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Symptomaticmanagementofnephroticsyndromeinchildren

OfficialreprintfromUpToDate
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Symptomaticmanagementofnephroticsyndromeinchildren
Author
PatrickNiaudet,MD

SectionEditor
TejKMattoo,MD,DCH,FRCP

DeputyEditor
MelanieSKim,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Sep2015.|Thistopiclastupdated:Feb28,2014.
INTRODUCTIONThenephroticsyndrome(NS)iscausedbyrenaldiseasesthatincreasethepermeability
acrosstheglomerularfiltrationbarrier.Itisclassicallycharacterizedbyfourclinicalfeatures,butthefirsttwoare
useddiagnosticallybecausethelasttwomaynotbeseeninallpatients:

NephroticrangeproteinuriaUrineproteinexcretiongreaterthan50mg/kgperday
HypoalbuminemiaSerumalbumin<3g/dL(30g/L)
Edema
Hyperlipidemia

IdiopathicNSisthemostcommonformofNSinchildren,representingmorethan90percentofcasesbefore10
yearsofageand50percentafter10yearsofage.ThemajorityofchildrenwithNSwillrespondtosteroidtherapy.
However,symptomatictreatmentisimportantintheearlycourseoftherapy,asresponsetosteroidtherapymay
takeseveralweeks.Symptomatictreatmentalsobecomesthemainstayoftherapyinchildrenwhofailtorespond
tosteroids,especiallyinthosewithgeneticmutationsthatcausetheirNS.
Thesymptomaticmanagementofnephroticsyndromeinchildrenwillbereviewedhere.Specifictreatmentof
nephroticsyndromeinchildrenisdiscussedseparately.(See"Treatmentofidiopathicnephroticsyndromein
children".)
EDEMA
SaltrestrictionEdemaistreatedbysaltrestrictionbecauserenalretentionofsodiumisoneoftwoprincipal
mechanismsthatleadtoedemainthenephroticsyndrome(NS).Inanalreadyedematouspatient,saltrestriction
alonewillnotsignificantlyimproveedema,butcanreducefurtheraccumulationoffluid.(See"Pathophysiologyand
treatmentofedemainpatientswiththenephroticsyndrome",sectionon'Evidencesupportingprimaryrenal
sodiumretention'.)
DiureticsAlthoughdiureticsarecommonlyusedinadultswithNS,theirroleinoftenseverelyhypoalbuminemic
childrenislessclear.Affectedchildrenmaybeintravascularlyvolumedepletedandaggressivediuresismaylead
tofurthervolumedepletion,therebypossiblyprecipitatingacuterenalfailureandincreasingtheriskofthrombosis
inthisalreadysusceptiblegroupofpatients[1,2].Rarely,diureticscancontributetoseverevolumedepletionthat
resultsinhypovolemicshock[3].(See"Complicationsofnephroticsyndromeinchildren",sectionon
'Hypovolemia'.)
Diureticsshouldonlybegivenincasesofsevereedemaandonlyifthereisnotsignificantintravascularvolume
depletion.Inastudyof30childrenwithNSandsevereedema,theuseoffractionalexcretionofsodium(FeNa)
distinguishedpatientswithvolumeexpansion(FeNa>2percent)fromthosewithvolumecontraction(FeNa<2
percent)[4].Diuretictherapyalonewasusedsuccessfullyin10of11patientswithFeNagreaterthan2percent.
InonepatientwithanelevatedFeNa,albuminwasaddedtodiuretictherapybecauseofariseinserumcreatinine
andthedevelopmentofhyponatremia.Thevolumecontractedgroup(ie,FeNa<2percent)alsohadhigherserum
renin,aldosterone,andantidiuretichormone.(See"Fractionalexcretionofsodium,urea,andothermoleculesin
acutekidneyinjury(acuterenalfailure)".)
Furosemidemaybegivenintravenouslyororallywithoutalbumin.Althoughitissomewhatlesseffective,itcanbe
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usefulwhengivenalone.Ongoingoraluseoffurosemidecanstillcausehypovolemiaandhypokalemia,andclose
monitoringofthepatientisrequired.
OtherdiureticsusedinchildhoodNSinclude:
ThiazidediureticThiazidediuretics,suchasmetolazone(2mg/kgperdose),incombinationwith
furosemide,appeartoenhancethenatriureticanddiureticeffectsoffurosemidealone[5].However,this
combinationofdiureticsisassociatedwithhypokalemia.
AmilorideAmilorideisapotassiumsparingdiureticthatdecreasessodiumchannelactivityofthecortical
collectingtubule.Therationaleforitsuseisthatrenalsodiumretentionisatleastinpartrelatedtoan
activationoftheepithelialsodiumchannel,whichisabolishedbyamiloride[6,7].Itcanbeusedin
combinationwithfurosemidetodecreasetheriskofhypokalemia.
Becauseofthepotentialforseriouscomplications,diureticmanagementshouldbesupervisedbyanephrologist
whohasexpertiseintreatingchildrenwithNS.
FurosemideandalbuminPatientswithanasarca(generalizedandmassiveedema)maybetreatedwith
furosemide(1to2mg/kgperdose)incombinationwithsaltpooralbumin(0.5to1g/kginfusedoverfourhours).
(See"Complicationsofnephroticsyndromeinchildren",sectionon'Anasarca'.)
Albuminraisestheintravascularoncoticpressureandtherebyprotectstheintravascularcompartmentagainst
volumecontraction.Albumininfusionalsoincreasesproteinbindingoffurosemide,whichimprovestherateof
deliverytothekidneyresultinginincreasedrenalsaltexcretion.(See"Pathophysiologyandtreatmentofedemain
patientswiththenephroticsyndrome",sectionon'Treatment'.)
Inaretrospectivestudy,albuminandfurosemidetherapyinchildrenwithNSeffectivelyremovedfluidwithamean
lossof0.4kg(1.2percentofbodyweight)perinfusion[8].However,theeffectistransientandcanbeassociated
withcomplicationsresultingfromincreasedvascularvolume,includinghypertensionandrespiratorydistress.Asa
result,aggressivediuresiswithalbuminandfurosemidetherapyshouldbereservedforpatientswithanasarcawho
haverespiratorycompromiseduetoascitesand/orpleuraleffusions,severescrotaledemasufficienttothreaten
perforation,peritonitis,orseveretissuebreakdown[1,9].Othermeasures,suchassaltandfluidrestriction,are
neededtopreventreaccumulationoffluid.(See"Etiology,clinicalmanifestations,anddiagnosisofnephrotic
syndromeinchildren",sectionon'Clinicalmanifestations'.)
FluidrestrictionAlthoughthereisdebateontheroleoffluidrestriction,initialrestrictionoffluidintaketoan
equivalentvolumeofthepatient'sinsensiblelossesplushis/herurineoutputwillresultinstabilizingthepatient's
weightwithoutfurtheraccumulationofedema.Inpatientswithhyponatremiawithaserumsodiumoflessthan135
mEq/L,fluidrestrictionisrequiredasfluidaccumulationisaresultofinappropriateantidiuretichormonesecretion,
secondarytointravascularvolumedepletion.(See"Maintenancefluidtherapyinchildren",sectionon'Sensibleand
insensiblewaterloss'.)
HYPERCOAGULABILITYNephroticpatientswithseverehypoalbuminemiaareatriskforthromboembolic
complications.Preventativemeasuresincluderegularambulation,avoidanceofhemoconcentrationresultingfrom
hypovolemia,avoidanceofcentralvenouscatheterifpossible,andearlytreatmentofsepsisorvolumedepletion
[10].(See"Complicationsofnephroticsyndromeinchildren",sectionon'Thromboembolism'and"Renalvein
thrombosisandhypercoagulablestateinnephroticsyndrome",sectionon'Pathogenesis'.)
Mostcliniciansdonotgiveprophylacticanticoagulationinitially.Thisisdueinlargeparttothelackofrandomized
trialstodeterminetheefficacyandsafetyofsuchanapproach[11].Insomecenters,prophylacticwarfarintherapy
isgiventohighriskpatientsincludingadolescents(>12yearsofage),orthosewithaserumalbumin
concentrationoflessthan2g/dL(20g/L),afibrinogenlevelofmorethan6g/L,oranantithrombinIIIlevelless
than70percentofnormal,althoughthereisnoevidencethatitisbeneficial[10].Alternatively,highriskpatients
canbetreatedwithlowdoseaspirinordipyridamole,althoughtherearenocontrolledtrialsthatdemonstratetheir
efficacyinthrombuspreventioninchildrenwithnephroticsyndrome(NS).
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TreatmentofvenousthromboembolismAnticoagulationismostofteninitiatedwithlowmolecularweight
heparin,suchasenoxaparin,atastartingdoseof1mg/kggivenevery12hours.Itcanbegivensubcutaneously
(avoidingtheneedforcentralvenouscatheterization),anditspharmacokineticprofileismorepredictablethan
unfractionatedheparin.AntifactorXaassayisusedfortherapeuticdrugmonitoring.Insituationswhereshorthalf
lifeandreversibleanticoagulationisnecessary,unfractionatedheparinisutilized.Theheparindosenecessaryto
obtainatherapeuticeffectisoftengreaterthannormalduetodecreasedantithrombinIIIlevel.Thrombolysisis
reservedonlyforseverecases.Inpatientswithpreviousthromboemboliccomplications,wewillstarttreatment
anticoagulationtherapyifthepatientremainsnephrotic,whichplacesthematcontinuedriskforthrombosis.(See
"Renalveinthrombosisandhypercoagulablestateinnephroticsyndrome",sectionon'Anticoagulationfora
thromboembolicevent'.)
INFECTION
BacterialNephroticchildrenareatincreasedriskofdevelopinginfection(eg,peritonitis,pneumonia,and
sepsis)duetoencapsulatedbacteria,inpartduetoreducedserumconcentrationsofimmunoglobulin,decreased
cellularimmunity,andtheadministrationofimmunosuppressivetherapy.Themostcommonagentis
streptococcuspneumoniaefollowedbyEscherichiacoli.(See"Complicationsofnephroticsyndromeinchildren",
sectionon'Bacterialinfection'.)
Prophylacticantimicrobialsarenotrecommended,butinfectionsthatdooccurshouldbepromptlytreated.
Althoughantibodyresponsecanbeblunted,allchildrenwithnephroticsyndrome(NS)shouldreceive23valent
polysaccharidevaccine(PPSV23)pneumococcalvaccine(ifnotalreadyimmunized).Althoughimmunizationis
ideallyadministeredwhenthechildisinremissionandoffofdailycorticosteroidtherapy,childrenwhoreceived
immunizationattheonsetoftheirNSwhileonhighdosedailyprednisonerespondedwitha10foldincreasein
antibodylevelstoPPSV23[12].Asaresult,inchildrenwithidiopathicNSandwhoaresteroiddependentresulting
inahighriskforpneumococcaldisease,administrationofPPSV23shouldbeconsidered.(See"Pneumococcal
(Streptococcuspneumoniae)polysaccharidevaccinesinchildren",sectionon'Indications'.)
VaricellaChildrenwithNSwhorequireimmunosuppressivetherapyareatincreasedriskfordeveloping
varicella.VaricellavaccinationhasbeenshowntobeeffectiveinchildrenwithNS,andshouldbegiventoall
patientswithnegativevaricellatiters[13].Itisideallyadministeredasatwodoseregimenwhenthechildisin
remissionandonlowdosealternativedaysoroffofcorticosteroidtherapy.
Incasesofexposureofpatientswhoarereceivingimmunosuppressivetherapyanddonothaveimmunityto
varicella,VariZIG,avaricellazosterimmuneglobulinproduct,canbeadministered.VariZIGshouldbe
administeredwithin96hoursoftheexposureatarecommendeddoseof125units/10kgbodyweight,uptoa
maximumof625units(fivevials)theminimumdoseis125units.Patientsshouldbemonitoredforvaricellafor28
daysafterexposure,sinceVariZIGmayprolongtheincubationperiod.AnypatientwhoreceivesVariZIGshould
receivevaricellavaccine.VaccineshouldbegivenfivemonthsafteradministrationofVariZIG.
Acyclovir,asyntheticnucleosideanalogthatinhibitsreplicationofhumanherpesviruses,iseffectivetherapyfor
primaryvaricellainfection.Itshouldbeinstitutedpromptlyinanypatientwhoisreceivingimmunosuppressive
therapyandexhibitsanysignofvaricellainfection.Acyclovirhasalsobeenusedprophylacticallyinchildren
exposedtovaricellawhilereceivingimmunosuppressivetherapy[14].(See"Vaccinationforthepreventionof
varicellazostervirusinfection:Chickenpox".)
OTHERDIETARYMEASURES
CaloricintakeIncreasedcaloricconsumptionasaresultofappetitestimulationofcorticosteroidtherapycan
leadtoexcessiveweightgain.Dietarymeasuresthatlimitexcessivecaloricconsumption,includingalowfatdiet,
willhelpchildrenavoidlargeweightgains.
CalciumandvitaminDAbnormalitiesinbonehistologycanbeseeninpatientswithnephroticsyndrome(NS),
primarilyduetotwoprocesses:
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LossofvitaminDbindingproteinInchildrenwithNS,urinarylossofvitaminDbindingproteinmayresult
inlowionizedcalciumand25OHVitaminD3(25hydroxycholecalciferol)concentrations[15].
Prolongedcorticosteroidtherapymayleadtoabnormalitiesinbonehistology[16]and,subsequently,
osteoporosis[17].However,onestudyusingdualenergyxrayabsorptiometrydidnotfindanydifferencein
spinalorwholebodymineralcontentofglucocorticoidtreatedchildrenwithNScomparedwithcontrol
patients[18].(See"Preventionandtreatmentofglucocorticoidinducedosteoporosis".)
Basedontheabove,calcium(500mg/day)andvitaminD(2000to4000units)supplementsoftenareprescribed
especiallywhentherearedocumentedlowcalciumand/orvitaminDconcentrationshowever,therearecurrently
nodatathathaveshownthisinterventiontobeeffective.
HYPERLIPIDEMIAPersistenthyperlipidemiaisariskfactorforatherosclerosisandmayplayaroleinthe
progressionofchronicrenalfailure.Thelipidabnormalitiesinducedbythenephroticsyndrome(NS)reversewith
remission.
TheoptimaltreatmentofhyperlipidemiainchildrenwithpersistentNSisunknown.InchildrenwithNS,statin
therapybasedonlimitedshorttermobservationaldataiseffectiveandsafeinreducingtotalandLDLcholesterol,
andtriglyceridelevels[19].Nevertheless,statinsshouldbeusedwithcautionuntilcontrolledstudiesare
performed[19].
Datafromadultswithpersistentproteinuriademonstratethefollowing:
Dietarymodificationhasbeenshowntohavelittlebenefit.
ThemostsuccessfulhypolipidemicagentswithpersistentNSarethestatins[20,21].Theseagentsgenerally
producefewsideeffectsandcanlowertheplasmatotalandlowdensitylipoprotein(LDL)cholesterol
concentrationsby20to45percent.Thereisasmallerreductionintriglyceridelevels.(See"Lipid
abnormalitiesinnephroticsyndrome",sectionon'Statins'.)
Basedontheaboveevidenceaswellasdataonthebenefitofstatintherapyinchildrenwithfamilial
hypercholesterolemia,wetreatchildrenwhoremainpersistentlynephroticandhavehyperlipidemiawithstatin
therapy.(See"InheriteddisordersofLDLcholesterolmetabolism",sectionon'Familialhypercholesterolemia'and
"Dyslipidemiainchildren:Management"and"Dyslipidemiainchildren:Management",sectionon'Rationaleand
criteriaforpharmacologictherapy'.)
LDLapheresiswithsteroidtherapyhasbeenproposedinpatientswithhyperlipidemiaandrefractorynephrotic
syndrome.Inonestudyinvolving11children,thistreatmentresultedincompleteremissioninfiveandpartial
remissionintwopatients[22].
AmorecompletediscussiononthetreatmentofhyperlipidemiainadultswithNSisfoundseparately.(See"Lipid
abnormalitiesinnephroticsyndrome",sectionon'Treatment'.)
HYPERTENSIONANDACEINHIBITORSChildrenwithnephroticsyndrome(NS)andpersistent
hypertensionaremorelikelytohavechronickidneydiseasewithpooroutcome.Asaresult,inpatientswith
hypertension,angiotensinconvertingenzyme(ACE)inhibitorsorangiotensinIIreceptorblockers(ARBs)arethe
preferredantihypertensiveagentsbecauseoftheirpotentialadditiveantiproteinuricbenefitandabilitytoslow
progressionofrenalimpairment.Themaximalantiproteinuriceffectisobservedafterfourweeks[23]the
antiproteinuriceffectcanbeincreasedbylowsaltdietand/ordiuretics[24].ACEinhibitorsandARBsshouldbe
terminatedifhyperkalemiacannotbecontrolledortheplasmacreatinineconcentrationincreasesmorethan30
percentabovethebaselinevalue.(See"Antihypertensivetherapyandprogressionofnondiabeticchronickidney
diseaseinadults".)
OtherantihypertensiveagentsthathavebeenusedinchildrenwithNSincludebetablockersandcalciumchannel
blockers.(See"Treatmentofhypertensioninchildrenandadolescents",sectionon'Pharmacologictherapy'.)
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SUMMARYANDRECOMMENDATIONSThemajorityofchildrenwithnephroticsyndrome(NS)willrespond
tosteroidtherapy.However,symptomaticmanagementisimportantintheearlycourseoftherapy,asresponseto
steroidtherapymaytakeseveralweeks,anditisthemainstayoftherapyinchildrenwhofailtorespondto
steroids.(See"Treatmentofidiopathicnephroticsyndromeinchildren".)
Symptomaticmanagementincludesthefollowing:
Inpatientswithpersistentproteinuria,saltandfluidrestriction,anddiuretics(aloneorincombinationwith
saltporealbumin)areusedtocontroledema.(See'Edema'above.)
Preventivemeasurestoavoidthromboemboliccomplicationincludemobilization,avoidanceof
hemoconcentrationresultingfromhypovolemia,andearlytreatmentofsepsisorvolumedepletion.We
suggestnotusingroutineprophylacticanticoagulationtherapyinchildrenwithNS(Grade2C).(See
'Hypercoagulability'aboveand"Renalveinthrombosisandhypercoagulablestateinnephroticsyndrome",
sectionon'Prophylacticanticoagulation'.)
ChildrenwithNSareatincreasedriskforbothbacterialandviralinfections.Werecommendthatthese
childrenreceive23valentpolysaccharidevaccine(PPSV23)pneumococcal,andvaricellavaccines(Grade
1B).(See'Infection'above.)
TheoptimaltreatmentofhyperlipidemiainchildrenwithpersistentNSisunknown.Basedupondatafrom
adultswithNSandhyperlipidemia,wesuggestadministeringstatintherapytochildrenwhoremain
persistentlynephroticandhavehyperlipidemia(Grade2B).(See'Hyperlipidemia'aboveand"Lipid
abnormalitiesinnephroticsyndrome",sectionon'Treatment'.)
ChildrenwithNSandpersistenthypertensionaremorelikelytohavechronickidneydiseasewithpoor
outcome.Inthesepatients,wesuggestangiotensinconvertingenzyme(ACE)inhibitorsorangiotensinII
receptorblockers(ARBs)beusedtotreattheirhypertensionbecauseoftheirpotentialadditiveantiproteinuric
benefitandabilitytoslowprogressionofrenalimpairment(Grade2B).(See'HypertensionandACE
inhibitors'aboveand"Antihypertensivetherapyandprogressionofnondiabeticchronickidneydiseasein
adults".)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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Topic6113Version12.0

Disclosures
Disclosures:PatrickNiaudet,MDNothingtodisclose.TejKMattoo,MD,DCH,FRCPNothingtodisclose.MelanieSKim,MD
Nothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthrougha
multilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriatelyreferenced
contentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
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