ChapterIXTheDiseasesofUrinarySystem

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Kidney---producingurine---importantfunctions

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Ureter,bladder,urethra---storingoreliminatingurineTheAnatomyoftheUrinarySystemWhichlaboratory?

FourbasicmorphologiccomponentsGlomeruli:immunologicallymediated

TubulesInterstitiumBloodvesselstoxic/infectiousagentsSomeagentsaffectmorethanonestructure.

Maintypesofurinarydiseases

?

Inflammation

---

glomerulonephritis

腎小球腎炎

---pyelonephritis

腎盂腎炎

Stone

urolithiasis---nephrolithiasis腎結(jié)石

---hydronephrosis腎盂積水

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

(transitionalcellcarcinoma)ImportantpointsNormalstructureofglomerulusGlomerularFiltration1.Glomerularfiltratingmembrane

Fenestratedendothelium---70~100nm

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

Visceralepithelium

---Podocytes

Slitdiaphragm20~30nmSievepore4~14nm

Cytoskeletonproteins(nephrin,podocin,etc.)Anegatively-chargedcoatGlycocalyxHighlyselectivealbuminproteinuria

2.Mesangialregion---axialareaofglomerulus

Mesangialcells(MsC)Mesangialmatrix<4MsC/mesangialareaCrescent3.Bowman’scapsuleHowtoaffectrenalfunctions?IGlomerulonephritisGNPrimaryGN---limitedinkidneyalongSecondaryGN---secondarytosystemicdiseasesAgroupofhypersensitivitydiseasestwocategories

EtiologyandPathogenesis

Glomerularinjurycausedbyimmunecomplexes

DepositionofcirculatingimmunecomplexesinglomeruliAntibodiesreactinginsituwithintheglomerulusIntrinsicglomerularantigens(fixed)MoleculesplantedwithintheglomeruliI.Circulatingimmunecomplex-mediatednephritis

Antigens:(1)exogenous:bacteria(streptococci),virus(HBV),Treponemapallidum(梅毒螺旋體),parasite,Plasmodiumfalciparum(惡性瘧原蟲),foreignserum,drug,toxin(2)endogenous:systemiclupuserythematousus(SLE,系統(tǒng)性紅斑狼瘡),macroglobulin(巨球蛋白),thyroglobulin(甲狀腺球蛋白),carcinoembryonicantigen(CEA)

Inmostcases,theincitingantigensareunkown.“Innocentbystander”

Antigen-antibodycomplexesareformedinthecirculationandthentrappedintheglomeruliImmunofluorescencestaining(IF):GranulardepositsAgIFAbEM:ElectrondensedepositsAg-AbcomplexesformedTrappedinglomeruliActivationofcomplementsRecruitmentofleukocytesInjuryIF:complementsdepositionIF:IgdepositionEM:electro-densedepositsLM:

inflammatoryinfiltrationIntrinsiccellsproliferationII.Insituimmunecomplexes-mediatednephritis

intrinsictissueantigen“planted”antigensfromthecirculation

Causedby1.

Anti-GlomerularBasementMembrane(GBM)disease

Antigen:NC1ofα3ofcollagenIV(fixed)Self-AbbindtoGBMorLBM

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

Ag---proximaltubularbrushborder(megalin)

ResemblinghumanmembranousGNIF:GranularpatternEM:Subepithelialelectrondensedeposit

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

Basicpathologicalchanges

ExtentofglomerularlesionDiffuse–almosteveryglomeruliinvolvedFocal–partial(<50%)glomeruliinvolvedGlobal–entirecapillaryloopSegmental–partialcapillaryloopFouressentialpathologicalchanges

Hypercellularity---

?

intrinsicglomerularcells(EnC,MsC,EpC)

?inflammatorycellsOutcome:

ReductionofGFR

Oliguria/anuria

<400ml<100ml24hrThickeningofGBM

?Depositionofimmunecomplexesandotherproteins---MaybeaccompaniedwithinterpositionofMsCandmatrix?IncreasedsynthesisofGBMcomponents

Outcome

Negative-chargedcomponents↓

GBMpermeability↑

Heavyproteinuria(3)Necrosisandinflammatoryexudation

FibroidnecrosisofcapillaryloopsInflammatoryexudation---protein,WBC,RBC

Outcome

HematuriaCasturiaHyalinosis,fibrosisandsclerosis

Hyalinosis---plasmaproteinsinsudatedfromthecirculation(FSGS)Fibrosis---crescent,destructionofBowman’scapsuleSclerosis---increasedmatrixinmesangiumthickeningofGBM

Outcome:

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

Clinicopathologiccorrelations

TheclassificationofGNHistologicalclassification

Primaryglomerulonephritis(GN)

DiffuseproliferativeGNCrescenticGNMembranousGNLipoidnephrosis(minimalchangedisease)FocalsegmentalglomerulosclerosisMembranoproliferativeGNIgAnephropathyChronicGNSecondaryGNSystemiclupuserythematosus(SLE)DiabetesmellitusAmyloidosisGoodpasturesyndromePolyarteritisnodosaWegenergranulomatosisHenoch-SchonleinpurpuraBacterialendocarditisHereditarydisorders……NephroticsyndromeDerangementincapillarywallsIncreasedpermeabilityofGBMHeavyproteinuria(>3.5gperday)DecreasedserumalbuminhypoalbuminemiaDecreasedplasmacollidosmoticpressureRetentionofsaltandwaterbythekidneyedemaSynthesisoflipoproteinsbyliverAbnormaltransportofcirculatinglipidparticlesImpairmentoflipoproteinsbreakdownHyperlipidemialipiduriaPlasmaproteinescapeintoultrafiltrateNephroticedemaPittingedema（凹陷性水腫）Minimal-changedisease(MCD,微小病變病)

Footprocessdisease（足突?。?/p>

Lipoidnephrosis（脂性腎?。〤linicalfeatures

1.Mostinyoungchildren2.Nephroticsyndrome(highly-selectivealbuminproteinuria)

ThemostcommoncauseofnephroticsyndromeinChildren3.Respondtocorticosteroidtherapy(>90%)

Pathogenesis

DisorderofTcellfunctionSecretionofcytokine(IL-8,TNF)Abnormalexpressionofcytoskeletonproteins

PodocyteinjuryIncreasedpermeabilityofGBM

Morphology

Gross:Enlargedpalekidneys“大白腎”

Grayyellowstrandsorspots黃色條紋SwollenLM:NearlynormalglomeruliCytoplasmiclipidsintubularepithelialcellsIF:GenerallynegativeEM：DiffuseeffacementofthefootprocessesMicrovilloustransformationReversibleaftercorticosteroidtherapy，concomitantwithremissionoftheproteinuria

Consequence

Goodprognosis(90%)

Afewcasesdependentonsteroidorresistant<5%chronicrenalfailureafter25yearsMembranousGN（MGN,膜性腎炎/?。?/p>

AspectrumofchangesintheGBM

Subepithelialimmunecomplexdeposits

GBMthickening

?

AbreactinginsitutointrisicorplantedAg

?AformofchronicimmunecomplexnephritisTwocategories?

Secondary(knownagents,15%)Drug,Underlyingmalignanttumors,Infections,SLEandotherautoimmunedisorders,globulin?Primary(unknownagents,85%)

resembleHeymannGNofrat

relatedtoHLAsusceptibilityAdirectactionofC5b-C9onpodocytes“Findingthemanipulatorbehindthescene(s)”抓出幕后黑手ReversetheinjuryIgG亞型染色有助區(qū)別Clinicalfeatures

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

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

EM:(I-IVstages)SpikesspikeConsequence

IndolentIn10years,10%dead&renalsufficiencyImprovementandrecovery(about10%-30%)

Focalsegmentalglomerulosclerosis

(FSGS,局灶節(jié)段性腎小球硬化）

FocalSegmental+sclerosisPrimary---Idiopathic,unknowncause

BookP310:Pathogenesis“FSGSandMCDarepartofacontinuumandthatMCDmaytransformintoFSGS.”－－－Anout-of-dateconceptTwoseparateentitiesSecondary---drugs(interferon-α,lithium),viruses(HIV),immunologicdiseases,physicalagents(obesity),andhereditarydiseasesPathogenesis

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

1.Morecommoninadults2.Nephroticsyndrome(nonselectiveproteinuria)3.Oftenaccompaniedwithhematuriahypertensionazotemia4.Poorresponsetocorticosteroidtherapy

5.SlowlyprogressiveMorphology

LM:Focal/segmentalsclerosiswithhyalinosisInitiallyjuxtamedullaryglomeruliaffectedWithseverinjuryoftubulesandinterstitiumPASstainingIF:SegmentalIgM+,C3+EM:

HyalinosislesionSegmentalincreaseofmesangialmatrixandthickenedGBMEffacementoffootprocessesConsequence

Poorprognosis,especiallyinadultsRenalfailureafter10years(about50%)Recurrencesin25%to50%patientsreceivingallograftsCirculatingmediatorsMembranoproliferativeGN

(MPGN,膜性增生性腎炎）

Membrano

ProliferativeThickenedGBMHypercellularityMsC&EnproliferationInfiltratingleukocytesOtherterms:LobularGN

MesangiocapillaryGN

TypingTypeI---Circulatingimmunecomplex

EM:predominantlysubendothelialdeposits

TypeII---Densedepositdisease(DDD)ComplementabnormalityExcessiveactivationofalternativecomplementpathway(PersistentlylowserumlevelofC3;IF:C3deposition)EM:intramembranousdeposits

TypeIII---A“variant”oftypeIEM:subepithelial&subendothelialdepositsClinicalfeatures

1.Nephroticsyndrome(2/3patients)Acombinednephrotic-nephricpicture2.SlowlyprogressiveMorphology

Gross:EnlargedpalekidneysLM:?HypercellularityMsC&EnproliferationInfiltratingleukocytes

?ThickenedGBM:Irregular

SubendothelialdepositsofimmunecomplexesMesangialinterposition

Anaccentuatedlobularappearance“分葉狀”

Silverstaining:“doublecontour”or“tramtrack”IF:

TypeIIgG+,C3+,C1q+,C4+TypeIIIgG+,C3+,noC1q,C4TypeIIIIgG+,C3+AgranularpatternalongtheglomerularcapillariesEM:

TypeISubendothelialdepositsTypeII(DDD)Intramembranousdeposit(ribbon-like)TypeIIISubepithelial,subendothelialandmesangialdeposits

TypeIMesangialinterpositionTypeIITypeIIIPrognosis

SlowlyprogressiveGenerallypoor(especiallyDDD)Recurrencein90%DDDpatientsafterkidneytransplantationThenephriticsyndromeHematuria

---injuryofcapillarywallsNecrosis,derangementofGBM,broken

↓DysmorphicredbloodcellsinurineOliguria&azotemia---hypercellularityGFR↓

→serumBUN/Creatine↑Hypertension---fluidretention&augmentedreninreleaseProteinuria&edema---notsevereAcutePostinfectiousGN(APGN)

APGNfollowsinfections

Otherterms:AcutediffuseproliferativeGNEndocapillaryproliferativeGNPoststreptococcal

acuteGNHypercellularity:MsC&EndothelialcellsThemostcommonandbestunderstoodGNClinicalfeatures

1.Morecommoninchildrenandyoungadults2.Infectionhistoryofstreptococcal(pharynx,skin)3.Abruptonset4.Nephriticsyndrome5.Elevatedserumanti-streptomysinOAbtiterlowcomplementlevel,formationofCIC

Morphology

Gross:EnlargedwithcongestionWithtinyredspeckles(flea-bitehemorrhage)

LM:DiffuseHypercellularity

Necrosis,crescentformation(in<30%glomeruli)ProliferationofMsC&endothelialcellsInfiltratingneutrophils/monocytesIF:IgG+,IgM+,C3+Starry-skypattern星空樣EM:Typical“humps”(Discretesubepithelialelectron-densedeposit)MsCproliferationwithneutrophilsinfiltrationConsequence

Goodprognosis(90%recovery)Progression(crescenticGN,sclerosingGN)IgAnephropathy(IgAN)

Berger’sdisease(1969)IgA-dominantdepositioninthemesangium

ThemostcommonglomerulardiseasePrimary

causesunknownpossiblyrelatedtogeneticinfluenceSecondaryHenoch-SchonleinpurpuraliverdiseasesdiseasesofgastrointestinaltractPathogenesisIgA---themainIginmucosalsecretionslowplasmaconcentrationmostlyinmonomericformInIgAN,polymericIgA1depositinthemesangiumC3deposit---activationofthealternativecomplementpathway?AnabnormalityinIgAproductionandclearance

Mostlikelyaconsequenceofdefectivemucosalimmunity

Clinicalfeatures

1.Morecommoninchildrenandyoungadults2.Typicalonset---

Grosshematuriaoccurswithin1or2daysofanonspecificupperrespiratorytractinfectionorgastroenteritis.3.Recurrentmicroscopicorgrosshematuria4.ElevationofserumIgA5.SlowlyProgressiveMorphology

LM:Wideningmesangium

ProliferationofMsCandmatrixNormalFocalDiffuseGlomerulosclerosis(endstage)IF:MesangialdepositionofIgA/C3EM:Electron-densedepositsinthemesangiumConsequence

Highlyvariablecourse

Slowlyprogressivetochronicrenalfailure

(morethan20yearsin15%-40%cases)CrescenticGN(CrGN)

Crescentsformation

In>50%glomeruliAnotherterm---RapidlyprogressiveGNClinicalfeatures

1.Mainlyinadult2.Acuterenalfailure3.Typing---Basedonimmunologicfindings

TypeI(anti-GBM)---anti-GBMdisease(Goodpasturesyndrome)

TypeII(immunecomplex)---Idiopathic,postinfectiousGN,LN,IgAnephropathy,H-SpurpuraTypeIII(pouci-immune)---ANCA+,vasculitis,idiopathic

Morphology

Gross:

EnlargedpalekidneysoftenwithredpetechialhemorrhagesLM:

Crescents(>50%)Proliferationofparietalcells&migrationofmonocytesandmacrophagesintotheurinaryspace

cellularcell-fibrousfibrouswithfibrinoidnecrosiswithproliferationofMsCandEnCwithseveretubularandinterstitiallesionCrescentCircumferentialIF:

typeIIgG+linearpatterntypeIIIg,complementgranularpatterntypeIIIUsuallynegativeFibrinogen/fibrinincrescentsEM:WrinklingofGBMwithfocaldisruptionsNoelectron-densedeposit(TypeI/III)

Electron-densedeposits(TypeII)

Prognosis

Poor(especiallycrescentsin>80%glomeruli)DependentonthenumberofcrescentsChronicGN

TheendstageofavarietyofGNs(Endstagekidneys)PathologicalbasisofchronicrenalfailureClinicalfeatures

1.Mostinadults2.Chronicrenalfailure3.Treatedwithrenaldialysisandrenaltransplantation

Morphology

Gross:symmetricallycontracted,diffuselygranularanincreaseinperipelvicfat

LM:

Glomerulosclerosis(>75%)AtrophyanddropoutoftubulesInterstitialfibrosisThickeningofarterialwall4種腎結(jié)構(gòu)均有變化IF:UsuallynegativevarieswithdifferentkindsofGNEM:IncreasedglomerularmatrixwithdepositedfibrouscollagenClinicopathologicalcorrelations1.Changesofurination---LossoftubularfunctionPolyuria,nocturia,lowosmoticurine2.Hypertension---fluidoverload,renin3.Anemia---inhibitionofmarrowfunction,EPO↓4.Azotemia,uremia---mostglomeruliobliteratedConsequence

VerypoorprognosisTreatmentwithrenaldialysisortransplantedkidney

EmphasisPathologicmorphologyofGNChangesoftubulesandinterstitiumareusuallynotspecificforglomerulardiseases.Pathogenesis(mechanisms)underliespathologicmorphology.Pathologicchangesunderliesclinicalmanifestations.Gross

LMIFEMDon’tlearneverythingbyrote.Don’tcramforexam.IIPyelonephritis?Causedbybacterialinfection?Aformoftubulointerstitialnephritis(TIN)primarilyinvolvingtheinterstitiumandtubules?MostarecausedbyGram-negativeentericorganisms?Itoccursintwoforms,acute&chronic

1.AcutePyelonephritis

AnacuteinflammatoryprocessNeutrophilspredominateAcommonsuppurativeinflammationEtiologyandPathogenesis

Sourceandrouteofentryoforganisms

?Hematogenousspread?Ascendinginfection---themostcommonMorecommoninfemales

Organisminvolved

Gram-negativeentericorganismsThemostcommonE.Coli

Predisposingfactors:UrethralinstrumentationTraumaoflowerurinarytractIncompetenceofthevesicoureteralorificeVesicoureteralrefluxClinicalfeatures

1.Systemicmanifestation---abrupt,chills,feverbloodWBC↑2.Backpain3.Manifestationofbladderandurethralirritation4.Urinechanges---pyuria,bacteriuriaMorphologyGross:OneorbothinvolvedEnlargedkidneyDiscrete,yellowishabscesseswithsurroundinghyperemiaabscess

LM:

AbscessformationwithintherenalparenchymaNeutrophilcastsandbacterialcoloniesintubules

2.

Chronicpyelonephritis

Usuallywithobstructiontotheurinarytract,orVesicoureteralrefluxClinicalfeatures1.Recurrenceofacutepyelonephritis2.Polyuria,nocturia,lowosmoticurine,electrolytesdisorders:Lossoftubularfunctiondecreaseofconcentratingabilitydecreaseofreabsorbtionorsecretionfunction3.Pyelograms:smallerrenalpapilladeformityofthecalycealsystem

Morphology

Gross:OneorbothaffectedUneven,irregular,coarse,depressedscars馬鞍樣

Generalizeddilatationofthecollectingsystem

LM:

?Focalscar?Atrophicordilatedtubulescontainingeosinophiliccolloidcasts“Thyroidization”

?Chronicinflammation(lymphoidfollicles)ininterstitium?ThickeningofBowman’scapsuleandperiglomerularfibrosis

SecondaryFSGS3.Consequence

Acutepyelonephritis–mostlyrecoveredChronicpyelonephritis

Poorprognosis-Chronicrenalfailure(endstagekidney)GN

PylonephritisCauseImmuneinjuryDirectbacterialinfectionPathologicchanges

Bothaffected;Glomerulilesions;Glomerulardepositsofimmunoglobulins,oftenwithvariouscomponentsofcomplementClinicalmanifestationsPyuria膿尿/bacteriuria;bladderandurethralirritation(dysuria,frequencyandurgency)hematuria,proteinuria,hypertention,azotemia,uremiaOneorbothaffected;Tubules&interstitiumlesions;Suppurativeinflammation“Different”IIITransplantRejection?Bothcell-andantibody-mediatedhypersensitivityresponsesofthehostdirectedagainsthistocompatibilitymoleculesonthedonorallograft?ThetargetMajorHistocompatibilityComplex(MHC抗原)HumanLeukocyteAntigen(HLA抗原)

Polymorphic&highlyvariableMechanismsT-cell-mediatedrejectionAntibody-mediatedrejectionClassification

HyperacuteRejection(超急性排異反應)AcuteRejection(急性排異反應)

ChronicRejection(慢性排異反應)

1.Hyperacuterejection(超急性排異反應)

?Occurswithinminutestoafewhours?Inpre-sensitizedhost:

Preformedanti-donorantibodiesarepresentinthecirculationoftherecipient.?Clinicalpresentation:Anuria,fever,norperfusiononrenalscanGross:

Cyanotic,mottled,flabbyandsoft,swollenWidespreadhemorrhagiccorticalnecrosisMayexcreteonlyafewdropsofbloodyfluidMORPHOLOGYLM:

(1)Widespreadacutearteritisandarteriolitis:FibrinoidnecrosisofwallsThrombosis(2)Ischemicnecrosis2.AcuteRejectionAcombinedprocess:cellular/humoral(antibody)ClinicalfeaturesAbruptScr↑,clinicalsignsofrenalfailure

Distinctpathologic,immunopathologic,clinicalfeaturesAcutecellularrejection

LM:

Extensiveinfiltrateofmononuclearcells

intubulesandinterstitiumInterstitialedema/hemorrhage

T-cells¯ophagesInflammatorycellsintheinterstitiumandbetweenepithelialcellsofthetubulesInterstitialinflammatoryEdema/interstitialhemorrhage

Acutehumoralrejection（antibody-mediated）

LM:(1)Vaculitis:NeutrophilicinfiltrationMarkedthickeningoftheintimaFibrinoidnecrosisThrombosisIF:Ab,complements,andfibrin

C4d+onPTC---Themarkerforhumoralrejection(2)Focalnecrosis“Lessacute”FocalnecrosisC4ddepositioninperitubularcapillaries3.Chronicrejection

?

Itprogressesslowlybecauseofpersistentorrecurrentimmunologicreaction.?Progressivelossofrenalfunction?MaybeconsideredasongoinghealingresponseGlomerulosclerosis&interstitialfibrosisareprominent.LM:

(1)Proliferativearteritis:

Pronounced,concentric,fibrousthickeningintima

“Onion-skin”

(2)Chronicglomerulopathy:

DuplicationofGBM

(3)Lossofnephronandinterstitialfibrosis(4)VariablemononuclearinfiltrateFoamcellsliningupalongtheinternalelasticaOcclusivefoamcells

C4ddepositionMethodsofincreasinggraftsurvivalBettermatchingofMHCmoleculesbeforetransplantationImmunosuppressionoftherecipientisapracticalnecessity

Opportunisticinfections

“Double-edgedsword”（雙刃劍）

EBV-inducedlymphomasHPV-inducedsquamouscellcarcinomasKaposisarcoma

IVDiabetesMellitusGlucosehomeostasisThreeinterrelatedprocesses:GlucoseproductionintheliverGlucoseuptakeandutilizationbyperipheraltissues,chieflyskeletalmusclesInsulin