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ProteinuriainAdults:ADiagnosticApproach
MICHAELF.CARROLL,M.D.,andJONATHANL.TEMTE,M.D.,PH.D.,UniversityofWisconsinMadisonMedicalSchool,Madison,Wisconsin
AmFamPhysician.2000Sep1562(6):13331340.
Proteinuriaisacommonfindinginadultsinprimarycarepractice.Analgorithmicapproachcanbeusedtodifferentiatebenigncausesofproteinuria
fromrarer,moreseriousdisorders.Benigncausesincludefever,intenseactivityorexercise,dehydration,emotionalstressandacuteillness.More
seriouscausesincludeglomerulonephritisandmultiplemyeloma.Alkaline,diluteorconcentratedurinegrosshematuriaandthepresenceofmucus,
semenorwhitebloodcellscancauseadipstickurinalysistobefalselypositiveforprotein.Ofthethreepathophysiologicmechanisms(glomerular,
tubularandoverflow)thatproduceproteinuria,glomerularmalfunctionisthemostcommonandusuallycorrespondstoaurinaryproteinexcretionof
morethan2gper24hours.Whenaquantitativemeasurementofurinaryproteinisneeded,mostphysiciansprefera24hoururinespecimen.However,
theurineproteintocreatinineratioperformedonarandomspecimenhasmanyadvantagesoverthe24hourcollection,primarilyconvenienceand
possiblyaccuracy.Mostpatientsevaluatedforproteinuriahaveabenigncause.Patientswithproteinuriagreaterthan2gperdayorinwhomthe
underlyingetiologyremainsunclearafterathoroughmedicalevaluationshouldbereferredtoanephrologist.
Proteinuriaoninitialdipstickurinalysistestingisfoundinasmuchas17percentofselectedpopulations.1Althoughawidevarietyofconditions,rangingfrombenign
tolethal,cancauseproteinuria,fewerthan2percentofpatientswhoseurinedipsticktestispositiveforproteinhaveseriousandtreatableurinarytractdisorders.2
Aknowledgeableapproachtothiscommonconditionisrequiredbecausethediagnosishasimportantramificationsforhealth,insuranceeligibilityandjob
qualifications.

DefinitionofProteinuria
Twentyfourhundredyearsago,Hippocratesnotedtheassociationbetweenbubblesonthesurfaceoftheurineandkidneydisease.3,4Today,proteinuriais
definedasurinaryproteinexcretionofgreaterthan150mgperday.Urinaryproteinexcretioninhealthypersonsvariesconsiderablyandmayreachproteinuric
levelsunderseveralcircumstances.Mostdipsticktests(e.g.,Albustin,Multistix)thatarepositiveforproteinarearesultofbenignproteinuria,whichhasno
associatedmorbidityormortality(Table1).
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TABLE1
CommonCausesofBenignProteinuria
Dehydration
Emotionalstress
Fever
Heatinjury
Inflammatoryprocess
Intenseactivity
Mostacuteillnesses
Orthostatic(postural)disorder

About20percentofnormallyexcretedproteinisalowmolecularweighttypesuchasimmunoglobulins(molecularweightabout20,000Daltons),40percentis
highmolecularweightalbumin(about65,000Daltons)and40percentismadeupofTammHorsfallmucoproteinssecretedbythedistaltubule.

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MechanismsofProteinuria
Normalbarrierstoproteinfiltrationbeginintheglomerulus,whichconsistsofuniquecapillariesthatarepermeabletofluidandsmallsolutesbuteffectivebarriersto
plasmaproteins.Theadjacentbasementmembraneandvisceralepithelialcellsarecoveredwithnegativelychargedheparansulfateproteoglycans.5
Proteinscrosstothetubularfluidininverseproportiontotheirsizeandnegativecharge.Proteinswithamolecularweightoflessthan20,000passeasilyacrossthe
glomerularcapillarywall.6Conversely,albumin,withamolecularweightof65,000Daltonsandanegativecharge,isrestrictedundernormalconditions.Thesmaller
proteinsarelargelyreabsorbedattheproximaltubule,andonlysmallamountsareexcreted.
Thepathophysiologicmechanismsofproteinuriacanbeclassifiedasglomerular,tubularoroverflow(Table27).Glomerulardiseaseisthemostcommoncauseof
pathologicproteinuria.8Severalglomerularabnormalitiesalterthepermeabilityoftheglomerularbasementmembrane,resultinginurinarylossofalbuminand
immunoglobulins.7Glomerularmalfunctioncancauselargeproteinlossesurinaryexcretionofmorethan2gper24hoursisusuallyaresultofglomerulardisease
(Table3).9
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TABLE2
ClassificationofProteinuria
TYPE

PATHOPHYSIOLOGICFEATURES

CAUSE

Glomerular

Increasedglomerularcapillarypermeabilitytoprotein

Primaryorsecondaryglomerulopathy

Tubular

Decreasedtubularreabsorptionofproteinsinglomerularfiltrate

Tubularorinterstitialdisease

Overflow

Increasedproductionoflowmolecularweightproteins

Monoclonalgammopathy,leukemia

AdaptedwithpermissionfromAbueloJG.Proteinuria:diagnosticprinciplesandprocedures.AnnInternMed198398:18691.

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TABLE3
CauseofProteinuriaasRelatedtoQuantity
DAILYPROTEINEXCRETION
0.15to2.0g

CAUSE
Mildglomerulopathies
Tubularproteinuria
Overflowproteinuria

2.0to4.0g

Usuallyglomerular

>4.0g

Alwaysglomerular

AdaptedwithpermissionfromMcConnellKR,BiaMJ.Evaluationofproteinuria:anapproachfortheinternist.ResidentStaffPhys199440:418.

Tubularproteinuriaoccurswhentubulointerstitialdiseasepreventstheproximaltubulefromreabsorbinglowmolecularweightproteins(partofthenormal
glomerularultrafiltrate).Whenapatienthastubulardisease,usuallylessthan2gofproteinisexcretedin24hours.Tubulardiseasesincludehypertensive
nephrosclerosisandtubulointerstitialnephropathycausedbynonsteroidalantiinflammatorydrugs.
Inoverflowproteinuria,lowmolecularweightproteinsoverwhelmtheabilityoftheproximaltubulestoreabsorbfilteredproteins.Mostoften,thisisaresultofthe
immunoglobulinoverproductionthatoccursinmultiplemyeloma.Theresultantlightchainimmunoglobulinfragments(BenceJonesproteins)produceamonoclonal
spikeintheurineelectrophoreticpattern.10Table411listssomecommondisordersofthethreemechanismsofproteinuria.
View/PrintTable

TABLE4
SelectedCausesofProteinuriabyType*
Glomerular

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Primaryglomerulonephropathy
Minimalchangedisease
Idiopathicmembranousglomerulonephritis
Focalsegmentalglomerulonephritis
Membranoproliferativeglomerulonephritis
IgAnephropathy
Secondaryglomerulonephropathy
Diabetesmellitus
Collagenvasculardisorders(e.g.,lupusnephritis)
Amyloidosis
Preeclampsia
Infection(e.g.,HIV,hepatitisBandC,poststreptococcalillness,syphilis,malariaandendocarditis)
Gastrointestinalandlungcancers

DetectingandQuantifyingProteinuria
Dipstickanalysisisusedinmostoutpatientsettingstosemiquantitativelymeasuretheurineproteinconcentration.Intheabsenceofprotein,thedipstickpanelis
yellow.Proteinsinsolutioninterferewiththedyebuffercombination,causingthepaneltoturngreen.Falsepositiveresultsoccurwithalkalineurine(pHmorethan
7.5)whenthedipstickisimmersedtoolongwithhighlyconcentratedurinewithgrosshematuriainthepresenceofpenicillin,sulfonamidesortolbutamideand
withpus,semenorvaginalsecretions.Falsenegativeresultsoccurwithdiluteurine(specificgravitymorethan1.015)andwhentheurinaryproteinsare
nonalbuminorlowmolecularweight.
Theresultsaregradedasnegative(lessthan10mgperdL),trace(10to20mgperdL),1+(30mgperdL),2+(100mgperdL),3+(300mgperdL)or4+(1,000
mgperdL).Thismethodpreferentiallydetectsalbuminandislesssensitivetoglobulinsorpartsofglobulins(heavyorlightchainsorBenceJonesproteins).12
Thesulfosalicylicacid(SSA)turbiditytestqualitativelyscreensforproteinuria.Theadvantageofthiseasilyperformedtestisitsgreatersensitivityforproteinssuch
asBenceJones.TheSSAmethodrequiresafewmillilitersoffreshlyvoided,centrifugedurine.Anequalamountof3percentSSAisaddedtothatspecimen.
Turbiditywillresultfromproteinconcentrationsaslowas4mgperdL(0.04gperL).Falsepositiveresultscanoccurwhenapatientistakingpenicillinor
sulfonamidesandwithinthreedaysaftertheadministrationofradiographicdyes.Afalsenegativeresultoccurswithhighlybufferedalkalineurineoradilute
specimen.
BecausetheresultsofurinedipstickandSSAtestsarecrudeestimatesofurineproteinconcentrationanddependontheamountofurineproduced,theycorrelate
poorlywithquantitativeurineproteindeterminations.6Mostpatientswithpersistentproteinuriashouldundergoaquantitativemeasurementofproteinexcretion,
whichcanbedonewitha24hoururinespecimen.Thepatientshouldbeinstructedtodiscardthefirstmorningvoidaspecimenofallsubsequentvoidingsshould
becollected,includingthefirstmorningvoidonthesecondday.Theurinarycreatinineconcentrationshouldbeincludedinthe24hourmeasurementtodetermine
theadequacyofthespecimen.Creatinineisexcretedinproportiontomusclemass,anditsconcentrationremainsrelativelyconstantonadailybasis.Youngand
middleagedmenexcrete16to26mgperkgperdayandwomenexcrete12to24mgperkgperday.Inmalnourishedandelderlypersons,creatinineexcretion
maybeless.
Analternativetothe24hoururinespecimenistheurineproteintocreatinineratio(UPr/Cr),determinedinarandomurinespecimenwhilethepersoncarrieson
normalactivity.13,14CorrelationbetweentheUPr/Crratioand24hourproteinexcretionhasbeendemonstratedinseveraldiseases,includingdiabetesmellitus,
preeclampsiaandrheumaticdisease.1517RecentevidenceindicatesthattheUPr/Crratioismoreaccuratethanthe24hoururineproteinmeasurement.18
Fortunately,theratioisaboutthesamenumericallyasthenumberofgramsofproteinexcretedinurineperday.Thus,aratiooflessthan0.2isequivalentto0.2g
ofproteinperdayandisconsiderednormal,aratioof3.5isequivalentto3.5gofproteinperdayandisconsiderednephroticrange(orheavy)proteinuria.

DiagnosticEvaluationofProteinuria
MICROSCOPICURINALYSIS
Whenproteinuriaisfoundonadipstickurinalysis,theurinarysedimentshouldbeexaminedmicroscopically(Figure1).Thefindingsofthemicroscopicexamination
andassociateddisordersaresummarizedinTable5.6Dysmorphicerythrocytesarearesultofcellinsultsecondarytoosmoticshiftinthenephron,indicating
glomerulardisease.Grosshematuriawillcauseproteinuriaondipstickurinalysis,butmicroscopichematuriawillnot.
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Proteinuria

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FIGURE1.
Algorithmforevaluatingthepatientwithproteinuria.

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TABLE5
InterpretationofFindingsonMicroscopicExaminationofUrine
MICROSCOPICFINDING

PATHOLOGICPROCESS

Fattycasts,freefatorovalfatbodies

Nephroticrangeproteinuria(>3.5gper24hours)

Leukocytes,leukocytecastswithbacteria

Urinarytractinfection

Leukocytes,leukocytecastswithoutbacteria

Renalinterstitialdisease

Normalshapederythrocytes

Suggestiveoflowerurinarytractlesion

Dysmorphicerythrocytes

Suggestiveofupperurinarytractlesion

Erythrocytecasts

Glomerulardisease

Waxy,granularorcellularcasts

Advancedchronicrenaldisease

Eosinophiluria*

Suggestiveofdruginducedacuteinterstitialnephritis

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Hyalinecasts

Norenaldiseasepresentwithdehydrationandwithdiuretictherapy

*AWrightstainoftheurinespecimenisnecessarytodetecteosinophiluria.
AdaptedfromLarsonTS.Evaluationofproteinuria.MayoClinProc199469:11548.

Findingssuggestiveofinfectiononmicroscopicurinalysismandateantibiotictreatmentandthenrepeateddipsticktesting.Nephrologyconsultationmaybe
warrantedifsedimentfindingsindicateunderlyingrenaldisease.

TRANSIENTPROTEINURIA
Iftheresultsofmicroscopicurinalysisareinconclusiveandthedipstickurinalysisshowstraceto2+protein,thedipsticktestshouldberepeatedonamorning
specimenatleasttwiceduringthenextmonth(whenproteinuria[3+or4+]isfoundonadipstickurinalysis,workupshouldproceedtoaquantitativeevaluationofa
specimen).Ifasubsequentdipsticktestresultisnegative,thepatienthastransientproteinuria.Thisconditionisnotassociatedwithincreasedmorbidityand
mortality,andspecificfollowupisnotindicated.

PERSISTENTPROTEINURIA
Whenadiagnosisofpersistentproteinuriaisestablished,adetailedhistoryandphysicalexaminationshouldbeperformed,specificallylookingforsystemic
diseaseswithrenalinvolvement(Table411).Amedicationhistoryisparticularlyimportant.A24hoururineproteinmeasurementoraUPr/Crratioonarandom
urinespecimenshouldbeobtained.Anadultwithproteinuriaofmorethan2gper24hours(moderatetoheavy)requiresaggressiveworkup.Ifthecreatinine
clearanceisnormalandifthepatienthasacleardiagnosissuchasdiabetesoruncompensatedcongestiveheartfailure,theunderlyingmedicalconditioncanbe
treatedwithclosefollowupofproteinuriaandrenalfunction(creatinineclearance).Apatientwithmoderatetoheavyproteinuriaandadecreasedcreatinine
clearanceoranunclearcauseshouldhavefurthertestingperformedinconsultationwithanephrologist.Table619listsspecifictestingthatshouldbeconsideredin
patientswithsubstantialproteinuria.
NOTE :TheCockcroftGaultformulaforestimatingcreatinineclearanceisshownbelow.

Forwomen,theresultingvalueismultipliedby0.85,idealbodyweighttobeusedinpresenceofmarkedascitesorobesity.6
View/PrintTable

TABLE6
SelectedInvestigationstoBeConsideredinProteinuria
TEST

INTERPRETATIONOFFINDING

Antinuclearantibody

Elevatedinsystemiclupuserythematosus

AntistreptolysinOtiter

Elevatedafterstreptococcalglomerulonephritis

ComplementC3andC4

Levelsarelowinglomerulonephritides

Erythrocytesedimentationrate

Ifnormal,helpstoruleoutinflammatoryandinfectiouscauses

Fastingbloodglucose

Elevatedindiabetesmellitus

Hemoglobin,hematocrit,orboth

Lowinchronicrenalfailurethatimpairshematopoiesis

HIV,VDRL,andhepatitisserologictests

HIV,hepatitisBandC,andsyphilishavebeenassociatedwithglomerularproteinuria

Serumalbuminandlipidlevels

Albuminleveldecreasedandcholesterollevelincreasedinnephroticsyndrome

Serumelectrolytes(Na+,K+,Cl, HCO3, Ca2+andPO42)

Provideascreeningexaminationforanyabnormalitiesfollowingrenaldisease

Serumandurineproteinelectrophoresis

Resultsareabnormalinmultiplemyeloma

Serumurate

Inadditiontostones,elevateduratecancausetubulointerstitialdisease

Renalultrasonography

Providesevidenceofstructuralrenaldisease

Chestradiograph

Canprovideevidenceofsystemicdisease(e.g.,sarcoidosis)

NEPHROTICSYNDROME

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Thenephroticsyndromeandproteinuriainthenephroticrangelocalizethepathologicprocesstotheglomerulus.Thediagnosticcriteriaofnephroticsyndrome
includeheavyornephroticrangeproteinuria,hypoalbuminemia,edema,hyperlipidemiaandlipiduria.Thediseaseprocesscanbeaprimaryorsecondary
glomerulonephropathy,aslistedinTable4.11Commonsecondarycausesarediabeticnephropathy,amyloidosisandsystemiclupuserythematosus.

ORTHOSTATICPROTEINURIA
Personsyoungerthan30yearswhoexcretelessthan2gofproteinperdayandwhohaveanormalcreatinineclearanceshouldbetestedfororthostaticor
posturalproteinuria.Thisbenignconditionoccursinabout3to5percentofadolescentsandyoungadults.Itischaracterizedbyincreasedproteinexcretioninthe
uprightpositionbutnormalproteinexcretionwhenthepatientissupine.Todiagnoseorthostaticproteinuria,spliturinespecimensareobtainedforcomparison.The
firstmorningvoidisdiscarded.A16hourdaytimespecimenisobtainedwiththepatientperformingnormalactivitiesandfinishingthecollectionbyvoidingjust
beforebedtime.Aneighthourovernightspecimenisthencollected.
Thedaytimespecimentypicallyhasanincreasedconcentrationofprotein,withthenighttimespecimenhavinganormalconcentration.Patientswithtrueglomerular
diseasehavereducedproteinexcretioninthesupineposition,butitwillnotreturntonormal(lessthan50mgpereighthours),asitwillwithorthostaticproteinuria.
Orthostaticproteinuriaisabenignconditionassociatedwithnormalrenalfunctionafteraslongas20to50yearsoffollowup.20,21Annualbloodpressure
measurementandurinalysisarerecommendedforthesepatients.

ISOLATEDPROTEINURIA
Aproteinuricpatientwithnormalrenalfunction,noevidenceofsystemicdiseasethatmightcauserenalmalfunction,normalurinarysedimentandnormalblood
pressuresisconsideredtohaveisolatedproteinuria.Proteinexcretionisusuallylessthan2gperday.Thesepatientshavea20percentriskforrenalinsufficiency
after10yearsandshouldbeobservedwithbloodpressuremeasurement,urinalysisandacreatinineclearanceeverysixmonths.7Isolatedproteinuriawithurinary
proteinexcretionofmorethan2gperdayisrareandusuallysignifiesglomerulardisease.7Thesepatientsneedfurthertesting,andanephrologyconsultation
shouldbeconsidered.

FinalComment
Theclinicalsignificanceofproteinuriavarieswidely.Asystematicapproachtoapatientwiththisfindingwillallowthecliniciantoefficientlydistinguishbetween
benignandpathologiccauses.Becomingfamiliarwiththediagnosticevaluation,includingtheincreasinglyvaluableUPr/Crratio,willassistthephysicianinmaking
anaccurateandtimelydiagnosis.Patientsforwhomthecauseoftheproteinuriaremainsunclearafteradiagnosticevaluationshouldbereferredtoanephrologist.
Inaddition,patientswithmorethan2gofproteinina24hoururinespecimenlikelyhaveaglomerularmalfunctionandshouldhaveanephrologyconsultation.

TheAuthors showallauthorinfo
MICHAELF.CARROLL,M.D.,iscurrentlyafacultymemberofWaukeshaFamilyPracticeResidencyProgram,Waukesha,Wis.Hecompletedaresidencyinfamily
practiceattheUniversityofWisconsinMadisonMedicalSchoolandanacademicfellowshipattheMedicalCollegeofWisconsin,Waukesha.Heisagraduateof
WayneStateUniversitySchoolofMedicine,Detroit,Mich....

REFERENCES showallreferences
1.PeggJF,ReinhardtRW,O'BrienJM.Proteinuriainadolescentsportsphysicalexaminations.JFamPract.198622:801....

MembersofvariousfamilypracticedepartmentsdeveloparticlesforProblemOrientedDiagnosis.ThisarticleisoneinaseriescoordinatedbytheDepartmentof
FamilyMedicineattheUnviersityofWisconsinMedicalSchool,Madison.GuesteditoroftheseriesisWilliamE.Scheckler,M.D.

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