内科学教学课件：肾小球疾病总论

GlomerulardiseasesAgroupofdiseases:pathologicalchanges:glomerularinjuryclinicalmanifestation:protenuria/hematuriacomplicatedcauses/mechanismsvariousclinicalmanifestationdifferentprognosismultipletreatmentPrimaryglomerulardiseasesSecondaryglomerulardiseasesHereditaryglomerulardiseasesImmunemechanismsHumoralCellmediatedNonimmunemechanismsinflammationGlomerulardiseasesImmunemechanismsdepositsofimmuno-complex(IC)antigen+antibodykidneydepositsExtrinsicdrug:nonhomologousserum,penicilinFoods:xenogenicproteinPathogens:specificserotypesstreptococci,HBV,HCVIntrinsicNucleus(SLE)Cytoplasm(ANCA)CellularmembraneAntigenoftumorAntigenofthyroidWhydoesICdepositintheglomeruliLargeareaofglomurularcapallariesMorechancesofcontactNetstructureofCICEasytodepositandsettledownDecreaseclearanceofCICclearancedysfunctionofmesangialcellsDisabilityofmononuclearmacrophageComponentorfunctiondefectofcomplementsBalanceofdepositandclearanceofICdeterminesthdsituationofthediseasesPersistenceofantigenClearancedysfunctionofmesangialcellsDisabilityofmononuclearmacrophageComponentorfunctiondefectofcomplementsICdeposit>clearanceNonimmunemechanismsGlomerularhypertensionHyperlipidemia(LDL-Cho)AdvancedglycosylationendproductsproteinglomerulosclerosisinflammationMediatorsofinflammationAgroupofmoleculeswhichactasmediatorsofinflammationandcomplicatedbiologicalfunctionOriginalmediatorsinkidneyExtrinsiccellsinkidneyInfiltrativeneutrophil,lymphocyte,mononuclearmacrophage,plateletintrinsiccellsinkidneyMesangialcells,tubularcells,endothelialcellsMediatorsofinflammationActiveoxygenandactivenitrogenLipidsComplementsCytokinesAdhensionmoleculesGrowthfactorsVasoactivesubstancesEffectsofinflammationmediatorsToarouseorpromoteProliferationofcellsAccumulationofextracellularmatrixChangesofhistologicalstructureExpressionofimmunomodulatingmoleculesandadhensionmoleculesMechanismofprimaryGNImmuneMesangialcells,tubularcells,endothelialcellsEssentialintheinitiationEssentialintheprogressiveperiodinflammationInflammationcellsExtrinsiccellsIntrinsiccellsInfiltrativeneutrophil,lymphocyte,mononuclearmacrophage,plateletInflammationmediatorsActiveoxygenandactivenitrogen,cytokines,growthfactors,chemotaticfactors,complments,vasoactivesubtances,coagulationandfibrolysissystem,enzymeGlomerularinjuriesNonimmuneSitesofpathologicalchangesMesangiummesangialcellmesangialmatrixBasementmembranePodocyteEndothelialcellPathogenesis

NormalglomerularstructureGlomerulartuftcomposed4majorcomponentsEndothelialcellsVisceralepithelialcellsorPodocytesMesangiumCapillaryloopbasementmembraneCapillarywallcarriesanetnegativechargeactsasboth

charge-selectivesize-selectivefilterGlomerularcapillarywall:

SizeselectivefilterThecapillarywallrestrictsthepassageoflargemoleculesintoBowman'sspace,whilethereislessrestrictionofsmallermolecules.Asradiiincrease,filtrationdecreases,approachingzeroatradii>4.2nmGlomerularcapillarywall:

Charge-SelectiveFilterThecapillarywallrestrictsthepassageofnegativelychargedmoleculessuchasalbuminwhileneutralsubstancespassmorefreelyandarerestrictedbysizefrompassingintoBowman'sspace.PathologicalchangesLMMesangialcells,matrixofmesangiumEndothelialcellsEpithelialcellsBasementmembraneLoopsofglomeruliEMFootprocessBasementmembraneHyperplasyofmesangium(electrondensedeposits)IFSites,appearances,typeofdeposits（IGorC）BasicalchangesProliferationFibrosisandsclerosisNecrosisInfiltrationofinflammationcellsExtentsofinjuryPrimaryGN:glomerularinjury-onlyordominatinginjurySecondaryGN:glomerularinjury-apartofsystematicdiseasesDiffuse:impairedglomeruli>50%Focal:impairedglomeruli>50%Global:impairedcapillaryloopsofaglomerule>50%Segmental:impairedcapillaryloopsofaglomerule<50%PathologicaltypesofprimaryGNMinimalchangeofglomerulonephritisFocalsegmentallesionsDiffuseglomerulonephritisUnclassifiedglomerulonephritisMinimalChangeDisease(MCD)MostcommoncauseofnephroticsyndromeinchildhoodInaprospectivestudyofuntreatedchildrenwithN.S.:minimalchangediseasewasfoundin76.6%.Only10%to30%ofadultcasesofnephroticsyndromePercentagesvaryindifferentpartsoftheworldTheclinicalonsetofnephroticsyndromeassociatedwith:upperrespiratoryinfectionwithroutineprophylacticimmunizationsOthergeneticandenvironmentalfactorsmayalsobeimportantMorphologicFeatures(LM&IF)LM:normalinglomeruli,tubulesandinterstitiumIF:Noimmunedepositsdiffuseeffacementoftheepithelialcell(podocyte)footprocessesMorphologicFeatures(EM)ClinicalCourseMostpatientswithMCDdevelopmildperiorbitaledemaasinitialcomplaint

Proteinuria:tobe"selective“primarilyofalbuminMicroscopichematuriaisrare(13to36%)Hypertension:alsounusualTreatment:Mostpatients(90%)respondtoan8weekcourseofsteroidsCytotoxicagents:maybeusedinsteroidresistantcases(~10%)Renalfailure:rareRelapsesarecommonFocalSegmentalGlomerulosclerosis(FSGS)

(a)oftenpresentwithsevereproteinuria(b)30-50%combinewithhypertension(c)HIVmayassociatedwithFSGS(d)subepithelial“hump”ofglomuerulusinelectronmicroscopy

FocalSegmentalGlomerulosclerosis(FSGS)Prevalenceinidiopathicnephroticsyndrome:10%ofchildhood15-20%ofcasesofadultSymptomsandsigns:commonwithproteinuriamicroscopichematuriaHypertensionPathogenesis:sclerosinglesionsandtheirprogressivenaturearedebatedhyperfiltration,increasedintracapillaryglomerularpressureMorphologicFeaturesLM:focalandsegmentalglomerularsclerosiswithcapillaryloopcollapse,hyalineandlipiddepositionandoftenadhesiontoBowman'scapsuleTheremainderoftheglomerulartuftisnormalinappearance;thustheterm'segmental'.Thelesionsareconsideredtobeginortobemorecommonnearthecorticomedullaryjunction.IF:DepositionofIgMandC3inthemesangiumorintheareasofsegmentalsclerosismaybeseen,butnoimmunecomplexdepositionispresent.EM:effacementofpodocytefootprocesses.Podocytedenudationmaybepresentfocallyasanearlylesion,andsegmentalsclerosismayalsobeseenClinicalCourseFSGSmaybe:

primary(idiopathic)secondarytoanumberofetiologicagent:

UnilateralrenalagenesisRenalablationSicklecelldiseaseMorbidobesity(withorwithoutsleepapnea)CongenitalcyanoticheartdiseaseHeroinnephropathyHIVnephropathyAgingkidneyMembranousGlomerulonephritis（MGN）

Antibodymediateddisease

ICslocalizetosubepithelialofthecapillaryloopbetweenouteraspectofGBMandpodocyteImmunecomplexes

developinsitudepositionofcirculatingICs(lesslikely)antibodymaybindtointrinsicglomerularantigenexogenousantigenplantedonthecapillarywallSerumcomplementlevelwasnormalClinicalManifestationmorecommoninadults(peak40-50y/o)mostlyolderthan30yearsatdiagnosis35-50%ofcasesofadultnephroticsyndromeMostpatientspresentwith:heavyproteinuria:mostcommonlyinnephroticrangeinsidiousinonsetfewpatientsaccompanyingmicroscopichematuriaMorphologicFeaturesCapillarywallsarethickenedandnumeroussubepithelial"spikes"arepresentoncapillariesofthisglomerulus,representingelaborationofbasementmembranebetweensubepithelialimmunedeposits.LMImmunofluorescenceMicroscopyDirectimmunofluorescencemicroscopyoffrozentissuedemonstratesbrightgranularstainingofthesubepithelialaspectofthecapillaryloopswithantibodytoIgGElectromicroscopyUltrastructurallynumeroussubepithelialelectrondensedepositsarepresent.Thedepositsareseparatedbybasementmembranecorrelatingwiththe"spikes"seenbylightmicroscopy.MembranoproliferativeGlomerulonephritis(MPGN)(mesangiocapillaryglomerulonephritis)ChronicprogressiveglomerulonephritisoccursinolderchildrenandadultsCirculatingimmunecomplexes(CIC)havebeenidentifiedin50%ofpatientsactivationofthecomplementsystemwithhypocomplementemia,isahallmarkofMPGN.MPGN(IF)TypeI:subendothelialandmesangialdepositsofIgGandC3MPGN(EM)ElectronmicroscopyElectronmicroscopyTypeI:depositsinsubendothelialandmesangialDuplicationofthecapillaryloopbasementmembranebetweenthedepositsandinterposedmesangium,andtheendothelialcells.ClinicalCourseofMPGNClinicalmanifestation:NephroticsyndromeAbnormalurinarysedimentwithnon-nephroticproteinuriaAcutenephritisLab.Data:depressedserumcomplementlevelsInsummaryProliferationofmesangiumcanpresentsinvarioustypesofGNProliferationandsubsequentstiffnessofmesangiummaybetheresultsofvarioustypesofGNFSGS:primary—laterphaseofthediseaseitselfsecondary—laterphaseofothertypeofGNCrescentscanpresentsindifferenttypesofGNClinicalmenifestationProteinuriaUrinaryproteintest—positiveUrinaryproteinexcretionrate>150mg/24hQuantity:Mild:<1.5g/dModerate:1.5-3.5g/dSevere:>3.5g/dHematuriaRBC>3/HP(fresh,10ml/sample,1500rmpcentrifugefor5min,sedimentobservation)GrosshematuriaRedcolorofurine,1mlblood/1LurineRBCfromglomeruliSqueezingthroughGBMChangingwhenpassingtubulewithdifferentosmosisDismorphicRBCPhasecontrastmicroscopyDismorphicRBC>50%,hypothesisofglomerularbleedingDismorphicRBC>50%,finaldiagnosisofglomerularbleedingUrinaryRBCvolumedistributioncurveDissymmetrycurveMCVofurinaryRBC<thatinbloodedemaGlomerulardiseasesGFR↓IntrinsicRASoraldosterone↑Watersodiumfiltration↓Watersodiumreadsorpation↑PrimaryWaterandsodiumretentionEffectivecirculationbloodvolumn↑edmaEffectivecirculationbloodvolumn↓LargeammountofurinaryproteinlosthypoalbuminemiaColloidosmoticpressure↓secondarywaterandsodiumretentionhypertentionGlomerulardiseasesPrimaryWaterandsodiumretentionVolumndependenthypertensionStimulus,suchasischemiaVessoconstrictivesubstances↑RASALDVessoactivesubstancesdependentVessodilatorysubstances↓PGI2,PGE2ClinicaltypesofGNGlomerulonephropathyConfinedconceptLeadingmanifestation:proteinuria/hematuriaExtensiveconceptGlomerulardiseasesGlomerulonephritisLeadingmanifestation:hematuria/proteinuriaClinicalmanifestationofGNinitiationhematuriaproteinuriaEdema,hypertentionRenalfailureAcuteGNacute100%100%frequentresumablerapidprogressiveGNacute100%100%frequentARFChronicGNlatentfrequentfrequentfrequentCRFLatentGNlatentfrequent<1g/d--AcuteglomerulonepritisEtiology:streptococcusothers:bacteriavirusesparasitesantigen:componentsofcytoplasm/membranefrequentlyCIC

PathologicalchangesEndocapillaryproliferativeGNAcutephaseProliferationofendothelial/mesangiumRecoveryphaseOnlymesangiumproliferation,sometimesminorinjureClinicalmanifestationEpidemiology:primarilychildren,sometimesadult/agedPreliminaryinfectionFrequentlytonsillitis,upperrespiratoryinfectionLatentperiod:1-3wOccasionallyskininfectionLatentperiod:longer,lessthan4wNephritissyndromeHematuria:100%,40%aregrosshematuriaProteinuria:frequently,<20%areNSEdema:>90%Hypertension:80%Renalfailure:mild,ARFLaboratoryfindingAcutephaseofinfectionofstrep.ElevatedASOtiterOnlythemarkerofinfection,notnephritisAcutephaseofimmunereactionSerumC3/totalcomplement↓,returnnormalwithin8wBloodCIC↑NaturalhistoryEdemaandhypertentionDisappearinonemonthHematuria,proteinuriaUsuallyreduceinonemonth,resolvein2-3monthsSomeresolvein6-8monthsC3:returntonormalintwomonthsdiagnosisPoints:Preliminaryinfection/latentperiodAcuteonsetSurelyhematuria,frequentlyedemaandhypertentionASO↑c3↓--dynamicchangeSelflimitationIndicationsofrenalbiopsyOligouria>1w,exceptECBV,insufficient,urinarytractobstruction,etcProgressiverenalfailureUnresolvedin2monthsUntypicalmanifestation,orwithNStreatmentSupportivetreatmentRestFoodandwaterRestrictiveintakeofNaCL<5g/dIfmoderatetosevereedemaorhypertentionWaterIfdecreasedurinevolumnProteinRenalfailure,butnotdialysisyetTreatmentofinfectionPenicilinfor2wTonsillectomyifrecurrentattacksoftonsillitisPatientisstable:Upro<1g/d,Urbc<10/HPPenicilinfor2wbeforeandafterthesurgerySymptomatictreatmentDiuresisAntihypertentiondialysisprognosisHematuria,proteinuriaUsuallyreduceinonemonth,resolvein2-3monthsSomeresolvein6-12months1%ARFdeath6-18%CGN?RapidlyprogressiveglumerulonephritisRapidlyprogressiveglumerulonephritissyndromeSomeinducedbyrespiratoryinfectionAcuteonset,rapidlyprogressiveRenalfailurewithinafewweekstoafewmonthsPrimaryRPGN:crescenticGNOtherprimaryGN:otherpathologicalchangeswithlotsofcrescentsSecondaryRPGN:SLE,SHP,etcType1AntiGBMType2ICType3Pauci-immuneLinearGBMdepositsGranularGBM/mesangiumdeposits-Anti-GBM+C3↓CIC↑70-80%smallvesselANCA+Theyoung/middleagedThemiddleaged/agedThemiddleaged/ageddiagnosisAcuteonsetRapidlyprogressiveRenalfailurewithinafewweekstoafewmonthsAcuterenalfailure-chronicrenalfailureTreatment-early!!!AimtohumoralimmunemechanismPlasmapheresisdiscardtheantibodiesplasmexchangeimmoadsorption,type1typ2Drugs:glucocorticoid+cytotoxicdrugsMP05.-1.0g/d,repeatifnecessaryCTXtype2-type3SymptomatictreatmentRenalfailureBalanceoffluid,electrolytesandacidbaseDialysisInfectionhypertensionprognosisHardlyrelieveMostlyCRF-deathRiskfactors:type1worst,type2worse,type3bad