高血压与肾病优选课件

Epidemiology ofRenal Disease inHypertensionRichard Bright,M.D.F.R.S.1789-1858Father of NephrologyEpidemiologyofRenalDiseaseRenal Disease in HypertensionEpidemiologyEffects of hypertension on the kidneyInteractions of hypertension and concomitant conditions on the kidneyAgeAtherosclerosisDiabetes mellitusRaceMorbidity&mortality associated with chronic renal disease Coronary artery diseaseProgression of chronic renal diseaseEnd Stage Renal Disease(ESRD)Hypertension as a consequence of ESRDRenalDiseaseinHypertensionRenal Disease in HypertensionA Historical PerspectiveTraube(Berlin,1856)“High Blood Pressure Is Needed”Postulated that arterial pressure was elevated to overcome mechanical resistance against blood flow through thickened arteries.Believed that increased blood pressure was necessary for excretory efficiency of the kidney.Promoted these concepts which were unchallenged for almost 80 years.Page(Cleveland,1934)“High Blood Pressure Is NOT Necessary”Developed renal clearance techniques that estimated renal blood flow in humans.Reduced elevated blood pressure without a fall in urea clearance.Demonstrated that early antihypertensive measures were not detrimental to renal function.Radical sympathectomy in essential&malignant hypertension safely lowered arterial blood pressure without loss of renal function.RenalDiseaseinHypertensionRisk Factors for Progression of Renal DiseaseCan be modifiedCannot be modifiedHypertensionAgeAlbuminuria/ProteinuriaEthnicityDyslipidemiaGenderHemoglobin A1CSmokingAnemiaCaP04RiskFactorsforProgressionESRD Due to Any CauseESRD Due to Any CauseIn 332,544 Men Screened for MRFITIn 332,544 Men Screened for MRFITAdjusted Relative RiskAdjusted Relative Risk Hypertension Men with optimal blood pressure was the reference category.Klag MJ,et al.N Engl J Med.1996;334(1):13-18.*p0.001ESRDDuetoAnyCauseIn332,5HTN Linked To Chronic Renal Disease Among HTN Linked To Chronic Renal Disease Among 332,544 Men Screened for MRFIT332,544 Men Screened for MRFIT8080-8485-8990-99100-109 110Age-Adjusted Rate of ESRDPer 100,000 Person-Years 180160-179140-159130-139120-129120Systolic BP(mm Hg)Diastolic BP(mm Hg)Adapted from Klag MJ,et al.N Engl J Med.1996;334(1):13-18.Massachusetts Medical SocietyHTNLinkedToChronicRenalDiIncidence Rates of Reported ESRD by Primary DiagnosisYearUnited States Renal Data System(USRDS)2000 Annual Data Report IncidenceRatesofReportedEDiabetes50%Hypertension27%Glomerulonephritis13%Other10%Primary Diagnoses for Patients Who Start DialysisUnited States Renal Data System(USRDS)2000 Annual Data Report DiabetesHypertensionGlomerulonPersons Initiating Treatment for ESRD Related to Diabetes in the USCDC Diabetes Surveillance,1997.PersonsInitiatingTreatmentfAmos A,McCarty D,Zimmet P.Diabetes Medicine.1997;14Suppl5:S1-85.Type I DiabetesType II DiabetesGlobal Estimates and Projectionsfor Incidence of Diabetes MellitusAmosA,McCartyD,ZimmetP.*p 0.0001United States Renal Data System(USRDS)2000 Annual Data Report Odds Ratio For ESRD By RaceRacial differences in ESRD in the USA from 1990 to 1998Racial differences in ESRD in the USA from 1990 to 1998reference*p0.0001UnitedStatesRenalEffect of Hypertension on Mortality Effect of Hypertension on Mortality in Diabetic Pima Indiansin Diabetic Pima IndiansAge-Adjusted Death Rates for Diabetic NephropathyAge-Adjusted Death Rates for Diabetic Nephropathy Sievers ML,et al.Circulation.1999;100(1):33-40.NormotensiveDiabeticsN=10 deathsHypertensiveDiabeticsN=75 deaths*p 0.65mg/mmol 7.0 mmol/L 160 mmHgMicroalbuminuriaComparedToTCrude Incidence Rates of Crude Incidence Rates of End Stage Renal Disease,By RaceEnd Stage Renal Disease,By RaceRacial differences in ESRD in the USA from 1990 to 1998Racial differences in ESRD in the USA from 1990 to 1998 United States Renal Data System(USRDS)2000 Annual Data Report CrudeIncidenceRatesofEndComorbidities in Renal Disease Patients(1999)Diabetes mellitus as a primary or contributing diagnosis.Diabetes mellitus that requires insulin treatment,which is a subset of the diabetes category.United States Renal Data System(USRDS)2000 Annual Data Report ComorbiditiesinRenalDiseasCrude Incidence Rates of Reported End Stage Renal DiseaseUnited States Renal Data System(USRDS)2000 Annual Data Report CrudeIncidenceRatesofRepoRacial Distribution for Comorbidities Racial Distribution for Comorbidities In Dialysis Patients(1999)In Dialysis Patients(1999)Diabetes mellitus as a primary diagnosis or contributing diagnosis.Diabetes mellitus that requires insulin treatment,which is a subset of the diabetes category.United States Renal Data System(USRDS)2000 Annual Data Report RacialDistributionforComorbCV Mortality in General Population(GP)&Dialysis Patients,By Race Sarnak MJ,Levey AS.Semin Dial.1999;12:69-76.CVMortalityinGeneralPopulaHypertension and Chronic Renal Disease:Hypertension and Chronic Renal Disease:Hemodynamic AbnormalitiesHemodynamic AbnormalitiesMean BPTotal SystemicVascular Resistance=XIncreased Cardiac Output Intravascular Volume Glomerular filtration Sodium excretion Extracellular Fluid Renal Nerve Activity Myocardial Performance Adrenergic ActivityIncreasedVasoconstriction Adrenergic Stimuli Angiotensin II Endothelin Endothelium-derived Contracting Factors ThromboxaneCardiacOutputDecreasedVasodilation Prostacyclin Nitric oxide EDHF*Textor SC.Atlas of Diseases of the Kidney,2001.*Endothelium-derived Hyperpolarizing FactorsHypertensionandChronicRenalPrevalence of HypertensionIn Chronic Renal DiseasesMCN=minimal change nephropathy CIN=chronic interstitial nephritis IgA=IgA nephropathyMGN=membranous glomerulonephritis APKD=adult-onset polycystic kidney disease DN=diabetic nephropathyMPGN=membranoproliferative glomerulonephritis FSGN=focal segmental glomerulonephritis Smith MC and Dunn MJ,in Hypertension.Laragh JH,Brenner BM.Raven Press;1995:2081-2101.PrevalenceofHypertensionInHypertension and Renal Disease:MechanismsScanning electron(top)and light(bottom)micrographs of a human glomerulustrc.ucdavis.edu/mjguinan/apc100/modules/Urinary/mammal/cortex1/cortex.htmltrc.ucdavis.edu/mjguinan/apc100/modules/Urinary/mammal/glomeruli0/glomeruli.htmlHypertensionandRenalDiseaseGlomerulusMesangial MatrixEfferent Renal ArterioleMesangial CellsRenal Sympathetic Nerves Bowmans CapsuleDistalConvoluted TubuleProximal Convoluted TubuleAdventitial Mast Cell/MacrophageComponents of the Normal NephronVascular Smooth Muscle CellsJuxtaglomerular CellsMacula DensaGlomerulusMesangialMatrixEffeGlomerular hypertensionHyperfiltrationGlomerular barrier dysfunctionProteinuriaMesangial cell hyperplasiaIntrarenal inflammatory processesEndothelial dysfunctionVSMC proliferationNormal KidneyNormal KidneyMechanisms of Renal Damage in HTNMechanismsB l o o d P r e s s u r eGlomerularhypertensionNormalFunctionalDecrease in GFRProteinuriaStructuralGlomular basement membrane changesExpanded mesangial matrixGlomerulosclerosisTubulo-interstitial fibrosisB l o o d P r e s s u r eConsequences of Renal Damage in HTNConsequencesRenal FailureRenal FailureFunctionalBloodPreEffects of Vasodilators in the Normal KidneyL-ArginineNOeNOS(-)(-)L-CitrullineEDHF(s)Pgl2(-)(-)PMNM Platelet(-)VSMCECEffectsofVasodilatorsinthImbalance in Factors Affecting Vascular Tone and StructureNephron destruction and renal failureAngiotensin IICatecholaminesEndothelin-1ROSCytokinesEDCFNitric OxideProstacyclinBradykininEDHFConstrictors/Growth PromotersDilators/Growth InhibitorsVascular tone and structureEDHF=endothelium-derived hyperpolarizing factorsROS=reactive oxygen speciesEDCF=endothelium-derived constricting factorsImbalanceinFactorsAffecting+=OONO_(-)ROS Reduces the Biological Effects of NOO2Afferent ArterioleL-ArginineNOeNOSL-CitrullineNEVSMCPMNM FibroblastECMastcell(+)+=OONO_(-)ROSReducestheRenin-Angiotensin CascadeAngiotensinogen Angiotensin I Angiotensin IIAT1AT2ATnBradykininInactivepeptidesNon-renin(eg tPA)Non-ACE(eg chymase)ACEReninRenin-AngiotensinCascadeAngioAngiotensin II(Ang II)generated in the afferent arteriole interacts with AT1 receptors on cellular components of the nephronAngiotensinogenAng IReninACEAng IIAT1R=AT1 ReceptorAngiotensinII(AngII)generaRole of Angiotensin II in Chronic Renal Disease Adhesion molecules Chemotactic factors Cell growth Apoptosis TGF-,CTGF PAI-1 Glomerular capillarypressure Single nephron GFRMacrophageinfiltrationAngiotensin IIMechanical stressMesangial changesOxidative stressProteinuriaNF-B activationGlomerulosclerosis&Tubulo-interstitial fibrosisRenaldiseaseNephronlossAdapted from Berk B.2001.RoleofAngiotensinIIinChrAngiotensin II Induces Oxidative Stress in the KidneyStimulation of Membrane NOX-1 Oxidase*Increased superoxide(O2)Increased thiobarbituric acid reactive substancesIncreased oxidized lipidsIncreased tissue protein carbonyl contentInduction of Heme Oxidase-1(HO-1)Activation of NF-BIncreased inflammatory cytokines*NAD(P)H OxidaseAngiotensinIIInducesOxidat O2 H2O2 H2O+O2O2Renal Sources of ROSNOX-1 oxidase*Xanthine oxidaseHeme oxygenase1Cyclo-oxygenaseLipoxygenaseCytochrome P450 mono-oxygenaseMitochondrial oxidative phosphorylation*NADP(H)oxidaseSuperoxidedismutaseCatalaseO2H2 O2 Endothelial Cells and H2O2 Vascular Smooth MuscleOxidative Stress:Endothelial Oxidative Stress:Endothelial Dysfunction and CAD/Renal Risk FactorsDysfunction and CAD/Renal Risk FactorsEndothelial DysfunctionApoptosisVasoconstrictionLeukocyteadhesionLipiddepositionThrombosisVSMCgrowthHypertensionSmokingDiabetesLDLHomocysteineEstrogendeficiencyO2EndothelialCelPivotal Role of ROS in Stimulus-Induced EC and Pivotal Role of ROS in Stimulus-Induced EC and VSMC Growth,Survival,and ApoptosisVSMC Growth,Survival,and ApoptosisPDGF,Thrombin,Norepinephrine,Ang II,TNF,Ox-LDL,High Glucose,VEGFROSArachidonate MetabolismMitochondrial ElectronTransport ChainCytochromeP450NOX-1 OxidaseXanthine OxidaseGrowth or HypertrophySurvivalApoptosis Caspases NF-B Akt ERKs JNKsSAPKs p38MAPKPotential Targetsof ROSSources of ROSGrowth/DeathSurvival SignalsPivotalRoleofROSinStimuluPathologic Processes Leading to Glomerular Injury and ProteinuriaAng IIIncreasedglomerularpressureAng IIUrinary proteinGlucoseAGEsGlycoxidation(glycation)Efferent arteriolarconstriction=angiotensin AT1 receptorPathologicProcessesLeadingtVascular and/or Tubular InjuryGlomerular cells Tubular cellsLymphocytes MacrophagesFibroblastsTGF-ET-1CTGFAng IIPAI-1PDGFbFGFTNF-IL-1FIBROSISFibrosis and Nephron Loss:A Renal Response to InjuryVascularand/orTubularInjuryTGF-TGF-plays a key role in extracellular matrix formation in mesangiumand interstitium that leadsto fibrosis and loss of nephron unitsTGF-TGF-playsakeyroleinbFGFPDGFAng IITSP1TGF-O2TGF-plays a key role in extracellular matrix formation in mesangiumand interstitium that leadsto fibrosis and loss of nephron unitsO2bFGFPDGFAngIITSP1TGF-O2TGF-TIMPbFGFPDGFAng IIProteases(-)(-)(+)(+)(+)TSP1ET-1PAI-1O2TGF-TGF-plays a key role in extracellular matrix formation in mesangiumand interstitium that leadsto fibrosis and loss of nephron unitsO2TIMPbFGFPDGFAngIIProteases(-)Angiotensin II:Role in Renal InjuryAngiotensin IIAT1RAT2RNF-BTNFR1TNFR2AngiotensinogenFibroblastsProliferation and differentiationMatrixFIBROSISInflammationCellular adhesion moleculesTubule cellsTNF-+Profibrotic cytokinesAngiotensinII:RoleinRenalAldosterone Promotes Renal Fibrosisby Multiple MechanismsAdrenalVascularAldosteronePAI-1Nitric oxidesynthesisNa+influxinto VSMCNorepinephrineuptake into VSMCAngiotensin IIAT1R bindingof Ang IIStimulatesInhibitsFibroblast collagen synthesisAldosteronePromotesRenalFibPathways Leading ToProgressive Renal FailureRenal growth factor&cytokine activationFibrogenesisSystemic hypertensionProgressive Loss of Filtration Surface AreaGFRRenal injury Nephron massGlomerular hypertensionRenal scarringHyperlipidemia Filtration of plasma proteins(Proteinuria)Proximal tubule protein uptakeRenal microvascular injuryInflux of monocytes and macrophagesTransdifferentiation of renal cells to fibroblast phenotypeBrenner BM,Keane WF.2001.PathwaysLeadingToProgressivClinical Trials in Hypertension and Renal Diseases Placebo+Other Antihypertensive Therapy (excluding ACEI,AIIA)Maintain prior antihypertensive therapy(excluding ACEI,AIIA)Los 100 mg+Other Antihypertensive Therapy(excluding ACEI,AIIA)Los 100 mgGoal BP 140/90 mmHgn=1520Los 50 mgPlaceboNIDDM Patientswith proteinuriaPlaceboClinicalTrialsinHypertensioThe Dual Significance of ProteinuriaProteinuria(albuminuria)results from injury to glomerular circulationIncreased proteinuria(albuminuria)is associated with progressive kidney diseaseIn diabetes and hypertension,proteinuria(albuminuria)is also an indicator of injury in the systemic circulationProteinuria(albuminuria)is associated with increased cardiovascular riskTheDualSignificanceofProteRenal Disease and HypertensionCore Concepts of TreatmentHypertension and proteinuria(albuminuria)are both independent variables that predict long-term decline in renal functionRenal disease is both a cause and consequence of hypertension Reduction of blood pressure reduces cardiovascular risk and renal riskReduction of proteinuria(albuminuria)may lower both cardiovascular risk and renal riskRenalDiseaseandHypertensionMeta Analysis:Lower Mean BP Meta Analysis:Lower Mean BP Results in Slower Rates of Decline in Results in Slower Rates of Decline in GFR in Diabetics and Non-DiabeticsGFR in Diabetics and Non-Diabetics95959898101101104104107107110110113113116116119119r=0.69;P 0.05MAP(mmHg)GFR(mL/min/year)130/85140/90UntreatedHTN0 0-2-2-4-4-6-6-8-8-10-10-12-12-14-14Parving HH,et al.Br Med J.1989.Moschio G,et al.N Engl J Med.1996.Viberti GC,et al.JAMA.1993.Bakris GL,et al.Kidney Int.1996.Klahr S,et al.N Eng J.Med 1994.Bakris GL.Hypertension.1997.Hebert L,et al.Kidney Int.1994.The GISEN Group.Lancet.1997.Lebovitz H,et al.Kidney Int.1994.Bakris GL,et al.Am J Kidney Dis.2000;36(3):646-661.Reprinted by permission,Harcourt Inc.MetaAnalysis:LowerMeanBPMeta Analysis:Lower Systolic BP Meta Analysis:Lower Systolic BP Results in Slower Rates of Decline in Results in Slower Rates of Decline in GFR in Diabetics and Non-DiabeticsGFR in Diabetics and Non-Diabetics130134138142146150154170180r=0.69;P .05SBP(mmHg)GFR(mL/min/year)UntreatedHTN0-2-4-6-8-10-12-14Bakris GL,et al.Am J Kidney Dis.2000;36(3):646-661.Parving HH,et al.Br Med J.1989.Moschio G,et al.N Engl J Med.1996.Viberti GC,et al.JAMA.1993.Bakris GL,et al.Kidney Int.1996.Klahr S,et al.N Eng J Med.1994.Bakris GL.Hypertension.1997.Hebert L,et al.Kidney Int.1994.The GISEN Group.Lancet.1997.Lebovitz H,et al.Kidney Int.1994.MetaAnalysis:LowerSystolicGoal BP Recommendations for Patients with DM or Renal DiseaseOrganizationYear Systolic BPDiastolic BPAmerican Diabetes Association 200113080National Kidney Foundation200013080Canadian Hypertension Society 199913080British Hypertension Society199914080WHO&International Society of Hypertension199913085Joint National Committee(JNC VI)199713085GoalBPRecommendationsforPaJNC-VI General Goals for BP ControlPre-existing condition%achievedBP goalsBP goals(mmHg)Essential Hypertension27%140/90Diabetes11%1.0 gram/24 h10%30 mg/gm)20.211.7Proteinuria(300mg/24h)18.310.6Microalbuminuria(30-300 mg/24h)1.9 1.1Keane WF,Eknoyan G.Am J Kidney Dis.1999;33(5):1004-1010FrequencyofProteinuria(AlbImpact of Blood Pressure Reduction Impact of Blood Pressure Reduction on Mortality in Diabeteson Mortality in DiabetesTrialConventionalcareIntensivecareRisk reductionP-valueUKPDS154/87144/8232%0.019HOT144/85140/8166%0.016Turner RC,et al.BMJ.1998;317:703-713.Hansson L,et al.Lancet.1998;351:17551762.Mortality endpoints are:UK Prospective Diabetes Study(UKPDS)“diabetes related deaths”Hypertension Optimal Treatment(HOT)Study “cardiovascular deaths”in diabeticsImpactofBloodPressureReducUK Prospective Diabetes Study(UKPDS)UK Prospective Diabetes Study(UKPDS)Major Results:Powerful Risk ReductionsMajor Results:Powerful Risk ReductionsBetter blood pressure control reducesStrokes by one thirdSerious deterioration of vision by one thirdDeath related to diabetes by one thirdBetter glucose control reduces Early kidney damage by one thirdMajor diabetic eye disease by one fourthTurner RC,et al.BMJ.1998;317:703-713.UKProspectiveDiabetesStudyDiabetes:Tight Glucose vs Tight BP Diabetes:Tight Glucose vs Tight BP Control and CV Outcomes in UKPDSControl and CV Outcomes in UKPDSStrokeAny DiabeticEndpointDMDeathsMicrovascularComplications-50-40-30-20-100%Reduction In Relative RiskTight Glucose Control(Goal 6.0 mmol/l or 108 mg/dL)Tight BP Control(Average 144/82 mmHg)32%37%10%32%12%24%5%44%Bakris GL,et al.Am J Kidney Dis.2000;36(3):646-661.Reprinted by permission,Harcourt Inc.*P 0.05 compared to tight glucose controlDiabetes:TightGlucosevsTig17%decreaseper10mmHgdecrementinBPp0.00010.515110120130140150160170UKPDS:Relationship Between BP Control UKPDS:Relationship Between BP Control And Diabetes-Related DeathsAnd Diabetes-Related DeathsMeansystolicbloodpressure(mmHg)Hazard ratioAdler AI,et al.BMJ.2000;321:412-419.Reprinted by permission,BMJ Publishing Group.17%decreaseper10mmHgdecreHOT Trial:BP Control Reduces Cardiovascular Events in DiabeticsHansson L,et al.Lancet.1998;351:17551762.Major CV events*1000 patient-yrs302520151050P 1.5 mg/dLCaptopriln=207Placebon=202P.001Lewis EJ,et al.N Engl J Med.1993;329(20):1456-1462.Years of follow-upACE-IIsMoreRenoprotectiveTACE-I Is More Renoprotective than ACE-I Is More Renoprotective than Conventional Therapy in Type 1 Diabetes Conventional Therapy in Type 1 Diabetes%change in proteinuria40200-20-40-60CaptoprilPlaceboP.001Decrease in mean arterial pressure(mmHg)202-4-6-8CaptoprilPlaceboNSLewis EJ,et al.N Engl J Med.1993;329(20):1456-1462.ACE-IIsMoreRenoprotectivetRelationship of Achieved Mean Arterial Relationship of Achieved Mean Arterial Pressure to Parameters of Renal Function Pressure to Parameters of Renal Function in Type 1 Diabetesin Type 1 DiabetesMeanarterialpressure(mmHg)*nFinal total proteinuria(mg/24h)Serumcreatinine(mg/dL)GFR(mL/min)#patients with final proteinuria 500 mg/24h 92471,073+1,535(418)+0.14-5.22792.199.9411,830+1,701(1,798)+0.38-6.211100107324,249+4,754(2,659)+0.38-11.62 107.164,882+2,878(5,825)+0.92-11.00Note:Values expressed as mean+SD.Data based on achieved blood pressures,not randomized blood pressure goals.*Mean of all pressure readings observed during the trial for each patient.P 0.05 when 92.1 mmHg.Lewis JB,et al.Am J Kidney Dis.1999;34(5):809-817.RelationshipofAchievedMeanImpact of ACE-I on BP and GFR:Acute and Chronic Effects*P0.05 compared to baselineBakris GL,Weir MR.Arch Intern Med.2000;160(5):685-93.American Medical AssociationGFR ml/min/1.73m2*ImpactofACE-IonBPandGFR:ARB(Losartan)Reduces Urinary Albumin and ARB(Losartan)Reduces Urinary Albumin and TGF-TGF-1 in Type 2 Diabetes with Microalbuminuria1 in Type 2 Diabetes with MicroalbuminuriaEsmatjes E,et al.Nephrol Dial Transplant.2001;16(Suppl1):90-93.16014013012024-hour Systolic BPP0.01 vs baselinemmHg4 Weeks 90 80 70 6024-hour Diastolic BPP0.03 vs baselineBaseline8 WeeksmmHg 50Urinary Albumin ExcretionP0.01 vs baseline100 90 80 70 60mcg/min 6 5 4 3 2 1TGF-P0.005 vs baselineBaseline4 Weeks 8 Weeksng/mLARB(Losartan)ReducesUrinaryLandmark Trials in Diabetics and Non-Diabetics Landmark Trials in Diabetics and Non-Diabetics with ESRD/Death as an Endpointwith ESRD/Death as an EndpointTrialYearEndpoint significanceAchieved BPCaptopril1993P=0.007141/82AIPRI1996P0.001139/82REIN1997P=0.03142/84RENAAL2001P=0.01142/77IDNT2001results pendingresults pendingLewis EJ,et al.N Engl J Med.1993;329(20):1456-1462.Maschio G,et al.N Engl J Med.1996;334(15):939-945.The GISEN Group.Lancet.1997;349:18571863.LandmarkTrialsinDiabeticsaLandmark Renal Trials inNon-Diabetics with ACE InhibitorsStudyDrugDosingSurvival BenefitStudy DurationAIPRIBenazepril10-20mg qdP1 to 45 ml/min45 ml/minCreatinine Clearance71%46%31%53%66%Maschio G,et al.N Engl J Med.1996;334(15):939-945.AIPRI:BaselinePrognosticFacREIN Study:ACE Inhibition in Proteinuric REIN Study:ACE Inhibition in Proteinuric Non-Diabetic NephropathyNon-Diabetic Neph