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肾脏病理生理学RenalpathophysiologyDepartmentofpathophysiology 肾功能泌尿功能内分泌功能通过泌尿排除代谢废物，并维持水、电解质和酸碱平衡，维持机体内环境的恒定。肾素PGsEPO1，25-OH2VD3 1.Excretoryfunction2.Regulatoryfunction3.Endocrineandmetabolicfunction 肾功能不全发展过程当各种原因引起肾功能障碍时：首先表现为泌尿功能障碍，继之引起体内代谢紊乱与内分泌功能障碍，严重时还可使各系统发生病理变化。分急性和慢性，但都以尿毒症告终。 ContentsBasicpathologicaltachesforrenalfailureAcuterenalfailure(ARF)Chronicrenalfailure(CRF)Uremia(尿毒症） 尿生成过程血浆经肾脏生成尿，是由肾小球滤过、肾小管的重吸收和分泌三个相联系的环节实现的。 PeritubularcapillaryRenaltubuleH2OH2OH2OUrine肾小球滤过Glomerularfiltration肾小管重吸收Tubularreabsorption肾小管分泌TubularsecretionFlowoffiltrateRenalcorpuscle尿液排泄Urinaryexcretion BasicpathologicaltachesforRFGlomerulardysfunctionTubulardysfunctionEndocrinedysfunction GlomerulardysfunctionDecreaseofGFR(Bloodflow,Glomerulareffectivefiltrationpressure,Kf)DecreaseofglomerularcapillarysurfaceareaAlterationsofpermeabilityofglomerularfiltrationmembrane(nephrin，CD2AP,etc) ACTN4:α-actinin-4;CD2AP:CD2-associatedprotein;GEC:glomerularendothelialcell;ILK:integrin-linkedkinase;ZO-1:tightjunctionproteinZO-1;CD151:tetraspaninCD151;TRPC6:transientreceptorpotentialcationchannel6;NCK:proteinadaptorNCK. RenaltubulardysfunctionDysfunctionoftheproximalconvolutedtubules(reabsorption)DysfunctionofHenle’sloopDysfunctionofthedistalconvolutedtubules ThefundamentalunitforrenalfiltrationandreabsorptionHCO3-H+/NH4+edema,polyuria,hyposthenuria,glycosuria,aminoaciduria,metabolicacidosis,isothenuria RenalendocrinedysfunctionRenin-angiotensin-aldosteronesystem(RAAS)↑Erythropoietein(EPO)↓1,25-dihydroxyvitaminD3↓Kallikrein-kinin-prostaglandin-system(KKPGS）↓Parathyroidhormone(PTH)andgastrin↑Arachidonicacid(AA)metabolismdisorder Erythropoietein(EPO) Arachidonicacid(AA)抑制水钠重吸收；刺激近球细胞释放肾素；脂氧合酶LTs（炎症介质）收缩血管 ClinicalExampleMale，68yearsold，puffiness,anuria.RepeatedtakingGentamicinandSMZforupperrespiratoryinfection.R:eyelidpuffiness，legswithpittingedemaChemicalexamination：urineprotein（++），urinespecificgravity:1.015，UNa:64mmol/L，serumcreatinine:809µmmol/L，UN:16.2mmol/L. Questions2.Whatisthemechanismofoliguria?Whatisthereasonofoliguria?3.Whataretheeffectsofoliguriaforbody？ Acuterenalfailure☻Conception☻☻☻Etiologyandpathogenesis☻☻☻Alterationsoffunctionandmetabolism Conceptionofacuterenalfailure(ARF)Aheterogenousgroupofdisorders,whichischaracterizedbyasudden(withinhourstodays)deteriorationofrenalfunctionandusuallyassociatedwitholiguriaorannuriaresultinginaccumulationinthebloodofnitrogenouswasteproductsthatwouldnormallybeexcrectedintheurine.Thepatientspresentoftenwithazotemia,waterintoxication,hyperkalemiaandmetabolicacidosis.各种原因→短期内→泌尿功能↓↓→内环境严重紊乱 Fatality20-70% PrerenalARF(肾前性ARF)EtiologyandclassificationofARFIntrarenalARF(肾性ARF)PostrenalARF(肾后性ARF) PrerenalARF(肾前性ARF)CauseTheeffectivecirculatingbloodvolume↓CharactersFunctionalARF＊尿量减少、尿钠<20mmol/L、＊尿肌酐/血肌酐>40；＊去除病因，肾功能迅速恢复。EtiologyandclassificationofARF MechanismsofPrerenalARFTheeffectivecirculatingbloodvolume↓renalbloodvolume↓GFR↓Renaltubularreabsorption↑oliguriaDisturbanceofhomeostasis CauseObstructionofurinarytracePrerenalARF(肾前性ARF)EtiologyandclassificationofARFPostrenalARF(肾后性ARF)CharactersFunctionalARFinearlystage Intrinsicrenaldiseases(mainlyATN)OrganicARFPrerenalARF(肾前性ARF)EtiologyandclassificationofARFPostrenalARF(肾后性ARF)IntrarenalARF(肾性ARF)CharactersCause 1.AcutetubularnecrosisAcuterenalischemiaAcuterenalpoisons（heavymetals,organicsolvents,drugs,biologicalagents)CausesofintrarenalARF 正常中毒正常肾与HgCL2中毒肾髓质之比较（200×）朱砂（硫化汞、循环泌尿系统）、甲基汞（神经系统、水俣病） 硫辛酸调控Nrf-2/HO-1通路对急性百草枯中毒大鼠肾损伤的保护作用 1.Acutetubularnecrosis2.IntrinsicrenaldiseasesacuteglomerulonephritisacuteinterstitialnephritisacutevascularnephritisCausesofintrarenalARF 分型：ARF肾前性（30~60%)肾性（20~40%)肾后性（1~10%)肾小球肾炎间质性肾炎血管疾病肾小管坏死中毒沉着物缺血 010203040506070FernandoL,1967，ARF,MadridpresentstudyPre-RenalRenalPost-Renal 急性肾功能衰竭(acuterenalfailure,ARF)Definitionetiologyandclassificationpathogenesis（oliguria?）renalfunction↓↓(oliguriaoranuria)causes？GFR↓↓ GFR↓ RenalbloodflowGlomerularfiltrationmembraneGlomerularFiltrationRate(GFR)Glomerulareffectivefiltrationpressure DysfunctionofglomerularfiltrationDecreaseofrenalbloodflowDecreaseofglomerulareffectivefiltrationpressureDecreaseofglomerularcapillarysurfaceareaAlterationsofpermeabilityofglomerularfiltrationmembrane NetFiltrationPressureBloodhydrostaticpressure(BHP)60mmHgoutColloidosmoticpressure(COP)-32mmHginCapsularpressure(CP)-18mmHginNetfiltrationpressure(NFP)10mmHgoutNFPBHP60outCOP32inCP10out18in RenalischemiaGlomerulopathyRenaltubularocclusionOriginalurinerefluxRenalcellinjuryPathogenesisofARFGlomerularfactorTubularfactor Renalischemia→GFR↓RenalarteryperfusionPre.↓PathogenesisofARFBp80-160mmHgRBF～Bp<80mmHgRBF↓,GFR↓,1/2-2/3Bp<40mmHgRBF=0 肾血流量和肾小球滤过率的自身调节RPF：肾血浆流量GFR：肾小球滤过率80180405.3 Contraction↑(CA,RAA,ET↑）Relaxing↓(PGE2↓,kinin↓）Renalischemia→GFR↓RenalarteryperfusionPre.↓RenalbloodvesselcontractionPathogenesisofARF EndothelialcellBloodflowNormal CellswellingDecreaseofbloodflowAcuterenalfailureCellinjurandaccumulationofplate SwellingofendothelialcellsPathogenesisofARFIntrarenalDICRenalischemia→GFR↓RenalarteryperfusionPre.↓Renalbloodvesselcontraction GFR↓RBF↓Perfusionpre.↓BloodvesselconstrictionBP↓CA,ET,RAS↑,PGE2,kinin↓RenalischemiaEndothelialswellingDIC AcutegromerularitsNormalAcutegromerularitsDecreaseofglomerularcapillarysurfacearea→GFR↓ RenalischemiaGlomerulopathyRenaltubularocclusionOriginalurinerefluxRenalcellinjuryPathogenesisofARFGlomerularfactorTubularfactor UrineflowDenudedtubularmembraneInjuredtubularcellsObstructionfromdebrisandnecroticcells RenaltubularobstructionRenalischemiaRenalintoxicationGromerularTubularTransfusionreactionCrushingsyndrome 1)TubularobstructionIschemianephrotoxinTubularobstruction→intra-pressure↑EPCfalloffGEFP↓TubularnecrosisGFR↓Oliguria→ARFCastDifferenttypebloodtransfusionExtrusionsyndromeStreptocide（SMZ）HbMb2.Renaltubulefactor ProteinCastsGranularCastRBCCastsEpithelialCastsinUrine RenalischemiaGlomerulopathyRenaltubularocclusionOriginalurinerefluxRenalcellinjuryPathogenesisofARFGlomerularfactorTubularfactor urineTubularcellinjuryBasemembraneinjuryNecroticobstruction TubularcellsBasemembraneRenaltoxinUrineNecroticcellanddebris InterstitialedemaTubuleandcapillarycompressedGFR↓OriginalrefluxtubuleobstructionOliguria RenalischemiaGlomerulopathyRenaltubularocclusionOriginalurinerefluxRenalcellinjuryPathogenesisofARFGlomerularfactorTubularfactor 肾小球因素肾小管因素 DamagedcellsRenalTubularcellEndothelialcellMesangialcellMechanismofcellinjury TubulorrhexiclesionNephrotoxiclesion 肾小管细胞坏死性损伤凋亡性损伤小管破裂性损伤:累及各段肾小管,基底膜破坏内皮细胞系膜细胞肾毒性损伤:累及近球小管,基底膜完整缺血中毒中毒内皮细胞肿胀内皮细胞受损→血小板聚集、微血栓形成→毛细管内凝血内皮细胞受损→舒血管因子↓缩血管因子↑→GFR↓AngⅡ、ADH、腺苷、庆大霉素、硝酸铀→系膜细胞收缩→GFR↓⒈受损细胞的种类及特征累及远端肾小管,微绒毛消失,核固缩,出现凋亡小体 NormalCellApoptoticcellCellundergoingapoptosis MechanismofcellinjuryATPanddysfunctionofionpumpsOxygenfreeradicalReducedGSHActivityofPLA2CytoskeletalstructuralchangesIncreaseincellapoptosis Na+、K+-ATP↓Ca2+-ATP↓Na+andwaterretention,cytoplasmfreeCa2+↑Ca2+overloadATP↓Ischemia,poisonsCellswellingOFRpro.↑clearance↓perioxidizingGSH↓PLA2↑PGs、LTsCellinjuryMitochondriaCa2+↑ADP、poisonsMechanismofcellinjury Mechanismofcellinjury (1)肾脏氧供特点(2)髓袢升支粗段（mTAL）及降支粗段(S3段)对缺氧敏感，与其位于低氧环境和主动重吸收耗氧量大有关(3)内源性调节因子与mTAL损伤：(4)肾中毒和肾缺血互相增强对肾小管损伤①腺苷②花生四烯酸(及)代谢产物③NO④血红素氧化酶(HO)／一氧化碳(CO)/HO在肾小管表达不同与ARF功能损伤有关的因素 MechanismofcellrepairThegeneticregulationbyhypoxiaandischemiaTheproductionandactiveofHSPFunctionofcytokinesReconstructionofcellularskeletonandrenaltubule Thegeneticregulationbyhypoxiaandischemia FIGURE1.Kidneytissueinjury(a–d)andrepair(e–h)overtimefollowing20minofbilateralrenalischemia/reperfusioninjury.MaleWistarratsweresubjectedtoshamorbilateralischemiabyclampingtherenalpediclesfor20minandthenremovingtheclampsandconfirmingreperfusion.Ratswereeuthanizedatvarioustimesandkidneytissueswerecollected.RepresentativephotomicrographsofH&E-stainedparaffin-embeddedkidneysections(at200×magnification)andimmunohistochemistryforKi67(at400×magnification)arepresentedfromthefollowingtimepoints:(a,e)Shamsurgery;(b,f)24h;(c,g)72h;and(d,h)120h.Allfieldswerechosenfromthecortexandoutermedulla.Arrowsinpanelsbandcindicatesloughingofcells,tubulardilationandnecrosis.Arrowsinpanelse–hshowKi67positivenucleiasanindicatoroftubularepithelialcellproliferation. Apoptosisinthekidneytissueovertimefollowing20minofbilateralrenalischemia/reperfusioninjury.MaleWistarratsweresubjectedtoshamorbilateralischemiabyclampingtherenalpediclesfor20minandthenremovingtheclampsandconfirmingreperfusion.Ratswereeuthanizedatvarioustimes,kidneytissueswerecollectedandtransferasedUTPnickendlabeling(TUNEL)immunostainingwasperformedtolabelapoptoticcells.Representativephotomicrographsat400×magnificationarepresented.ArrowsinpanelsshowTUNELpositivenucleiasanindicatoroftubularepithelialcellapoptosis. Thegeneticregulationbyhypoxiaandischemia Thegeneticregulationbyhypoxiaandischemia TheproductionandactiveofHSP Functionofcytokines Functionofcytokines FunctionofcytokinesThemainpathwaysoftheeffectsofEPO. ApoptoticpathwaysinfluencedbyEPO Renalischemia,renalpoisonsRenalarterialvasoconstriction(RAS↑,ET↑,NO↓,PGI2↓)OFR↑,Na+-K+ATPasedysfunctionIntrarenalDICInjuryofrenaltubularcellsSwellingofendothelialcellsRenalbloodflow↓TubularobstructionPassivebackflowGEFP↓Intrapressure↑,tubularurine↓GFR↓OliguriaThemechanismofacuterenalfailurecausedbyacuterenalischemia ClinicalExampleMale，68yearsold，puffiness,anuria.RepeatedtakingGentamicinandSMZforupperrespiratoryinfection.R:eyelidpuffiness，legswithpittingedemaChemicalexamination：urineprotein（++），urinespecificgravity:1.015，UNa:64mmol/L，serumcreatinine:809ummol/L，UN:16.2mmol/L.2.Whatisthemechanismofoliguria?Whatisthereasonofoliguria?3.Whataretheeffectsofoliguriaforbody？ Acuterenalfailure,ARFDefinitionCausesandclassificationPathogenesisAlterationsofmetabolismandfunction OligurictypeARFNonoliguricARFAlterationsofmetabolismandfunction OligurictypeARFTheoliguricstageThediureticstageTherecoverystageChangesoffunctionandmetabolism OligurictypeARFTheoliguricstageUrinousalterationsOliguriaAnuriaoliguria：400ml/d>urineoutput>100ml/danuria：urineoutput<100ml/dChangesoffunctionandmetabolism OligurictypeARFTheoliguricstageUrinousalterations(1)oliguria,anuria(2)AlterationofurinouscotentsHyposthenuria，urinoussodium↑，hematuria，albuminuria，cylindruriaChangesoffunctionandmetabolism IndexFunctionalARIOrganicARIUrinegravity>1.020（↑）<1.015（↓）osmoticpressure>500（↑）<400（↓）Urinenatrium<20（↓）>40（↑）Urinecreatine/bloodcreatine>40：1（↑）<20：1（↓）Urineroutine(-)(+)DifferencesbetweenfunctionalARFandorganicARF 2.Azotemiaurea↑↑creatinine↑↑uricacid↑NPN↑OligurictypeARFTheoliguricstage1.UrinousalterationsChangesoffunctionandmetabolism Themarkedincreaseofnonproteinnitrogen(NPN)content,suchurea，creatinine,uricacid,etc(>28.6mmol/L)Azotemia OligurictypeARFTheoliguricstage1.Urinousalterations2.Azotemia3.WaterintoxicationChangesoffunctionandmetabolism OligurictypeARFTheoliguricstage1.Urinousalterations2.Azotemia3.Waterintoxication4.HyperkalemiaChangesoffunctionandmetabolism ChangesoffunctionandmetabolismOligurictypeARFTheoliguricstage1.Urinousalterations2.Azotemia3.WaterintoxicationHyperkalemiaMetabolicacidosis OligurictypeARFTheoliguricstageThediureticstage1.TherecoveryofGFR2.Theremoveoftubularobstruction3.Theweakfunctionofnewborntubule4.OsmoticdiuresisUrineoutput>400ml/dRenalfunctionisnotrecovery!!!Changesoffunctionandmetabolism OligurictypeARFTheoliguricstageThediureticstageTherecoverystageChangesoffunctionandmetabolism GFR和肾小管损害程度较轻病程较短症状较轻预后较好非少尿型与少尿型可相互转化OligurictypeARFNonoliguricARF不少尿，尿比重低而固定，尿钠低，氮质血症。Changesoffunctionandmetabolism Acuterenalfailure,ARFDefinitionCausesandclassificationPathogenesisAlterationsofmetabolismandfunctionPreventionandtreatment TreatingthecausesandprecipitatingfactorsTreatingtheconsequencesoliguricstage1.RestrictFluidandsodium2.Treathyperkalemiaproperlyandemergetically3.Correctmetabolicacidosis4.Acutedialysiswhennecessary1.Maintainthebalanceofwaterandelectrolyte2.SupportivecareandtherapyContinuousdialysiswhennecessaryNewtherapiesdiureticstagePathophysiologicalbasisfortreatment ARF治疗新进展半胱氨酸蛋白酶抑制剂、NOS合酶抑制剂、ROS清除剂减轻上皮细胞损伤；生长因子促进小管上皮细胞修复；抗ICAM-1、E-选择素、IL-18抗体和α-MSH阻断白细胞和上皮细胞相互作用；精氨酸-甘氨酸-天冬氨酸多肽防治肾小管阻塞；心房钠尿肽、钙通道阻断剂和ET拮抗剂增加肾血流。 Chronicrenalfailure，CRFConceptionEtiologyPathogenesisAlterationsofmetabolismandfunction Whatischronicrenalfailure?CRFisasyndromeofimpairedhomeostasisowingtostructuraldamage(reducedfunctionalnephrons)ofthekidneys.Thedisturbancesarecharacterizedbymetabolicacidosis,hypocalcemia,hyperphosphatemia,alterationinVitaminDmetabolismandthepresenceofcertaintoxicmaterialsInbodyfuid. DefinitionEtiologyRenaldiseases★chronicglomerulonephritisRenalvasculardiseasesChronicurinaryobstructionChronicrenalfailure Renaldisease：慢性肾小球肾炎最常见,占50-60%西方国家:糖尿病ChronicglomerulonephritisNormal病因Polycystickidneydisease ThecommoncausesofCRF1970’syears：1.Chronicglomerulonephritis2.chronicinterstitialnephritis3.DiabetesnephropathySince1990：1.Diabetesnephropathy(USA40%)2.hypertention(USA33%) 3.Chronicglomerulonephritis(USA10%) UrolithiasisUrolithiasisHydronephrosis Chronicrenalfailure，CRFDefinitionEtiologyClinalcourse ClinicalcouseGFRAzotemiaStageofdecreasedrenalreserve50-70%without↓Stageofrenalinsufficiency<50%mild↓Stageofrenalfailure10-25%marked↓Stageofuremia<10%severe 255075100内生肌酐清除率占正常值的%临床表现肾功能不全肾功能衰竭尿毒症无症状期 Chronicrenalfailure，CRFDefinitionEtiologyClinicalcoursesPathogenesis PathogenesisofCRFIntactnephronhypothesisTrade-offhypothesisGlomerularHyperfilitrationhypothesisBricker’shypothesizes Pathogenesis-hypothesisIntactnephronhypothesis(健存肾单位减少)causesProgressivelossofnephronsRemainingnephrons↓RenalfunctionfailtocompensateChronicrenalfailure PathogenesisIntactnephronhypothesisTrade-offhypothesisothermetabolicdisorderscausesProgressivelossofnephronsbloodconcentrationofsomesolutes↑Relatedregulatoryfactors(suchashormones)↑ PathogenesisIntactnephronhypothesisTrade-offhypothesisGFR↓P↑normalPTH↑Newlesion(acidosis,osteomalacia)(excret↑)Aprocessthatorganismdevelopsanewlesionbycorrectingandolddamage PathogenesisIntactnephronhypothesisTrade-offhypothesisGlomerularhyperfilitrationhypothesiscausesProgressivelossofnephronsglomerularfiltrationpressureinfewerintactnephron↑IntactnephronsfibrosisandscarringRenalfunctionfailtocompensate PathogenesisofCRFIntactnephronhypothesisTrade-offhypothesisGlomerularHyperfilitrationhypothesisInterstitialandtubularcellinjuryhypothesisBricker’shypothesizes 为什么CRF会进行性发展？血液动力学变化（肾小球高滤过）代谢变化（肾小管高代谢）尿毒症毒素(甲基胍,PTH,H+,等)细胞因子-生长因子-血管活性物质遗传因素：“肾衰基因”基因多态性（如ACE基因）其他 PathogenesisActivationofRASOxidationandstressAldosteroneAlbuminuriathefunctionofprimarydiseaseSecondaryprogressiveglomerularfibrosis ActivationofRAS ActivationofRAS 肾小管萎缩间质纤维化肾单位进行性损坏间质单个核细胞侵润释放某些细胞因子和生长因子刺激成纤维细胞细胞外基质增多小管内液Fe++的生成氧自由基增多ATP合成增加补体旁路激活(C3途经)膜攻击复合物形成(C5b-9)肾小管氧耗增加慢性肾衰高血糖，高血压Oxidationandstress Oxidationandstress Aldosterone Aldosterone Albuminuria Albuminuria Albuminuria Albuminuria Albuminuria Albuminuria Albuminuria Albuminuria Albuminuria Albuminuria AlbuminuriaMoleculesinvolvedinpotentialmechanismsinthedevelopmentofproteinuria-inducedrenaltubulointerstitialinjury. 慢性肾功能衰竭(chronicrenalfailure)DefinitionEtiologyClinicalcoursesPathogenesisAlterationsoffunctionandmetobolism ChronicrenalfailureDefinitionEtiologyClinicalcoursesPathogenesisAlterationsoffunctionandmetobolism AlterationsoffunctionandmetobolismAlterationofurineUrineoutputnocturiaAsymptomcharacterizedbyurinatingatnightmorethanonday AlterationsoffunctionandmetobolismAlterationofurineUrineoutputnocturiapolyuria>2500ml/24h1.Intactnephronhyperfiltration2.Osmoticdiuresis3.Renalconcentrativefunction↓PolyuriabutNPNincrease! intactnephronandGFRAlterationsoffunctionandmetobolismAlterationofurineUrineoutputnocturiapolyuriaoliguria AlterationsoffunctionandmetobolismAlterationofurineUrineoutputUrineosmoticpressureEarlystage：hyposthenuria,specificgravity≦1.020（concentration，dilutionnormal）Laterstage：isosthenuria,specificgra.1.008~1.012（concentration，dilution） hematuria，albuminuria，cylindruriaAlterationsoffunctionandmetobolismAlterationofurineUrineoutputUrineosmoticpressureAlterationofurinouscotents AlterationsoffunctionandmetobolismAlterationofurineAzotemia(NPN↑)urea，creatinine，uricacid↑↑Clearancerateofendogenouscrestinine↓ AlterationsoffunctionandmetobolismAlterationofurineAzotemia(NPN↑)Water,electrolytesimbalance 1.水代谢失调进水↑→水中毒进水↓→脱水2.钠代谢失调—CRF的肾为“失盐性肾”∵渗透性利尿、甲基胍抑制重吸收Na+摄入↑→钠潴留摄入↓→低钠血症 血磷↑主要是GFR↓所致。血钙↓主要是肠道吸收钙减少所致。[Ca][P]=常数;1,25-(OH)2D3↓;肠道吸收钙减少;肠粘膜损伤。3.钾代谢失调—肾排K+固定，与摄入量无关早期:正常（∵醛固酮↑、肾小管上皮钠泵↑）晚期:高钾血症，低钾血症4.钙磷代谢障碍 早期：肾小管功能泌H+保碱功能↓，AG正常晚期：GRF，固定酸排泄障碍，AGAlterationsoffunctionandmetobolismAlterationofurineAzotemia(NPN↑)Water,electrolytesimbalanceMetabolicacidosis AlterationsoffunctionandmetobolismAlterationofurineAzotemia(NPN↑)Water,electrolytesandacid-baseimbalanceRenalhypertension 1.Sodiumandwaterretention–sodium-dependenthypertension2.Renin↑--renin-dependenthypertension3.BP-decreasingsubstancefromkidney↓--PGA2↓PGE2↓۩RenalhypertensionAhypertensioncausedbyintrinsicRenaldiseases AlterationsoffunctionandmetobolismAlterationofurineAzotemia(NPN↑)Water,electrolytesandacid-baseimbalanceRenalhypertensionRenalosteodystrophy(肾性骨营养不良） 1.P,Ca2+↓,PTH↑2.1,25(OH)2D3↓3.Chronicmetabolicacidosis۩RenalOsteodystrophyAseriouscomplicationofCRF(especially,ofuremia),whichincludesrenalrickets(forchildren),adultosteomalacia,osteitisfibrosa,osteoporosis,osteosclerosis,etc. ۩RenalOsteodystrophy 囊性纤维性骨炎骨质软化症 CKD-MBD概念以往用语：“肾性骨病”和“肾性骨营养不良”，未能很好地包含钙、磷代谢紊乱的内容。2005年在国际肾脏病一体化治疗协调委员会（K/DIGO）召开的矿物质代谢及其骨病的会议上提出统一用语为“慢性肾脏病的矿物质和骨代谢异常”（ChronicKidneyDisease-MineralandBoneDisorder，CKD-MBD）。 CKD-MBD表现是全身性疾病，常具有下列一个或一个以上：1.钙、磷、甲状旁腺激素（PTH）或维生素D代谢异常；2.骨转化、矿化、骨容量、骨骼线性生长或骨强度的异常；3.血管或其他软组织钙化。 CKD-MBD特点普遍性全身性致残性间接致死性-高磷与高死亡率相关——知晓率低！ 我国目前对CKD-MBD的治疗现状：很少早期监测与治疗大多在严重SHPT（已经出现骨骼畸形）才开始使用活性VitD制剂治疗方法、药物剂量、疗程不统一缺乏严密的监测（尤其是PTH等）若PTH过度抑制，ABD随之发生血钙、磷及CaXP过高，转移性钙化发生PTX未得到普及 SHPTPTHPTH加重Ca.P代谢异常皮肤搔痒贫血神经系统异常心、血管病变骨吸收增加，陷窝形成纤维组织增生新骨形成也增加骨痛，骨骼畸形全身多脏器损害转移性钙化继发性甲状旁腺功能亢进症SecondaryHyperparathiyroidism(SHPT) 异常骨改变-骨骼畸形骨软化及继发性甲旁亢均可致骨骼畸形。骨盆口呈“心形”，四肢关节干骺端增宽、骨性关节面呈毛刷状改变,胸廓畸形呈鸡胸状，颌面骨呈“狮面”样改变。 SHPT实验室检查血清总钙及游离钙通常降低或正常血清磷水平升高甲状旁腺激素水平升高(正常值10-65pg/ml）骨特异性碱性磷酸酶水平升高骨钙素（Osteocalcin)水平升高 SHPT治疗降低血磷纠正低血钙药物治疗－活性维生素D的应用介入治疗－甲状旁腺组织注射酒精或1,25(OH)2D3；甲状旁腺切除术(次全及全切术加自体移植)始终贯穿充分透析 AlterationsoffunctionandmetobolismAlterationofurineAzotemia(NPN↑)Water,electrolytesandacid-baseimbalanceRenalhypertensionRenalosteodystrophyTendencytohemorrhage(出血倾向）※主要是血小板功能抑制 AlterationsoffunctionandmetobolismAlterationofurineAzotemia(NPN↑)Water,electrolytesandacid-baseimbalanceRenalhypertensionRenalosteodystrophyTendencytohemorrhageRenalanemia（肾性贫血）Aprogressiveanemiaandacommoncomplicationofadvancedrenaldisease. 肾性贫血：正常色素性正细胞性贫血 EPO↓ToxicsubstancesinhibitthebonemarrowtomakeRBCs3.Dysfunctionofutilizationofironandprotein4.ToxicsubstancesdestroyRBCs5.Bleedinginducedbyplateletdysfunction۩RenalAnemia 尿毒症(uremia)概念急、慢性肾衰的严重阶段，水、电解质和酸、碱平衡失调等内环境严重紊乱以及代谢产物和毒物大量潴留引起的自体中毒症状。 发病机制--尿毒症毒素的作用※尿毒症毒素的种类和作用PTH胍类化合物尿素胺类中分子毒素其他物质 PTH↑骨盐溶解→肾性骨营养不良钙盐沉积皮肤和神经末梢→皮肤瘙痒胃泌素→胃酸↑→消化道溃疡钙进入神经轴突→周围神经损伤破坏血脑屏障→钙和铝沉积在脑→尿毒症痴呆软组织坏死蛋白质分解→氮质血症高脂血症贫血 尿毒症毒素(UremicToxins)氢(H+),磷(P)尿素:甲酰化氨基酸，甲酰化蛋白质,氢酸盐肌酐;胍类:甲基胍、琥珀胍酸酚类；多胺,其它胺类；吲哚：羟基吲哚甲状旁腺激素（PTH)β2－MG（β2微球蛋白〕“新毒素”：糖基化终未产物(AGE)终末氧化蛋白(AOPP)、同型半胱氨酸(Hcy) 尿毒症(uremia)概念发病机制机能代谢变化各系统功能障碍和物质代谢紊乱集各系统症状于一身 尿毒症时的功能代谢变化及其机制泌尿功能障碍↑水、电解质和酸碱平衡紊乱↑氮质血症↑贫血、出血↑高血压↑各系统的功能障碍和物质代谢紊乱 神经系统：尿毒症性脑病表现：大脑抑制早期晚期淡漠、疲乏、记忆力↓记忆力、判断力、定向力、计算力障碍，欣快感、抑郁感，妄想、幻觉→嗜睡、昏迷发生机制①毒性物质蓄积→神经细胞变性②电解质和酸碱平衡紊乱③肾性高血压→脑血管痉挛→脑缺血缺氧、脑细胞膜通透性↑→脑水肿 消化系统表现：厌食→恶心、呕吐、腹泻、口腔粘膜溃疡→消化道出血等消化系统症状是尿毒症患者最早出现和最突出的症状可能机制尿素酶消化道排出尿素↑氨↑→胃粘膜→炎症、溃疡肾实质破坏→胃泌素灭活↓；PTH↑→胃泌素释放↑→胃泌素↑→胃酸↑→溃疡 常死于充血性心力衰竭、心律紊乱机制：钠水潴留→心力衰竭、肺水肿晚期可发生尿毒症性心包炎心血管系统尿毒症毒性物质→心包→尿毒症性心包炎高血压、贫血、血管硬化；高血钾、低血钙、酸中毒、高脂血症加重 呼吸系统临床表现：尿毒症酸中毒呼吸加深加快严重→呼吸中枢兴奋性↓→潮式呼吸、kussmaul呼吸严重肺水肿、纤维蛋白性胸膜炎、肺钙化各种原因→肺毛细血管通透性↑→肺水肿磷酸钙在肺组织内沉积→肺钙化尿素→纤维蛋白性胸膜炎氨味尿素唾液酶氨 免疫系统主要表现为：细胞免疫反应明显受到抑制，而体液免疫反应正常或稍减弱功能低下严重感染毒性物质→抑制淋巴细胞分化、成熟或对其有毒性作用 皮肤变化面色苍白或呈黄褐色——贫血或黑色素↑所致皮肤瘙痒——继发性甲状旁腺功能亢进所致形成尿素霜——体液内高浓度尿素所致细小的带白色结晶堵塞汗腺 代谢紊乱糖代谢蛋白质代谢脂肪代谢外周组织对胰岛素反应降低负氮平衡和低白蛋白血症高脂血症 内分泌系统激素临床表现增加减少催乳激素黄体生成素胃泌素醛固酮胰高血糖素甲状旁腺激素1，25-（OH）2D3促红细胞生成素睾丸酮泌乳男子乳房女性化溃疡高血压葡萄糖耐量降低骨质疏松骨软化症（佝偻病）贫血性欲减退 尿毒症(uremia)概念发病机制机能代谢变化防治原则 防治原则治疗原发病防止肾过度负荷透析疗法肾移植 2013NSFC 2013NSFC 2013NSFC 2013NSFC NSFC 外伤致严重急肺伤引起急性呼衰和急性肾衰的机理是什么？机体会发生什么样的血气变化和酸碱及电解质紊乱？ ThankYou!
