急進(jìn)性腎小球腎炎英文課件

急進(jìn)性腎小球腎炎

rapidlyprogressiveglomerulonephritis急進(jìn)性腎小球腎炎

(rapidlyprogressiveglomerulonephritis)Nephriticsyndrome(急性腎炎綜合征) Proteinuria:usually<3g/day Hematuria:redcellcasts Bloodpressureoftennormal，sometimesincreaseRenalfailureoverdays/weeks（腎功能數(shù)天或數(shù)周內(nèi)惡化）Earlyoliguriaoranuria(早期出現(xiàn)少尿或無尿)一、EtiologyandPathogenesis1.morbidityUSA：1/1,000,000China:unknown,

DepartmentofNephrology,PekingUniversityFirstHospital80年代20例;90年代100例2.TypeofimmunopathogenesisThreeTypesClassificationTypeI:AntiglomerularbasementmembraneTypeII:ImmunecomplexTypeIII:Pauciimmune,50-80%vasculitisFiveTypesClassificationTypeI:AntiglomerularbasementmembraneTypeII:ImmunecomplexTypeIII:Pauciimmune+ANCA(+) TypeIV:I+ANCA(+)

TypeV:III+ANCA(-)

3.Classification

PrimaryglomerulopathyPrimaryCrescenticglomerulonephritisCrescenticglomerulonephritis,

onthebasisoftheotherprimaryglomerulardiseases

(Mesangialcapillaryglomerulonephritis)Infection-associated(postbacterialendocarditis)Multi-systemdisease（LN）Drug-related

(PTU)二、PathologyCrescenticGN:theproliferativecellularresponseoutsidetheglomerulartuftbutwithinBowman’sspacethatisknownasacrescentbecauseofitsshapeonhistologiccross-section.新月體性腎炎(毛細(xì)血管外增生性腎小球腎炎)

(crescenticglomerulonephritis)Diagnosticcriteria:glomeruluscrescentformation>50%

Affectedareaofglomerularcapsule>50%TypeofCrescent

cellulous

fibrous

cellularfibrous

TypeI:Immunofluorescencemicroscopy,IgGandC3,lineardeposition,alongcapillarywallTypeII:IgGandC3,granulardeposition,mesangiumandcapillarywall;proliferationofendothelialandmesangialcells;TypeIII:

noorpauciimmunedepositscrescenticglomerulonephritis

CellularcrescentandpinkfibrindepositionMassonx260crescenticglomerulonephritis

largescale

fibrocellularcrescentPASx260三、Clinicalmanifestation

1.TypeI:

TheclinicalmanifestationofGoodpasture’sdisease(抗GBM病)arisefromlunghemorrhageand/orrapidlyprogressiveglomerulonephritis.Between50%and75%ofpatientspresentwithacutesymptomsoflunghemorrhageandarefoundtobeinastateofadvancedrenalfailure.

Usuallysymptomsareconfinedtotheprecedingfewweeksormonths,butveryrapidprogressionormuchslowerprogressionmayoccur.BackgroundofGoodpasture’sdisease

—Milestone1919年由Goodpasture首先報(bào)道1例18歲男性病人，發(fā)燒、咯血、急性腎衰竭1967年Lerner等發(fā)現(xiàn)抗GBM抗體1984年Wieslander等發(fā)現(xiàn)(IV)NC1為主要靶抗原1995年Kalluri等發(fā)現(xiàn)3(IV)NC1為主要靶抗原DefinitionandclinicalType

AntiGBM-Abdepositioninthecirculationandorgan

-onlylunghemorrhage;-RPGNTypeI(Antiglomerularbasementmembranenephritis)-Goodpasturedisease（2）Morbidity

發(fā)病率：1/百萬RPGN中占10%-20%腎小球腎炎中占1%-2%單純肺出血？我國發(fā)病率不詳北京大學(xué)病例逐年上升發(fā)病率變化？認(rèn)識和檢測水平提高？（3）EtiologyPathogenesisisunclear,environmentalfactors

causedtheexposureofGBMantigen?Beforeflu-likesymptoms：20%-60%FluvirusA2？Hydrocarbon---Inducedorexacerbated

？汽油、柴油有機(jī)溶劑，油漆發(fā)膠殺蟲劑強(qiáng)氧化劑如次氯酸裝修(4)Predisposingfactorsmoke抗GBM抗體陽性者吸煙率稍高？發(fā)生肺出血機(jī)會大？造成肺泡內(nèi)皮細(xì)胞通透性升高，抗原暴露？geneticsusceptibility孿生子發(fā)生率高，家族聚集現(xiàn)象HLA-DR2HLA-DRB1*1501HLA-DR15（5）PathogenesisAntiGBM-Abdirectparticipate抗體滴度與病情平行？動物模型以腎小球基底膜成分為抗原注射抗GBM抗體直接轉(zhuǎn)移試驗(yàn)移植腎復(fù)發(fā)Alport綜合癥腎移植后TargetAntigenofantiGBM-Ab腎小球基底膜IV型膠原3鏈非膠原區(qū)1（

3(IV)NC1

）主要存在于GBM和TBM肺基底膜其它：眼、主動脈、脈絡(luò)叢、耳蝸和神經(jīng)肌肉接頭等StructureofGBM(6)ClinicalmanifestationTwopeaks21-30yearsoldand51-70yearsold，genderdifferences？Onsetandmorehidden－UremiaattackorhemoptysisRaremulti-systemdamageMildhypertensionMoreperformancefortheRPGNpulmonaryhemorrhage72%-94%50%-80%beforenephritisAccompaniedbyDifficultybreathing：44%-72%Cough：18%-41%Smokemaybeinducelunghemorrhage;lunghemorrhageisusefulforearlydiagnose?Causingdeath!Youngman，antiGBM-Ab(+)，pulmonaryhemorrhageoccurredthedayaftersmokingYoungman，antiGBM-Ab(+)，Pulmonaryhemorrhageoccurredthedayaftersmoking，Suffocation，Autopsyshowed肺泡出血(Alveolarhemorrhage)，Inflammatorycellinfiltrationalveolarseptum,Hemosiderin-positivecells抗GBM抗體合并ANCA(IV型)發(fā)生率20%-35%臨床表現(xiàn)可類似小血管炎ANCA陽性者應(yīng)注意查抗GBM抗體治療反應(yīng)和預(yù)后取決于抗GBM抗體治療前治療后xx，F(xiàn)/21，F(xiàn)ever,jointpain,hemoptysisfor2months。cANCA(+)、antiGBM-Ab(+)腎功能正常的抗GBM抗體陽性患者!可達(dá)15%-36%表現(xiàn)為Goodpasture病肺出血輕重不等腎受累多表現(xiàn)為鏡下血尿,腎活檢為輕度系膜增生性腎小球腎炎抗GBM抗體多滴度低,陰轉(zhuǎn)快.療效肯定可能為早期表現(xiàn)?(7)LaboratoryexaminationHematuria,proteinuriaandNSisnotcommonGFRprogressivelydecreasedANCA(+)（1/4-1/3）Anemia78-100%30%ASO

,butnoevidenceofstreptococcalinfectionEarlyanti-GBMantibody(+)DetectofAntiGBM-Ab

directimmunofluorescence

需要腎活檢敏感性和特異性差不客觀indirectimmunofluorescence

新鮮冰凍腎組織敏感性和特異性差不客觀ELISA-GBM可溶性抗原人或牛

(IV)NC1牛

3(IV)NC1Pathologicalexaminationlightmicroscope

：crescent,nocellproliferation,GBMdisruptelectronmicroscope：GBMandBowmancapsulebreakfluorescence

：IgG+/-C3lineardeposition約50%不典型病情嚴(yán)重發(fā)生在其他腎小病基礎(chǔ)上抗體滴度依賴多數(shù)腎小球受累新月體類型比較均一directimmunofluorescenceGP-IgGRPGN-II-IgAcrescentformation(8)Therapy首選強(qiáng)化血漿置換(intensiveplasmaexchange

)

2－4L/dornextday，plasmaor5%AlbuminUsuallyantibodynegativeafter14timesapplicationoffreshfrozenplasmatopreventbleedingbeforebiopsySideeffects：BloodproductstransmitteddiseasesMP沖擊(pulsemethylprednisolonetherapy)0.5-1.0/d，consecutiveor3timeseveryotherdaySideeffects：Waterandsodiumretention，hypertension,highbloodsugar強(qiáng)的松(Prednisone)：1mg/kg/d，6-8wCTX(cyclophosphamide

)50mgbid----6-8g(9)PrognosistheworstprognosisinRPGN,moredevelopmenttoESRDpulmonaryhemorrhagecanbelife-threateningStartingwithabetterprognosisthankidney？Indicationsforplasmaexchangetostop

-Oliguria

-Scr＞600mol/L

-biopsyshowedmorethan85%glomerularinvolvement

IndicationforrenaltransplantationSixmonthsafteranti-GBMantibodynegativeFocusonimprovingtheprognosisofpatientsEarlydiagnosisTimelydetectionofanti-GBMantibodyAttentiontopatientswithpulmonaryhemorrhageWithorwithoutkidneydamageTimelyplasmaexchangetreatment

?Patientshavenephroticsyndrom;CICpositiveC3

2.TypeII(Immunecomplex)

免疫復(fù)合物介導(dǎo)的新月體性腎炎

(1)免疫復(fù)合物性新月體型腎炎的疾病構(gòu)成

composition

北京大學(xué)（n=47）美國北卡（n=36）Primary15（32%）？IgAN17（36%）5（14%）LN9（19%）12（33%）HSP3（6%）5（14%）MPGN1（2%）3（8%）APSGN1（2%）4（11%）Fiberglomerulopathy07（19%）(2)Featureofclinicalmanifestationandlaboratoryexamination

Clinicalfeatures

ComposedbyavarietyofdifferentdiseasesMorecommoninmiddle-agedNephroticsyndromemorecommon（45%）LaboratoryfeaturesANA、C3

、Cryoglobulin冷球蛋白（＋)、CIC(＋)。ANCAandAntiGBM-Ab(-)(3)PathologicfeatureofrenalbiopsyLightmicroscopeCrescenticglomerulonephritisCellproliferationAddictedtotheredproteincomplex

(Mesangial,subendothelial…)ImmunofluorescenceIgG+C3granularormassivedepositionelectronmicroscopecontributetoclassification(4)Therapy

MP沖擊：(pulsemethylprednisolonetherapy)0.5-1.0/d，連續(xù)或隔日3次;1-3個(gè)療程強(qiáng)的松(Prednisone):1mg/kg/d環(huán)磷酰胺CTX(cyclophosphamide

)：

50mgbid----6-8g70%-80%有效，有全身表現(xiàn)(ANCA－)者，如血管炎更有效。3.TypeIII(Smallvesselpauce-immunevasculitis)

少免疫沉積型新月體性腎炎

(1)FeatureofclinicalmanifestationmorbiditymostcommoninwesterncountriesNotuncommoninChinaMostlycausedbysmallvesselvasculitis50%-90%ANCA(+)MPO-ANCAorPR3-ANCAMulti-systeminvolvementclinicallyMorecommoninoldage,butcanbefoundinanyage系統(tǒng)性血管炎命名分類(denominationandcategorization)（ChapelHill，1994）大血管(largeartery)巨細(xì)胞（顳）動脈炎Takayasu動脈炎中血管(medium-sizedartery)結(jié)節(jié)性多動脈炎（經(jīng)典型結(jié)節(jié)性多動脈炎）Kawasaki病小血管(arteriole)韋格納肉芽腫?。╓egener’sgranulomatosis,WG）變應(yīng)性肉芽腫性血管炎（Churg-Strausssyndrome,CSS）顯微鏡下型多血管炎（Microscopicpolyangitis,MPA）過敏性紫癜原發(fā)性冷球蛋白血癥性血管炎皮膚白細(xì)胞碎裂性血管炎

ANCA陽性小血管炎

(ANCAcorrelated

polyangitis)themostcommonautoimmunediseaseinwesterncountries

英國：發(fā)病率僅次于RA

我國：不少見北京大學(xué)腎臟病研究所近7年共新診斷500例ClinicalmanifestationsofrenaldamageforSmallvesselvasculitis

Hematuria,proteinuriaAcuterenalfailuremayoccurslowlymayrapidlyprogressiveglomerulonephritismanynon-oliguricImmunopathologyandelectronmicroscopy-traceornegativeLightmicroscopeGlomerular：Loopnecrosisandcrescenticglomerulonephritis，rangingfromoldandnewFibrinoidnecrosisofsmallarteriesrareIndirectimmunofluorescenceforantineutrophilcytoplasmicantibodies(ANCA).a)Cytoplasmicpattem(cANCA)causedbyANCAwithspecificityforproteinase3(PR3)b)Perinuclearstaining(pANCApattem)causedbyANCAwithspecificityformyeloperoxidase(MPO).1）Wegener’sgranulomatosisoccursinassociationwithnecrotizinggranulomatousinflammation,whichmostoftenaffectstherespiratorytract.2）Churg-Strausssyndromisvasculitisoccurringinassociationwithasthma,eosinophilia,andnecrotizinggranulomatousinflammation;3）MicrscopicpolyangitisisvasculitisoccurringintheabsenceofevidenceforWGorCSS,i.e.intheabsenceofasthma,eosinophilia,andevidencefornecrotizinggranulomatousinflammation;

TheclinicalmanifestationsofWG,MPAandCSSareextremelyvariedbecausetheyareinfluencedbythesitesofinvolvement,theactivityandthechronicityofinvolvement.RenalinvolvementisverycommoninWGandMPAandlessfrequentinCSS,includehematuria,proteinuria,andrenalfailure(RPGN,AGNandCGN).

Generalizednonspecificmanifestationareoftenpresent,suchasfever,malaise,anorexia,weightloss,myalgiasandarthralgias.Manypatientstracetheorganoftheirdiseasetoa“flu-like”(流感樣)illness.Therapy誘導(dǎo)治療(inductivetreatment)：

3--12個(gè)月維持治療(Maintenancetreatment)：

1-2年不推薦單獨(dú)應(yīng)用糖皮質(zhì)激素!2003UpToDate6/03inductivetreatment

糖皮質(zhì)激素和CTX強(qiáng)的松劑量：1mg/kg·d10-15mg/d維持0.5-1年CTX口服：2-3mg/kg·d靜點(diǎn)：0.5-1.0g/m上述劑量直到病情緩解monthstoonetotwoyears2003UpToDate6/03誘導(dǎo)治療：預(yù)防卡氏肺孢子蟲感染

(infectionbypneumocystiscarinii)TMP-SMX：復(fù)方新諾明Trimethoprim

：甲氧芐啶Sulfamethoxazole：磺胺甲惡唑，新諾明激素合并細(xì)胞毒藥物的小血管炎患者推薦應(yīng)用推薦小劑量維持Onedouble-strengthtabletTwice2003UpToDate6/03甲基強(qiáng)的松龍（MP）沖擊療法肺出血小動脈/或袢壞死新月體性腎小球腎炎

--MP7-15mg/kg·d(0.5-0.8/d)X3,1-3個(gè)療程注意副作用：高血壓，高血糖和水鈉潴留指征(indication)方案(treatmentplan

)血漿置換療法（PE）-合并抗GBM抗體-急性腎衰竭依賴透析-肺出血maintenanetherapyAzathioprine(硫唑嘌呤)2mg/kg/d糖皮質(zhì)激素:小劑量或停用其它細(xì)胞毒藥物霉酚酸酯(MMF)多用于維持治療1.5-2.0g半年,0.75-1.0g半年來氟米特已經(jīng)用于維持治療20-30mg/d終末期腎衰患者的治療透析只要有腎外活動病變，還應(yīng)積極治療腎移植控制活動病變后可移植ANCA滴度不影響移植腎存活DiagnosisanddifferentialdiagnosisofRPGN

1）引起少尿性急性腎衰竭的非腎小球疾病---急性腎小管壞死---急性過敏性間質(zhì)性腎炎---梗阻性腎病2）引起急進(jìn)性腎炎綜合征的其它腎小球病---繼發(fā)性急進(jìn)性腎炎---原發(fā)性腎小球疾病(一)Intensiveimmunosuppressive regimens(