r=0. 857, P<0.001) (Fig. 1). A nega- tivecorrelationbetweenMELDscore(r=−0.498;P=0.025)

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Table1 Distributionofclinicalvariablesfrom20individ- ualswithlivercirrhosisdecompensatedinascites.

Characteristics Allindividuals

n=20

Age(years)^a 56.1±6.8

Male(%) 70.0

Caucasian(%) 66.7

HepatitisB(%)^b 22.2

HepatitisC(%)^b 44.4

Alcoholism(%)^b 61.1

Diabetesmellitus(%)^c 37.5

Hypertension(%)^c 56.3

HCC(%) 15.0

HistoryofupperGIbleeding(%)^c 60.0

SBPpresent(%)^c 13.3

Useofdiuretics(%)^c 28.6

HCC,hepatocellularcarcinoma;GI,gastrointestinal;SBP,spon- taneousbacterialperitonitis.

aMean±standarddeviation.

b Availablefor18patients.

c Availablefor16patients.

andserumcreatinine(r=−0.498;P=0.025)wasevidenced.

Therewerenosigniﬁcant correlationsbetween theNa/Ku

ratioandage,plateletcount,serumsodium,AST,ALT,direct bilirubin,albuminandINR.

PerformanceoftheNa/K_uratioinpredicting24h urinarysodiumexcretion

TheAUROCforNa/KuinthepredictionofNau24h<78mequiv.

was0.948±0.046,P=0.001(Fig.2).Table3showsindetails

8,00

6,00

4,00

2,00

,00

0 50 100 150 200 250 300

Cretion

Figure1 ScatterplotofNa/Kurinesampleratioagainst24h urinesodiumexcretion(r=0.857;P<0.001).

thediagnosticperformanceoftheNa/Kuratioinpredicting Nau24h<78mequiv. For the Na/Ku ratio, the classical cut- off (≤1.0) showed 70% positive predictive value (PPV) to diagnoseNau24hdosage<78mequiv.withnegativepredictive value (NPV) of 90%, accuracy of 80%, 88% sensitivity and speciﬁcityof75%.

Discussion

CirrhosisisthetwelfthleadingcauseofdeathintheUnited StatesofAmerica.¹⁷Severalauthorsevaluatedpatientswith decompensatedlivercirrhosisascites.Usually, thestudied

Table2 Distributionoflaboratoryvariablesfrom20individualswithlivercirrhosisdecompensatedinascitesaccordingtothe 24-hurinesodiumexcretion(Nau24h).

Characteristics Allindividuals

n=20

Nau24h<78mequiv.

n=12

Nau24h≥78mequiv.

n=8

P^c

Creatinine(mg/dL)^a 1.0±0.4 1.1±0.4 0.8±0.2 0.029

Urea(mg/dL)^b 36.0 44.0 21.5 0.069

Haemoglobin(g/dL)^a 10.7±2.9 9.9±2.7 12.0±2.8 0.116

Platelets(/mm³)^b 83,500 83,500 82,000 0.787

Serumsodium(mequiv./L)^b 137.5 137.0 138.0 0.811

Spoturinesodium(mequiv./L)^b 37.5 21.5 137.0 0.001

SerumK(mequiv./L)^a 4.2±0.7 4.3±0.9 4.1±0.4 0.605

SpoturineK(mequiv./L) 34.6±11.7 31.1±10.7 39.8±11.7 0.104

AST(xULN)^a 2.5±1.6 3.1±1.7 1.6±0.7 0.027

ALT(xULN)^a 1.1±0.4 1.1±0.4 1.1±0.5 0.975

ALP(xULN)^b 0.7 0.8 0.7 0.589

GGT(xULN)^b 1.7 1.5 2.0 0.939

Directbilirubin(mg/dL)^b 0.8 1.1 0.3 0.013

Albumin(g/dL)^a 2.6±1.0 2.4±1.0 3.0±1.0 0.201

Prothrombinactivity(%)^a 55.3±24.0 48.0±25.0 66.3±18.8 0.096

MELD^a 11.8±9.3 16.3±9.3 5.0±3.5 0.002

K, potassium; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; GGT, gamma- glutamyltransferase;xULN,timestheupperlimitofnormal;MELD,modelforendstageliverdisease.

aMean±standarddeviation.

b Median.

c Student’sttest,Mann---WhitneyorFisher’sexacttestwhenappropriated.

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Table3 Diagnosticperformanceofspoturinesodium-to-potassiumratio(Na/Ku)ratioinpredicting24-hurinesodiumexcretion (Nau24h)<78mequiv.

Cut-off Accuracy(%) Sensibility(%) Speciﬁcity(%) PPV(%) NPV(%)

Na/Ku <1.0 80 88 75 70 90

PPV,positivepredictivevalue;NPV,negativepredictivevalue.

populationispredominantlycomposedbymen,59---74%,age rangingfrom53.6to60years.^18---20Inthisstudyithasbeen observed that 70% of subjects were male; mean age was 56.1years,whichcoincideswiththatdescribedinliterature.

Withregardtotheaetiologyofcirrhosis,itvariesaccording totheprevalenceofthediseasesonthestudiedarea,witha higherprevalenceofHBV(64.8%)inChina,higherincidence ofalcoholiccirrhosis(76.4%)inGermany(19)andBarcelona (44.7%).¹⁸ Thepresentstudydemonstratedahigherpreva- lenceof HCV ascomparedto Europeand Asia, thelatter beinganareaofhighprevalenceofHBV²¹andexhibitshigh prevalenceofalcoholismasacauseofchronicliverdisease.

In cirrhosis, the development of ascites and diuretic response are determined by the renin---angiotensin--- aldosterone and renal sodium handling.²² This study observed that patients presenting with more severe liver disease (MELD, creatinine, bilirubin, AST) are those who havelowesturinarysodiumexcretion.Likewise,Cholongitas etal.recentlydemonstratedthatthefactorsindependently associatedwithpoor urinarysodiumexcretion incirrhosis arealbumin,creatinineandNa/Ku.¹¹

The Na/Ku ratio emerged as an option to Nau24h in evaluatingthe ability ofcirrhotic patients withascites to excretesalt. Duringascitestreatment, absenceof weight loss may be secondary topoor response to diuretics or a consequence of non-adherence to low sodium diet. It is importanttorecognizethesedifferencestoavoidpossible

1,0

0,8

0,6

0,4

0,2

0,0

0,0 0,2 0,4 0,6 0,8 1,0

1 - Specificity

Sensitivity

ROC Curve

Figure2 ROCcurveofNa/Kratioin‘‘spot’’urinesamplein predicting24hurinesodiumexcretionlowerthan78mequiv.

complicationscausedbyunnecessaryincreaseindosageof adiuretic,suchashepaticencephalopathy,renaldysfunc- tionandelectrolytedisturbance,andcomplicationscaused bythedrainageoflargevolumesofasciticfluidbyparacen- tesis asmechanical trauma andcirculatory dysfunction.²³ Despitethegood performanceof theAUROCfor Na/Ku in thepredictionofNau24h<78mequiv.,thesedatashouldbe cautiouslyinterpreted,asNa/Ku rationis non-linear.Nev- ertheless,respectablenegativepredictivevalue,accuracy, sensitivityandspecificityweregoodenoughtosupportits routineuse. Furthermore,thesefindings aresupported by previous studies. After extensive literature review it has beenverifiedthatonlyeightstudies^9---15,24 comparedNa/Ku

ratiowith Nau24h dosage in orderto identifypoor urinary sodium excretion (Nau24h<78mequiv.), and only three of themarecompletearticles.^13,14,24Twostudiesarelettersto theeditor^11,15andthreeareabstractspublishedincongress annals^9,10,12,oneof whichisunavailablefor consultation.⁹ Thesestudieshaveidentiﬁeddifferentcut-offsfortheNa/Ku

ratio. The cut-off point of 1 currently recommended by American Association for the Study of Liver Diseases,¹ is themostsensitive andspecific 64---95%and75---92%.^10---12,15 However,Rojpalakornetal.haveidentifiedlowspecificity (6%)fortheclassiccut-off,thushasquestionedtheirprac- ticalapplication.²⁴ In the present study, besides the high sensitivityandspecificitydemonstratedfor1cutoffNa/Ku

ratio,ithasbeenfoundstrongpositivecorrelationbetween Na/Ku ratioandNau24h,previouslydemonstratedby Pinto- Marquesetal.¹⁵Othercut-offpointsfortheNa/Kuratiohave beenstudied.Thecut-offs1.25and2.5havedemonstrated aspeciﬁcityandasensitivityrangingfrom72%to88%and 85%to96%,respectively.^13,14

Stiehm et al. analysed 729 specimens of urine in 21 patients, a similar number of individuals included in this study.¹⁰ The circadian variability was assessed analysing theNa/Ku ratioaccordingtodiureticadministrationindif- ferentday periodsand nodifferencesweredemonstrated betweengroups.Likewise,Parketal.analysedtwodosages Na/Kuratio,inthemorningandafternoontocheckwhether thenotuniformsodiumexcretionduringthedayinterfere inthe ratios inferred.¹⁴ Apparently theurinary potassium excretion varies in accordance with sodium, maintaining theproportionatdifferenttimesofday.Thepresentstudy evaluated only a single urine sample from each patient, aspreviously published by El-Bokl etal. and Rojpalakorn etal.^13,24

Basedonthesedata,weconcludethattheNa/Kuratio cutoffpointof1.0maybesensitiveandspeciﬁctoassess theabilityofsodiumexcretioninpatientswithlivercirrhosis andascites and it correlates strongly withNau24h dosage, whichenablestheutilizationofthissimpleandusefultest intheroutineevaluationofthesepatients.

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Ethical disclosures

Protection of human and animal subjects.The authors declarethatnoexperimentswereperformedonhumansor animalsforthisstudy.

Conﬁdentialityofdata.Theauthorsdeclarethattheyhave followedtheprotocolsoftheirworkcentreonthepublica- tionofpatientdataandthatallthepatientsincludedinthe studyreceivedsufﬁcientinformationandgavetheirwritten informedconsenttoparticipateinthestudy.

Righttoprivacyandinformedconsent.Theauthorshave obtainedthe written informed consentof the patients or subjectsmentionedinthearticle.Thecorrespondingauthor isinpossessionofthisdocument.

Conﬂicts of interest

Theauthorshavenoconﬂictsofinteresttodeclare.

Acknowledgments

Thispaperispresentedaspartialfulﬁlmentoftherequire- mentsfortheMedicalDoctor(MD)degreefromtheFederal UniversityofSantaCatarina.

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