肾病综合征 (英文)

NEPHROTICSYNDROMENephroticSyndrome

Proteinuria(“nephroticrange”>3.5g/24h) Hypoalbumimenia(serumalbumin<30g/L) Edema Hyperlipidemia Lipiduria2NEPHROTICSYNDROME

ItisimportanttorealizethattheNSisnotadisease;itisasyndromecausedbymanydifferentrenaldiseases

Theglomerulardiseasesthatcausenephroticsyndromegenerallycanbedividedintoprimaryandsecondaryetiologies.3NEPHROTICSYNDROME

Primary/idiopathicnephroticsyndrome(PNS/INS)isassoiatedwithglomerulardiseaseintrinsictothekidney.

Secondarynephroticsyndrome(SNS)referstoanentityextrinsictothekidney.430%7%3%5%HISTOLOGYOFINS

Approximate incidence

PRIMARYRENALDISEASEMinimal-changedisease(MCDFocalglomerulosclerosis(FGS)Membranousglomerulonephritis(MGN)Membranoproliferativeglomerulonephritis(MPGN)Others:mesangialproliferateglomerulonephritis,IgAnephropathyRapidlyprogressiveglomerulonephritis(RPGN)75%15%15%5HISTOLOGYOFINS

Nephroticsyndromeis15timesmorecommoninchildrenthaninadults.

MostcasesofprimarynephroticsyndromeinchildrenareduetoMCD.Theageatonsetvarieswiththetypeofnephroticsyndrome.

Inadults,themostcommonformofglomerulopathycausingnephroticsyndromeisMGN,followedbyFSGS.6PATHOPHYSIOLOGYOFINSThenephroticsyndromeisaclinicalcomplexcharacterizedbyanumberofrenalandextrarenalfeaturesthemostprominentofwhichare:

heavyproteinuria(inpractice>3.0to3.5g/pe/24hours),whichleadstohypoproteinemia,

decreasedlevelsofserumalbumin(albumin<3g/dl-hypoalbuminemia),

severeedema,

elevatedserumlipids(hyperlipidemia),

andhypercoagulability7PROTEINURIA8REGULATIONOFPROTEINEXCRETIONBYTHENORMALKIDNEYGlomerularfiltration–sizebarrier–chargebarrierRe-absorptionatproximaltubule–98%offilteredproteinreabsorbed9MECHANISMSOFINCREASEDPROTEINEXCRETIONASSOCIATEDWITHDISEASE•Abnormalglomerularfilter–Selectiveproteinuria(“lossofchargebarrier”)–Non-selectiveproteinuria(“lossofsizebarrier”)•Proximaltubulardysfunction•Overloadproteinuria10CLASSIFICATIONOFPROTEINURIATYPEPATHOPHYSIOLOGIC FEATURESCAUSEGLOMERULARIncreasedglomerularcapillarypermeabilitytoproteinPrimary(Minimalchangedisease,IdiopathicMembranousGlomerulonephritis)orsecondaryglomerulopathy(AmyloidosisPreeclampsiaInfection)TUBULARDecreasedtubularreabsorptionofproteinsinglomerularfiltrateTubularorinterstitialdiseaseHypertensivenephrosclerosisOVERFLOWIncreasedproductionoflow-molecular-weightproteinsHemoglobinuriaMyoglobinuriaMultiplemyelomaAmyloidosis11CAUSEOFPROTEINURIAASRELATEDTOQUANTITY

CAUSEMildglomerulopathiesTubularproteinuriaOverflowproteinuriaUsuallyglomerularAlwaysglomerular

DAILYPROTEINEXCRETION0.15to2.0g2.0to4.0g>3.5gTubularproteinurianeverexceeds2gper24handnevercausesNS

Urinaryexcretionofmorethan3.5gper24hoursis alwaysglomerulardisease12

NON-PATHOLOGICFORMSOFPROTEINURIA

Orthostaticproteinuria–typicallyinhealthyteensandyoungadults–occursuponassuminguprightposition–usuallylessthan2g/24h

Functionalproteinuria–patientswithnormalkidneysbutexperiencing:-highfever-congestiveheartfailure-exposuretocold-resolveswithresolutionofprecipitatingeventPersonsyoungerthan30yearswhoexcretelessthan2g

ofproteinperdayandwhohaveanormalcreatinineclearanceshouldbetestedfororthostaticproteinuria13HYPOALBUMINEMIA

mostcommonclinicalcorrelateofsevereproteinuriawithalmostalwaysassociatedwithhypoalbumemia

relationshipbetweenproteinuriaandhypoalbuminiaisvariable

variabilitypartlydependsonliver’scapacitytosynthesizealbumin

6-10percentofalbuminpoolnormallycatabolizeddaily14HYPOALBUMINEMIAINNEPHROTICSYNDROMEMAYRESULTFROM:

Increasedloss(inurine)orcatabolism(filteredalbuminincreasedtubularreabsorptionenhancedcatabolismbytubularcells;increasedrenalcatabolisminpartoffsetbydecreasedextrarenalcatabolism.

Decreasedsynthesisofalbumin(hepaticsynthesisinnephroticsyndromeisnormalorincreased,butbelowmaximalrateachievedinotherhypoalbuminemicstates)

Changesinalbumindistribution(someevidenceforredistributionintoothercapillarybeds)15HYPOALBUMINEMIA

Highglomerularpermeabilityleadstohyperalbuminuriaand,eventually,tohypoalbuminemia.

Hypoalbuminemialowerstheplasmacolloidosmoticpressure,causinggreatertranscapillaryfiltrationofwaterandthedevelopmentofedema.

Capillaryhydrostaticpressureandthegradientofplasmatointerstitialfluidoncoticpressuredeterminethemovementoffluidfromthevascularcompartmenttotheinterstitium.

Fluidthatisnotabsorbedbackintothevascularsystemuntilithasreachedthevenousendofthecapillarybedisusuallyabsorbedbythelymphaticsandreturnedbacktothevascularspace.16HYPOALBUMINEMIAResponsestodecreasedbloodvolume

Decreasedrenalperfusion,reninrelease,sequentialgenerationofangiotensinII,aldosterone,andsubsequentsodiumreabsorption

ADHreleaseandresultantwaterretentionatcollectingduct

DecreasedatrialnatureticpeptidereleaseandresultantdecreasedsodiumexcretionEdemaisresultofsaltandwaterretention17HYPERLIPIDEMIA

Clinicalcorrelateofsevereproteinuria

Totalplasmacholesterollevelsincreaseasproteinuriabecomesheavy

LevelsoftriglyceridesonlymildlyincreasedPathogenesis

lossofalbumin&associatedhypoalbuminemiadirectly orindirectlystimulateshepaticproteinsynthesis

reducedcolloidosmoticpressureresultsinincreased albuminandlipoproteinsynthesisanddecreased catabolismoflipoproteinsinnephroticsyndrome

increaseintotalplasmaandLDLcholesterolwitha normalorreducedHDLcholesterolincreasedriskof prematureatherosclerosis18HYPERCOAGULABILITY(I)

Lowzymogenfactors,factorIX,factorXI.

Inreasedprooagulatorycofators,factorV,factorVIII

Increasedfibrinogenlevels

Decreasedoaulatoryinhibitors:antithrombinIII(butproteinCandSincreased)

Alteredfibrinolyticsystem(α2-antiplasminincreased,plasminogendecreased)

Increasedplateletreactivity:thromoytosisIncreasedreleasereactioninvitro(ADP,thrombin,collagen,arachidonicacid,epinephrine)

Alteredendothelialcellfuntion19HYPERCOAGULABILITY(II)Patientscandevelopspontaneousperipheralarterialorvenousthrombosis,renalveinthrombosis,andpulmonaryembolism.Clinicalfeaturesofacuterenalveinthrombosisinclude•suddenonsetofflankorabdominalpain,•grosshematuria,•aleft-sidedvaricocele(thelefttesticularveindrainsintotherenalvein),•increasedproteinuria,andanacutedeclineinglomerularfiltrationrate.•Chronicrenalveinthrombosisisasymptomatic.20METABOLICCOMPLICATIONS

MetaboliccomplicationsofNSincludeproteinmalnutritionandiron-resistantmicrocytichypochromicanemiaduetotransferrinloss.

HighglomerularpermeabilitycausestheexcretionofvitaminD–bindingproteinandcomplexesintheurine,leadingto

(1)malabsorptionofcalciumanddevelopmentofbonedisease(eg,osteitisfibrosacystica)becauseofenhancedparathyroidhormoneproductionand

(2)osteomalaciabecauseofimpairmentinmineralization.21SYMPTOMSANDSIGNS

Mostoften,theedemaismobile-detectedintheeyelidsinthemorningandintheanklesafterambulation.

Oliguriaandevenacuterenalfailuremaydevelopbecauseofhypovolemiaanddiminishedperfusion.22COMPLICATIONS

ProlongedNSmayresultinnutritionaldeficiencies,includingproteinmalnutritionresemblingkwashiorkor,brittlehairandnails,alopecia,stuntedgrowth,demineralizationofbone,glucosuria,hyperaminoaciduriaofvarioustypes,K+depletion,myopathy,decreasedtotalCa,tetany,andhypometabolism.

Spontaneousperitonitismayoccur,andopportunisticinfectionsareprevalent.Thehighincidenceofinfectionisthoughttobeduetotheurinarylossofimmunoglobulins.

Coagulationdisorders,withdecreasedfibrinolyticactivityandepisodichypovolemia,areaseriousthromboticrisk(notably,renalveinthrombosis).2324

MINIMALCHANGEDISEASE

90%childhoodnephroticsyndrome

Commoninyoungadults

15%totaladultcases

Steroidresponsive(80%)

steroidsensitive’

2ndlinetherapyAssociations

NSAIDs

Paraneoplastic

Hodgkin’sdisease25MINIMALCHANGEDISEASE26MINIMALCHANGEGN:Synonyms:

Incidence: Etiology: Clinical Features: Lab Features: Pathology: Clinical Course:

Nildisease,lipoidnephrosis,footprocess disease

80%ofnephroticsyndromein children(1-8yrs.),mostlymale. Adultsin2nd-3rddecade. Idiopathic.Lossofnetnegative chargeoncapillarybasement membrane. Nephroticsyndrome.Historyof recentURIin30%.Association withHodgkin’slymphoma. OverlapwithFSGSpatients. Selectiveproteinuria.Nospecific laboratoryfindings. LM-Normal.IF-Negative. EM-Focalfusion/lossoffoot processes.Spontaneousremissionin25-40%.Completeremissionin65-70%ofpatients.SteroidresistantpatientsmayprogresstoFSGS.27

FSGSMostcommonidiopathicnephroticsyndromeinadults(33%)IncreasingincidenceMorecommoninblacksTreatmentverydifficult28FSGSMildModerateCollapsing

ASSOCIATIONS

Idiopathic Morbidobesity Heroinabuse HIVinfection NSAID (Minimalchangedisease)Normal29Lab:MesangioproliferativeGNIncidence:Commontype,AlmostallagesClinical:Almosteveryonehashematuria.PartofthemwithNephroticsyndrome.Slowprogression.Notspecial,mayIgAincrease.Path:DiffuseproliferativeGNinmesangialregion.Electron-densedeposits.ClinicalSlowprogression.NormallynohypertensionorGFRlossCourse:30MEMBRANOUSGNSynonyms:Epimembranous,extramembranousGNIncidence:40-60Years,50%ofadultnephroticsyndrome.Etiology:Immunecomplexdisease.Idiopathicinmostpatients,associatedwithinfections,drugs,carcinomas,andheavymetals.Clinical:Nephroticsyndromein80%,asymptomaticproteinuriain20%.Microscopichematuria.Lab:Non-selectiveproteinuria±hematuria.Path:Diffuse,uniformBMthickeningwithsubepithelialprojections(“spikes”).Diffuse,coarselygranularIgGandC3depositsalongbasementmembranes.Electron-densesubepithelialdeposits.ClinicalCourse:Excellentprognosisinchildren.SomeadultsdevelopESRD.Exclusionofotherdiseasesisrequired.31MEMBRANOUSGN32Lab:MEMBRANOPROLIFERATIVEGNIncidence:Childrenandyoungadults(5-25years).Etiology:ChronicimmunecomplexGN.Associatedwithchronicinfections,SLE,cancer,cirrhosis,heroinabuse,etc.Clinical:Nephroticsyndromein50%,acutenephriticsyndromein20%.RecenthistoryofURIin50%.Hypertensionand/orrenalinsufficiency.Hypocomplementemiaofclassicandalternatepathways.C3nephriticfactor(C3NEF).Circulatingimmunecomplexes.Path:DiffuseproliferativeGNwiththickeningoftheglomerularcapillarywalls,,andGBMsplitting(“tram-tracking”).Diffuse,coarselygranularC3andIgGdepositsalongGBMs.Electron-densesubendothelialdeposits.ClinicalProgressivedeteriorationofrenalfunction±shortCourse:remissions.ESRDwithin10yearsin50%of childrenand80%ofadults.33MEMBRANOPROLIFERATIVEGN

TypeI