糖尿病肾病课件

糖尿病肾病61DiabeticNephropathy糖尿病肾病62Diabeticnephropathyistheleadingcauseofchronicrenalfailureintheindustrialisedworld.Itisalsooneofthemostsignificantlong-termcomplicationsintermsofmorbidityandmortalityforindividualpatientswithdiabetes.Diabetesisresponsiblefor30-40%ofallend-stagerenaldisease(ESRD)casesintheUnitedStates.Althoughbothtype1diabetesmellitus(insulin-dependentdiabetesmellitus[IDDM])andtype2diabetesmellitus(non–insulin-dependentdiabetesmellitus[NIDDM])leadtoESRD,thegreatmajorityofpatientsarethosewithNIDDM.糖尿病肾病63Theglomeruliandkidneysaretypicallynormalorincreasedinsizeinitially,thusdistinguishingdiabeticnephropathyfrommostotherformsofchronicrenalinsufficiency,whereinrenalsizeisreduced(exceptrenalamyloidosisandpolycystickidneydisease).糖尿病肾病64

SignsandSymptoms

Approximately25%to40%ofpatientswithDM1ultimatelydevelopdiabeticnephropathy(DN),whichprogressesthroughfivepredictablestages.糖尿病肾病65Stage1(veryearlydiabetes)Increaseddemanduponthekidneysisindicatedbyanabove-normalglomerularfiltrationrate(GFR).Hyperglycemialeadstoincreasedkidneyfiltration(seelater)ThisisduetoosmoticloadandtotoxiceffectsofhighsugarlevelsonkidneycellsIncreasedGlomerularFiltrationRate(GFR)withenlargedkidneys糖尿病肾病66Stage2(developingdiabetes)ClinicallysilentphasewithcontinuedhyperfiltrationandhypertrophyTheGFRremainselevatedorhasreturnedtonormal,butglomerulardamagehasprogressedtosignificantmicroalbuminuria(smallbutabove-normalleveloftheproteinalbuminintheurine).Significantmicroalbuminuriawillprogresstoend-stagerenaldisease(ESRD).Therefore,alldiabetespatientsshouldbescreenedformicroalbuminuriaonaroutinebasis.糖尿病肾病67Stage3(overt,ordipstick-positivediabetes)Glomerulardamagehasprogressedtoclinicalalbuminuria.BasementmembranethickeningduetoAGEPTheurineis"dipstickpositive,"containingmorethan300mgofalbuminina24-hourperiod.Hypertension(highbloodpressure)typicallydevelopsduringstage3.糖尿病肾病68Stage4(late-stagediabetes)Glomerulardamagecontinues,withincreasingamountsofproteinalbuminintheurine.Thekidneys’filteringabilityhasbeguntodeclinesteadily,andbloodureanitrogen(BUN)andcreatinine(Cr)hasbeguntoincrease.Theglomerularfiltrationrate(GFR)decreasesabout10%annually.Almostallpatientshavehypertensionatstage4.糖尿病肾病69Stage5(end-stagerenaldisease,ESRD)GFRhasfallento<10ml/minandrenalreplacementtherapy(i.e.,haemodialysis,peritonealdialysis,kidneytransplantation)isneeded.糖尿病肾病610糖尿病肾病611糖尿病肾病612糖尿病肾病613CAPILLARYENDOTHELIUMBASEMENTMEMBRANEFOOTPROCESSESOFPODOCYTESFILTRATIONSLITFENESTRATION糖尿病肾病614NORMALGBM.LEFT-asingleglomerulus.Thereareonemillionoftheseineachkidney.RIGHT-acloseupoftheGBM(G)aroundpartofonetinybloodvesselinaglomerulus(redcircleinlefthanddiagram)糖尿病肾病615GlomerularHistology:

Theglomerularcapillarywalliscomposedofanendothelialcelllayer(bloodside),athickbasementmembrane,andepithelialcelllayer(urineside).

(i)GlomerularEndotheliumThe

glomerularendotheliumisfenestrated.Thefenestrae(0.07to0.1mm-micrometers-inmaximaldiameter)allowthepassageofelectrolytes,proteins,andglobulin.However,platelets(3mm),redcells(7mm)andneutrophils(15mm)can'tpassthroughtheendotheliallayer.糖尿病肾病616(ii)

GlomerularBasementMembrane(GBM):TheGBMisatri-laminarstructure,0.3micronsinthickness,composedofcollagen,proteoglycansandlaminin.Itisproductofthefusionoftheendothelialandepithelialbasementlaminae.ThedensecentralGBMarea,orlaminadensa,isduetotheoverlappingofthetwolaminae.

Around50%oftheGBMiscollagenIV.糖尿病肾病617ThenegativechargeoftheGBMhasbeenattributedtothepresenceoftheheparansulphateproteoglycan(HSPG)calledperlecan.Thesenegativelychargedmoleculesaregeometricallyarrangedinclustersseparatedbyabout0.003µmfromeachother.Thisanionicmolecularsieverestrictsthepassageofmoleculesaccordingtosizeandcharge.Water,salts,glucose,aminoacidsandneutral,orcationic,moleculeswithradiilessthat0.0035µmarefilteredwithrelativeease.Thealbuminmoleculemeasures0.0035µmandisnegativelycharged.Thereforeitsfiltrationisrestricted.糖尿病肾病618Presenceofproteinintheurineisasignthateitherthechargeorthedistancebetweentheanionicclusters,orboth,arepathologicallyaltered.Thepresenceofredcellsintheglomerularurine,iscertainindicationofGBMruptures.OtherclassicalconstituentsofthebasementmembranearetypeIVcollagen,laminin,andentactin.糖尿病肾病619Glomerularmesangium:Theintra-capsularglomerularcapillarynetworkiskepttogetherbythemesangiumthatisiscomposedofmesangialcellstypeIandII,andothertissuematrix.MesangialtypeIcellsaremonocyteswithphagocyticfunctions.Thesecellscanextendcytoplasmicprojectionsintotheglomerularcapillary.Theyalso"clean"themesangiumofmaterialsthatleakfromthecapillarylumenintothematrix.Thesecellsarestimulatedbycytokinestoproducefreeradicalsandcytotoxicpeptides.糖尿病肾病620MesangialtypeIIcellsaremyofibroblastswiththeabilitytocontractuponADHandangiotensinstimulation.Theircontractioncausesareductionoftheeffectiveglomerularfiltrationarea.MesangialMatrixisatissuemeshcomposedofdifferenttypesofcollagens(I,III,IV),lamininandproteoglycans.糖尿病肾病621 Threemajorhistologicchangesoccurintheglomeruliofpersonswithdiabeticnephropathy.Mesangialexpansionisdirectlyinducedbyhyperglycemia,perhapsviaincreasedmatrixproductionorglycosylationofmatrixproteins.GBMthickeningoccurs.Glomerularsclerosisiscausedbyintraglomerularhypertension(inducedbyrenalvasodilatationorfromischemicinjuryinducedbyhyalinenarrowingofthevesselssupplyingtheglomeruli).糖尿病肾病622GlomerularHyperfiltrationGlucoseprovidesanosmoticdiureticeffectResultisincreasedrenalfiltration,leadingtoglomerularhypertrophyGlomerularpressureincreasesKidneyrespondswithhypertrophyofepitheliumandendotheliumAcceleratesglomerularcellfailureResultisprematureglomerulosclerosis糖尿病肾病623MetabolicPerturbations

OxidantStress-relatedtoglomerularhypertrophyandabnormalmetabolismNon-enzymaticglycosylationofmacromolecules-particularlybasementmembrane(BM)ActivationofglucosemetabolizingenzymesCytokineandotherhumoralimbalances糖尿病肾病624NonenzymaticGlycosylationBiochemicalstudieshaveshownthatbasementmembranesindiabetesincludeexcessamountsoftypeIVcollagen,themaincomponentofbasementmembranes,anddecreasedamountsofproteoglycansBothchangesdecreasethepermeabilityofcapillariesanddisturbleukocytediapedesis,oxygendiffusion,nutritionandmetabolicwasteremoval.AlteredchargeonBMmayexplainalbuminuriaMacrophagereceptoractivationleadstoIL1,TNFproductionwhichstimulatesmatrixAGEPformationleadstoabnormalcollagen,increasedtoxicoxygenspecies糖尿病肾病625HumoralImbalancesinDMNephropathy

InsulinDeficiencyElevatedGlucagonConcentrationsIncreasedTransformingGrowthFactor

(TGF)-ßIncreasedangiotensinIIAbnormallyregulatedthromboxanesandendothelinsAbnormalinsulinlikegrowthfactor(IGF)-1Elevatedplateletderivedgrowthfactor(PGDF)糖尿病肾病626RoleofTGF-ß

StimulatesextracellularmatrixsynthesisInhibitsextracelluularmatrixdegradationUpregulatesproteaseinhibitors;downregulatesmatrixdegradingenzymesStimulatessynthesisofintegrins(matrixreceptors)Keyroleinglomerularandtubuloepithelialhypertrophy,basementmembranethickening,andmesangialmatrixexpansionTGF-ßhasbeenimplicatedinanumberofchronic,scarringdiseases糖尿病肾病627糖尿病肾病628AngiotensinIIandThrombospondin(TSP1)canbothstimulatetheproductionoftransforminggrowthfactor-β(TGF-β)bytubuloepithelialcellsandfibroblasts.TGF-β,inturn,causesproliferationoffibroblastsandtubuloepithelialcells.TGF-βultimatelyincreasesextracellularmatrixproteins,likelybyseveralmechanisms.TGF-βstimulatesproductionofseveralgrowthfactorsincludingbasisfibroblastgrowthfactor(bFGF)andplateletderivedgrowthfactor(PDGF)thatstimulatetheformationofextracellularmatrix(ECM)proteins.糖尿病肾病629

Ultrastructuralchangesoftheglomerularbasementmembraneindiabeticnephropathyrevealedbynewlydevisedtissuenegativestainingmethod.

ThenormalhumanGBMshowedafinemeshworkstructureconsistingoffibrilsformingthesmallpores.Thediameteroftheseporeswasslightlysmallerthanthatofhumanalbuminmolecules.TheGBMinpatientswithdiabeticnephropathyshowedirregularthickening.Athighermagnification,unknowncavitiesandtunnelstructures,whichwerenotseeninnormalcontrols,wereobservedinthethickenedGBM.糖尿病肾病630Insomeportions,thesecavitiespresentedahoneycomb-likeappearance.Thediametersofthecavitiesandtunnelswerefarlargerthanthedimensionsofalbuminmolecules.TheseenlargedstructuresarebelievedtoallowserumproteinmoleculestopassthroughtheGBMfromthecapillarylumentotheurinaryspace.TheseresultssuggestthatthecauseofmassiveproteinuriaindiabeticnephropathyisthedisruptionofthesizebarrieroftheGBM.

糖尿病肾病631Glomerularandvascularpathologyislinkedtohyperglycemia.Changesinglomerularbasementmembranestructureoccurveryearlyindiabeticnephropathy,beforeevenmicroalbuminuriaisapparent.CollagenIVdepositionisdirectlystimulatedbyhyperglycaemiaandincreasedurinarylevelsindicatechangesintheglomerularbasementmembrane.Contributingfactorsincludetheformationofadvancedglycosylationendproducts(AGEs)duetonon-enzymaticglycosylationofcapillarybasementmembranes,asaconsequenceoflong-termhyperglycaemia.糖尿病肾病632Non-enzymaticglycosylationhasrecentlyattractedincreasinginterestasacrucialpathophysiologiceventbehindallthesehyperglycaemia-relatedalterationsandinthepathophysiologyofthedevelopmentofdiabeticcomplications.Proteinsandlipidsexposedtoaldosesugarsgothroughreactionswhicharenotenzyme-dependent,andgenerationofreversibleSchiffbasesorAmadoriproductstakeplace.Later,throughfurthermolecularrearrangements,irreversibleadvancedglycosylationendproducts(AGEs)areformed.Thisprocessalsotakesplaceduringnormalageing,butindiabetestheirformationisacceleratedtoanextentrelatedtothelevelanddurationofhyperglycaemia.糖尿病肾病633Hencelargestudieshaveshownadelayinonsetorslowingoftheprogressionofthesecomplicationsifnearnormo-glycaemiacanbemaintained.Theglycatedproteinscross-link,contributingtobasementmembrane(andmesangial)thickening,(culminatinginthekidneyinnodularglomerulosclerosis),aswellaslossofthenormalselectivepermeability(leadingtoproteinuria,retinalhardexudatesandmicrohaemorrhages).糖尿病肾病634ThepotentialpathophysiologicalsignificanceofAGEsisassociatedwiththeiraccumulationinplasma,cellsandtissuesandtheircontributiontotheformationofcross-links,generationofreactiveoxygenintermediatesandinteractionswithparticularreceptorsoncellularsurfacesAGEshavedirecteffectsonthehostresponsebyaffectingtissuestructures,e.g.byincreasingcollagencross-links,whichisfollowedbychangesincollagensolubilityandturnover.ThickeningofbasementmembranesispartlyduetoglycosylationofmembraneproteinsorentrapmentofglycosylatedserumproteinsintobasementmembraneItisevidentthatAGEscaninteractwithcellfunctions,tissueremodellingandinflammatoryreactionsinseveraldifferentways.糖尿病肾病635糖尿病肾病636糖尿病肾病637WhenAngIIisincreased,greaterAT1receptor-mediatedconstrictionofefferentthanafferentarteriolesincreasessinglenephronglomerularfiltrationrateandraisesintraglomerularpressure,causingglomerularhypertension.SustainedorsevereincreasesinintraglomerularpressurecanleadtoGBMdamage,glomerularendothelialdysfunction,andultimately,extravasationofproteinintoBowman’scapsule.Inadditiontohypertension,conditionslikediabetesthatareassociatedwithincreasedoxidativestress(increasedformationofreactiveoxygenspecies)independentofhypertensionandglyco-oxidativemodificationofproteins(AGEs)comprisingtheglomerularbasementmembranecanleadtoextravasationofprotein.糖尿病肾病638糖尿病肾病639Glomerularhypertensioncanleadtoinjurytotheglomerularbasementmembranecausingittoleakplasmaproteinsintotheurine.Attemptsbytheproximaltubulestoreabsorbthisfilteredproteincausesinjurytothetubularcells,activatesaninflammatoryresponse,andisassociatedwiththedevelopmentoflipidmetabolicabnormalitiesthatcreatefurtheroxidativestressonthealreadycompromisedglomerulus.Theresultanttubularinflammatoryresponseandrenalmicrovascular