1、Epidemiology of Renal Disease in Hypertension,Richard Bright, M.D.F.R.S. 1789-1858 Father of Nephrology,Renal Disease in Hypertension Epidemiology,Effects of hypertension on the kidney Interactions of hypertension and concomitant conditions on the kidney Age Atherosclerosis Diabetes mellitus Race Mo
2、rbidity & mortality associated with chronic renal disease Coronary artery disease Progression of chronic renal disease End Stage Renal Disease (ESRD) Hypertension as a consequence of ESRD,Renal Disease in Hypertension A Historical Perspective,Traube (Berlin, 1856) “High Blood Pressure Is Needed” Pos
3、tulated 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 (Clevela
4、nd, 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 sympath
5、ectomy in essential & malignant hypertension safely lowered arterial blood pressure without loss of renal function.,Risk Factors for Progression of Renal Disease,ESRD Due to Any Cause In 332,544 Men Screened for MRFIT Adjusted Relative Risk,Hypertension, Men with optimal blood pressure was the refer
6、ence category.,Klag MJ, et al. N Engl J Med. 1996;334(1):13-18.,* p0.001,HTN Linked To Chronic Renal Disease Among 332,544 Men Screened for MRFIT,Adapted from Klag MJ, et al. N Engl J Med. 1996;334(1):13-18. Massachusetts Medical Society,Incidence Rates of Reported ESRD by Primary Diagnosis,Year,Uni
7、ted States Renal Data System (USRDS) 2000 Annual Data Report WWW.USRDS.ORG,Diabetes 50%,Hypertension 27%,Glomerulonephritis 13%,Other 10%,Primary Diagnoses for Patients Who Start Dialysis,United States Renal Data System (USRDS) 2000 Annual Data Report WWW.USRDS.ORG,Persons Initiating Treatment for E
8、SRD Related to Diabetes in the US,CDC Diabetes Surveillance, 1997.,Amos A, McCarty D, Zimmet P. Diabetes Medicine. 1997;14Suppl5:S1-85.,Type I Diabetes,Type II Diabetes,Global Estimates and Projections for Incidence of Diabetes Mellitus,* p 0.0001,United States Renal Data System (USRDS) 2000 Annual
9、Data Report WWW.USRDS.ORG,Odds Ratio For ESRD By Race Racial differences in ESRD in the USA from 1990 to 1998,Effect of Hypertension on Mortality in Diabetic Pima Indians Age-Adjusted Death Rates for Diabetic Nephropathy,Sievers ML, et al. Circulation. 1999;100(1):33-40.,Normotensive Diabetics N=10
10、deaths,Hypertensive Diabetics N=75 deaths,*p 0.001,*,Risk of Ischemic Heart Disease Related to SBP and Microalbuminuria,Borch-Johnsen K, et al. Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997.,N=2,085; 10 year follow-up,Microalbuminuria Compared To Traditional Risk Factors For Ischemic Heart Dis
11、ease,N=2,085; 10 year follow-up,Borch-Johnsen K, et al. Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997.,A/C ratio 0.65mg/mmol, 7.0 mmol/L, 160 mmHg,Crude Incidence Rates of End Stage Renal Disease, By Race Racial differences in ESRD in the USA from 1990 to 1998,United States Renal Data System (
12、USRDS) 2000 Annual Data Report WWW.USRDS.ORG,Comorbidities 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 Da
13、ta Report WWW.USRDS.ORG,Crude Incidence Rates of Reported End Stage Renal Disease,United States Renal Data System (USRDS) 2000 Annual Data Report WWW.USRDS.ORG,Racial Distribution for Comorbidities In Dialysis Patients (1999), Diabetes mellitus as a primary diagnosis or contributing diagnosis. Diabe
14、tes mellitus that requires insulin treatment, which is a subset of the diabetes category.,United States Renal Data System (USRDS) 2000 Annual Data Report WWW.USRDS.ORG,CV Mortality in General Population (GP) & Dialysis Patients, By Race,Sarnak MJ, Levey AS. Semin Dial. 1999;12:69-76.,Hypertension an
15、d Chronic Renal Disease: Hemodynamic Abnormalities,Mean BP,Total Systemic Vascular Resistance,=,X,Increased Cardiac Output Intravascular Volume Glomerular filtration Sodium excretion Extracellular Fluid Renal Nerve ActivityMyocardial Performance Adrenergic Activity,Increased Vasoconstriction Adrener
16、gic Stimuli Angiotensin II Endothelin Endothelium-derivedContracting Factors Thromboxane,Cardiac Output,Decreased Vasodilation Prostacyclin Nitric oxide EDHF*,Textor SC. Atlas of Diseases of the Kidney, 2001.,*Endothelium-derived Hyperpolarizing Factors,Prevalence of Hypertension In Chronic Renal Di
17、seases,MCN=minimal change nephropathy CIN=chronic interstitial nephritis IgA=IgA nephropathy MGN=membranous glomerulonephritis APKD=adult-onset polycystic kidney disease DN=diabetic nephropathy MPGN=membranoproliferative glomerulonephritis FSGN=focal segmental glomerulonephritis,Smith MC and Dunn MJ
18、, in Hypertension. Laragh JH, Brenner BM. Raven Press; 1995:2081-2101.,Hypertension and Renal Disease: Mechanisms,Scanning electron (top) and light (bottom) micrographs of a human glomerulus,trc.ucdavis.edu/mjguinan/apc100/modules/ Urinary/mammal/cortex1/cortex.html,trc.ucdavis.edu/mjguinan/apc100/m
19、odules/ Urinary/mammal/glomeruli0/glomeruli.html,Glomerulus,Mesangial Matrix,Efferent Renal Arteriole,Mesangial Cells,Renal Sympathetic Nerves,Bowmans Capsule,Distal Convoluted Tubule,Proximal Convoluted Tubule,Adventitial Mast Cell/Macrophage,Components of the Normal Nephron,Vascular Smooth Muscle
20、Cells,Juxtaglomerular Cells,Macula Densa,Glomerular hypertension Hyperfiltration Glomerular barrier dysfunction Proteinuria Mesangial cell hyperplasia Intrarenal inflammatory processes Endothelial dysfunction VSMC proliferation,Normal Kidney,Mechanisms of Renal Damage in HTN,Mechanisms,B l o o d P r
21、 e s s u r e,Functional Decrease in GFR Proteinuria Structural Glomular basement membrane changes Expanded mesangial matrix Glomerulosclerosis Tubulo-interstitial fibrosis,B l o o d P r e s s u r e,Consequences of Renal Damage in HTN,Consequences,Renal Failure,Effects of Vasodilators in the Normal K
22、idney,L-Arginine,NO,eNOS,(-),(-),L-Citrulline,EDHF(s),Pgl2,(-),(-),PMN,M,Platelet,(-),VSMC,EC,Imbalance in Factors Affecting Vascular Tone and Structure,Nephron destruction and renal failure,EDHF= endothelium-derived hyperpolarizing factors ROS= reactive oxygen species EDCF= endothelium-derived cons
23、tricting factors,+,=,OONO_,(-),ROS Reduces the Biological Effects of NO,Afferent Arteriole,L-Arginine,NO,eNOS,L-Citrulline,NE,VSMC,PMN,M,Fibroblast,EC,Mast cell,(+),Renin-Angiotensin Cascade,Angiotensinogen, Angiotensin I, Angiotensin II,AT1,AT2,ATn,Bradykinin,Inactive peptides,Non-renin (eg tPA),No
24、n-ACE (eg chymase),ACE,Renin,Angiotensin II (Ang II) generated in the afferent arteriole interacts with AT1 receptors on cellular components of the nephron,Angiotensinogen,Ang I,Renin,ACE,Ang II,AT1R,Role of Angiotensin II in Chronic Renal Disease, Adhesion molecules Chemotactic factors Cell growth
25、Apoptosis TGF-, CTGF PAI-1, Glomerular capillarypressure Single nephron GFR,Macrophage infiltration,Angiotensin II,Mechanical stress Mesangial changes Oxidative stress Proteinuria NF-B activation,Glomerulosclerosis & Tubulo-interstitial fibrosis,Renal disease,Nephron loss,Adapted from Berk B. 2001.,
26、Angiotensin II Induces Oxidative Stress in the Kidney,Stimulation of Membrane NOX-1 Oxidase* Increased superoxide (O2) Increased thiobarbituric acid reactive substances Increased oxidized lipids Increased tissue protein carbonyl content Induction of Heme Oxidase-1 (HO-1) Activation of NF-B Increased
27、 inflammatory cytokines,*NAD(P)H Oxidase,O2 H2O2 H2O+O2,Renal Sources of ROS,NOX-1 oxidase* Xanthine oxidase Heme oxygenase1 Cyclo-oxygenase Lipoxygenase Cytochrome P450 mono-oxygenase Mitochondrial oxidative phosphorylation,*NADP(H) oxidase,Superoxide dismutase,Catalase, O2 Endothelial Cells and H2
28、O2 Vascular Smooth Muscle,Oxidative Stress: Endothelial Dysfunction and CAD/Renal Risk Factors,Endothelial Dysfunction,Apoptosis,Vasoconstriction,Leukocyte adhesion,Lipid deposition,Thrombosis,VSMC growth,Hypertension,Smoking,Diabetes,LDL,Homocysteine,Estrogen deficiency,Pivotal Role of ROS in Stimu
29、lus-Induced EC and VSMC Growth, Survival, and Apoptosis,PDGF, Thrombin, Norepinephrine, Ang II, TNF, Ox-LDL, High Glucose, VEGF,ROS,Arachidonate Metabolism,Mitochondrial Electron Transport Chain,Cytochrome P450,NOX-1 Oxidase,Xanthine Oxidase,Growth or Hypertrophy,Survival,Apoptosis, Caspases, NF-B,
30、Akt, ERKs, JNKs,SAPKs, p38MAPK,Potential Targets of ROS,Sources of ROS,Growth/Death Survival Signals,Pathologic Processes Leading to Glomerular Injury and Proteinuria,Ang II,Increased glomerular pressure,Ang II,Urinary protein,Glucose,AGEs,Glycoxidation (glycation),Efferent arteriolar constriction,=
31、angiotensin AT1 receptor,Vascular and/or Tubular Injury,Glomerular cells Tubular cells Lymphocytes Macrophages Fibroblasts,TGF- ET-1 CTGF Ang II PAI-1,PDGF bFGF TNF- IL-1,FIBROSIS,Fibrosis and Nephron Loss: A Renal Response to Injury,TGF-,TGF- plays a key role in extracellular matrix formation in me
32、sangium and interstitium that leads to fibrosis and loss of nephron units,bFGF,PDGF,Ang II,TSP1,TGF-,O2,TGF- plays a key role in extracellular matrix formation in mesangium and interstitium that leads to fibrosis and loss of nephron units,TIMP,bFGF,PDGF,Ang II,Proteases,(-),(-),(+),(+),(+),TSP1,ET-1
33、,PAI-1,O2,TGF-,TGF- plays a key role in extracellular matrix formation in mesangium and interstitium that leads to fibrosis and loss of nephron units,Angiotensin II: Role in Renal Injury,Angiotensin II,AT1R,AT2R,NF-B,TNFR1,TNFR2,Angiotensinogen,Fibroblasts,Proliferation and differentiation,Matrix,FI
34、BROSIS,Inflammation,Cellular adhesion molecules,Tubule cells,TNF-,+,+,Profibrotic cytokines,Aldosterone Promotes Renal Fibrosis by Multiple Mechanisms,Adrenal,Vascular,Aldosterone,PAI-1,Nitric oxide synthesis,Na+ influx into VSMC,Norepinephrine uptake into VSMC,Angiotensin II,AT1R binding of Ang II,
35、Stimulates,Inhibits,Fibroblast collagen synthesis,Pathways Leading To Progressive Renal Failure,Renal growth factor & cytokine activation,Fibrogenesis,Systemic hypertension,Progressive Loss of Filtration Surface Area,GFR,Renal injury,Nephron mass,Glomerular hypertension,Renal scarring,Hyperlipidemia
36、,Filtration of plasma proteins (Proteinuria), Proximal tubuleprotein uptake,Renal microvascularinjury,Influx of monocytes and macrophages,Transdifferentiation of renal cells to fibroblast phenotype,Brenner BM, Keane WF. 2001.,Clinical Trials in Hypertension and Renal Diseases,The Dual Significance o
37、f Proteinuria,Proteinuria (albuminuria) results from injury to glomerular circulation Increased proteinuria (albuminuria) is associated with progressive kidney disease In diabetes and hypertension, proteinuria (albuminuria) is also an indicator of injury in the systemic circulation Proteinuria (albu
38、minuria) is associated with increased cardiovascular risk,Renal Disease and Hypertension Core Concepts of Treatment,Hypertension and proteinuria (albuminuria) are both independent variables that predict long-term decline in renal function Renal disease is both a cause and consequence of hypertension
39、 Reduction of blood pressure reduces cardiovascular risk and renal risk Reduction of proteinuria (albuminuria) may lower both cardiovascular risk and renal risk,Meta Analysis: Lower Mean BP Results in Slower Rates of Decline in GFR in Diabetics and Non-Diabetics,Parving HH, et al. Br Med J. 1989. Mo
40、schio 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 Kidne
41、y Dis. 2000;36(3):646-661. Reprinted by permission, Harcourt Inc.,Meta Analysis: Lower Systolic BP Results in Slower Rates of Decline in GFR in Diabetics and Non-Diabetics,r = 0.69; P .05,SBP (mmHg),GFR (mL/min/year),Untreated HTN,0,-2,-4,-6,-8,-10,-12,-14,Bakris GL, et al. Am J Kidney Dis. 2000;36(
42、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 a
43、l. Kidney Int. 1994.,Goal BP Recommendations for Patients with DM or Renal Disease,JNC-VI General Goals for BP Control,Coresh J, et al. Arch Intern Med. 2001;161(9):1207-1216.,Frequency of Proteinuria (Albuminuria) in the United States,Keane WF, Eknoyan G. Am J Kidney Dis. 1999;33(5):1004-1010,Impac
44、t of Blood Pressure Reduction on Mortality in Diabetes,Turner 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
45、diabetics,UK Prospective Diabetes Study (UKPDS) Major Results: Powerful Risk Reductions,Better blood pressure control reduces Strokes by one third Serious deterioration of vision by one third Death related to diabetes by one thirdBetter glucose control reduces Early kidney damage by one third Major
46、diabetic eye disease by one fourth,Turner RC, et al. BMJ. 1998;317:703-713.,Diabetes: Tight Glucose vs Tight BP Control and CV Outcomes in UKPDS,Stroke,Any Diabetic Endpoint,DM Deaths,Microvascular Complications,-50,-40,-30,-20,-10,0,% Reduction In Relative Risk,Tight Glucose Control(Goal 6.0 mmol/l
47、 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 control,UKPDS: Relationship Between BP Control And Diabetes-Related Deaths,Mean
48、systolic blood pressure (mmHg),Hazard ratio,Adler AI, et al. BMJ. 2000;321:412-419. Reprinted by permission, BMJ Publishing Group.,HOT Trial: BP Control Reduces Cardiovascular Events in Diabetics,Hansson L, et al. Lancet. 1998;351:17551762.,Major CV events* 1000 patient-yrs,*includes all myocardial infarction, all strokes, and all other CV deaths,Landmark ACE Inhibitor Trials in Diabetics,
