clinical approach to pediatric proteinuria

This is a practical approach to proteinuria

1. Clinical Approach to
Pediatric
Proteinuria
Dr. SiminSadeghi
E-Mail: [email protected]
1

2. Epidemiology
•Theprevalenceofproteinuriaonarandomurinespecimeninotherwiseasymptomatic
school-agedchildrenandadolescentsisapproximately5%to15%basedonmultiple
largescalestudies
•Thisfindingdecreasessubstantiallywithrepeatedurinesamples
•Onestudyexamined4repeatedurinespecimensfromeachofapproximately9,000
children(8–15yearsold);1of4specimenswaspositiveforproteinin10.7%ofpatients,
butonly0.1%had4of4specimenspositivewithpersistentproteinuria
•Theprevalenceincreaseswithincreasingageandpeaksinadolescence.Onestudy
reportedthatthepeakprevalenceinfemalesis13yearsofageandinboysis16yearsof
age
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3. 3

4. Definitions
•Proteinuriaisdefinedasproteinexcretiongreaterthan100mg/m2perday
ormorethan0.2mgprotein/mgcreatinine(alsoknownasaurine
protein/creatinineratio([Up/c]>0.2)onasinglespoturinecollection
•inneonatesandinfants:ahigheramountofproteinexcretion,upto300
mg/m2
•Nephrotic-rangeproteinuriaisdefinedasgreaterthan1,000mg/m2perday
orgreaterthan50mg/kgperday,oraUp/cgreaterthan2onasinglespot
urinecollection
4

5. Measurement Methods
Proteinuriacanbeevaluatedusingthefollowingmethods:
•Urinarydipstickreagent
•SulfoSalicylicAcid(SSA)turbiditytests
•Randomorfirstmorningurine(FMU)forspoturineprotein-to-
creatinineratio(UPCR)
•The24hoursurinaryproteinandcreatinine,urineprotein
electrophoresis,urinarymicroalbumin
5

6. The urinary dipstick reagent test
•isroutinelyusedinclinicalpractice
•Itishighlysensitivesolelyforthemeasurementofalbumin
concentrationviacolorimetricreactions
•Itsmainlimitationisthatitcannotdetectothertypesof
proteinssuchasplasmaproteins,globulins,andlow-
molecular-weightproteins
6

7. 7

8. The urinary dipstick reagent test
Thegradedscaleisstatedasfollows:
•negative(lessthan10mg/dL)
•trace(10-29mg/dL)
•1+(30-100mg/dL)
•2+(100-300mg/dL)
•3+(300-1,000mg/dL)
•4+(>1,000mg/dL)5)
•ThedipsticklargelydetectsalbuminanddoesnottendtodetectLMWproteins.
8

9. False-positiveurinedipstickforprotein:
•Highspecificgravity(ie,aconcentratedurine)
•Veryalkaline
•Macroscopichematuria,pyuria
•Contaminationwithantisepticagentsoriodinatedradiocontrastagents
False-negativeresults:
•inpatientswithverydiluteurinespecimens
•indiseasestateswherealbuminisnotthepredominanturinaryprotein
9

10. The qualitative SSA turbidity test
•Isnotroutinelyusedinclinicalpracticeforassessmentof
proteinuria
•Ithasthepotentialtodetectabroadrangeofurinaryproteins
includingalbumin,immunoglobulins,andBence-Jones
•Thisturbidometricmethodoftestingisusefulinthediagnosis
ofmultiplemyeloma,characterizedbytheexcretionoflight-
chainIg
•TheSSAreagentisaddedtoafreshurinespecimen,andthe
degreeofturbidityiscorrelatedwiththeamountofproteinuria
basedonapredeterminedscale
10

11. The qualitative SSA turbidity test
Falsepositive:
•recentexposuretoradiographiccontrastmaterial,
highconcentrationsofpenicillinorcephalosporin
antibiotics,orwithhighuricacidconcentrationinthe
urine
Falsenegative:
•highlybufferedalkalineordilutedurinespecimens
11

12. Random or first morning urine (FMU)
Calculationofaurineprotein-to-creatinineratioinarandomorspot
urinesampleespeciallywhentestedinthefirstmorningurine
specimen
•Ratiohigherthan0.8-1.0aregenerallyconsideredabnormalininfants
lessthan6monthsofage
•Ratiolessthan0.5areconsiderednormalforchildren6-24monthsof
age,
•lessthan0.2forchildrenolderthan24monthsofageandadult
12

13. Random or first morning urine (FMU)
FalselyelevatedUrinep/cwhenthereisnotenoughcreatinine
excreted:
•childrenwithlowmusclemassorseveremalnutrition,duetothe
lowrateofcreatinineexcretion
•underestimationoftheratiowhenthereisaveryconcentrated
samplewithahighcreatininelevelintheurine
13

14. The 24 hours urinary protein
The24hoursurinespecimencollectionisstillthegoldstandardforquantitative
urinalysis.Variationsinquantificationcanbereducedusingthebodysurfacearea.
Thisresultsinthefollowings:
•normal,≤4mg/m2/hour
•proteinuria,4-40mg/m2/hour
•nephrotic-rangeproteinuria,>40mg/m2/hour
Amoreaccuratemethod24-hoururinecollection
Adequacyofa24-hoururinecollectionmaybeverifiedbymeasurementofurine
creatinine,whichisapproximately15to20mg/kgidealbodyweightinfemalesand20
to25mg/kgbodyweightinmales.
14

15. Urine protein electrophoresis
•Evaluatedonaurinebagspecimenininfantsorfroma
cleancatchurinecollectioninolderchildrenand
adolescents
•Thistestingwillelucidatethepercentofproteinuria
content,thatis,albumin,beta2-microglobulin,alpha
globulins,monoclonalproteins,etc
•Ifamalignancyinvolvingtheover-productionof
immunoglobulinsissuspected,aurineimmunofixation
electrophoresiscanalsobeassessed.
15

16. Urine microalbuminlevel :
•urinemicroalbumintocreatinineratio(MA:Cr)canbecalculated,similarto
aurineprotein-tocreatinineratio
•Thenormalrangeislessthan20–30mgofurinealbuminpergramof
creatinineonafirstmorningspecimen
•Microalbuminuriaasaurinealbuminexcretionlevelof20–200mg/min/
1.73m2or30–300mgalbuminpergramcreatinineper24handfrank
proteinuriaasgreaterthan200mg/min/1.73m2
•Thisratioshouldbeassessedonafirstmorningurinespecimen.Inpatients
withtypeIandtypeIIdiabetesmellitus,microalbuminuriahasbeenshown
innumerousstudiestobeapredictorofprogressiverenaldiseaseand
potentiallycardiovascularmorbidityandmortality
16

17. Classification 17Classification
Transient
Orthostatic Persistent

18. Transient Proteinuria
•Proteinurianotedon1or2occasionsbutnotpresentonsubsequent
testing,isoftenseeninthecontextoffever,exercise,stress,seizures,
andhypovolemic/dehydrationstatus,coldexposure.
•Itistemporaryanddisappearswhentheincitingfactorisresolved
•Transientproteinuriamaynotbeassociatedwithanysignificantrenal
disease.
•Proteinuriadoesnotexceed1+to2+inthiscaseusingtheurinedipstick
method.
•CausedbyhemodynamicchangesintheglomerularbloodflowAlthough
thesechangesresultinincreasedproteindiffusion,furtherevaluationor
treatmentforthesechildrenisunnecessary.
18

19. Orthostatic Proteinuria
•Characterizedbyincreasedproteinexcretionintheuprightposition,
whichreturnstonormalwhenthepatientisrecumbent
•Orthostaticorposturalproteinuriaismorecommoninolderchildrenand
adolescents,accountingforapproximately5%ofproteinuria
•Thistypeofproteinuriaisusuallyasymptomaticandcaneasilybedetected
usingurinaryscreeningtests
•Thisconditionhasthehallmarkofincreasedproteinexcretioninthe
uprightposition.
19

20. 20
•Urinarydipsticktestingviafirstmorningurine
collection,(UPr/UCr),and24-hurine
collectionscanallbeusedfordiagnosis,but
24-hcollectionsarerarelyrequirediftheFMU
iscollectedappropriately
•ThecollectionofFMUiscriticalforits
diagnosis.Thepatientsmustfullyvoid
themselvesofurinebeforegoingtobedand
collecttheFMUimmediatelyafterwakingup

21. 21

22. 22
•Onaverage,thesepatientsexcretelessthan1gofproteinin24
hoursintheuprightposition,andthisnormalizestolessthan50
mgin8hoursofsupineposition
•Inthistypeofproteinuria,thetotalurinaryproteinexcretionmay
beincreasedupto1g/day,butitrarelyexceedsthislevel
•Itisdiagnosedwhenafirstmorningurinesampleislessthan0.2
mgprotein/mgcreatinineinthesettingofaUp/cgreaterthan
0.2,orpositiveurinedipstickforproteinuria,inarandomurine
sample

23. 23
•Othersymptoms(hematuria,edema,hypertension,
andrenaldysfunction)mustbeabsent.
•Theexactetiologyoforthostaticproteinuriaisstill
unclear
•Multiplefactors:
•renalhemodynamicchanges
•partialleftrenalveincompression
•increasedpermeabilityofthecapillarywalls
•circulatingimmunecomplexes

24. 24
•Mostofthestudiesarenotonpediatriccases,andlate-onset
glomerulosclerosishavebeenreported.Therefore,periodic
monitoringofthespotFMUtestandbloodpressurehavebeen
recommended
•Studiesfromthe1960stothe1990sonupto40to50yearsafter
thediagnosisoforthostaticproteinuriahavereportedabenign
courseforthiscondition,wheremortalityisnotshowntobe
greaterthantheaveragehealthypopulationwithsimilar
demographiccharacteristicsintheabsenceofotherclinical
evidenceofrenaldisease.

25. Fixed Proteinuria
•IsdefinedasFMUthatshows≥1+ondipstickreagenttestwith
UPCRof≥0.2orwithaurinespecificgravity>1.015
•Fixedproteinuriamaybeindicativeofunderlyingrenal
pathology.Therefore,iffixedproteinuriaonFMUisfoundafter
threeormoreurinalysisperformedeveryfewweeks,these
patientsrequiredclosefollow-upandshouldbefurther
evaluated
•Persistentproteinuriamaybesubclassifiedasglomerular,
tubular,oroverflow
25

26. Overflow Proteinuria
•IncreasedexcretionofLMWproteinsthatresultsfrom
markedoverproductionofLMWproteins,leadingtoalevel
thatexceedstubularreabsorptivecapacity
•Multiplemyelomaisthemostcommoncauseofoverflow
proteinuria.Anotherexampleofoverflowproteinuriais
foundinpediatricpatientswithmyoglobinuria.
26

27. Tubular Proteinuria
•Increasedexcretionofproteinsduetointerferencewith
proximaltubularreabsorption
•mostoftenappearsasaresultofinjurytotheproximaltubule
andinthepediatricpopulationismorecommonlysecondary
ratherthanprimaryinnature
•Tubulardamage,ofteninducedbyvariousdrugexposuresor
circulatorycompromise,resultsinimpairedabilitytoreabsorb
theLMWproteins,whicharenormallyfilteredbytheglomerulus
andreabsorbedbytheproximaltubule
27

28. •Theamountoftubularproteinsexcretedintubulardiseasesis
generallysmallerthanthatinglomerularproteinuria,whichis
lessthan2g/day
•Dent’sdiseaseisanX-linkedrecessivedisorderofthe
proximaltubulescharacterizedbyhypercalciuria,low-
molecularweightproteinuria,andnephrolithiasis.Mostofthe
casesofDent’sdiseasehavemutationsthatinactivatethe
voltagegatedchloridetransporternamedCLC-5.
•PatientswithLowesyndrome(alsocalledthe
oculocerebrorenalsyndromeofLowe),generallyhave
proximaltubulopathy,bilateralcataracts,andhypotonia
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29. 29
•Secondaryratherthanprimarycausesoftubular
proteinuriaaremorelikelytobeencounteredin
children(suchasacutetubularnecrosisand
acuteinterstitialnephritis)
•Oneshouldtakenoteofafewprimarycauses
thatmaybeconsidered,includingbutnotlimited
tocystinosis,polycystickidneydisease,Wilson
disease,andmitochondrialdisordersandsickle
celldiseasenephropathy

30. Glomerular Proteinuria
•Minimalchangediseasealsocalledlipoidnephroticsyndromecanbe
mostlyseeninselectiveproteinuriapediatricpatients
•Mostformsofglomerulonephritisarefollowedbynonselective
proteinuria
•Thisdegreeofselectivitycanbedeterminedbymeasuringalbuminand
otherproteinsofhighermolecularweightssuchastransferrinorIgG
•HighlyselectiveproteinuriamayhaveanIgG:albuminratioofcanplay
animportantroleintheirprogression
30

31. Glomerular Proteinuria
•Theabnormallyhighpassageofproteinsacrosstheglomerular
capillarywallandmesangiummayaggravateglomerularinjury
•Persistentproteinuriaoftenindicatesunderlyingrenalpathology
•Glomerularcausesforproteinuriaaremorecommonthan
tubulointerstitialcausesofproteinuria
31

32. Amongthemostcommoncausesofprimaryglomerular
proteinuria:
•Minimalchangedisease(MCD)representsoneofthemost
commonpresentationsofidiopathicnephroticsyndrome.It
classicallypresentsinchildren(mostbetween3and9yearsofage)
asedema,alowalbuminlevel(25%ofbirthweight)
•AcutepostinfectiousGNandHSPareknowntobesecondary
causesofglomerularproteinuria
•Lupusnephritis,whichisthetermusedtodescribetherenal
(usuallyglomerular)involvementofsystemiclupuserythematosus
(SLE)
•Renaldiseaseispresentin50%to75%ofchildrenwithSLEandis
oneoftheleadingcausesofmorbidityandmortality
32

33. •NotethatpersistentproteinuriaisassociatedwithCKD
•Proteinuriathatispersistentmaybethefirstsignofglomerular
damageorlossofrenalfunction
•Ithaslongbeenestablishedthatthedegreeofproteinuriais
associatedwithprogressionofCKD
•Notonlydoesproteinserveasanindicatorofrenaldamage,but
itisalsorecognizedasaperpetratorofongoingrenaldamage
•Assuch,childrenwhopresentwithpersistentproteinuriashould
undergoevaluationofrenalfunction,andathoroughhistory
detailinganysignificantillnessesorprenatalorperinataleventsis
essentialtohelpdeterminepossiblecauses
33

34. Isolated proteinuria
•Asymptomaticproteinuriainanotherwisehealthypatientwithnormal
physicalexamfindings,bloodpressurereadings,urinarysediment,and
laboratoryfindingsatthetimeofdiagnosis.Usuallythedegreeof
proteinuriaislessthan2gin24h
•Themajorityoftheseindividualsdonothaveprogressiverenaldisease,
althoughinsomestudies,aminorityofrenalbiopsyspecimensrevealed
abnormalhistologysuchasfocalsegmentalglomerulosclerosis
•Somestudiespredicta20%riskforprogressiverenaldamageovera10-
yearperiod.Therefore,aninitialthoroughevaluationaswellasclose
long-termmonitoringisindicated,andareferraltoapediatric
nephrologistisrecommended.
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35. Persistent asymptomatic proteinuria
•Thisisthetypeofproteinurianotassociatedwithhematuriabut
proteinuriapersistsonFMUformorethan3months
•Theprevalenceofpersistentproteinuriainchildrenmaybeashighas6%
•Thistypeisnotassociatedwithedemaandtheaverageamountof
proteinsexcretedisapproximately<2gr/day
•Causesofpersistentasymptomaticproteinuriaincludemembranousand
membranoproliferative glomerulonephritis, pyelonephritis,
developmentalanomalies,hereditarynephritis,hepatitisBinfection,
and“benign”proteinuria
35

36. Persistent asymptomatic proteinuria
•Theevaluationshouldstartwiththoroughhistoryandphysical
examination
•Iftheresultsofthelaboratorytestsarewithinnormalrangewith
theindicationoflowgradeproteinuria(150-1,000mg/day),renal
biopsyisnotrecommended,asitisraretofindevidencefor
progressiverenaldisease
•Thesepatientsshouldbesubjectedtoannualevaluationincluding
physicalexaminations,routinebloodpressuremonitoring,and
laboratorytestslikeurinalysis,24hoursurinespecimencollection,
andcreatinineclearance
36

37. Evaluation of Proteinuria
History:
•Symptomsofhypertension,oliguria,polyuria,weightloss,skinlesions,
jointsymptoms,recentinfections,previousabnormalurinalyses,and
recentintakeofmedications(suchasNSAIDs,gold,angiotensinconverting
enzymeinhibitors(ACEi),andpenicillamine)
•Familyhistoryofhypertension,renaldisease,autoimmunedisease,and
visualimpairmentordeafnessshouldalsobeconsidered
•Growthisanimportantclueforchronicdiseasessuchasrenaldiseaseand
needstobemeasured
•Bloodpressurealsoneedstoberoutinelymeasured
•Signsofedema,flankpain,fluidoverload,organomegaly,rashes,anemia,
jointswelling,andsymptomsofosteodystrophyshouldbeexamined.
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38. 38

39. •Thefirststepistoconfirmthatthechildrenhavefixedproteinuriaon
FMU
•Patientswithapositiveurinedipstick(1+)ofproteinshouldhavea
completeUAandquantificationofproteinuriawithaspotUp/c,
preferablyinafirstmorningurinesample
•Thissampleisbestobtainedbycompletelyemptyingthebladder
beforegoingtosleep(discardingthaturine)andcollectingtheurine
onawakening,beforeanyotheractivityisperformed
•Nofurtherevaluationisnecessaryifthefirstmorningurinesample
hasanormalUp/cof0.2orlessbecausethemostlikelydiagnosisis
orthostaticproteinuriaandhistoricallyisnotassociatedwithlong-
termsequelae
•Still,somepediatricnephrologistswouldadviserepeatingafirst
morningvoidonayearlybasisinpatientswhocontinueto
demonstrateproteinuria
39

40. •Ifthechildrenhavefixed
proteinuriaonFMUon
threeseparateoccasions,U
p/cisgreaterthan0.2the
followingevaluationis
required
40
•Acompleteurinalysisevaluationof
thechildrenwithfixedproteinuriais
requiredtodeterminetheabsence
orpresenceofhematuriawith
dysmorphicoreumorphicredblood
cells,pyuria,urineeosinophils,or
crystals.

41. Step2:
Laboratorytests,suchaselectrolytebalance,renalfunctiontest,
completebloodcount,testsforserumalbumin,andcomplement3or4
(C3orC4)activitylevelsshouldalsobeexamined.Theanti-streptolysin
Otiters,antinuclearantibodylevels,andDNaseBtitersmayalsobe
consideredincertainsituations,24hoursurinespecimencollectionmay
benecessaryforthisstep
•Chestx-rayandkidneyultrasoundimagingshouldbeperformedto
determinevolumeoverloadorrenalstructuralabnormalities
•FurtherstudiesmayincludehepatitisBandCtests,morespecific
laboratorystudiesonvasculitisorautoimmunediseasesaswellasthe
typeofproteinuria
41

42. PossibleIndicationsforPercutaneousRenal
BiopsyinPatientswithPersistentProteinuria
•Elevated serum creatinine concentration
•Persistent macroscopic or microscopic hematuria or heavy
proteinuria (>1 g/day)
•Hypertension
•Persistent hypocomplementemia
•Consider with frequently relapsing, steroid-dependent and steroid-
resistant nephrotic syndrome
•Family history of chronic renal disease or end-stage renal disease
•Parental anxiety
42

43. 43

44. Take Home Massage
•Transientandorthostaticproteinuriarendersanexcellentlong-term
prognosis
•whileisolatedandpersistentproteinuriaoftenportendspoorer
long-termoutcomes
•Initialevaluationandcontinuedlong-termmonitoringofthese
patientscansignificantlyalterpotentialprogressionofthe
underlyingprocess
•Familyandage-appropriatepatienteducationandcounselingshould
beperformedatorsoonafterthediagnosisofsignificantproteinuria
isconfirmedandthencontinuedovertimebyamultidisciplinary
team
44

45. 45