1、Hypertension in NEPHROLOGYRenal diseaseloss of nephrons Systemic hypertensionProteinuriaProgressive decline in GFRIntroductionParallels Between Hypertension in 1972 and Kidney Disease in 2005 Recent documentation of effective therapy Treatment of a silent disease to reduce risk for a disastrous outc
2、ome Simple screening Advantages for patients,physicians,industryChronic Kidney DiseaseStage 1;GFR 90 mL/min.1.73m2Stage 2;GFR 60-90 mL/min.1.73m2Stage 3;GFR 30-60 mL/min.1.73m2Stage 4;GFR 15-30 mL/min.1.73m2Stage 5;GFR 15 mL/min.1.73m2Cockcroft-Gault equation(140-age)x weight in kgCreatinine clearan
3、ce=-x 0.85(if women)(72 X serum creatinine)Modified MDRD GFRGFR(mL/min.1.73m2)=186 x sCr-1.154 x age-0.203 x 0.742(if women)Stages of Chronic Kidney DiseaseStages of Chronic Kidney Disease 3.6 Million6.5 Million15.5 Million700,000300,000NHANES 2004 Stage VStage V GFR90 ml/min/m2?Walking the dog2006.
4、American College of Physicians.All Rights Reserved.MAJOR RISK FACTORS FOR CARDIOVASCULAR DISEASEHYPERTENSIONHYPERLIPIDEMIASMOKINGFAMILY HISTORYOBESITYDIABETESCHRONIC KIDNEY DISEASEPHYSICAL INACTIVITYAGE 55 IN MEN,65 IN WOMENWhy are CKD/ESRD Patients Predisposed to CV Disease?INFLAMMATION plus CaP de
5、positionCV DISEASE AND DEATHCKD/ESRDANEMIALVH/CHFLIPIDSHTNCAD and PVDWhy are CKD/ESRD Patients Predisposed to CV Disease?30-50%of ESRD patients have INFLAMMATION(increased CRP,increased IL-6,decreased albumin)Increased CRP is a primary marker for inflammation predicting cardiovascular disease in nor
6、mal adults Increased CRP is the primary marker for increased cardiovascular mortality on dialysis CKD/ESRD patients have metastatic calcification(coronary arteries)because of secondary hyperparathyroidism and elevated PO4 levels.Microalbuminuria and proteinuria as a risk factor for CAD and CVA marke
7、r of endovascular healthMiettinen H et al,Stroke 27:2033,1996 Prevalence of HTN in CKD80%of patients with glomerulonephritis and 30%of patients with chronic interstitial disease are hypertensive.0102030405060708090stage 1stage 2stage 3stage 4%normalhypertensionHypertension and renal function00.10.20
8、.30.40.50.60.70.80.91stage 1stage 2stage 3stage 4Probability of HTRelative risk of ESRD according to quintile BPMRFIT studyN=332,544 men How important is systemic blood pressure control?Hypertension in CKDPathophysiology thought to be both pressor-and volume-related,thus CKD patients respond to both
9、 vasodilators as well as diuretics/sodium restriction.As kidney function declines closer to ESRD,volume-dependent hypertension becomes more important.Often on dialysis,we can remove antihypertensive agents as we bring the patient down to their dry weight with ultrafiltration.Concept of Glomerular Hy
10、pertensionConcept of Glomerular Hypertension Normally,increased glomerular capillary pressure(PGC)is good,as it results in increased GFR.Increased PGC is not good in a kidney that is already damaged=GLOMERULAR HYPERTENSION.Increased PGC occurs with:Increased systemic blood pressure Increased efferen
11、t artery vasoconstriction(angiotensin II)Increased afferent artery dilation(protein loads,calcium channel blockers)GFRProteinuriaAldosterone releaseGlomerular sclerosisA IIAtherosclerosis*VasoconstrictionVascular hypertrophyEndothelial dysfunctionLV hypertrophyFibrosisRemodelingApoptosisStrokeDeath*
12、Preclinical data.LV=left ventricular;MI=myocardial infarction;GFR=glomerular filtration rate.HypertensionHeart FailureMIRenal FailureAngiotensin II plays a central role in organ damageRenin Angiotensin Aldosterone SystemAngiotensinogenNon-ACE pathways(eg,chymase)Vasoconstriction Cell growth Na/H2O r
13、etention Sympathetic activationReninAngiotensin IAngiotensin IIACECough,angioedemaBenefits?BradykininInactivefragments Vasodilation Antiproliferation(kinins)AldosteroneAT2AT1PGCAAEAA IIAngiotensin II Effects on Glomerular Capillary PressurePGCAAEAA IIAngiotensin II Causes Glomerular HypertensionPGCA
14、AEAHow does blood pressure relate to progression of CKD?BPIn a sick kidney,increased glomerular capillary pressure(GLOMERULAR HYPERTENSION)causes progression of the CKD(increased fibrosis)Angiotensin II and CKDAngiotensin IIPGC Injury to Glomerular cells ProteinuriaO2.and TGF-Scarring/FibrosisAngiot
15、ensin II One of the most potent vasoconstrictors critical in maintenance of blood pressure Renal actionsIncreased sodium reabsorptionIncreased sodium reabsorptionIncreased GFR by increasing glomerular capillary Increased GFR by increasing glomerular capillary pressurepressureA II Blockade Experiment
16、al datawith diabetic rats at 70 weeksACE Inh/ARB AII BP Proteinuria/Renal DiseaseAnderson S et al,Kidney Int 36:526,1989Glomerular Pressure40s 64 46 56 Treatment to Prevent Progression of CKD to Kidney Failure Intensive glycemic control lessens progression from microalbuminuria in type 1 diabetes-DC
17、CT,1993 Antihypertensive therapy with ACE Inhibitors lessens proteinuria and progression-Giatras,et al.,1997-Psait,et al.,2000-Jafar,et al.,2001 Low protein diets lessen progression-Fouque,et al.,1992-Pedrini,et al.,1996-Kasiske,et al.,1998Meta-AnalysesMeta-AnalysesTreatment goal for hypertension in
18、 the general population has remained relatively the same for the last decade.GuidelinesBP targetBritish Hypertension Society(2004)140/85JNC VII(2003)1 gram/24 hours or diabetic kidney disease140/90 mmHg(JNC 7)130/80 mmHg(ADA,JNC 7)130/80 mmHg(JNC 7,K/DOQI)125/75 mmHg(NKF)Chobanian AV et al.JAMA.2003
19、;289:25602571.American Diabetes Association.Diabetes Care.2002;25:134147.National Kidney Foundatrion.Am J Kid Dis.2002;39(suppl 1):S1S266.Target Blood Pressure vShould be lower than the general populationvShould be tailored according to:What should be the treatment goal for renal disease?the severit
20、y of renal failure the severity of the proteinuriaAggressive BP Control,Proteinuria and CKD Progression what is the optimal BP for CKD?Klahr S et al,N Engl J Med 330:877,1994*GOAL BP1 gm proteinuriaSteps every clinician should take to reduce the incidence and/or progression of CKDn Aggressive BP red
21、uctionn Use of agents that interfere with the RAASSteps to Reduce Renal DiseaseBP control,GFR decline and proteinuriaIntense BP controlAn initial reduction in proteinuria of 1.0 g/d slower mean decrease in GFR by 0.92 0.31 mL/miny,GFR 25-55by 1.32 0.46 mL/miny,GFR 15-24Progression of CKD and BPConti
22、nued ramiprilSwitched to ramipril2Ruggenenti et al.Lancet 1998;352:1252-1256.REIN follow-up trialchronic nephropathy and proteinuria3g/day2530354045Core study Follow-up trialGFR decline(mL/min/1.73m /month)-0.44ml/min per month-0.10ml/min per month-0.81ml/min per month-0.14ml/min per monthAASK:ACEI
23、vs CCB in Hypertensive Renal DiseaseAgodoa LY et al.JAMA.2001;285:27192728.GFR Event,ESRD,or Death252015105003122436AmlodipineRamiprilCumulative Incidence,%MonthsP=0.005CCB arm terminated prematurely because ACEI and beta blocker demonstrated clear superiorityCardiovascular mortalityNon-cardiovascul
24、ar mortalityHans L.Hillege,et al.,Circulation,2002,106:1777 End-organ damage and mortality in general populationThe Effect of Angiotensin-Converting Enzyme Inhibition on Diabetic Nephropathy 409 Type I diabetics ages 18-49 with nephropathy(U protein500 mg and S Cr 1.5 mg/dl:Captopril reduced doublin
25、g of S Cr by 48%over 4 years.Captopril reduced ESRD(dialysis or transplant)or death by 50%over 4 years.Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan RENAAL 1513 Type II diabetics with nephropathy (U alb/Cr ratio 300 or U prot 500 mg and S Cr 1.3-3.0 mg/dl)Prospective,ra
26、ndomized,double-blinded multicenter(250)trial Two arms Losartan(50-100 mg)to keep BP135/85)and nephropathy(proteinuria 900 mg,S Cr 1.0-3.0 mg/dl)Prospective,randomized,double-blinded,multicenter(210)trial Three arms:Irbesarten,amlodipine,and placeboLewis EJ et al,New Engl J Med 345:851,2001IDNT ARB
27、Reduction of Renal Failure Lewis EJ et al,N Eng J Med 345:851,200120%33%23%ARB Effects of Type II DM Nephropathy-RENAAL and IDNTEndpoints RENAALIDNTComposite16%20%S Cr Doubling25%33%ESRD28%23%ACE Inhibitors and CKD ProgressionMeta-analysis-Jafar T,Ann Intern Med 135:73-87,2001 11 randomized controll
28、ed trials comparing ACE inhibitors vs.other medications in treatment of hypertension in 1860 nondiabetic patients with CKD(S Cr=2.3).Results:ACE Inhibitors lowered BP and proteinuria.Results:ACE inhibitors decreased risk of ESRD by 31%,combined risk of progression of renal insufficiency and developm
29、ent of ESRD by 30%independent of BP lowering effects.Proportion of Patients With First Event,%LIFE:Primary Composite EndpointMonthsDahlf B et al.Lancet.2002;359:9951003.0612182430364248546066Intent-to-Treat0246810121416LosartanAtenololAdjusted Risk Reduction 13.0%,P=0.021Unadjusted Risk Reduction 14
30、.6%,P=0.009There was no significant difference in BP between groups at all time pointsPatients;non-diabetic patients affected by proteinuric renal diseaseMAP 98 mmHgTreatment;telmisartan 80mg,once dailySystolic BP change 135 11 to 122 13 mmHgDiastolic BP change 84.4 8.1 to 75.9 8.5 mmHgmean BP101 8
31、to 91 9 mmHg Proteinuria1.60 0.90 to 1.06 0.63 g/24 hCupisti A et al.,Biomed Pharmacother,2003,57:169What is the evidence that combining an ACEI and an ARB will have additive benefits?COOPERATE:Study DesignDesign:Randomized,double-blind trial in 263 patients with non-diabetic renal diseasePrimary Co
32、mposite of time to doubling of sCr/ESRDEndpoint:Randomization:Losartan 100 mg/day+AHT*as neededTrandolapril 3 mg/day+AHT*as neededDuration:3 yrsTarget BP:SBP 130 mmHgDBP 5 grams/day)DeZeeuw D et.al Kidney Int.,1989,Mishra SI et.al,Curr Hypertens Rep,20052006.American College of Physicians.All Rights
33、 Reserved.Take Home Points CKD is very common;patients have endothelial dysfunction,and die from cardiovascular disease.Hypertension occurs in a large proportion of CKD patients.Hypertension causes progression of CKD,and reduction in BP to 125/75 slows progression optimally.Angiotensin blockade slows progression of CKD independent from BP effects.Moderate hyperkalemia or mild increases in creatinine should not stop use of the medications.Early Treatment Makes a DifferenceBrenner,et al.,2001
