病理学英文版教学课件：08 The Diseases of Urinary System

TheDiseasesofUrinarySystem

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Kidney---producingurine---importantfunctions

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Ureter(输尿管),bladder,urethra（尿道）---storingoreliminatingurineTheAnatomyoftheUrinarySystemFourbasicmorphologiccomponentsGlomeruli:immunologicallymediated

TubulesInterstitiumBloodvesselstoxic/infectiousagentsSomeagentsaffectmorethanonestructure.

Maintypesofurinarydiseases

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Inflammation

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glomerulonephritis

肾小球肾炎

---pyelonephritis

肾盂肾炎

Stone

urolithiasis尿石症

---nephrolithiasis肾结石

---hydronephrosis肾盂积水

Tumor---renalcellcarcinoma---Wilmstumor---urothelialcarcinoma

(transitionalcellcarcinoma)NormalstructureofglomerulusGlomerularFiltration1.Glomerularfiltratingmembrane

Fenestratedendothelium---70~100nm

Glomerularbasementmembrane(GBM)---NegativelychargedAmeshworkoffinefibrils(Col-IV,laminin)Embeddedinanamorphousmatrix(FN)Richinheparinsulfate/glycosaminoglycanPAS/PASMstaining(+)

Visceralepithelium

---Podocytes

Slitdiaphragm20~30nmSievepore4~14nm

Cytoskeletonproteins(nephrin,podocin,etc.)Anegatively-chargedcoatGlycocalyx2.Mesangialregion---axialareaofglomerulus

Mesangialcells(MsC)

系膜细胞Mesangialmatrix

系膜基质<4MsC/mesangialareaCrescent3.Bowman’scapsuleHowtoaffectrenalfunctions?Agroupofhypersensitivitydiseasesaffectingglomeruli2categoriesPrimaryGN---limitedinkidneyalong,unknowncauseSecondaryGN---secondarytosystemicdiseasesGlomerulonephritis，GN

EtiologyandPathogenesis

Glomerularinjurycausedbyimmunecomplexes

DepositionofcirculatingimmunecomplexesinglomeruliAntibodiesreactinginsituwithintheglomerulusIntrinsicglomerularantigens(fixed)Moleculesplantedwithintheglomeruli循环免疫复合物型肾炎Circulatingimmunecomplex-mediatednephritis

Antigens:(1)exogenous:bacteria(streptococci),virus(HBV),Treponemapallidum(梅毒螺旋体),parasite,Plasmodiumfalciparum(恶性疟原虫),foreignserum,drug,toxin(2)endogenous:systemiclupuserythematosus(SLE,系统性红斑狼疮),macroglobulin(巨球蛋白),thyroglobulin(甲状腺球蛋白),carcinoembryonicantigen(CEA)

Inmostcases,theincitingantigensareunknown.“Innocentbystander”

Antigen-antibodycomplexesareformedinthecirculationandthentrappedintheglomeruliAg-AbcomplexesformedTrappedinglomeruliActivationofcomplementsRecruitmentofleukocytesInjuryIF:complementsdepositionIF:IgdepositionEM:electro-densedepositsLM:

inflammatoryinfiltrationIntrinsiccellsproliferationImmunofluorescencestaining(IF):GranulardepositsAgIFAbEM:ElectrondensedepositsII.原位免疫复合物型肾炎Insituimmunecomplexes-mediatednephritis

intrinsictissueantigen“planted”antigensfromthecirculation

Causedby抗肾小球基膜型肾炎Anti-GlomerularBasementMembrane(GBM)disease

Antigen:NC1ofα3ofcollagenIV(fixed)Self-AbbindtoGBMorLBM肺出血肾炎综合征

Goodpasturesyndrome---simultaneouslungandkidneylesions<1%GNCrescenticGNRapidlyprogressiveGNIF:linearpatternEM:Noelectrondensedeposit2.HeymannGNofrat

Ag---proximaltubularbrushborder(megalin)

ResemblinghumanmembranousGNIF:GranularpatternEM:Subepithelialelectrondensedeposit

Othercauses:DNA,bacteriaproducts,virusprotein---“plantedantigens”Antibody-mediatedglomerularinjury

Basicpathologicalchanges

ExtentofglomerularlesionDiffuse

弥漫–almosteveryglomeruliinvolvedFocal

局灶–partial(<50%)glomeruliinvolvedGlobal

球性–entirecapillaryloopSegmental

节段性–partialcapillaryloopFouressentialpathologicalchanges

细胞增多

Hypercellularity---

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intrinsicglomerularcells(EnC,MsC,EpC)

•inflammatorycellsOutcome:

ReductionofGFR

Oliguria/anuria

<400ml<100ml24hr基膜增厚ThickeningofGBM

•Depositionofimmunecomplexesandotherproteins---MaybeaccompaniedwithinterpositionofMsCandmatrix•IncreasedsynthesisofGBMcomponents

Outcome

Negative-chargedcomponents↓

GBMpermeability↑

Heavyproteinuria(3)坏死和炎性渗出Necrosisandinflammatoryexudation

FibroidnecrosisofcapillaryloopsInflammatoryexudation---protein,WBC,RBC

Outcome

HematuriaCasturia透明变性，纤维化和硬化

Hyalinosis,fibrosisandsclerosis

Hyalinosis---plasmaproteinsinsulatedfromthecirculationFibrosis---crescent,destructionofBowman’scapsule,mainlyI&IIICo.Sclerosis---increasedmatrixinmesangiumthickeningofGBM,IVCo.

Outcome:

GlomerulosclerosisUremiaSyndromeManifestationsNephriticsyndromeHematuria,azotemia,variableproteinuria,oliguria,edema,andhypertension(APGN)RapidlyprogressiveglomerulonephritisAcutenephritis,proteinuria,andacuterenalfailure(crescenticGN)Nephroticsyndrome>3.5g/dayproteinuria,hypoalbuminemia,hyperlipidemia,lipiduria,edema(MCD,MGN,MPGN)ChronicrenalfailureAzotemia➙uremiaprogressingformonthstoyearsAsymptomaticurinaryabnormalitiesSubtleormild

Clinicopathologiccorrelations

TheclassificationofGN

Primaryglomerulonephritis(GN)

DiffuseproliferativeGNCrescenticGNMembranousGNLipoidnephrosis(minimalchangedisease)FocalsegmentalglomerulosclerosisMembranoproliferativeGNIgAnephropathyChronicGNHistologicalclassification

SecondaryGNSystemiclupuserythematosus(SLE)DiabetesmellitusAmyloidosisGoodpasturesyndromePolyarteritisnodosaWegenergranulomatosisHenoch-SchonleinpurpuraBacterialendocarditisHereditarydisorders……NephroticsyndromeDerangementincapillarywallsIncreasedpermeabilityofGBMHeavyproteinuria(>3.5gperday)DecreasedserumalbuminhypoalbuminemiaDecreasedplasmacollidosmoticpressureRetentionofsaltandwaterbythekidneyedemaSynthesisoflipoproteinsbyliverAbnormaltransportofcirculatinglipidparticlesImpairmentoflipoproteinsbreakdownHyperlipidemialipiduriaPlasmaproteinescapeintoultrafiltrateNephroticedemaPittingedema（凹陷性水肿）Minimal-changedisease(MCD,微小病变病)

Footprocessdisease足突病

Lipoidnephrosis脂性肾病Clinicalfeatures

1.Mostinyoungchildren2.Nephroticsyndrome(highly-selectivealbuminproteinuria)

ThemostcommoncauseofnephroticsyndromeinChildren3.Respondtocorticosteroidtherapy(>90%)

Pathogenesis

DisorderofTcellfunctionSecretionofcytokine(IL-8,TNF)Abnormalexpressionofcytoskeletonproteins

PodocyteinjuryIncreasedpermeabilityofGBM

Morphology

Gross:Enlargedpalekidneys“大白肾”

Grayyellowstrandsorspots黄色条纹SwollenLM:NearlynormalglomeruliCytoplasmiclipidsintubularepithelialcellsIF:GenerallynegativeEM：DiffuseeffacementofthefootprocessesMicrovillustransformationReversibleaftercorticosteroidtherapy，concomitantwithremissionoftheproteinuria

Consequence

Goodprognosis(90%)

Afewcasesdependentonsteroidorresistant<5%chronicrenalfailureafter25yearsMembranousGN（MGN膜性肾炎/病）

AspectrumofchangesintheGBM

Subepithelialimmunecomplexdeposits

GBMthickening

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AbreactinginsitutointrisicorplantedAg

•AformofchronicimmunecomplexnephritisTwocategoriesSecondary(knownagents,15%)Drug,Underlyingmalignanttumors,Infections,SLEandotherautoimmunedisorders,globulin

Primary(unknownagents,85%)

resembleHeymannGNofrat,cross-reactwithantigenexpressedbypodocytes

may

relatedtoHLAsusceptibility

AdirectactionofC5b-C9onpodocytesandMsC“Findingthemanipulatorbehindthescene(s)”抓出幕后黑手ReversetheinjuryClinicalfeatures

1.Morecommoninadults2.Nephroticsyndrome(nonselectiveproteinuria)3.Insidiousonset,slowprogression4.Notusuallyrespondtocorticosteroidtherapy

MorphologyGross:EnlargedpalekidneysLM:Uniform,DiffusethickeningofcapillarywallIF:IgG+,C3+,granularpatternalongtheGBMEM:Subepithelialdeposition

EM:(I-IVstages)SpikesspikeConsequence Indolent

40%ofpatientssufferprogressivediseaseinrenalfailureafter2to20years

about10%-30%Improvementandrecovery

Focalsegmentalglomerulosclerosis

(FSGS,局灶节段性肾小球硬化症）

FocalSegmental+sclerosisPrimary---Idiopathic,unknowncause“FSGSandMCDarepartofacontinuumandthatMCDmaytransformintoFSGS.”

－－Anout-of-dateconcept

Secondary---drugs(interferon-α,lithium),viruses(HIV),immunologicdiseases,physicalagents(obesity),andhereditarydiseasesPathogenesis

Glomerularcapillarypressure,glomerularhypertrophy,hyperlipidemia/obesity,podocyteinjury,geneticaldefectsofcytoskeletalproteins,circulatingcytokines……ChangesofpodocytephenotypeIncreasedpermeabilityofGBMEntrapmentofplasmaproteinsandlipids——HyalinosisHallmarkClinicalfeatures

1.Morecommoninchild2.Nephroticsyndrome(nonselectiveproteinuria) increasinglycommoncauseofnephroticsyndromeinadults,and

remainsafrequentcauseinchildren

3.Oftenaccompaniedwithhematuria,hypertension,azotemia4.Poorresponsetocorticosteroidtherapy

5.SlowlyprogressiveMorphology

LM:Focal/segmentalsclerosiswith