急进性肾小球肾炎英文课件

急进性肾小球肾炎

rapidlyprogressiveglomerulonephritis急进性肾小球肾炎

(rapidlyprogressiveglomerulonephritis)Nephriticsyndrome(急性肾炎综合征) Proteinuria:usually<3g/day Hematuria:redcellcasts Bloodpressureoftennormal，sometimesincreaseRenalfailureoverdays/weeks（肾功能数天或数周内恶化）Earlyoliguriaoranuria(早期出现少尿或无尿)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.新月体性肾炎(毛细血管外增生性肾小球肾炎)

(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首先报道1例18岁男性病人，发烧、咯血、急性肾衰竭1967年Lerner等发现抗GBM抗体1984年Wieslander等发现(IV)NC1为主要靶抗原1995年Kalluri等发现3(IV)NC1为主要靶抗原DefinitionandclinicalType

AntiGBM-Abdepositioninthecirculationandorgan

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

发病率：1/百万RPGN中占10%-20%肾小球肾炎中占1%-2%单纯肺出血？我国发病率不详北京大学病例逐年上升发病率变化？认识和检测水平提高？（3）EtiologyPathogenesisisunclear,environmentalfactors

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

？汽油、柴油有机溶剂，油漆发胶杀虫剂强氧化剂如次氯酸装修(4)Predisposingfactorsmoke抗GBM抗体阳性者吸烟率稍高？发生肺出血机会大？造成肺泡内皮细胞通透性升高，抗原暴露？geneticsusceptibility孪生子发生率高，家族聚集现象HLA-DR2HLA-DRB1*1501HLA-DR15（5）PathogenesisAntiGBM-Abdirectparticipate抗体滴度与病情平行？动物模型以肾小球基底膜成分为抗原注射抗GBM抗体直接转移试验移植肾复发Alport综合症肾移植后TargetAntigenofantiGBM-Ab肾小球基底膜IV型胶原3链非胶原区1（

3(IV)NC1

）主要存在于GBM和TBM肺基底膜其它：眼、主动脉、脉络丛、耳蜗和神经肌肉接头等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抗体合并ANCA(IV型)发生率20%-35%临床表现可类似小血管炎ANCA阳性者应注意查抗GBM抗体治疗反应和预后取决于抗GBM抗体治疗前治疗后xx，F/21，Fever,jointpain,hemoptysisfor2months。cANCA(+)、antiGBM-Ab(+)肾功能正常的抗GBM抗体阳性患者!可达15%-36%表现为Goodpasture病肺出血轻重不等肾受累多表现为镜下血尿,肾活检为轻度系膜增生性肾小球肾炎抗GBM抗体多滴度低,阴转快.疗效肯定可能为早期表现?(7)LaboratoryexaminationHematuria,proteinuriaandNSisnotcommonGFRprogressivelydecreasedANCA(+)（1/4-1/3）Anemia78-100%30%ASO

,butnoevidenceofstreptococcalinfectionEarlyanti-GBMantibody(+)DetectofAntiGBM-Ab

directimmunofluorescence

需要肾活检敏感性和特异性差不客观indirectimmunofluorescence

新鲜冰冻肾组织敏感性和特异性差不客观ELISA-GBM可溶性抗原人或牛

(IV)NC1牛

3(IV)NC1Pathologicalexaminationlightmicroscope

：crescent,nocellproliferation,GBMdisruptelectronmicroscope：GBMandBowmancapsulebreakfluorescence

：IgG+/-C3lineardeposition约50%不典型病情严重发生在其他肾小病基础上抗体滴度依赖多数肾小球受累新月体类型比较均一directimmunofluorescenceGP-IgGRPGN-II-IgAcrescentformation(8)Therapy首选强化血浆置换(intensiveplasmaexchange

)

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

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

-Oliguria

-Scr＞600mol/L

-biopsyshowedmorethan85%glomerularinvolvement

IndicationforrenaltransplantationSixmonthsafteranti-GBMantibodynegativeFocusonimprovingtheprognosisofpatientsEarlydiagnosisTimelydetectionofanti-GBMantibodyAttentiontopatientswithpulmonaryhemorrhageWithorwithoutkidneydamageTimelyplasmaexchangetreatment

½Patientshavenephroticsyndrom;CICpositiveC3

2.TypeII(Immunecomplex)

免疫复合物介导的新月体性肾炎

(1)免疫复合物性新月体型肾炎的疾病构成

composition

北京大学（n=47）美国北卡（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冲击：(pulsemethylprednisolonetherapy)0.5-1.0/d，连续或隔日3次;1-3个疗程强的松(Prednisone):1mg/kg/d环磷酰胺CTX(cyclophosphamide

)：

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

少免疫沉积型新月体性肾炎

(1)FeatureofclinicalmanifestationmorbiditymostcommoninwesterncountriesNotuncommoninChinaMostlycausedbysmallvesselvasculitis50%-90%ANCA(+)MPO-ANCAorPR3-ANCAMulti-systeminvolvementclinicallyMorecommoninoldage,butcanbefoundinanyage系统性血管炎命名分类(denominationandcategorization)（ChapelHill，1994）大血管(largeartery)巨细胞（颞）动脉炎Takayasu动脉炎中血管(medium-sizedartery)结节性多动脉炎（经典型结节性多动脉炎）Kawasaki病小血管(arteriole)韦格纳肉芽肿病（Wegener’sgranulomatosis,WG）变应性肉芽肿性血管炎（Churg-Strausssyndrome,CSS）显微镜下型多血管炎（Microscopicpolyangitis,MPA）过敏性紫癜原发性冷球蛋白血症性血管炎皮肤白细胞碎裂性血管炎

ANCA阳性小血管炎

(ANCAcorrelated

polyangitis)themostcommonautoimmunediseaseinwesterncountries

英国：发病率仅次于RA

我国：不少见北京大学肾脏病研究所近7年共新诊断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”(流感样)illness.Therapy诱导治疗(inductivetreatment)：

3--12个月维持治疗(Maintenancetreatment)：

1-2年不推荐单独应用糖皮质激素!2003UpToDate6/03inductivetreatment

糖皮质激素和CTX强的松剂量：1mg/kg·d10-15mg/d维持0.5-1年CTX口服：2-3mg/kg·d静点：0.5-1.0g/m上述剂量直到病情缓解monthstoonetotwoyears2003UpToDate6/03诱导治疗：预防卡氏肺孢子虫感染

(infectionbypneumocystiscarinii)TMP-SMX：复方新诺明Trimethoprim

：甲氧苄啶Sulfamethoxazole：磺胺甲恶唑，新诺明激素合并细胞毒药物的小血管炎患者推荐应用推荐小剂量维持Onedouble-strengthtabletTwice2003UpToDate6/03甲基强的松龙（MP）冲击疗法肺出血小动脉/或袢坏死新月体性肾小球肾炎

--MP7-15mg/kg·d(0.5-0.8/d)X3,1-3个疗程注意副作用：高血压，高血糖和水钠潴留指征(indication)方案(treatmentplan

)血浆置换疗法（PE）-合并抗GBM抗体-急性肾衰竭依赖透析-肺出血maintenanetherapyAzathioprine(硫唑嘌呤)2mg/kg/d糖皮质激素:小剂量或停用其它细胞毒药物霉酚酸酯(MMF)多用于维持治疗1.5-2.0g半年,0.75-1.0g半年来氟米特已经用于维持治疗20-30mg/d终末期肾衰患者的治疗透析只要有肾外活动病变，还应积极治疗肾移植控制活动病变后可移植ANCA滴度不影响移植肾存活DiagnosisanddifferentialdiagnosisofRPGN

1）引起少尿性急性肾衰竭的非肾小球疾病---急性肾小管坏死---急性过敏性间质性肾炎---梗阻性肾病2）引起急进性肾炎综合征的其它肾小球病---继发性急进性肾炎---原发性肾小球疾病(一)Intensiveimmunosuppressive regimens(