内科学教学课件：Nephrotic Syndrome

NephroticSyndromeOverviewDefinitionnephroticsyndromePathologyofprimarynephroticsyndromeandclinicalfeaturesDiagnosisandDifferentialdiagnosisComplicationsTreatmentofprimarynephroticsyndromeSecondarynephroticsyndrome-Diabeticnephropathy-Lupusnephritis-RenalAmyloidosis-HBV-associatednephropathy

ThemostcommonsyndromeofkidneydiseaseAcuteNephriticsyndromeNephroticsyndromeAsymptomaticurinaryabnormalitiesAcuterenalfailureorRapidlyprogressiverenalfailureChronickidneydisease(Table1)

(一)急性肾炎综合征(二)肾病综合征(三)无症状性尿检异常(四)急性及急进性肾衰竭综合征(五)慢性肾脏病(表1)2012KDIGO指南更新再强调：

蛋白尿水平及GFR是评估CKD进展的重要指标图注：绿色：低风险（如没有其他肾脏疾病的标志物）；黄色：中度增加风险；桔色：高风险；红色：非常高风险持续性蛋白尿诊断标准和范围Kidneyinter.,Suppl.2012;2:337–414.

Pathophysiology:ProteinuriaFigure3.

lessthan150mg/24

hoursInnormalconditionalittleproteincanbeavailableinurineThreemainmechanismofproteinuriaGlomerular(increasefiltration)Tubular(decreasereabsorption)Overflow(markedoverproduction ofaparticularproteinNephroticSyndromeItisnotadiseasebutagroupofsignsandsymptomspresentswithedemaproteinuriausually>3.5g/24hrsserumalbumin<30g/Lotherfeatures:hyperlipidaemia,andhypercoaguablestatePathophysiologyPathologyofPrimaryNephtoticSyndromeMinimalChangeDiseaseMesanginalProliferativeGlomerulonephritisFocalSegmentalGlomerulosclerosisMembranousNephropathyMembranoproliferativeGlomerulonephritis(MPGN)NormalglomerulusLightmicrographofanormalglomerulus.Thereareonly1or2cellspercapillarytuft,thecapillarylumensareopen,thethicknessoftheglomerularcapillarywall(longarrow)issimilartothatofthetubularbasementmembranes(shortarrow),andthemesangialcellsandmesangialmatrixarelocatedinthecentralorstalkregionsofthetuft(arrows).CourtesyofHelmutGRennke.

Lightmicrographofanessentiallynormalglomerulusinminimalchangedisease.Thereareonly1or2cellspercapillarytuft,thecapillarylumensareopen,thethicknessoftheglomerularcapillarywallsisnormal,andthereisneitherexpansionnorhypercellularityinthemesangialareasinthecentralorstalkregionsofthetuft(arrows).CourtesyofHelmutGRennke.

MinimalchangediseaseMinimalchangediseaseMinimalchangediseaseElectronmicrographofanormalglomerularcapillaryloopshowingthefenestratedendothelialcell(Endo),theglomerularbasementmembrane(GBM),andtheepithelialcellswithitsinterdigitatingfootprocesses(arrow).TheGBMisthinandnoelectrondensedepositsarepresent.Twonormalplateletsareseeninthecapillarylumen.CourtesyofHelmutRennke,MD.

NormalglomerulusElectronmicrographinminimalchangediseaseshowinganormalglomerularbasementmembrane(GBM),noimmunedeposits,andthecharacteristicwidespreadfusionoftheepithelialcellfootprocesses(arrows).CourtesyofHelmutRennke,MD.

MinimalchangediseaseMinimalChangeDiseaseMostfrequentcauseofnephroticsyndromeinchildren.generalizededemawithnormalrenalfunctionandselectiveproteinuria.Hematuriaisabsentandpatientsarenormotensive.LM-Normal.IF-Negative.EM-footprocessfusion.Respondsreadilytosteroids,althoughrelapsesarecommon.Thelongtermprognosisisexcellent.SteroidresistantpatientsmayprogresstoFSGS.

FocalSegmentalGlomerulosclerosis

Occursinchildrenandadults,representingabout10%ofallcasesofnephroticsyndrome.Hematuria,hypertension,andnonselectiveproteinuriamaybepresent.LM:focalsegmentalglomerularsclerosis(hyalinosis)isseen.IF:IgMandC3inthesescleroticareas.Oftenpoorlyresponsivetosteroids.Childrenmayrespondmorefavorablythanadults.

Figure6.Lightmicroscopicappearancesinfocalsegmentalglomerulosclerosis.Segmentalscarswithcapsularadhesionsinotherwisenormalglomeruli.

MembranousnephropathyMostcommoncauseinadults.Especiallyelderlypeople.LM:glomerularbasementmembranethickeningwithnocellularproliferation.IF:granulardepositsofIgGandC3alongthebasementmembrane.EM:thickeningofbasementmembraneandfootprocessfusion.Theprognosisisvariable.Spontaneousremissionsoccurinsomecaseswhereasothersprogressslowlytochronicrenalfailure.Steroidsandimmunesuppressiveagentsmaybeeffectiveinretardingtheprogressiontorenalfailure.

ImmunofluorescencemicroscopyofMN(IgG)MembranousnephropathyLightmicrographofmembranousnephropathy,showingdiffusethickeningoftheglomerularbasementmembrane(longarrows)withessentiallynormalcellularity.Notehowthethicknessoftheglomerularcapillarywallsismuchgreaterthanthatoftheadjacenttubularbasementmembranes(shortarrow).Therearealsoareasofmesangialexpansion(asterisks).Immunofluorescencemicroscopy(showinggranularIgGdeposition)andelectronmicroscopy(showingsubepithelialdeposits)aregenerallyrequiredtoconfirmthediagnosis.CourtesyofHelmutRennke,MD.

ElectronmicrograpsshowsstageIImembranousnephropathy.Electrondensedeposits(D)arepresentinthesubepithelialspaceacrosstheglomerularbasementmembrane(GBM)andundertheepithelialcells(Ep).Newbasementmembraneisgrowingbetweenthedeposits,leadingtoaspikeappearanceonsilverstain.CourtesyofHelmutRennke,MD.

MembranousnephropathyComplicationsInfectionCoagulationdisordersAcuterenalfailureProteinmalnutritionanddyslipidemiaTheimpairmentofnormaldefenseisnotwellunderstood;

LowlevelsofimmunoglobulinGInfectionPatientswiththenephroticsyndromearesusceptibletoinfection,whichwastheleadingcauseofdeathinchildrenwiththenephroticsyndromebeforeantibioticsbecameavailable.Pneumococcalinfections,especiallyperitonitis,wereparticularlycommonComplicationsdecreasedlevelsofantithrombin

,plasminogen(urinarylosses),

hyperfibrinogenemiaincreasedplateletactivation

10to40percentofpatientsdevelopvenousthromboemboli,particularlydeepveinandrenalveinthrombosis

Renalveinthrombosiscanpresentacutelyor,muchmorecommonly,inanindolentmanner.

Theacutepresentationincludesflankpain,grosshematuria,andadeclineinrenalfunction..

Thromboembolism

Hypercoagulability

Hypovolemia

InterstitialedemaRenalperfusion↓ObstructionoftubularlumenRenalveinthrombosisNonsteroidalantiinflammatorydrugsAndotherdrugsPre-renalRenalfailureAcuteRenalFailurehypoalbuminemia,MalnutritionRetardationnegativenitrogenbalancehyperlipidemiaUrinarylossofhormones:vitamineD,T3andT4Edemaofthegastrointestinaltract:anorexiaandvomitInfectionImmunoglobin↓↓ThrombosisandemboliCardiovasculardiseaseeventsacceleratedatherosclerosisProteinmalnutrition

AmyloidosisLupusnephritisDiabeticnephropathyNephroticsyndromeassociatedmalignanceDifferentialDiagnosisRestDietary:sodiumandwaterrestriction(approximately3g/day)DiureticsLowerintraglomerularpressureStatintherapydonotrecommendroutineprophylacticanticoagulation.Generaltherapy(Nonimmunosuppressivetherapies

)TreatmentImmunosuppressivetherapyTreatmentGlucocorticoidsOtherimmunosuppressiveagents

—

Cyclophosphamide

orcyclosporineA

aloneorincombinationwithprednisonforrelapsing,glucocorticoid-dependentdiseaseorglucocorticoid-resistdisease.Dailyoralprednisone

(1mg/kgperdaytoamaximumof80mg/day)Asingledoseuponawakening(usuallybetweesevenandnineAM)Someclinicianspreferalternate-dayprednisonefromthebeginningtominimizethetoxicityoflong-termdailyprednisone,ataninitialdoseof2mg/kgeveryotherday(toamaximumdoseof120mg)Minimumofeightweeks,maximumduration

is16weeksSlowtaperingisperformedbothtosustaintheremissionandtoavoidadrenalsuppressionGlucocorticoidtherapyResponsetoGlucocorticoidtherapy

Acompleteremissionisareductioninproteinuriato300mg/day.Apartialresponseisareductioninproteinuriaof50percent,withabsolutevaluesbetween300mgand3.5g/day.Arelapseisreturnofproteinuriatoapproximately3.5gm/dayinpatientswhohadpreviouslyundergoneacompleteorpartialremission.Glucocorticoid-dependencereferstorelapsewhilerequirementforcontinuationofsteroidstomaintainremissionGlucocorticoid-resistancereferstolittleornoreductioninproteinuriaafter16weeksofadequateprednisone

therapy.Infectiousdisease:HeightenedriskoftypicalinfectionsOpportunisticinfections:HerpeszosterEndocrine:DiabetesmellitusBone:Osteoporosis

Gastrointestinal:Pepticulcerdisease,Pancreatitis,UGBEye:Elevatedintraocularpressure/glaucoma,ExophthalmosCardiovascular:HypertensionDermatologicandsofttissue:Skinthinningandpurpura,Cushingappearance,Acne.Majorsideeffectsassociatedwithcorticosteroidtherapy

Cyclophosphamide（CTX）

Azathioprine

（AZA）

Cyclosporine

（CysA）

Mycophenolate（MMF）

Tacrolimus(FK506)ImmunosuppressiveagentsNotthefirstchoiseanddon’tusealoneFrequentlyrelapsing,glucocorticoid-dependentorglucocorticoid-resistcasesImmunosuppressiveagentsA12-weekcourseof2mg/kgperdayofcyclophosphamide

Cumulativedoseof168mg/kgNeutropeniaandinfection—BonemarrowsuppressionGonadaltoxicity—atotaldosegreaterthan200to300mg/kgforCTX,Malignancy—acutelymphoblasticleukemia.AlopeciaandhemorrhagiccystitisLiverfunctioninjury.Otherscyclophosphamide－mostcommonlyuse

AlkylatingagentsCyclosporineatadoseof3to5mg/kgperdaytomaintainwholebloodtroughlevelsof100to200µg/LatleastsixmonthsCyclosporinesolutioncanbemixedwithmilk,chocolatemilk,ororangejuice(butnotgrapefruitjuice)atroomtemperature.Tacrolimusis0.05mg/kgperdaytomaintainwholebloodtroughlevelsbetween3and5µg/L.Thedosemaybeincreasedtoachieveahighertroughlevelbetween5and8µg/L,ifthereisnoreductioninproteinuriabytwomonths,providingtherenalfunctionhasnotworsened.

DOSAGEANDADMINISTRATIONCalcineurininhibitorsNephrotoxicity

—Hypertension

—

causedbyrenalvasoconstrictionandsodiumretention,Neurotoxicity—

severeheadache,visualabnormalities,andseizuresMetabolicabnormalities

—

GlucoseintoleranceInfections

—

Bacterial,viralandfungalinfectionsRiskofmalignancy

Othersideeffects

—

Gastrointestinalsideeffectsincludeanorexia,nausea,vomiting,diarrheaandabdominaldiscomfort

AdverseeffectassociatewithCalcineurininhibitorsThetargetdosageofMMFisgenerallybetween1.5to2gramsdaily.Startingwithlowerdosesatfirst(eg,500mgdailyforseveraldays)mayimprovepatients'gastrointestinaltoleranceofMMFAdverseeffect:Bonemarrowsuppression:cytopenias,requireregularmonitoringGastrointestinal

—

nearly75percentinitiallyhadgastrointestinal(GI)symptoms,includingnausea,diarrhea,andabdominalcramping.ThesesymptomsweretoleratedbetterwithtimeMycophenolatemofetil:

(MMF)

Treatedwithheparin

followedbywarfarinThegoalINRis1.5to2.0Durationofanticoagulation

—

Warfarin

therapyisgivenforaminimumof6to12months.Aslongasthepatientremainsnephrotic.Serumalbuminbelow2.0g/dL(20g/L)OptimaltherapyofhypercoagulabilityLotension,Losartan,Vasartan

,etclowerintraglomerularpressure,reductioninproteinexcretion,slowtherateofdiseaseprogression.Itisnotdependanttotheantihypertensiveeffect.Itispositivelyrelatedtothedoseofdrug.ACEI

and

ARBAcuterenalfailureHyperkalemiaNotices:Hypovolummia,useNSAIDtogetherSideeffectsPathologyIncidenceInfectionHematuriaHypertensionRenalinjuryTreatmentPrognosisMCDchildren（75％）commonlyseen－－－90％steroidsgoodFSGS5－15%younger＋（65％）+(30%)+(10%)1/3

sensitive,dependentandresistrespectively

about10yearstoESRDMsPGN30%youngerandadult＋＋＋normalsomesensitive,somenotaccordingpathologyMembranousGNelderlyrarerareSteroid+cytotoxic1/4spontaneousremissions,progressslowlyMPGNyounger＋grosshematuria＋＋+(25％)resistpoorClinicalFeaturesandPathologyofPrimaryNephroticSyndrome20percentofcasesofsteroid-resistantNSareduetomutationsoftheNPHS1,NPHS2,WT1gene.Inpatientswithsteroid-resistantNSduetogenemutation,

wedonotrecommendimmunosuppressivetherapyOptimaltreatmentofSRNSnotduetoageneticdisorderis

unknown,Acombinationofcyclosporine

andprednisoneisrecommended,.Alternatively,cyclophosphamide,andtacrolimus

havealsobeenused.Hotpoints1:AboutFSGSSecondaryGlomerularDisease–-SecondarynephroticsyndromeWhytalkaboutdiabeticnephropathy?MostcommonsinglecauseESRDintheUS,Europe,andJapan17milliondiabeticsintheUS20-30%diabetics(bothtypeIandtypeII)developdiabeticnephropathy40%ESRDinUSrelatedtodiabeticnephropathyDefinitionAmicrovascularcomplicationofdiabetesmarkedbyalbuminuria,elevatedbloodpressure,andadeterioratingcoursefromnormalrenalfunctiontoESRD.ClinicalfeaturesGraduallyprogressiveproteinuriaMicroalbuminuriaisfirstclueBlandurinesediment–noRBCs,casts,etcGraduallydecreasingGFRPatientsasymptomatic,butdevelopworseninghypertensionNature

courseClinicalStagesofDN(Type1)1ststage:Renalenlargementandhyperfiltration2ndstage:Reversemicroalbuminuria,UAEisnormal(5-15).3rdstage:Microalbuminuria,incipientnephropathy(6-15Y)20-199ug/min30-299mg/24hcollection4thstage:Macroalbuminuria,overtnephropathy(10-15Y)>200ug/min>300mg/24hcollection5thstage:Progressiverenalfailureandsevereproteinuria(15-25Y)HowtodistinguishfromanotherkidneydiseaseLikelydiabetes:MacroalbuminuriaMicroalbuminuria,andPresenceofdiabeticretinopathyType1diabetesforatleast10yearsNoactiveurinarysedimentLikelyanothercauseofCKD:AbsenceofretinopathyRapidlydecreasingGFRhematuriaRefractoryhypertensionSignsorsxofothersystemicdiseaseTreatmentEarlyscreening TightglycemiccontrolHTNmanagementUseACEIasfirstline,ifnottolerated,useARB.UsethemaximumdoseastoleratedLupusnephritisSystemiclupuserythematosus(SLE)isamultisystem,autoimmuneds.withantibodiesdirectedagainstawidevarietyofcellularcomponentsLupusnephritisisoneofthemostseriousmanifestationsof(SLE).Frequency,race,sexandage

TheprevalenceofSLEis1caseper2000inthegeneralpopulation.SLEismorecommoninblackpeople,HispanicpeopleandAsianthaninwhitepeople.lupusnephritismorecommoninfemalesandtypicallyoccursinpatientsaged20-40years;clinicalrenaldiseasewithaworseprognosisismorecommoninmaleswithSLE.

ClinicalfeaturesVariousorgansystemsareeffected,likeskin,joints,serousmembranes,heart,neurologic,bloodandthekidneys.Rash,oralornasalulcers,synovitis,fatigue,fever,arthritis,serositis,edema,etc.ClinicalsignsLaboratoryStudiesTestsofSLEdiseaseactivityDiseaseactivity:ANA,anti-dsDNA,C3,C4,andCH50

,ESRorCRP.Creatine,urea,urialysisRenalbiopsyisusefulindeterminingprognosisandtreatment.IF:Fullhouse.LupusNephritisStageFeaturesStageINormallookingglomeruliStageIIMesangialexpansionStageIIIFocalproliferative<50%StageIVDiffuseProlif.>50%stageVMembranousStageVIAdv.sclerosinglesionsPathologyoflupusnephritisTreatmentLupusnephritiscantransformfromoneclasstotheotheroverthecourseofthedisease.CorticosteroidtherapyshouldbeinstitutedClassIV(themostaggressiveform)isusuallytreatedwithsteroidsandcyclophosphamide.OtherimmunosuppressantlikeMMF,cyclosporinehasbeenusedinthesecases.Treathypertensionaggressively.Preventosteoporosisetc.AmyloidosisAmyloidosisisaclinicaldisordercausedbyextracellulardepositionofinsolubleabnormalfibrilsthatinjuretissue.AmyloidosisALamyloid(primaryamyloid)associatedwithplasmacelldisorders,mostlyovertmyelomaAAamyloid(secondaryamyloid)isanacutephasereactantassociatedwithchronicinflammatorydiseasesliketuberculosis,osteomyelitis,rheumatoidarthritisandbronchiectasisMorecommoninelderlyTheamyloidisaneosinophilicextracellularsubstance,Congoredstainpositiveandblue-greenbirefringence.AmyloidosisArangeofclinicalpresentationswithrenal,heart,gastrointestine,localdepositionandotherproblemsRenalfailureandnephroticrangeproteinuriaarethemostcommonrenalpresentationAbnormalelevatingofMonoclonalIginbloodandlightchains(BenceJones)inurineinALamyloid.Relatedrenaldisordersincludelightchaindepositdisease,fibrillaryGNandimmunotactoidGNPrognosisforispoor.MonoclonalpatternSPEPUrinarymonoclonalproteinPanelB:Adense,localizedband(redasterisk)representingamonoclonalproteinofgammamobilityisseenonserumproteinelectrophoresisonagarosegel(anodeonleft).PanelA:Densitometertracingofthesefindingsrevealsatall,narrow-basedpeak(redasterisk)ofgammamobilityandareductioninthenormalpolyclonalgammaband.Themonoclonalbandhasadensitometricappearancesimilartothatofalbumin(alb),andhasbeenlikenedtoachurchspire.PanelB:Thisfigureillustratesthecelluloseacetateelectrophoreticpatternofaurinesample.Itrevealsadensebandofproteinwithbetamobility.PanelA:Densitometertracingshowsatall,narrow-basedpeakofbetamobility.Thesefindingsareconsistentwithaurinemonoclonalprotein(BenceJonesprotein);NormalpatternofSPEPCLINICALMANIFESTATIONSRenaldisease

—

asymptomaticproteinuriaorclinicallyapparentnephroticsyndromeCardiomyopathy

—

systolicordiastolicdysfunctionandheartfailure.syncopeduetoarrhythmiaheartblock,andanginaorinfarctionduetoaccumulationofamyloidinthecoronaryarteries.Gastrointestinaldisease

—

Hepatomegalywithorwithoutsplenomegaly.Bleeding,gastroparesis,constipation,etc.Neurologicabnormalities

—

Mixedsensoryandmotorperipheralneuropathyand/orautonomicneuropathyMusculoskeletaldisease

—pseudohypertrophy,alargetongueHematologicabnormalities

—bleedingdiathesis,factorXdeficiencySkinmanifestations

—waxythickening,easybruising,andsubcutaneousnodulesorplaques.Purpura,inaperiorbitaldistribution(raccooneyes).Others:Pulmonary,visualabilityLightmicrographofglomerularamyloidosisshowsnodular,amorphousmaterial(arrows)extendingfromthemesangiumintothecapillaryloopsandnarrowingorclosingthecapillarylumens.ThenodulesaremoreamorphousthanthoseseenindiabeticnephropathybutdemonstrationofamyloidfibrilsonelectronmicroscopyordemonstratinggreenbirefringenceonCongoredstainingisrequiredtoconfirmthediagnosis.CourtesyofHelmutRennke,MD.

Congoredstainviewedunderpolarizedlightofarenalbiopsyfromapatientwithrenalamyloidosis.Greenbirefringence(whitearrows)ofinterstitialamyloiddepositscanbeseen.CourtesyofHelmutRennke,MD.

Electronmicrographshowingexpansionofthemesangiumbyamyoidfibrilsmeasuringbetween9and11nanometersindiameter.Thefibrillarappearanceisbestappreciatedatthearrow.Thesefibrilsaresmallerthanthoseseeninfibrillaryglomerulonephritis.CourtesyofHelmutRennke,MDRenaltubularamyloidosisAmyloidosiswithmarkeddepositioninthetubularbasementmembranesonlightmicroscopy(leftpanel,arrows).TheamyloiddepositsshowgreenbirefringencewhenviewedunderpolarizedlightwithCongoredstain(rightpanel).CourtesyofHelmutRennke,MD.OutcomeSurvivalfromonsetofsymptomsvariesfrom1moto10yr.Therateofdiseaseprogressionisvariableanddependsontheextentoforganinvolvement.Henoch-SchönleinpurpuranephritisHSPisasmall-vesselvasculitischaracterizedbypurpura,