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Evaluationofproteinuria
DiagnosticApproach
Urgentconsiderationsexistforthiscondition,clicktoview

Proteinuriaisoftendiagnosedincidentallyonroutinedipsticktestingofurinesamples.Atothertimes,anappropriateindexofsuspicionisrequiredto
specificallyrequesturinalysisforproteinmeasurement.Itisimportanttodistinguishbenign,selflimitingetiologiesfrommoresignificantillness.Whilethelist
ofdifferentialdiagnosesforproteinuriaincludesalmostalletiologiesofkidneydisease,itisusefultoconsiderseveralprincipleswhenevaluatingproteinuria.
Ingeneral,diseasesthataffectpreglomerularstructures(e.g.,mediumvesselvasculitis,heartfailure),macroscopicstructuralabnormalities(e.g.,cystic
kidneydisease,urinarytractobstruction),lowerurinarytractinfection,ischemia,andmedicationtoxicityoftenresultinminimaltolowgradeproteinuria.
Etiologiesofsignificantproteinuriatypicallyincludeglomerulardiseasesandplasmacelldyscrasias.Thepresenceofhematuriawithovertproteinuria
suggestsglomerulonephritis.Whileexceptionsdoexist,itishelpfultoworkwithinthisframework.
Proteinuriaitselftypicallyhasfewsignsorsymptoms.Nephroticrangeproteinuriamay,onoccasion,resultinfoamyurine,althoughnormalratesofprotein
excretioncanalsoproducefoamiftheurineishighlyconcentrated.Edemamaybepresent,andwithsevereongoingproteinuria,malnutrition,weightloss,
andinfectionmayresult.Nephroticrangeproteinuriamayresultinpleuraleffusionsandascites,withresultantshortnessofbreathandabdominal
distention.

Historicalfactors

Transientproteinuria(fromfever,heavyphysicalexertion,urinarytractinfection,urologichemorrhage,orthostaticproteinuria)maypresentwithtransient
symptoms.
Theseincludefever,recentstrenuousexercise,dysuria,urgency,frequency,foulsmelling/cloudyurine,and/ortrauma.
Demographically,ageandethnicityareimportanthistoricalfactors.
Age
Presentationofproteinuriainchildren/adolescentsiscommonlyduetoorthostaticproteinuriaandminimalchangedisease.
Minimalchangediseaseandmembranousnephropathyarealsocommoninolderpatients.
Ethnicity
Focalsegmentalglomerulosclerosisandhypertensivenephrosclerosisaremorecommoninblackpeople.
ThereisahighincidenceofIgAnephropathyinAsians.
Symptomsofpersistentproteinuriavaryaccordingtothecause.
Swellingmaybeasymptomofminimalchangedisease,focalsegmentalglomerulosclerosis,membranousnephropathy,membranoproliferative
glomerulonephritis,IgAnephropathy,SLE,postinfectiousglomerulonephritis,amyloidosis,lightandheavychaindepositiondiseases,fibrillaryand
immunotactoidglomerulopathy,lightchaincastnephropathy,hemolyticuremicsyndrome(HUS),orthromboticthrombocytopenicpurpura(TTP).
PatientswithIgAnephropathy,antiglomerularbasementmembrane(antiGBM)disease(Goodpasturesyndrome),cystickidneydisease,or
aristolochicacidnephropathymaydescribegrosshematuria.
Painmaybeasymptomofcystickidneydisease,urinarytractobstruction,mediumandsmallvesselvasculitis,heavymetalpoisoning,renalvein
thrombosis,andrhabdomyolysis.PatientswithFabrydiseasemayhaveaburningsensationofthehandswithexerciseandheat.
Alteredbowelhabitmaybeasymptomofhypercalciuria(constipation)andHUS(diarrhea).
SeizuresmaybesymptomsofTTPandSLE.
Polyuriamaybeasymptomofhypercalciuria,Dentdisease,andurinarytractobstruction.
OcularsymptomsmaybepresentinpatientswithFabrydisease,diabeticnephropathy,hypertension,andcystickidneydisease.
Respiratorysymptomsmaybeassociatedwithmediumandsmallvesselvasculitis,IgAnephropathy,andsclerodermalrenalcrisis.
Pastmedicalhistorycanrevealusefulinformation.
Lymphomaandstemcelltransplantmaybeassociatedwithminimalchangedisease.
HIV,hypertension,diabetes,priorrenalinjury,andobesitymaybeassociatedwithfocalsegmentalglomerulosclerosis.
SLE,hepatitisB,hepatitisC,syphilis,andstemcelltransplantmaybeassociatedwithmembranousnephropathy.
SLE,hepatitisC,postinfectiousglomerulonephritis,endocarditis,cryoglobulinemia,andthromboticmicroangiopathymaybeassociatedwith
membranoproliferativeglomerulonephritis.
Upperrespiratoryinfection,Crohndisease,orceliacdiseasemaybeassociatedwithIgAnephropathy.
Autoimmunediseasewithrash,photosensitivity,oralulcers,arthritis,serositis,renaldisease,neurologicchanges,andhematologicdiseasemaybe
associatedwithSLE.
Recentinfection(typicallystreptococcal,canbestaphylococcal)maybeassociatedwithpostinfectiousglomerulonephritis.
Arthritis,familialMediterraneanfever,multiplemyeloma,ormonoclonalgammopathymaybeassociatedwithamyloidosis.
Multiplemyelomaandmonoclonalgammopathymayalsobeassociatedwithlightandheavychaindepositiondiseases.
Multiplemyeloma,monoclonalgammopathy,hepatitisC,andlymphomamaybeassociatedwithfibrillaryandimmunotactoidglomerulopathy.
RapidlyprogressiverenalfailuremaybeassociatedwithantiGBMdisease(Goodpasturesyndrome).
Recentnephrotoxicinjurysuchashypotension,mechanicalventilation,andischemiamaybeassociatedwithacutetubularinjury.
Uveitisfromtubulointerstitialnephritisanduveitissyndrome,viralinfection,andsystemicdisease(e.g.,sarcoidosis,Sjogrendisease)maybe
associatedwithinterstitialnephritis.
MultiplemyelomamaybeassociatedwithFanconisyndrome.
Kidneystonesmaybeassociatedwithhypercalciuria.
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Kidneystonesmaybeassociatedwithhypercalciuria.
Chronickidneydisease,rickets,andnephrocalcinosismaybeassociatedwithDentdisease.
Anemiaandchronickidneydiseasebetweenagesof30and50yearsmaybeassociatedwitharistolochicacidnephropathy.
Benignprostatichyperplasia,kidneystones,urinaryretention,andgynecologiccancermaybeassociatedwithurinarytractobstruction.
Cerebralhemorrhage,stroke,andchildhoodnephronophthisismaybeassociatedwithcystickidneydisease.
Insulinresistance/diabetes,dyslipidemia,andobesitymaybeassociatedwithmetabolicsyndrome.
Diabetesandretinopathyisassociatedwithdiabeticnephropathy.
Eyedisease,peripheralandcoronaryarterialdisease,CHF,hypohidrosis,GIdysmotility,andrenalfailuremaybeassociatedwithFabrydisease.
RecentEscherichiacoliinfection,diarrhea,priorhistoryofHUS/TTP,andpriorbonemarrowtransplantmaybeassociatedwithHUS/TTP.
PregnancyorpostpartumstatemaybeassociatedwithHUS.
Sclerodermaisassociatedwithsclerodermarenalcrisis.
Multiorgandisorder,neuropathy,headache,CVA,andacuterenalfailuremaybeassociatedwithmediumandsmallvesselvasculitis.
Recentcrushinjury,prolongedimmobility,orviralinfectionmaybeassociatedwithrhabdomyolysis.
Familyhistorymaybepositiveforthefollowingdiseases.
AtypicalHUS/TTP
Fanconidisease
Dentdisease.
Occupational/socialhistorymayberelevant.
Industrial/environmentalexposurestooldpaintandmoonshinearecommonsourcesforheavymetal(lead)poisoning.
PatientswithantiGBMdisease(Goodpasturesyndrome)andidiopathicnodularglomerulosclerosisoftenhavepositivesmokinghistories.
Drughistorymayalsorevealimportantinformation.
Nonsteroidalantiinflammatorydrugs(NSAIDs),interferon,andlithiummaybeassociatedwithminimalchangedisease.
Bisphosphonatesandheroinusemaybeassociatedwithfocalsegmentalglomerulosclerosis.
NSAIDs,gold,andpenicillaminemaybeassociatedwithmembranousnephropathy.
NSAIDS,aminoglycosides,amphotericinB,zoledronicacid,oralphosphatebowelpreparations,andIVcontrastmaybeassociatedwithacutetubular
injury.
NSAIDs,antibiotics,allopurinol,andprotonpumpinhibitorsmaybeassociatedwithinterstitialnephritis.
HeavymetalexposureandmedicationssuchastenofovirmaybeassociatedwithFanconisyndrome.
Aristolochicacidandotherweightlossmedicationsmaybeassociatedwitharistolochicacidnephropathy(previouslycalledChineseherb
nephropathy).Aristolochicacidweightlossmedicationsmayalsobeassociatedwithtubulointerstitialdisease.
Cyclosporine,clopidogrel,gemcitabine,andbevacizumab(vascularendothelialgrowthfactorinhibitor)maybeassociatedwithHUSorTTP.
Prednisonemaybeassociatedwithsclerodermarenalcrisis.
Statinsandcocainemaybeassociatedwithrhabdomyolysis.

Physicalexam

Signsoftransientproteinuria(fromfever,heavyphysicalexertion,urinarytractinfection,urologichemorrhage,orthostaticproteinuria)arepresent.
Theymayincludeelevatedtemperature>100.4F(38.0C),flankpain(ifpyelonephritis),bladdertendernessonpalpation,and/orgrosshematuria.
Therearenospecificfindingsforheavyphysicalexertionororthostaticproteinuria.
Signsofpersistentproteinuriavaryaccordingtothecause.
Fevermaybeasignofinterstitialnephritis,Fabrydisease,HUS,andTTP.
Volumeoverload(intheformofpleuraleffusion,ascites,orperipheraledema)maybeasignofminimalchangedisease,focalsegmental
glomerulosclerosis,membranousnephropathy,membranoproliferativeglomerulonephritis,IgAnephropathy,SLE,postinfectiousglomerulonephritis,
amyloidosis,lightandheavychaindepositiondiseases,fibrillaryandimmunotactoidglomerulopathy,lightchaincastnephropathy,HUS,orTTP.
Hypertensionitselfmaycauseproteinuria,ormaybeasignofothercauses,includingHUS,TTP,sclerodermarenalcrisis,glomerulardisease,IgA
nephropathy,SLE,postinfectiousglomerulonephritis,amyloidosis,lightandheavychaindepositiondisease,fibrillaryandimmunotactoid
glomerulopathy,lightchaincastnephropathy,metabolicsyndrome,andFabrydisease.
Neurologicweaknessmaybeasignofhypercalciuria,heavymetalpoisoning,SLE,diabeticneuropathy,andmediumandsmallvesselvasculitis.
Alteredmentalstatusmaybeasignofhypercalciuria,TTP,mediumandsmallvesselvasculitis,heavymetalpoisoning,andSLE.
HighBMImaybeasignofmetabolicsyndrome,Fabrydisease,andfocalsegmentalglomerulosclerosis.
Rashmaybeasignofmembranoproliferativeglomerulonephritis,cryoglobulinemia,interstitialnephritis,HUS,TTP,mediumandsmallvessel
vasculitis,heavymetalpoisoning,Fanconisyndrome,andSLE.

Whototest

Patientswithchronickidneydisease.Inthesepatients,measurementandtreatmentofproteinuriaisanappropriatehealthcarequalityperformance
measure. [3] [38] [39]
Patientswithhypertensionrequirescreeningformoderatelyincreasedalbuminuriaatdiagnosisandthenannuallyinhighriskgroups(e.g.,diabetes
mellitus,reducedkidneyfunction). [40]
PatientswithtypeIdiabetesmellitusrequireannualscreeningformoderatelyincreasedalbuminuriaat5yearsafterdiagnosis,andpatientswithtype
IIdiabetesmellitusrequirescreeningattimeofdiagnosis. [41]
Patientswithmetabolicsyndrome.
Aspartoftheevaluationofpatientswithedema,acutekidneyinjury,hematuria,orsystemicdisease(e.g.,cirrhosis,HIVinfection,vasculitis).
Routinetestingofthegeneralpopulationisnotrecommendedbyprofessionalsocieties.

Howtotest

Itisimportanttodistinguishpersistentandtransientproteinuria.Thepresenceofdipstickpositiveproteinuriaon2urinesamplesseparatedby1to2weeks
indicatespersistentproteinuriaandwarrantsquantificationandfurtherevaluation. [3] Itisimportanttohaveahighindexofsuspicionforpersistent
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indicatespersistentproteinuriaandwarrantsquantificationandfurtherevaluation. [3] Itisimportanttohaveahighindexofsuspicionforpersistent
proteinuria.Forexample,whileurinarytractinfectionisacommoncauseoftransienthematuriaandmild(1+)proteinuria,itisimportanttoatleastconsider
moreseriousetiologiesoftheseurinaryabnormalitieswhenevertheyareencountered.Followuptestingisimportantiftheclinicalsituationwarrants.If
orthostaticproteinuriaissuspected,theproteintocreatinineratioinafirstmorningvoidedurinespecimenshouldbecomparedwiththeratiofroma
randomsamplelaterintheday.Theabsenceofproteinuriainthemorningsampleandpresenceinthedaytimesampleconfirmsorthostaticproteinuria.
Whilequalitativedipsticktestingisstillwidelyused,anegativedipstickdoesnotexcludethepresenceofproteinuria.Screeningformoderatelyincreased
albuminuriamaybemoresensitiveforthedetectionofearlyglomerulardiseasethanmeasuringtotalproteinexcretion,buteithermethodmaybeused.
Semiquantitativetesting(orpreferablydirectmeasurementofaspotor24hoururinesample)forcalculationofaproteintocreatinineratiois
recommended.Spoturinefromafirstmorningvoidispreferredbutanuntimedurinesampleisacceptable.Theuseofquantitativemethodsisparticularly
importantwhenconcernfornonalbuminproteins(e.g.,lightchainsinmultiplemyeloma)exists.Whilequalitativemethodsmaybeusedfortheinitial
detectionofproteinuria,quantitativemethodsshouldbeusedforconfirmationandongoingfollowup. [3]
Studieshavenotevaluatedthesensitivityandspecificityofonetimeproteinuriatestingforthediagnosisofchronickidneydisease.Intraindividual
variabilityofurinaryalbuminishigh.Reportedcoefficientsofvarianceestimatesrangefrom30%to50%.Upto37%ofpeoplewithmoderatelyincreased
albuminuriaandaglomerularfiltrationrate(GFR)of60mL/minuteper1.73m^2orgreaterdidnothavemoderatelyorseverelyincreasedalbuminuriaon
repeatedtesting2monthslater. [42]

Furthertests
ThepresenceofpersistentproteinuriashouldpromptevaluationofkidneyfunctionbyestimationofGFRfromserumcreatinineand/orcollectionof24hour
urineforcreatinineclearance.GFRcanbeestimatedbytheChronicKidneyDiseaseEpidemiologyCollaboration(CKDEPI)formulaortheModificationof
DietinRenalDisease(MDRD)equation.GFRcalculatorsareavailableonline.http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm[National
KidneyFoundation:calculatorsforhealthcareprofessionals]InpatientswithaGFR>60mL/minute/1.73m^2,MDRDmayunderestimatetruekidney
function.Forthesepatients,24hoururinecollectionformeasurementofcreatinineclearancemaybemoreaccurate.Inpatientswithovertproteinuria,
renalimagingbyultrasoundorasimilarlyappropriatemodalityshouldbeobtained.Theworkupofproteinuriaissimilarforglomerular,tubular,andoverflow
proteinuria.Furtherlaboratoryevaluationisdirectedbytheresultsofacomprehensivehistoryandphysicalexam.Unlesstheclinicalhistory
overwhelminglysupportstubularproteinuria,glomerularproteinuriaistypicallyevaluatedfirst.Ininstancesoftubularoroverflowproteinuria,these
diagnosesareoftenrenderedinthecourseofroutineevaluation.
Furthertestingforalbuminuriaincludes:
Lipidprofileforassessmentofmetabolicriskfactors
HbA1cforassessmentofdiabetesmellitus
Clinicalassessmentandpossiblyechocardiographyforheartfailure
Measurementofbloodpressure.
Furthertestingforovertproteinuriaincludes:
Reviewingmedicationlistforpotentiallyoffendingagents
CBCwithdifferentialtoscreenforhematologicdisorders
Urinalysiswithmicroscopicexamtoassessforglucosuria,hematuria,andpyuria
HIVtestingifthereisclinicalsuspicionofHIV
HepatitisBandCtestingifthereisclinicalsuspicionofinfection
ANAifthereisclinicalsuspicionofautoimmunediseasesuchasSLE
DoublestrandedDNAantibodyifthereisclinicalsuspicionofSLE
CH50,C3,andC4ifthereisclinicalsuspicionofSLE,postinfectiousglomerulonephritis,cryoglobulinemia/hepatitisC,ormembranoproliferative
glomerulonephritis
Antineutrophilcytoplasmicantibody(ANCA)ifthereisclinicalsuspicionofANCAassociatedvasculitis
Serumandurineproteinelectrophoresiswithimmunofixation/serumfreelightchainmeasurementifthereisclinicalsuspicionofaplasmacelldyscrasia
Rheumatoidfactorifthereisclinicalsuspicionofcryoglobulinemia/hepatitisC
CryoglobulinsifthereisclinicalsuspicionofhepatitisCorcryoglobulinemicvasculitis
Antiglomerularbasementmembrane(antiGBM)antibodyifthereisclinicalsuspicionofantiGBMdisease(Goodpasturesyndrome).
Renalbiopsymayberequiredforprognosticandtherapeuticdecisionmaking,andtosecureadiagnosisifoneisnotreadilyapparentfromhistoryand
serologictesting.
Additionally,ifpredominatelytubularproteinuriaissuspectedfromclinicalhistoryorinitialworkup,thefollowingtestsmaybeofvalue:
Heavymetalscreeningforassessingheavymetalpoisoning
Evaluationforglucosuria,phosphaturia,andrenaltubularacidosisforassessingFanconisyndrome(ifall3presentinthesettingoftubularproteinuria)
Urinaryalbumin/beta2microglobulinratioofapproximately1to13(consistentwithtubularproteinuria).
Thefrequencyoffollowupproteinmeasurementvariesbasedontheclinicalscenario.Formalguidelinesrecommendyearlymeasurementinpatientswith
diabetesmellitusandhighriskpatientswithhypertension.Althoughspecificrecommendationsdonotexistforpatientswithabnormalrenalfunction,in
general,patientsaretypicallyreevaluatedandproteinexcretionremeasured3to4timesperyear.Aparticularpatientmayrequiremoreorlessfrequent
monitoringdependingontheircircumstances.

ReferencedArticles

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