Management of hypertension in CKD

Hypertension is an important cause of ESRD Hypertension is common in patients with CKD and accelerate the progression of renal failure Key Question Can effective antihypertensive therapy prevent the development of ESRD and retard the progression of CKD ?

Age and change of renal function Prevalence of low GFR <60 ml/mkn/1.73㎡,%> Prevalence of decreased kidney function (GFR < 60 mL/min/1.73 m2 ) in the overall noninstitutionalized US population, as well as by history of diabetes and presence of hypertension: NHANES III, 1988 to 1994. overall diabetes hypertension no DM and no HT

Three major causes of ESRD

loss of nephrons Renal disease Progressive decline in GFR Systemic hypertension Proteinuria

CKD: Common pathway in disease progression RENAL INJURY Nephron mass Glomerular capillary hypertension Glomerular permeability to macromolecules Filtration of plasma proteins  Proteinuria Excessive tubular protein reabsorbtion Tubulo-interstitial inflammation SYSTEMIC HYPERTENSION RENAL SCARRING

MAJOR RISK FACTORS FOR CARDIOVASCULAR DISEASE OBESITY DIABETES CHRONIC KIDNEY DISEASE PHYSICAL INACTIVITY AGE > 55 IN MEN, > 65 IN WOMEN HYPERTENSION HYPERLIPIDEMIA SMOKING FAMILY HISTORY

Why are CKD/ESRD Patients Predisposed to CV Disease? ANEMIA LVH/CHF LIPIDS HTN INFLAMMATION plus CaP deposition CV DISEASE AND DEATH CAD and PVD

Why 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 normal 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.

Miettinen H et al, Stroke 27:2033, 1996 Microalbuminuria and proteinuria as a risk factor for CAD and CVA – marker of endovascular health Miettinen H et al, Stroke 27:2033, 1996

Prevalence of HTN in CKD 80% of patients with glomerulonephritis and 30% of patients with chronic interstitial disease are hypertensive.

Hypertension and renal function % 90 80 normal 70 hypertension 60 50 40 30 20 10 stage 1 stage 2 stage 3 stage 4 1 0.9 0.8 0.7 0.6 Probability of HT 0.5 0.4 0.3 0.2 0.1 stage 1 stage 2 stage 3 stage 4

How important is systemic blood pressure control? Relative risk of ESRD according to quintile BP MRFIT study N= 332,544 men

Hypertension in CKD Pathophysiology thought to be both pressor- and volume-related, thus CKD patients respond to both 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 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 efferent artery vasoconstriction (angiotensin II) Increased afferent artery dilation (protein loads, calcium channel blockers)

A II Angiotensin II plays a central role in organ damage Atherosclerosis* Vasoconstriction Vascular hypertrophy Endothelial dysfunction Stroke Hypertension A II LV hypertrophy Fibrosis Remodeling Apoptosis Heart Failure MI Death GFR Proteinuria Aldosterone release Glomerular sclerosis Renal Failure *Preclinical data. LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate.

Non-ACE pathways (eg, chymase) Renin Angiotensin Aldosterone System Non-ACE pathways (eg, chymase) Vasoconstriction Cell growth Na/H2O retention Sympathetic activation Angiotensinogen AT1 Renin Angiotensin I Angiotensin II ACE Aldosterone AT2 Cough, angioedema Benefits? Vasodilation Antiproliferation (kinins) Inactive fragments  Bradykinin

Angiotensin II Effects on Glomerular Capillary Pressure PGC AA EA A II

Angiotensin II Causes Glomerular Hypertension PGC AA EA A II

How does blood pressure relate to progression of CKD? PGC AA EA BP In a sick kidney, increased glomerular capillary pressure (GLOMERULAR HYPERTENSION) causes progression of the CKD (increased fibrosis)

PGC  Injury to Glomerular cells  Proteinuria Angiotensin II and CKD Angiotensin II PGC  Injury to Glomerular cells  Proteinuria O2. and TGF-  Scarring/Fibrosis

Angiotensin II One of the most potent vasoconstrictors – critical in maintenance of blood pressure Renal actions Increased sodium reabsorption Increased GFR by increasing glomerular capillary pressure

A II Blockade – Experimental data with diabetic rats at 70 weeks ACE Inh/ARB  AII  BP  Proteinuria/Renal Disease Anderson S et al, Kidney Int 36:526, 1989 Glomerular Pressure 40s 64 46 56

Goals of Treatment of HTN in CKD To preserve renal function: maintain GFR and reduce proteinuria To reduce CV morbidity and mortality :most clinical trials in past have excluded patients with CKD

What should be the treatment goal? Treatment goal for hypertension in the general population has remained relatively the same for the last decade. Guidelines BP target British Hypertension Society (2004) < 140/85 JNC VII (2003) <140/90

(JNC 7, K/DOQI) <125/75 mmHg Target Blood Pressure For Individuals With: BP Goal: Hypertension (no diabetes or renal disease) <140/90 mmHg (JNC 7) <130/80 mmHg (ADA, JNC 7) Diabetes Mellitus Renal Disease with proteinuria >1 gram/24 hours or diabetic kidney disease <130/80 mmHg (JNC 7, K/DOQI) <125/75 mmHg (NKF) Clinical trials have convincingly demonstrated that aggressive treatment of hypertension can reduce the risk of cardiovascular disease and associated morbidity and mortality. BP goals are set lower as renal impairment becomes increasingly more severe. It is recommended in JNC 7 that hypertension be managed by achieving and maintaining SBP below 140 mmHg and DBP below 90 mmHg and lower if tolerated.1 For diabetes mellitus, the American Diabetes Association and JNC 7 recommends goals of <130 mmHg for SBP and <80 mmHg for DBP.2 For chronic kidney disease without proteinuria, the National Kidney Foundation recommends maintaining SBP below 135 mmHg and DBP below 85 mmHg. With proteinuria or diabetic kidney disease, their recommendation drops to <125 mmHg for SBP and <75 mmHg for DBP.3 1. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA. 2003;289:2560–2571. 2. American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care. 2002;25:199–201. 3. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidn Dis. 2002;39(suppl 1):S1–S266. Chobanian AV et al. JAMA. 2003;289:2560–2571. American Diabetes Association. Diabetes Care. 2002;25:134–147. National Kidney Foundatrion. Am J Kid Dis. 2002;39(suppl 1):S1–S266.

What should be the treatment goal for renal disease? Should be lower than the general population Should be tailored according to : the severity of renal failure the severity of the proteinuria

Klahr S et al, N Engl J Med 330:877, 1994 Aggressive 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 BP<125/75 if >1 gm proteinuria

Steps to Reduce Renal Disease Steps every clinician should take to reduce the incidence and/or progression of CKD Aggressive BP reduction Use of agents that interfere with the RAAS Hypertension not only plays an important role in the development and progression of renal damage, as seen in diabetes, but is a major risk factor for the increased cardiovascular morbidity and mortality seen in these patients.1 Inhibiting the RAAS plays an essential role in the treatment of hypertension and diabetes-related complications.1 For this reason, the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) acknowledges that hypertension with chronic kidney disease is a high-risk condition with a compelling indication for the use of an ACEI or an ARB.2   1. Deferrari G, Ravera M, Deferrari L, Vettoretti S, Ratto E, Parodi D. Renal and cardiovascular protection in type 2 diabetes mellitus: angiotensin II receptor blockers. J Am Soc Nephrol. 2002;13(suppl 3):S224–S229. 2. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA. 2003;289:2560–2571.

BP control, GFR decline and proteinuria Intense BP control An initial reduction in proteinuria of 1.0 g/d  slower mean decrease in GFR by 0.92 ± 0.31 mL/min·y, GFR 25-55 by 1.32 ± 0.46 mL/min·y, GFR 15-24

Progression of CKD and BP

REIN follow-up trial chronic nephropathy and proteinuria>3g/day 45 Continued ramipril Switched to ramipril -0.44ml/min per month 2 40 -0.10ml/min per month GFR decline (mL/min/1.73m /month) 35 -0.81ml/min per month 30 -0.14ml/min per month 25 Core study Follow-up trial Ruggenenti et al. Lancet 1998;352:1252-1256.

AASK: ACEI vs CCB in Hypertensive Renal Disease CCB arm terminated prematurely because ACEI and beta blocker demonstrated clear superiority GFR Event, ESRD, or Death 25 P = 0.005 20 15 Amlodipine Cumulative Incidence, % 10 Ramipril 5 3 12 24 36 Months Agodoa LY et al. JAMA. 2001;285:2719–2728.

End-organ damage and mortality in general population Cardiovascular mortality Non-cardiovascular mortality Adjusted effect of UAC on hazard function. Solid line shows estimated relation when logarithmic hazard is modeled as linear function of log(UAC). Dotted lines are 95% confidence limits for more general functional relation, as estimated by P-splines. Hatched area represents upper and lower limit of current definition of microalbuminuria (20 to 200 mg/L). Hans L. Hillege, et al., Circulation, 2002, 106:1777

Lewis EJ et al , New Engl J Med 329:1456-62, 1993 The Effect of Angiotensin-Converting Enzyme Inhibition on Diabetic Nephropathy 409 Type I diabetics ages 18-49 with nephropathy (U protein>500 mg and S Cr <2.5) Prospective, double-blinded multicenter (30) trial randomized to captopril vs. placebo for 3 years Lewis EJ et al , New Engl J Med 329:1456-62, 1993

ACE Inhibition and Type I DM Nephropathy If S Cr > 1.5 mg/dl: Captopril reduced doubling of S Cr by 48% over 4 years. Captopril reduced ESRD(dialysis or transplant) or death by 50% over 4 years. 3) These effects were independent of effects on blood pressure. Lewis EJ et al, New Engl J Med 329:1456, 1993

Brenner BM et al, New Engl J Med 345:861-869, 2001 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, randomized, double-blinded multicenter (250) trial Two arms – Losartan (50-100 mg) to keep BP<140/90 vs. placebo for 3.4 years Brenner BM et al, New Engl J Med 345:861-869, 2001

RENAAL – ARB Reduction of Renal Failure 16% 25% 28% 20% Brenner BM et al, N Eng J Med 345:861, 2001

Irbesarten Diabetic Nephropathy Trial (IDNT) 1715 Type II diabetics with hypertension (BP >135/85) 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 placebo Lewis EJ et al, New Engl J Med 345:851, 2001

IDNT – ARB Reduction of Renal Failure 23% 20% 33% Lewis EJ et al, N Eng J Med 345:851, 2001

ARB Effects of Type II DM Nephropathy - RENAAL and IDNT Endpoints RENAAL IDNT Composite 16% 20% S Cr Doubling 25% 33% ESRD 28% 23%

ACE Inhibitors and CKD Progression Meta-analysis -Jafar T, Ann Intern Med 135:73-87, 2001 11 randomized controlled 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 development of ESRD by 30% independent of BP lowering effects.

Proportion of Patients With First Event, % LIFE: Primary Composite Endpoint 2 4 6 8 10 12 14 16 Intent-to-Treat There was no significant difference in BP between groups at all time points Atenolol Losartan Proportion of Patients With First Event, % Adjusted Risk Reduction 13.0%, P = 0.021 Unadjusted Risk Reduction 14.6%, P = 0.009 6 12 18 24 30 36 42 48 54 60 66 Months Dahlöf B et al. Lancet. 2002;359:995–1003.

Patients; non-diabetic patients affected by proteinuric renal disease MAP > 98 mmHg Treatment; telmisartan 80mg, once daily Systolic BP change 135 ± 11 to 122 ± 13 mmHg Diastolic BP change 84.4 ± 8.1 to 75.9 ± 8.5 mmHg mean BP 101 ± 8 to 91 ± 9 mmHg Proteinuria 1.60 ± 0.90 to 1.06 ± 0.63 g/24 h Cupisti A et al., Biomed Pharmacother, 2003, 57:169

What is the evidence that combining an ACEI and an ARB will have additive benefits?

COOPERATE: Study Design Design: Randomized, double-blind trial in 263 patients with non-diabetic renal disease Primary Composite of time to doubling of sCr/ESRD Endpoint: Randomization: Losartan 100 mg/day + AHT* as needed Trandolapril 3 mg/day + AHT* as needed Duration: 3 yrs Target BP: SBP <130 mmHg DBP <80 mmHg *Antihypertensive therapy (excluding other ACEIs or other ARBs). Nakao N et al. Lancet. 2003;361:117–124.

Proportion Reaching Endpoint, % Doubling of Serum Creatinine or Progression to ESRD 30 Trandolapril Losartan Combination 25 20 Proportion Reaching Endpoint, % 15 10 5 P = 0.02 5 12 18 24 30 36 Months after Randomization Number at Risk Losartan 89 88 84 79 65 59 47 Trandolapril 86 85 83 75 72 63 58 Combination 88 87 86 83 76 73 67 Nakao N et al. Lancet. 2003;361:117–124.

Additive antiproteinuric effect of ACEI and ARB in patients with IgA nephropathy Russo, et al., Am J Kid Dis, 1999, 33

Hypertension and CKD: summary Most patients with CKD have hypertension Lowering BP (<130/80) important for reducing CV and renal risk: Lower targets for proteinuric patients Angiotensin blockade slows progression of CKD independent from BP effects. ACEI/ARBs first line therapy Diuretics/Na restriction often necessary > 2 drugs are often needed Blood pressure response as well as proteinuria should be monitored

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