高血压与肾病优选课件

1、Epidemiology ofRenal Disease inHypertensionRichard Bright, M.D.F.R.S.1789-1858Father of NephrologyEpidemiology ofRenal Disease Renal Disease in HypertensionEpidemiologyEffects of hypertension on the kidneyInteractions of hypertension and concomitant conditions on the kidneyAgeAtherosclerosisDiabetes

2、 mellitusRaceMorbidity & mortality associated with chronic renal disease Coronary artery diseaseProgression of chronic renal diseaseEnd Stage Renal Disease (ESRD)Hypertension as a consequence of ESRDRenal Disease in HypertensionRenal Disease in HypertensionA Historical PerspectiveTraube (Berlin, 185

3、6) “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

4、 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

5、renal function.Radical sympathectomy in essential & malignant hypertension safely lowered arterial blood pressure without loss of renal function.Renal Disease in HypertensionRisk Factors for Progression of Renal DiseaseCan be modifiedCannot be modifiedHypertensionAgeAlbuminuria/ProteinuriaEthnicityD

6、yslipidemiaGenderHemoglobin A1CSmokingAnemiaCaP04Risk Factors for Progression ESRD Due to Any CauseIn 332,544 Men Screened for MRFITAdjusted Relative RiskHypertension Men with optimal blood pressure was the reference category.Klag MJ, et al. N Engl J Med. 1996;334(1):13-18.* p0.001ESRD Due to Any Ca

7、useIn 332,5HTN Linked To Chronic Renal Disease Among 332,544 Men Screened for MRFIT8080-8485-8990-99100-109110Age-Adjusted Rate of ESRDPer 100,000 Person-Years180160-179140-159130-139120-129120Systolic BP (mm Hg)Diastolic BP (mm Hg)Adapted from Klag MJ, et al. N Engl J Med. 1996;334(1):13-18. Massac

8、husetts Medical SocietyHTN Linked To Chronic Renal DiIncidence Rates of Reported ESRD by Primary DiagnosisYearUnited States Renal Data System (USRDS) 2000 Annual Data Report Incidence Rates of Reported EDiabetes50%Hypertension27%Glomerulonephritis13%Other10%Primary Diagnoses for Patients Who Start D

9、ialysisUnited States Renal Data System (USRDS) 2000 Annual Data Report DiabetesHypertensionGlomerulonPersons Initiating Treatment for ESRD Related to Diabetes in the USCDC Diabetes Surveillance, 1997.Persons Initiating Treatment fAmos A, McCarty D, Zimmet P. Diabetes Medicine. 1997;14Suppl5:S1-85. T

10、ype I DiabetesType II DiabetesGlobal Estimates and Projectionsfor Incidence of Diabetes MellitusAmos A, McCarty D, Zimmet P. * 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 1998reference* p 0.0001

11、United States RenalEffect of Hypertension on Mortality in Diabetic Pima IndiansAge-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 mmHgMicroalbuminuria Compar

12、ed To TCrude Incidence Rates of End Stage Renal Disease, By RaceRacial differences in ESRD in the USA from 1990 to 1998 United States Renal Data System (USRDS) 2000 Annual Data Report Crude Incidence Rates of End Comorbidities in Renal Disease Patients (1999) Diabetes mellitus as a primary or contri

13、buting 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 Comorbidities in Renal DiseasCrude Incidence Rates of Reported End Stage Renal DiseaseUnited States Renal Data System (USRDS

14、) 2000 Annual Data Report Crude Incidence Rates of RepoRacial Distribution for Comorbidities 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 Ren

15、al Data System (USRDS) 2000 Annual Data Report Racial Distribution for ComorbCV Mortality in General Population (GP) & Dialysis Patients, By Race Sarnak MJ, Levey AS. Semin Dial. 1999;12:69-76.CV Mortality in General PopulaHypertension and Chronic Renal Disease: Hemodynamic AbnormalitiesMean BPTotal

16、 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

17、 Factors ThromboxaneCardiacOutputDecreasedVasodilation Prostacyclin Nitric oxide EDHF*Textor SC. Atlas of Diseases of the Kidney, 2001.*Endothelium-derived Hyperpolarizing FactorsHypertension and Chronic RenalPrevalence of HypertensionIn Chronic Renal DiseasesMCN=minimal change nephropathy CIN=chron

18、ic 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 P

19、ress; 1995:2081-2101.Prevalence of HypertensionIn Hypertension and Renal Disease:MechanismsScanning electron (top) and light (bottom) micrographs of a human /mjguinan/apc100/modules/Urinary/mammal/cortex1//mjguinan/apc100/modules/Urinary/mammal/glom

20、eruli0/glomeruli.htmlHypertension and Renal DiseaseGlomerulusMesangial MatrixEfferent Renal ArterioleMesangial CellsRenal Sympathetic Nerves Bowmans CapsuleDistalConvoluted TubuleProximal Convoluted TubuleAdventitial Mast Cell/MacrophageComponents of the Normal NephronVascular Smooth Muscle CellsJux

21、taglomerular CellsMacula DensaGlomerulusMesangial MatrixEffeGlomerular hypertensionHyperfiltrationGlomerular barrier dysfunctionProteinuriaMesangial cell hyperplasiaIntrarenal inflammatory processesEndothelial dysfunctionVSMC proliferationNormal KidneyMechanisms of Renal Damage in HTNMechanismsB l o

22、 o d P r e s s u r eGlomerular hypertensionNormal FunctionalDecrease 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 FailureFunctionalB l

23、o o d P r e Effects of Vasodilators in the Normal KidneyL-ArginineNOeNOS(-)(-)L-CitrullineEDHF(s)Pgl2(-)(-)PMNMPlatelet(-)VSMCECEffects of Vasodilators in thImbalance in Factors Affecting Vascular Tone and StructureNephron destruction and renal failureAngiotensin IICatecholaminesEndothelin-1ROSCytok

24、inesEDCFNitric OxideProstacyclinBradykininEDHFConstrictors/Growth PromotersDilators/Growth InhibitorsVascular tone and structureEDHF= endothelium-derived hyperpolarizing factorsROS= reactive oxygen speciesEDCF= endothelium-derived constricting factorsImbalance in Factors Affecting+ = OONO_ (-)ROS Re

25、duces the Biological Effects of NOO2Afferent ArterioleL-ArginineNOeNOSL-CitrullineNEVSMCPMNMFibroblastECMastcell(+)+ = OONO_ (-)ROS Reduces the Renin-Angiotensin CascadeAngiotensinogen Angiotensin I Angiotensin IIAT1AT2ATnBradykininInactivepeptidesNon-renin(eg tPA)Non-ACE(eg chymase)ACEReninRenin-An

26、giotensin CascadeAngioAngiotensin II (Ang II) generated in the afferent arteriole interacts with AT1 receptors on cellular components of the nephronAngiotensinogenAng IReninACEAng IIAT1R= AT1 ReceptorAngiotensin II (Ang II) generaRole of Angiotensin II in Chronic Renal Disease Adhesion molecules Che

27、motactic factors Cell growth Apoptosis TGF-, CTGF PAI-1 Glomerular capillarypressure Single nephron GFRMacrophageinfiltrationAngiotensin IIMechanical stressMesangial changesOxidative stressProteinuriaNF-B activationGlomerulosclerosis& Tubulo-interstitial fibrosisRenaldiseaseNephronlossAdapted from B

28、erk B. 2001.Role of Angiotensin II in ChrAngiotensin 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

29、(HO-1)Activation of NF-BIncreased inflammatory cytokines*NAD(P)H OxidaseAngiotensin II Induces Oxidat O2 H2O2 H2O+O2O2Renal Sources of ROSNOX-1 oxidase*Xanthine oxidaseHeme oxygenase1Cyclo-oxygenaseLipoxygenaseCytochrome P450 mono-oxygenaseMitochondrial oxidative phosphorylation*NADP(H) oxidaseSuper

30、oxidedismutaseCatalase O2 H2 O2 Endothelial Cells and H2O2 Vascular Smooth MuscleOxidative Stress: Endothelial Dysfunction and CAD/Renal Risk FactorsEndothelial DysfunctionApoptosisVasoconstrictionLeukocyteadhesionLipiddepositionThrombosisVSMCgrowthHypertensionSmokingDiabetesLDLHomocysteineEstrogend

31、eficiency O2 Endothelial CelPivotal Role of ROS in Stimulus-Induced EC and VSMC Growth, Survival, and ApoptosisPDGF, Thrombin, Norepinephrine, Ang II, TNF, Ox-LDL, High Glucose, VEGFROSArachidonate MetabolismMitochondrial ElectronTransport ChainCytochromeP450NOX-1 OxidaseXanthine OxidaseGrowth or Hy

32、pertrophySurvivalApoptosis Caspases NF-B Akt ERKs JNKsSAPKs p38MAPKPotential Targetsof ROSSources of ROSGrowth/DeathSurvival SignalsPivotal Role of ROS in StimuluPathologic Processes Leading to Glomerular Injury and ProteinuriaAng IIIncreasedglomerularpressureAng IIUrinary proteinGlucoseAGEsGlycoxid

33、ation (glycation)Efferent arteriolarconstriction=angiotensin AT1 receptorPathologic Processes Leading tVascular and/or Tubular InjuryGlomerular cells Tubular cellsLymphocytes MacrophagesFibroblastsTGF-ET-1CTGFAng IIPAI-1PDGFbFGFTNF-IL-1FIBROSISFibrosis and Nephron Loss: A Renal Response to InjuryVas

34、cular and/or Tubular InjuryTGF-TGF- plays a key role in extracellular matrix formation in mesangiumand interstitium that leadsto fibrosis and loss of nephron unitsTGF-TGF- plays a key role inbFGFPDGFAng IITSP1TGF-O2TGF- plays a key role in extracellular matrix formation in mesangiumand interstitium

35、that leadsto fibrosis and loss of nephron unitsO2bFGFPDGFAng IITSP1TGF-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 unitsO2TIMPbFGFPDGFAng IIProteases(

36、-)Angiotensin II: Role in Renal InjuryAngiotensin IIAT1RAT2RNF-BTNFR1TNFR2AngiotensinogenFibroblastsProliferation and differentiationMatrixFIBROSISInflammationCellular adhesion moleculesTubule cellsTNF-+Profibrotic cytokinesAngiotensin II: Role in Renal Aldosterone Promotes Renal Fibrosisby Multiple

37、 MechanismsAdrenalVascularAldosteronePAI-1Nitric oxidesynthesisNa+ influxinto VSMCNorepinephrineuptake into VSMCAngiotensin IIAT1R bindingof Ang IIStimulatesInhibitsFibroblast collagen synthesisAldosterone Promotes Renal FibPathways Leading ToProgressive Renal FailureRenal growth factor & cytokine a

38、ctivationFibrogenesisSystemic hypertensionProgressive Loss of Filtration Surface AreaGFRRenal injuryNephron massGlomerular hypertensionRenal scarringHyperlipidemiaFiltration of plasma proteins(Proteinuria) Proximal tubule protein uptakeRenal microvascular injuryInflux of monocytes and macrophagesTra

39、nsdifferentiation of renal cells to fibroblast phenotypeBrenner BM, Keane WF. 2001.Pathways Leading ToProgressivClinical Trials in Hypertension and Renal Diseases Placebo + Other Antihypertensive Therapy (excluding ACEI, AIIA)Maintain prior antihypertensive therapy (excluding ACEI, AIIA) Los 100 mg

40、+ Other Antihypertensive Therapy (excluding ACEI, AIIA)Los 100 mgGoal BP 140/90 mmHgn = 1520Los 50 mgPlaceboNIDDM Patientswith proteinuriaPlaceboClinical Trials in HypertensioThe Dual Significance of ProteinuriaProteinuria (albuminuria) results from injury to glomerular circulationIncreased proteinu

41、ria (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 riskThe Dual Significance of ProteRenal Disease and H

42、ypertensionCore 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

43、 of proteinuria (albuminuria) may lower both cardiovascular risk and renal riskRenal Disease and HypertensionMeta Analysis: Lower Mean BP Results in Slower Rates of Decline in GFR in Diabetics and Non-Diabetics9598101104107110113116119r = 0.69; P 0.05MAP (mmHg)GFR (mL/min/year) 130/85140/90Untreated

44、HTN0-2-4-6-8-10-12-14Parving 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

45、al. Kidney Int. 1994.Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.Reprinted by permission, Harcourt Inc.Meta Analysis: Lower Mean BP Meta Analysis: Lower Systolic BP Results in Slower Rates of Decline in GFR in Diabetics and Non-Diabetics130134138142146150154170180r = 0.69; P .05SBP (mmHg)G

46、FR (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

47、.Hebert L, et al. Kidney Int. 1994.The GISEN Group. Lancet. 1997.Lebovitz H, et al. Kidney Int. 1994.Meta Analysis: Lower Systolic Goal BP Recommendations for Patients with DM or Renal DiseaseOrganizationYear Systolic BPDiastolic BPAmerican Diabetes Association200113080National Kidney Foundation2000

48、13080Canadian Hypertension Society199913080British Hypertension Society199914080WHO & International Society of Hypertension199913085Joint National Committee (JNC VI)199713085Goal BP Recommendations for PaJNC-VI General Goals for BP ControlPre-existing condition% achievedBP goalsBP goals (mmHg)Essent

49、ial 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):1004-1010Frequency of Proteinuria (AlbImpact of Blood Pressure Reduction on Mortality in DiabetesTrialConventional

50、careIntensivecareRisk 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

51、 “cardiovascular deaths” in diabeticsImpact of Blood Pressure ReducUK Prospective Diabetes Study (UKPDS) Major Results: Powerful Risk ReductionsBetter blood pressure control reducesStrokes by one thirdSerious deterioration of vision by one thirdDeath related to diabetes by one thirdBetter glucose co

52、ntrol reduces Early kidney damage by one thirdMajor diabetic eye disease by one fourthTurner RC, et al. BMJ. 1998;317:703-713. UK Prospective Diabetes Study Diabetes: Tight Glucose vs Tight BP Control and CV Outcomes in UKPDSStrokeAny DiabeticEndpointDMDeathsMicrovascularComplications-50-40-30-20-10

53、0% 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: Tight Glucose v

54、s Tig17% decrease per 10 mmHg decrement in BPp0.00010.515110120130140150160170UKPDS: Relationship Between BP Control And Diabetes-Related DeathsMean systolic blood pressure (mmHg)Hazard ratioAdler AI, et al. BMJ. 2000;321:412-419.Reprinted by permission, BMJ Publishing Group.17% decrease per 10 mmHg

55、 decreHOT 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-I Is More Renoprotective

56、 TACE-I Is More Renoprotective than 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-I Is More Renoprotective tRelationship

57、of Achieved Mean Arterial Pressure to Parameters of Renal Function in 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)+0.38-6.21110

58、0107324,249 + 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

59、al. Am J Kidney Dis. 1999;34(5):809-817.Relationship of Achieved Mean Impact 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*Impact of ACE-I on BP and GFR:ARB (Losartan) R

60、educes Urinary Albumin and TGF-1 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