病理生理学课件

肿瘤(tumor)Carcinoma癌Sarcoma

肉瘤Leukemia白血病良性恶性癌症(cancer)恶性肿瘤依然是现代医学面临的重要挑战之一。恶性肿瘤已经成为人类死亡的第一或第二元凶。

恶性肿瘤:人类死亡的第一或第二元凶现代医学面临的重要挑战之一儿童肿瘤发病率在逐渐升高。在5-10岁儿童中，恶性肿瘤在造成死亡病种中排名第一位。提高肿瘤防治水平和寻找治疗肿瘤的新方法已成为科学家和临床医学家所面临的最大挑战。多因素、多步骤第一节肿瘤病因学PottP(1775):VolkmanandBell(1870’s):Rehn(1880’s):YamagiwaandIchikawa(1915):CookJames(1933):Chemicalcarcinogen童年时当过烟囱清扫工的男性患阴囊癌的比率增高长期与石蜡油和焦油接触的工人易患皮肤癌接触苯胺的工人发生泌尿道膀胱肿瘤反复用煤焦油涂擦兔耳成功地诱发了皮肤癌证明多种化学致癌物(Benzopyrene)与动物肿瘤的关系PottP(1775):VolkmanandBell(1870’s):Rehn(1880’s):YamagiwaandIchikawa(1915):CookJames(1933):ChemicalcarcinogendirectindirectPro-carcinogenβ-丙内酯、硫酸二甲酯、氮芥、溶肉瘤素、亚硝酸胺类、二（氯甲）醚等巴豆油、糖精、苯巴比妥多环芳香烃、芳香胺类、亚硝胺、黄曲霉素进入机体后，无需代谢活化即有致癌作用的化学致癌物

单独作用无致癌作用，但对其它致癌物具有促进作用进人体内后，必需经过体内代谢活化，才具致癌作用IndirectCarcinogenprecarcinigenProximatecarcinigenUltimatecarcinigen前致癌物未经代谢活化的、不活泼的间接致癌物

近致癌物经代谢转变为化学性质活泼、寿命极短的致癌物

终致癌物带正电荷的亲电子物质IndirectCarcinogenprecarcinigenProximatecarcinigenUltimatecarcinigenCytochromeP-450(CYP):phaseIenzymesactbyaddingOatomontothesubstrateinduciblebypolycyclicaromaticandchlorinatedhydrocarbons.largelyresponsibleforthemetabolicactivationanddetoxication.PhaseIIenzymes:actonoxidizedsubstratesmethyltransferases,acetyltransferases,glutathionetransferases,uridine5'-diphosphoglucuronosyltransferases,sulfotransferases,nicotinamide-adeninedinucleotide(NAD)-andnicotinamide-adeninedinucleotidephosphate(NADP)-dependentalcohol,aldehydeandsteroiddehydrogenases,quinonereductases,NADPHdiaphorase,azoreductases,aldoketoreductases,transaminases,esterases,andhydrolases.CytochromeP-450(CYP):phaseIenzymesactbyaddingOatomontothesubstrateinduciblebypolycyclicaromaticandchlorinatedhydrocarbons.largelyresponsibleforthemetabolicactivationanddetoxication.PhaseIIenzymes:actonoxidizedsubstratesmethyltransferases,acetyltransferases,glutathionetransferases,uridine5'-diphosphoglucuronosyltransferases,sulfotransferases,nicotinamide-adeninedinucleotide(NAD)-andnicotinamide-adeninedinucleotidephosphate(NADP)-dependentalcohol,aldehydeandsteroiddehydrogenases,quinonereductases,NADPHdiaphorase,azoreductases,aldoketoreductases,transaminases,esterases,andhydrolases.IndirectCarcinogenprecarcinigenProximatecarcinigenUltimatecarcinigencarcinogen

DNAadductsMetabolicactivationTobacco-specificnitrosamines,TSNAAromaticaminesDNAdamagedetoxicationDNArepairmalignant代谢激活速率高而代谢解毒率低或DNA修复功能低下的个体肿瘤易感性高

TobaccoPolycyclicarimatichydrocarbon,PAHEllermannandBang(1905,丹麦):chickenleukemiaRous(1911，美国):Roussarcomavirus(RSV)Shope(1933):Burkitt(1962):viruslymphomaEpsteinandbarr(1964):EBvirusviruscarcinogenDNAvirusRNAvirus用无细胞的滤液首次证实病毒与恶性肿瘤有病因学上的关系用滤液成功地诱发了鸡的肉瘤

将病毒所致的野兔乳头状瘤进行皮下移植实验，发生浸润性鳞癌发现病毒可以引起淋巴瘤在Burkitt淋巴瘤细胞培养液中发现EB病毒DNAvirus与动物或人类肿瘤有关的致瘤性NDA病毒：病毒的核心是由DNA和蛋白质组成的复合体

DNA病毒一般没有细胞内同源物乳-多-空病毒类腺病毒类疱疹病毒类乙型肝炎病毒类痘病毒类

转化蛋白E1A、E1BSV40

T抗原HPV16、HPV18

E6、E7转化蛋白Rbp53核蛋白病毒的致癌作用发生在病毒进入细胞后复制的早期阶段，相关的瘤基因多整合至宿主细胞DNA上。共同特征：某些NDA病毒在染色体上的定位具有倾向性，往往表现为累及多个染色体的位点，可能涉及到染色体的脆性部位和原瘤基因的位点.DNAviruspermissivecellDNAvirusDNAvirusDNAvirusDNAvirusDNAvirusDNAvirusDNAvirusDNAvirusDNAviruslyticinfectionDNAvirusDNAvirusabortiveinfectionNon-permissivecell早期:产生转化蛋白晚期:形成病毒颗粒细胞裂解基因组整合到细胞的DNA中，使细胞发生转化retrovirusRNALTRgagpolenvLTRRNAvirusRNAprovirusLTRgagpolenvLTR123LTRLTR123gagpolenvNon-defectivevirustheRoussarcomavirus(RSV):theRSVtransforminggene(designatedv-src)washomologoustoahostcellulargene(c-src)60KD、具有酪氨酸激酶活性的PP60蛋白，参与信号转导途径，与多种肿瘤发病相关

C-srcLTRgagpolenvLTR123LTRgag

polLTR123defectivevirusAcutelytransformingretroviruses

canrapidlycausetumorswithindaysafterinjection.Theseretrovirusescanalsotransformcellculturestotheneoplasticphenotype.Chronicorweaklyoncogenicretrovirusescancausetissue-specifictumorsinsusceptiblestrainsofexperimentalanimalsafteralatencyperiodofmanymonths.Althoughweaklyoncogenicretrovirusescanreplicateinvitro,thesevirusesdonottransformcellsinculture.种族分布差异家族聚集现象遗传缺陷遗传因素流行病学分析家系分析细胞遗传学研究分子遗传学研究染色体水平分子/基因水平Retinoblastoma

themostcommonintraocularcancerinchildrenIncidence：1of13,500-25,000livebirthsSites:unilateral(20%hereditary),bilateral(allhereditary)Onsettime:Bilateral-12m,unilateral-18m,Most(90%):<3yChromosomalmechanismswhichresultinlossofheterozygosityforallelesattheretinoblastomapredisposition(RB1)locusKnudson：遗传性肿瘤综合征具有恶变倾向的癌前病变（多发性、良性）Li-Fraumeni综合征：易发软组织肿瘤、乳腺癌、脑瘤遗传基础：P53基因生殖细胞突变遗传易感基因DNArecombinanttechniquesDNAtransfectionOncogeneKaryotypicanalysisMolecularclone慢性粒细胞性白血病（CML）Bcr-abl酪氨酸激酶激酶底物DNArecombinanttechniquesDNAtransfectionKaryotypicanalysisMolecularcloneOncogenehomogeneouslystainingregions[HSR]Tumorsuppressorhereditarynonpolyposiscolorectalcancer(HNPCC)syndromesmutator/DNA-mismatchrepair-involvedgenesTumorsuppressormutator/DNA-mismatchrepair-involvedgenesOncogeneOncogene第二节：癌基因（Oncogene）Oncogenesareessentialforhumanlifeactivity,whosenormalfunctionistocontrolcellulargrowthanddifferentiation/apoptosisor,indifferentterms,cellbirthandcelldeath.Correspondingly,theirstructuraland/orfunctionalalterationsleaduncontrolledcellulargrowthandabnormaldifferentiation/apoptosis3T3cells生长因子生长因子受体信号传递分子转录因子MechanismsofOncogeneActivation

ORFRSProto-oncogeneORFRSORFRSORFRSmutationamplificationORFRSRSRe-arrangementdeletionPointmutationRas15-20%K-rasN-rasH-rascarcinomas30%:lungadenocarcinomas50%coloncarcinomas90%:pancreaticcarcinomasBloodmalignanciesExon12insersionPartialkaryotypesoftrypsin-Giemsa-bandedmetaphasecellsdepictingnonrandomchromosomalrearrangementsobservedinlymphoidmalignantdiseases.t(4;11)(q21;q23)inALLt(1;19)(q21;p13)inpre-BcellALLt(8;14)(q24;q32)inB-cellALLandBurkitt'slymphomainv(14)9q11q32)inT-cellleukemia/lymphomat(8;14)(q24;q11)inT-cellleukemia/lymphomat(14;18)(q32;q21)inB-cellNHL8q24:MYCgene18q21:BCL214q32:IGHq32q32q32141414q32q32q32141414rasFamily.Therasfamilyofoncogenes(homologoustotheratsarcomavirus)hasthreeprimarymembers(H-ras,K-ras,andN-ras)whichareamongthemostcommonactivatedoncogenesfoundinhumancancer.Therasgenescodeforaprotein(p21)thatislocatedontheinnersurfaceoftheplasmamembrane,hasGTPaseactivity,andmayparticipateinsignaltransduction.rasoncogenesareactivatedbypointnucleotidemutationsthataltertheaminoacidsequenceofp21.rasinCarcinogen-InducedTumorsMiceharboringthemutatedH-rastransgenedevelopedtumorsexclusivelyinthelungswithinweeksfollowingbirth.Ninetypercentofthesetumorshadtransforminggenesinthe(NIH)3T3assay;thegenewasK-rasinalllungtumors.Studiesinmicewithcarcinogen-inducedlungcancersimplicategenesoftherasfamilyinthecarcinogenesisprocess.MouselungtumorsinducedbytetranitromethanecontainedmutatedK-rasgenes.Inmoststudies,K-rasmutationswereconfinedtoadenocarcinomasofthelungandoccurredin30%oftumors.Mutationswerenotobservedinadenocarcinomasfromnonsmokers.K-rasmutationappearstobeanindependentprognosticfactorthatindicatesapoorprognosisandisunrelatedtoconventionalstagingcriteria,suchastumorsizeorlymphnodemetastases.Inallpatientsstudied,mutationsoccurredinasingleallele.isthecaseforadenocarcinomaofthecolon.rasmutationscaninfluencethedifferentiationoftumorcells.Forexample,infectionofSCLCcelllineswiththeHarveymurinesarcomavirusaltersthephenotypeofcells.

Followinginfection,thevariantSCLCcelllinedevelopedfeaturesofalargecellundifferentiatedlungcarcinoma,includingincreasedcarcinoembryonicantigenandkeratinexpression.Studiesdonesofarfavortheinterpretationthatrasactivationcontributestoprogressioninlungcancer.rasapparentlyisactivatedinaboutone-thirdofadenocarcinomasarisinginpatientswithahistoryofheavysmoking.However,premalignantlunglesionshavenotbeenstudiedtodetermineifsuchmutationsexistattheprecancerousstage,asisthecaseforadenocarcinomaofthecolon.HumanStudies.AntisensewasusedtostudytheeffectsofeliminatingexpressionofamutantK-rasoncogeneinNSCLCcells.Aselectivedecreaseinmutantoncogeneexpressionswasachieved,associatedwithdecreasedgrowthofcancercellsasheterograftsinnudemice.Antisense/iRNA/ribozymetechnology:Thistechniqueprovidesanopportunitytodeterminetheeffectsofselectiveinhibitionofoncogenicproteinexpressiononthemalignantphenotype.Thisstudyandsubsequentconfirmatoryonesshowedthatreversalofasinglegeneticabnormalitywassufficienttopreventhumancancercellsfromformingtumors.Thus,itmaynotbenecessarytoreverseallthegeneticlesionsinacancercelltoachieveatherapeuticeffect.AntisensewasusedtostudytheeffectsofeliminatingexpressionofamutantK-rasoncogeneinNSCLCcells.Aselectivedecreaseinmutantoncogeneexpressionswasachieved,associatedwithdecreasedgrowthofcancercellsasheterograftsinnudemice.Antisense/iRNA/ribozymetechnology:Thistechniqueprovidesanopportunitytodeterminetheeffectsofselectiveinhibitionofoncogenicproteinexpressiononthemalignantphenotype.Thisstudyandsubsequentconfirmatoryonesshowedthatreversalofasinglegeneticabnormalitywassufficienttopreventhumancancercellsfromformingtumors.Thus,itmaynotbenecessarytoreverseallthegeneticlesionsinacancercelltoachieveatherapeuticeffect.Theseobservationsraisetheintriguingpossibilityofspecificgenetherapyforcancer.Theseobservationsraisetheintriguingpossibilityofspecificgenetherapyforcancer.Genesequencescouldbedeliveredtotumorcellsviaviralvectorsthatspecificallyinhibitexpressionoftheoncogenesactivatedinthecancercell.Suchconstructswouldberelativelynontoxicbecause,asintheexampleabove,theycouldtargetasinglegenewhosefunctionmaybeassumedbyotherredundantgenesofthesamefamily.第三节：抑癌基因

（tumorsuppressorgene

）（antioncogene）如果其功能失活或出现基因缺失、突变等异常，将导致细胞恶性转化而形成肿瘤。

这类基因作为细胞的刹车而起作用。它们编码的蛋白能够抑制细胞的生长，阻止细胞恶性转变。抑癌基因的生物学功能与癌基因相反，是机体细胞在身生长、增殖、分化和凋亡等生命过程中的负调控信号。确定一种抑癌基因在理论上需符合三个基本条件：①该基因在与恶性肿瘤组织相对应的正常组织中必需正常表达；②恶性肿瘤中这种基因应有功能失活、结构改变或表达缺陷；③将这种基因的野生型导入基因异常的肿瘤细胞内，可部分或全部逆转肿瘤的恶性表型。遗传性肿瘤发病早，肿瘤表现为多发性或双侧性散发性肿瘤发病迟，肿瘤表现为单发性或单侧性Knudson：

twohithypothesis

1978年Francke13q141983年Cavenee等lossofheterozygosity，LOH染色体13q14处的DNA标志。1986年，美国三个实验室分别独立克隆了该基因RbSMG2G1CellcycleQuiescence(G0)G2G1SMCellcyclecyclinscyclinsCDKcyclinsCDKCDKIG2G1SMCellcycleDPE2FDNAsynthesis-relatedgenesE2FRbPE2FCyclinD1CDK4RbPPPPPRbPPPPPE2FE2FE2FE2FDPE2FDNAsynthesis-relatedgenes“Tobeagreatchampionyoumustbelieveyouarethebest.Ifyou’renot,pretendyouare….!”

–MuhammadAli

TOPICS

IntroductionAcuterenalfailureChronicrenalfailure

UremiaFunctionsofkidneyThekidneysexcretethesecompoundswithwatertomakeurine.

Theyalsoeliminateexcessbodywaterwhileselectivelyreabsorbingusefulchemicalsandallowingwastetopassfreelyintothebladderasurine.

Theyallowyoutocontinuetoconsumeavarietyoffoods,drugs,vitaminsandsupplements,additives,andexcessfluidswithoutworrythattoxicby-productswillbuilduptoharmfullevels.Thekidneysareapairofsmallorgansthatlieoneithersideofyourspineataboutwaistlevel.Theyactasfiltersthatkeepyourbloodfreeofby-productsandtoxins.Thekidneysplayanessentialroleinmaintainingelectrolyteandacid-basebalance.

Theyproducesomehormonesincludingrenin,prostaglandins,erythropoietin,andactivevitaminD.

So,theyarecrucialintheregulationofbloodpressure,formationofmaturedredbloodcells,andmetabolismofcalciumandphosphorus.FunctionsoftheKidneyWasteexcretionElectrolytebalanceFluidbalancepHOsmolalityHormoneproductionAnatomyofKidneyManifestationofrenaldysfunctionGlomerulus

·decreased

GFR·glomerularfiltrationmembranepermeabilityalterationRenaltubule

·concentrativefunctiondecline(hyposthennuria/isosthennuria)·water,electrolyte,acid-basedisorder·othersEndocrinedisorder

·hypertension·anemia·renalosteodystrophy·others体内VitD3的代谢过程

紫外线25-羟化酶1α-羟化酶7-脱氢胆固醇VitD325-(OH)VitD31,25-(OH)2VitD3

（皮肤）（肝微粒体）（肾线粒体）AcuteRenalFailure,ARFDefinitionEtiology&classification

PrerenalfailureIntrinsicrenalfailurePost(obstructive)renalfailure

PathogenesisClinicalmanifestationTherapyDefinitionAcuterenalfailure(ARF)isdefinedasaprecipitousandsignificant(>50%)decreaseinglomerularfiltrationrate(GFR)overaperiodofhourstodays,withanaccompany-ingaccumulationofnitrogenouswastesinthebody.急性肾功能衰竭的定义

急性肾功能衰竭（acuterenalfailure，ARF）是指各种病因引起双侧肾脏在短期内泌尿功能急剧降低，导致机体内环境出现严重紊乱的病理过程和临床综合症。肾泌尿功能障碍表现为GFR迅速下降，出现少尿无尿；内环境紊乱主要表现为氮质血症、高钾血症和代谢性酸中毒。急性肾功能衰竭根据尿量减少与否，分为少尿型（成人每日尿量少于400ml）和非少尿型（成人每日尿量大于400ml）两种类型。急性肾衰病情凶险，临床较常见，但若及时诊治，预后较好。EtiologyPre-renal(~70%ofcases)

resultingfromimpairedbloodflowtooroxygenationofthekidneys.Intrinsic-renal(~25%ofcases)

resultingfrominjurytoormalformationofkidneytissues.Post-renal(<5%ofcases)

resultingfromobstructionofurinaryflowbetweenthekidneyandurinarymeatus.CausesPrerenalfailure-Diseasesthatcompromiserenalperfusion

Decreasedeffectivearterialbloodvolume-Hypovolemia,CHF,liverfailure,sepsisRenalarterialdisease-Renalarterialstenosis(atherosclerotic,fibromusculardysplasia),embolicdisease(septic,cholesterol)

肾前性急性肾功能衰竭的发生机制

肾前性因素休克的原因（失血、失液、感染、急性心衰、严重过敏反应）和其它（肝肾综合征）

ADH

有效循环血量

Ald

血压降低

肾灌流压

肾血管收缩

肾血流量

肾小球有效滤过压

GFR

尿量

Intrinsicrenalfailure-Diseasesoftherenalparenchyma,specificallyinvolvingtherenaltubules,glomeruli,interstitiumATN,ischemia,toxins(eg,aminoglycosides,radiocontrast,hemepigments,cisplatin,myelomalightchains,ethyleneglycol)Interstitialdiseases-Acuteinterstitialnephritis,drugreactions,autoimmunediseases(eg,systemiclupuserythematosus[SLE]),infiltrativedisease(sarcoidosis,lymphoma),infectiousagents(Legionnairedisease,hantavirus)AcuteglomerulonephritisVasculardiseases-Hypertensivecrisis,polyarteritisnodosa,vasculitisPostrenalfailure-DiseasescausingurinaryobstructionfromtheleveloftherenaltubulestotheurethraTubularobstructionfromcrystals(eg,uricacid,calciumoxalate,acyclovir,sulfonamide,methotrexate,myelomalightchains)Ureteralobstruction-Retroperitonealtumor,retroperitonealfibrosis(methysergide,propranolol,hydralazine),urolithiasis,papillarynecrosisUrethralobstruction-Benignprostatichypertrophy;prostate,cervical,bladder,colorectalcarcinoma;bladderhematoma;bladderstone;obstructedFoleycatheter;neurogenicbladder.CausesofARFintertiarycarehospitalsetting急性肾功能衰竭病因与分类肾前性ARF（早期为功能性ARF

）

有效循环血量减少引起肾血流量急剧减少是肾前性ARF发生的关键因素。肾性ARF（亦称器质性ARF）

由肾脏实质病变引起。急性肾小管坏死（acutetubularnecrosis，ATN）是临床上最常见、最重要的ARF类型，约占ARF的75%～80%。肾后性ARF

因双侧性尿路梗阻引起，如尿路结石、肿瘤、前列腺疾患等。PathogenesisofARFDecreasedrenalbloodflowRenalhypoperfusionVasoconstrictionVascularobstructionRedistributionofrenalbloodflowI.RenalhemodynamicsfactorsTubuleinjuryTubuleobstructionPassivebackflowII.NephronalfactorsAcuteRenalFailure,Intrinsic

AcuteTubularNecrosisRenalhypoperfusion/ischemiaNephrotoxicagents(bothendogenousandexogenous)Mortality50%Bronchopulmonaryinfections,sepsis,cardiovasculardisease,bleedingdisordersCompleteRecovery25%,Incomplete20%,NoRecovery5%AcuteTubularNecrosis

NephrotoxicAgentsExogenousAntibioticsContrast DiureticsChemotherapeuticsAnalgesicsSolvents,metals,chemicalsHIVmedsAntiulcermedsAnestheticsEndogenousPigmentnephropathyCrystaldepositionTumor-specificsyndromesAcuteTubularNecrosisCellHypoxiaDepletionofATPImpairedfunctionOfplasmamembranesAndATPasesCa++imbalanceNa-KimbalanceCellSwellingDisruptcytoskeletonActivatephospholipasesFormationofxanthineoxidaseUncouplingofoxidativephosphorylationHypoxanthineDisruptlipidbilayerReperfusioninjuryFreeradicalsAcuteTubularNecrosisLeadsto…LossofcellpolarityBrushborderlossImpairedcell-celladhesionImpairedtightjunctionEndresults…ImpairedsoluteandwatertransportSloughingoftubulecells

obstructionBackleakageoffiltrate急性肾功能衰竭的发病机制

急性肾衰发病机制的中心环节是GFR的降低。一肾血流动力学异常肾血流急剧减少

肾灌注压下降

肾血管收缩

肾血管阻塞

肾内血流重分布

二肾小管损伤肾小管阻塞原尿返流三肾小球超滤系数降低

Characteristics&clinicalcoursesOliguricphaseDiureticphaseRecoveryphaseOliguricphaseUsuallylastingfor1to6weeks,theaveragedurationisbetween7&10days.Featuresofurine:I.OliguriaorAnuriaII.HematuriaandcastsIII.LowspecificgravityandosmolalityIV.Urinary[Na+]above20mMAzotemia

MetabolicacidosisHyperkalemiaHypervolemia/HypertensionOthers:edema,waterintoxication，tachypneaUrinaryIndicesinARFPrerenalARFATNUrinary[Na+],mEq/L<20>40UrinetoplasmaCr>40<20Urineosmolality>500<400Urinespecificgravity>1.020<1.015RenalFailureIndex<1>1FENa<1>1ResponsetoIVFGoodPoor功能性肾衰和器质性肾衰（ATN）的鉴别

功能性肾衰

器质性肾衰尿液性质

尿比重

尿渗透压

尿钠尿肌酐/血肌酐尿常规治疗与反应

>1.020<1.015>500mOsm/L<400mOsm/L<20mmol/L>40mmol/L>40<20正常蛋白尿、管型、红细胞、白细胞

应迅速补充血容量需严格控制补液量使肾血流恢复，GFR

量出而入补液后尿量迅速增多尿量持续减少病情明显好转甚至使病情恶化MuddyBrownCastRedCellCastWhiteCellCastsDiureticphaseAshealingbegins,improvementisreflectedintheproductionofmorethan400mlofurineperday.Fluidandelectrolyteabnormalities.Crmaystillrisefor1-2moredays.RecoveryphaseARF的主要机能代谢变化和临床表现

一少尿期

1.

少尿、无尿

2.

氮质血症：指肾功能衰竭时，由于GFR下降，含氮的代谢产物如尿素、肌酐、尿酸等在体内蓄积，引起血中非蛋白氮的含量增加（＞28.6mmol/L，或＞40mg/dl）。

3.

水中毒：当肾排水功能障碍的情况下，一旦水摄入稍多，就易造成稀释性低钠血症，大量水份进入细胞内，引起脑水肿、肺水肿、心力衰竭。因此对少尿期ARF患者，要严格控制摄入水量。

4.

高血钾：主要由GFR降低和肾小管泌钾障碍引起，机体代谢分解增强使钾释放增多及酸中毒引起细胞内钾向细胞外转移，都能促使血钾进一步增高。严重高血钾可导致室颤和心跳骤停。高钾血症是ARF患者第一周死亡的最常见原因。

5.

代谢性酸中毒：主要由GFR降低、肾小管排酸保碱作用减退、体内分解代谢加强使固定酸产生过多等原因引起。二多尿期

经过少尿期后，当每天尿量大于400ml，说明病人已进入多尿期。进行性尿量增多是肾功能开始恢复的一个标志。多尿期的早期，GFR仍较正常为低，主要因肾小管修复再通而修复的肾小管浓缩功能仍很差，一方面排出代谢产物的能力不足，一方面出现多尿。这时患者仍可存在氮质血症，也可能存在高钾血症。尿量过多常使患者发生水、电解质紊乱，主要倾向是脱水、低血钾和低血钠，所以对这些病人要注意预防。三恢复期

患者自我感觉好转，逐步能自理生活和进行劳动。尿量逐渐恢复正常，血尿素氮和肌酐也接近正常。Nonoliguricacuterenalfailure非少尿型ARF近年来有逐渐增多的趋势；这可能与病人医疗意识加强、医疗诊治手段提高及肾毒性抗生素广泛应用有关。其机制为：①不同肾单位受损程度不一，小部分肾单位的肾血流量和肾小球滤过功能存在；②肾小管重吸收功能障碍远较肾小球滤过功能降低为重；③肾髓质形成高渗状态的能力降低，使尿液浓缩功能下降，故发病后尿量无明显降低，在400～1000ml/d左右。非少尿型ARF较少尿型ARF病情轻、预后好，但因症状轻而不太明显，容易延误病人的就诊或引起医生的漏诊。非少尿型ARF不及时治疗，则会转化为少尿型ARF。ManagementRenalDietAcidosisHyperuricemiaHypertensionVolumeoverloadProteinLoadNewerAgents：ANFDialysisKidneyTransplantationHospitalinpatientswithARF~50%mortalityrateDialysisindicationsI.SerumabnormalitiesunresponsivetomedicaltherapySevereAcidosisSevereHyperkalemiaII.UremiaMentalstatuschanges(usuallydelirium)NauseaandvomitingPericarditis(pericardialfrictionrub)III.VolumeOverloadPeritonealDialysisHemodialysisBloodiscirculatedthroughartificialcellophanemembranethatpermitsasimilarpassageofwaterandsolutesChronicRenalFailure,CRFDefinitionEtiologyPathogenesisClinicalmanifestationTherapyDefinitionChronicrenalfailure(CRF)isdefinedasapermanentreductioninglomerularfiltrationrate(GFR)sufficienttoproducedetectablealterationsinwell-beingandorganfunction.ThisusuallyoccursatGFRbelow25ml/min.CRFischaracterizedbyprogressiveandirreversiblelossoflargenumbersoffunctioningnephrons.Seriousclinicalsymptomsoftendonotoccuruntilthenumberoffunctionalnephronsfallstoatleast70percentbelownormal.Infactrelativelynormalbloodconcentrationsofmostelectrolytesandnormalbodyfluidvolumescanstillbemaintaineduntilthenumberoffunctioningnephronsdecreasesbelow20-30percentofnormal.慢性肾功能衰竭的定义慢性肾功能衰竭是由于各种肾脏疾病引起肾单位进行性破坏，以致残存的有功能的肾单位不能充分排出代谢废物和维持内环境恒定的缓慢发展的一种肾功能损害的病理过程。机体逐渐出现代谢废物和毒物的潴留，水、电解质与酸碱平衡紊乱，以及肾内分泌功能障碍，并可伴有全身各系统功能受损的临床症状。因为肾组织的破坏是逐渐发生的，而且肾脏又有较强的代偿能力，故慢性肾衰常常是缓慢发展，病程迁延数月、数年以至更长的时间，最后常导致尿毒症而死亡。尿毒症是指急、慢性肾功能衰竭最危重的阶段。

CausesofCRFAnydisorderthatpermanentlydestroysnephronscanresultinchronicrenalfailure.MostcommoncausesofCRFare:DiabeticnephropathyHypertensivenephrosclerosisGlomerulonephritisInterstitialnephritisPolycystickidneydisease慢性肾功能衰竭的病因

凡能引起肾实质进行性破坏的疾患，均可引起慢性肾功能衰竭。其中以慢性肾小球肾炎为最常见，约占CRF的50%～60%。

（1）肾脏疾患：慢性肾小球肾炎、慢性肾盂肾炎、肾结核、肾肿瘤、全身性红斑狼疮。（2）肾血管疾患：高血压肾小动脉硬化等。（3）尿路慢性梗阻：尿路结石、前列腺肥大等。（4）全身代谢性疾病：糖尿病肾病等。（5）其他：药物性肾损伤等。ClinicalcoursesofCRFFourstagesofdecreasedrenalfunctionmaybevisualized:

Silent–GFRupto50ml/min.Renalinsufficiency–GFR25to50ml/min.Renalfailure–GFR5/10to25ml/minEnd-stagerenalfailure(ESRF)–GFRlessthan5/10ml/min.StageDescriptionGFRLevelNormalkidneyfunctionHealthykidneys90mL/minormoreStage1KidneydamagewithnormalorhighGFR90mL/minormoreStage2KidneydamageandmilddecreaseinGFR60to89mL/minStage3ModeratedecreaseinGFR30to59mL/minStage4SeveredecreaseinGFR15to29mL/minStage5KidneyfailureLessthan15mL/minorondialysisStagesofChronicKidneyDisease

慢性肾功能衰竭的发展过程和分期

内生肌酐清除率

氮质血症

临床表现（ml/min）代偿期

>50无

无任何症状。但不能负荷额

外的水、电解质和酸碱失代偿期

肾功能不全期

20-50轻、中度

轻度消化道症状和贫血

肾功能衰竭期

10-20较重

明显多尿、夜尿和水、电解

质、酸碱紊乱

尿毒症期

<10严重

全身中毒症状明显，各脏器

系统功能障碍

PathogenesisThemostintriguingaspectofCRFisthatcompensatorymechanismsallowlossof90%ofGFRbeforemanifestationsoftheuremicsyndromeareevident.ThusavarietyofadaptationscompensateforthedecreasedGFRandallowanewsteadystateofexternalbalancetoexist,butontheotherhandcontributetotheuremicsyndrome.Inspiteoftheseadaptations,thehallmarkofCRFisthelossofflexibilityinrespondingtochallengestoexternalloadofsolutesandwater.

IntactNephronhypothesis

Tubulointerstitialcellinjury

Trade-offhypothesisIntactNephronHypothesisNephronsfunctioningindiseasedkidneysmaintainglomerulo-tubularbalance.Thatis,filtrationandnetexcretionofvarioussubstancesarecoordinated.(e.g.withnormalrenalfunction,usually50-60%offilteredureaisreabsorbedfromthetubules.InCRFitmayfallto30%tomaintainbalance).TheMagnificationPhenomenonalthoughnephronsindiseasedkidneysfunctionhomogeneously,theyaltertheirhandlingofgivensolutesasneededtomaintainbalanceofthesesolutes.Thatis,nephronscanmagnifytheirexcretionofagivensolute.(e.g.tubularcreatinineexcretionis<10%withnormalrenalfunction.InCRFitmayincreaseto30%).Trade-offHypothesisThemechanismsthataremagnifiedtomaintainindividualsolutecontrolmayhavedeleteriouseffectsonothersystems.Thistrade-offisseenintheincreasedparathyroidhormone(PTH)secretionseeninCRFwhichenhancesrenalphosphorusexcretion.PTHhasbeenimplicatedinthepathogenesisofmanydisturbancesofuremia(sleep,sex,bone,disease,anemia,lipidemia,vasculardisease).AsrenaldiseaseprogressesandGFRdecreases,highlevelPTHnolongermaintainsthephosphateexcretion.TheexcessivePTHmayresultinfurthersideeffects,suchasosteomalacia,depositofcalciumphosphatesaltsintosofttissueanddamageofcardiovascular,neuralsystems.慢性肾功能衰竭的发病机制健存肾单位进行性减少矫枉失衡肾小管-间质损害

钙磷代谢的矫枉失衡

慢性肾脏疾患

肾单位↓

GFR↓GFR↓↓

VitD3

血磷↓肾排磷↓肾排磷↓↓酸中毒肾排磷↑血磷↑、血钙↓血磷↑↑

肾小管重吸收磷↓PTH↑血钙↓↓（健存肾单位）血钙↑溶骨肾性骨营养不良

“矫正”“失衡”内生肌酐清除率Ccr=[尿肌酐]

尿量/分[血肌酐]*正常值：90－140ml/min*无肌酐饮食2－3天后测定。*无肌酐饮食：摄入蛋白质<40g/天，禁肉食，避免剧烈运动。ClinicalmanifestationsofCRFLossofnephron’sfunctiontoexcretewaterandsolutes.Characteristicsofurine:

urinevolume,osmotic&gravity,