Hypertension and the Kidney

Transcript

1 ก ก ก ก ก ก 2549 Hypertension and the Kidney ก 1

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3 Content 1. ก ก 5 2. ก ก 6 3. ก ก ก ก ก 8 5. ก ก ก Kidney as a cause of hypertension 12 ก ก 7. Hypertension as a Cause of Kidney Disease 14 ก 8. Hypkalemia A Clue for Secondary Hypertension Diuretic Therapy in Hypertension Target Organs Damage in Hypertensive Patients and Role of New Generation Calcium 23 Channel Blocker ก 11. Target organ protection of Newer CCB 24 ก ก 12. Medical Treatment for Renovascular Disease 26 ก ก 13. Renal arterial Disease: Renal stenting Nonpharmacologic Treatment of Hypertension in CKD 33 ก 15. Angiotensin Converting Enzyme Inhibitors (ACEIs) versus 38 Angiotensin Receptor Blockers (ARBs) in Chronic Kidney Disease ก ก 165. Hypertension in Hemodialysis Exhibition List Other sponsors 46 3

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7 ก ก ก ก 2549 ก ก ก ก ก ก ก ก ก ก ก ก ก ก Hypertension and The Kidney ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก 7

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10 ก ก ก 2549 Hypertension and The Kidney ก Breakfast Symposium by Pfizer (Thailand) Ballroom 2 Holistic Approach in Hypertension Patients at Risk ก ก Moderator ก ก ก Ballroom 3 ก ก ก Kidney as a Cause of Hypertension Ballroom 3 ก ก Hypertension as a Cause of Kidney Disease Ballroom 3 ก Moderator ก ก ก Coffee Break and Visit Exhibition Hypokalemia: a Clue for Secondary Hypertension Ballroom Diuretic Therapy in Hypertension Ballroom 3 Moderator Luncheon symposium by Solvay Pharma (Thailand) Co,.Ltd Ballroom 2 Target Organs Damage in Hypertensive Patients and Role of New Generation Calcium Channel Blockers ก ก ก Moderator

11 Debate: Medical vs Interventional Treatment for Renovascular Disease Ballroom 3 ก ก Moderator ก Symposium Management of Hypertension in Chronic Kidney Disease Patients Non-Pharmacologic Treatment Ballroom 3 ก Angiotensin Converting Enzyme Inhibitors Versus Angiotensin Receptor Blockers ก ก Hypertension in hemodialysis Moderator ก ก ก 1600 Coffee Break and Visit Exhibition 11

12 Kidney as a cause of hypertension Surasak Kantachuvesiri,MD Ramathibodi Hospital Essential hypertension afflicts 15%-20% of the human population (James and Baker, 1990). The regulation of blood pressure involves a number of physiological systems, such as nervous, endocrine, and cardiorenal systems. Each of these systems and processes is known or hypothesized to be influenced by a variety of genetic and environmental factors (Ward, 1990). The kidney plays a major role in regulation of extracellular fluid volume and composition. Sustained alterations of blood pressure require resetting of renal mechanisms maintaining salt-water balance (Guyton, 1991). Epidemiolgic studies showed the association of high salt intake with hypertension (Luke, 1993) suggesting the importance of renal sodium handling and blood pressure regulation. In addition, the remission of hypertension after renal transplantation has been reported (Curtis et al., 1983). The findings of normal body sodium, plasma volume and extracellular fluid volume in established essential hypertensives are found with an observed right shift and resetting of the pressure-natriuresis curve (Brown et al., 1974). These alterations in renal hemodynamics and the renal rennin-angiotensin system were postulated to be central to inducing hypertension (Ruilope et al., 1994). Other authors have argued that the primary renal abnormality initiating essential hypertension is a congenital reduction in filtration surface area leading to a limited capacity to excrete a sodium load (Brenner and Anderson, 1992). Reduced nephron number either congenital or acquired arising from disease or surgery will often give rise to systemic hypertension. In support of this, acquired kidney diseases either renal parenchymatous disease or renovascular disease are found to be the most common causes of hypertension in the young patients. Monogenic disorders causing blood pressure variation in man reported so far has been attributed to the abnormality of renal sodium excretory function. Genetic diseases resulting to renal sodium retention and hypertension include glucocorticoid remediable aldosteronism (GRA), Liddle s syndrome, Apparent mineralocorticoid excess (AME) syndrome. In addition to these monogenic forms of hypertension, the genetic basis of familial hypokalemic alkalosis with low blood pressure has been elucidated. Mutations in genes encoding the thiazide-sensitive Na-Cl cotransporter (NCCT) in distal convoluted tubules result in Gitelman s syndrome, which includes hypocalciuria, hypomagnesemia, and typically clinical presentation with predominant muscular signs and symptoms as a result of hypokalemia (Simon et al., 1996). Another disease called Bartter s syndrome, an autosomal recessive disorder characterized by hypokalemic alkalosis, salt wasting and hypotension, is differentiated from Gitelman s syndrome by the presence of hypercalciuria, normomagnesemia and a neonatal, more severe presentation. Molecular genetic approaches demonstrated the heterogeneous genetic basis of disease. Mutation in three different genes (all expressed in the thick ascending limb (TAL) of Henle s loop and involved in NaCl reabsorption) have been identified including genes encoding bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) (Simon et al., 1996), apical ATP-sensitive K + channel (ROMK) (Simon et al., 1996), and renal chloride channel in the basolateral membrane (CLCNKB) (Simon et al., 1997). These mutations impair sodium chloride reabsorption in the TAL, thereby producing salt wasting, hypovolemia, and activation of the renin-angiotensin-aldosterone system. 12

13 References 1. Brenner, B. M., and Anderson, S. (1992). The interrelationships among filtration surface area, blood pressure, and chronic renal disease. J Cardiovasc Pharmacol 19(Suppl 6), S1-S7. 2. Brown, J. J., Lever, A. F., Robertson, J. I. S., and Schalekamp, M. A. (1974). Renal abnormality of essential hypertension. Lancet 1, Curtis, J. J., Luke, R. G., Dustan, H. P., Kashgarian, M., Whelchel, J. D., Jones, P., and Diethelm, A. G. (1983). Remission of essential hypertension after renal transplantation. N Eng J Med 308, Guyton, A. C. (1991). Blood pressure control-special role of the kidneys and body fluids. Sciences 252, James, G. D., and Baker, P. T. (1990). Human population biology and hypertension, J. H. Laragh and B. M. Brenner, eds. (New York, NY: Raven Press publishers). 6. Luke, R. G. (1993). Essential hypertension: a renal disease? Hypertension 21, Ruilope, L. M., Lahera, V., Rodicio, J. L., and Romero, J. C. (1994). Are renal hemodynamics a key factor in the development and maintenance of arterial hypertension in humans? Hypertension 23, Simon, D. B., Bindra, R. S., Mansfield, T. A., NelsonWilliams, C., Mendonca, E., Stone, R., Schurman, S., Nayir, A., Alpay, H., Bakkaloglu, A., RodriguezSoriano, J., Morales, J. M., Sanjad, S. A., Taylor, C. M., Pilz, D., Brem, A., Trachtman, H., Griswold, W., Richard, G. A., John, E., and Lifton, R. P. (1997). Mutations in the chloride channel gene, CLCNKB, cause Bartter s syndrome type III. Nature Genet 17, Simon, D. B., Karet, F. E., Hamdan, J. M., DiPietro, A., Sanjad, S. A., and Lifton, R. P. (1996). Bartter s syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nature Genet 13, Simon, D. B., Karet, F. E., RodriguezSoriano, J., Hamdan, J. H., DiPietro, A., Trachtman, H., Sanjad, S. A., and Lifton, R. P. (1996). Genetic heterogeneity of Bartter s syndrome revealed by mutations in the K+ channel, ROMK. Nature Genet 14, Simon, D. B., NelsonWilliams, C., Bia, M. J., Ellison, D., Karet, F. E., Molina, A. M., Vaara, I., Iwata, F., Cushner, H. M., Koolen, M., Gainza, F. J., Gitelman, H. J., and Lifton, R. P. (1996). Gitelman s variant of Bartter s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nature Genet 12,

14 Hypertension as a Cause of Kidney Disease ก ก ก ก ก ก ก ก. ก ก ก ก ก 25% ก กก 35 ก ก 30% ก 40% ก ก ,736 ก ก dialysis ก กก 25% ก กก ก ก ก ก ก ก ก ก ก ก 10 ก กก 50 ก ก ก ก ก ก ก ก ก (granular surface) ก ก arteriosclerosis, arteriololsclerosis, glomerulosclerosis interstitial fibrosis ก ก ก nephrosclerosis benign malignant ก ก arterioles ก hyalinization intima media ก ก benign nephrosclerosis ก ก intima media fibrinoid necrosis ก ก malignant nephrosclerosis benign ก ก benign ก ก กก ก nephrosclerosis ก 2 ก ก ก intima media arterioles lumen ก nephron ก ก ก nephron ก nephron arteriolosclerosis ก ก nephron ก ก hyperfiltration ก glomeruli กก protein barrier glomeruli proteinuria ก ก ก renal tubules interstitium protein load ก ก ก ก ก ก ก ก ก ก nephron ก ก ก nephron ก ก ก ก ก ก hyperfiltration กก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก DOQI Guidelines AJKD 2004;43 (supple 1):s

15 Hypkalemia A Clue for Secondary Hypertension,. (secondary hypertension) ก ก ก ก ก ก ก ก ก ก ก (target organ damage) ก ก (hypokalemia) secondary hypertension ก ก (pathophysiology) ก (renal potassium excretion) ก ก ก (collecting tubules) ก principal cell ก ก ก luminal fluid K channel apical border ก K channel ก ก ก luminal fluid epithelial sodium (Na) channel (ENaC) ก mineralocorticoids (aldosterone, deoxycorticosterone) ก ก ก principal cell ก mineralocorticoid receptor (MR) ก ก ก ก ก ก ก ก (metabolic alkalosis) ก ก (H + ) ก ก ก 1) ก principal cell ก 2) mineralocorticoid activity ก ก ก ก ก (genetic) ก (acquired) ก ก ก ก ก ก ก ก plasma aldosterone level, plasma renin activity (PRA), ratio plasma aldosterone plasma renin, plasma urine cortisol 1 ก (hypertension with hypokalemia) ก ก ก ก (essential hypertension) thiazide ก secondary aldosteronism ก primary hyperaldosteronism ก ก adrenal adenoma ( Conn s syndrome ), Cushing s syndrome endogenous ก ก glucocorticoids, ก renal artery stenosis (renovascular hypertension) 15

16 1. ก ก ก (hypertension with hypokalemia) ก Plasma aldosterone Normal Plasma renin activity Normal Plasma cortisol Normal Normal Normal mineralocorticoid activity ก ก mineralocorticoid ก ก ก กก ก ก ก ก ก ก mineralocorticoid ก ก ก principal cell ก ก ก กก ก mineralocorticoid ก volume expansion ก ก ก ก ก ก ก ก ก ก 80 primary hyperaldosteronism ก ก ก ก ก ก Glucocorticoid-remediable aldosteronism (GRA) glucocorticoid-suppressible hyperaldosteronism ก ก low-renin severe hypertension ก ก autosomal dominant variable penetrance ก ก plasma aldosterone ก ก ก ก ACTH ก angiotensin II ก ก ก glucocorticoid dexamethasone ก ก ACTH ก aldosterone ก ก ก ก ก GRA ก 18-hydroxycortisol 18-oxocortisol ก ก ก ก ก GRA ก chimeric gene ก ก ACTH promotor 11-β-hydroxylase (CYP11B1) (unequal crossing over) promotor region aldosterone synthase (18-β-hydroxylase) (CYP11B2) ก ( 8) ก ก chimeric gene Southern blotting long polymerase chain reaction (PCR) screening test prenatal diagnosis secondary hyperaldosteronism กก ก ( renal artery stenosis renovascular hypertension) ก ก ก renin ก ก (renin-producing tumors) ก ก hemangiopericytomas benign juxtaglomerular apparatus ก renin ก ก 16 Disorders Primary aldosteronism, Glucocorticoidremediable aldosteronism (GRA) Renovascular HT, Renin-producing tumors, Malignant hypertension Liddle s syndrome Apparent mineralocorticoid excess (AME) Cushing s syndrome (all types)

17 ก ก ก mineralocorticoid aldosterone ก ก ก plasma aldosterone plasma renin activity 11-β-hydroxysteroid dehydrogenase (11-β-HSD deficiency) congenital acquired mineralocorticoid activity ก 11-β-HSD cortisol cortisone ก mineralocorticoid receptor (MR) 11-β-HSD cortisol ก mineralocorticoid ก MR primary aldosteronism plasma aldosterone ก (liquorice) carbenoxolone mineralocorticoid activity ก 11-β-HSD ก ก ก apparent mineralocorticoid excess (AME) syndrome ก ก mutation ก 11-β-HSD ก ก autosomal recessive ก ก low-renin, lowaldosterone hypertension, hypokalemia, metabolic alkalosis ก urine free cortisol metabolite cortisol (tetrahydrocortisol) ก urine free cortisone metabolite cortisone (tetrahydrocortisone) ก AME ก ก spironolactone aldosterone ก ก ก ก Liddle s syndrome Liddle ก ก ก early-onset severe hypertension, hypokalemia, metabolic alkalosis plasma renin plasma aldosterone ก ก triamterene ก ก spironolactone aldosterone receptor antagonist ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก autosomal dominant ก ก ก Liddle s syndrome amiloride-sensitive ENaC apical membrane (luminal border) principal cells ก ENaC ก α-, β-, γ-subunits Liddle s syndrome mutations ก β- γ- subunits ENaC 16 ก ก ENaC apical membrane principal cells ก ENaC ก ก ก ก ก saltdependent hypertension ก ก ก ก ก renin aldosterone ก ก ก ก ก ก activating mutation mineralocorticoid receptor plasma renin activity aldosterone adrenogenital syndromes ก ก desoxycorticosterone ก cortisol ก ก 17-α-hydroxylase 25 ก 11-β-hydroxylase familial glucocorticoid resistance กก mutations glucocorticoid receptor cortisol ก stroids ก mineralocorticoid activity glucocorticoid ก (glucocorticoid excess) 1 3 Cushing s syndrome ectopic ACTH production glucocorticoid ก GFR ก ก ก principal cell ก ก ก cortisol ก ก mineralocorticoid receptor 17

18 Diuretic Therapy in Hypertension ก 1. ก ก Global Burden of Disease Study ก (cardiovascular disease, CVD) (..2020) 2 ก (..1990) 1 ก ก ก CVD ก ก 2 1) (unhealthy diet) 2) ก กก ก (physical inactivity) 3) 4) glucose intolerance 5) hyperlipidemia 6) (hypertension, HT) ก ก ก ก HT ก 1,000 essential HT ก ก (mean survival) 20 ก ก ก CVD ก กก ก diuretics ก ก HT ก ก Na + ก ก HT 4 ( 1) HT ก ก ก Na + ก ก ก HT ก Na + Diuretics ก ก ก Na + ( 2) ก Na + ก ก ก 5 HT ก ก diuretics ก ก HT ก thiazides, loop diuretics, K-sparing diuretics thiazide ก ก HT กก loop diuretics ก Na + ก loop diuretics (furosemide bumetamide) ก ก thiazide (6 ก 12 ก torasemide loop diuretic ก ) ก กก Na + ก renninangiotensin-aldosterone system (RAAS) ก Na + ก ก HT thiazides ก ก vasodilatation vascular resistance ก ก ก ก 1) thiazides ก ก digitalis-like natriuretic hormone cellular Na-K-ATPase pump Na + Ca 2+ ก ก ก ก 2) thiazides ก K + channel K + -sparing diuretics triamterene amiloride ก HT aldosterone antagonists ก spironolactone eplerenone ก cardiac renal fibrosis 18

19 1 ก ก Na + ก ก 4 2 ก Na + 3. ก ก ก ก diuretics ก ก HT ก thiazides ก hydrochlorothiazide (HCTZ) ก ก ก ก ก HT ก Veterans Administration Cooperative (VA Coop) Trials 7,8 ก HCTZ ก 50 ก./ CVD HT diastolic blood pressure (DBP) ก ก Multiple Risk Factor Intervention Trial 9 ก chlorthalidone ( long acting thiazides) 50 ก. CVD ก HCTZ 100 ก. chlorthalidone ก ก diuretics ก ก ก HT ก ก ก ก HT ก β-blocker, α-blocker, calcium channel blocker (CCB), angiotensin converting enzyme inhibitor (ACEI) angiotensin receptor blocker (ARB) 19

20 ก ก meta-analysis ก ก ก placebo-controlled trial ก chlorthalidone non-chlorthalidone thiazides ก ก HT ก ก ก thiazides ก class effect 10 ก ก meta-analysis ก Blood Pressure Lowering Treatment Trialists Collaboration ก diuretics b blocker ก ก ACEI CCB HT ก 75,000 ก ก ก stroke, coronary heart disease (CHD), heart failure (HF), CVD death all-cause mortality ก ก ก Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) 12 Second Australian National Blood Pressure Study (ANBP2) 13 HT กก 45, /84. ก ก ALLHAT ก HT diuretics) 3 ก 1) chlorthalidone 2) ACEI (lisinopril) 3) CCB (amlodipine) 4) α blocker (doxazosin) ก ก กก ก ก doxazosin ก ก ก ก CHF ก CHD mortality ก ก ก primary endpoint fatal nonfatal CHD ก secondary endpoint ก ก ก ก stroke ก ACEI ก ก CHF ก ACEI CCB ก ก 2 ก ก diuretics diuretics 2 ก ก ก chlorthalidone ก ก ก ก ก ANBP2 13 HT 6,083 ก CVD ก ALLHAT ACEI HCTZ 5 ก ก HT 2 ก ACEI ก ก CVD ( ก ก ) ก all-cause mortality ก ก HF ก Blood Pressure Lowing Treatment Trialists Collaboration ก ก metaanalysis 29 ก ก ก กก 700,000 ก 4. ก ก diuretics ก ก HT diuretics ก ก HT ก ก metabolic กก diuretics ก ก dyslipidemia, hypokalemia, hyperuricemia impaired glucose metabolism, new-onset diabetes (NOD) CVD ก thiazide ก ก sudden cardiac death ก ก thiazide ก ก thiazide chlorthalidone 6.25 ก ก. ก 25 ก./ HCTZ 12.5 ก. 25 ก. ก 50 ก./ ก thiazide ก ก ก sexual dysfunction, ก ( ก ) 5. diuretics conventional thiazide ก ก HT กก ก ก (gluideline) 5.1 essential hypertension JNC 7 18 (2003) diuretics thiazide ก (first choice) HT ก European Society of Hypertension (2003) 19 ก HT กก ( ก α blocker) thiazide ก (one of the first choices) WHO/ISH (2003) 20 diuretics 20

21 ก isolated systolic hypertension British Hypertension Society (2004) 21 diuretics ACEI ARB ก 5.2 HT with compelling indications ก HT ก ก HT ก HT ก 6. diuretics ก ก HT 6.1 Indapamide 23 thiazide 2-methyl indoline ring lipophilic indapamide ก natriuresis ก ก kaliuresis ก hypokalemia ก ก indapamide ก ก end-organ, sympathetic nerve activation, voltage-operated Ca 2+ channels, ก ก prostacyclin ก indapamide sustained release (SR) HT ก ก candesartan (8 ก.) amlodipine (5 ก.) (The X-CELLENT main study 24, The X-CELLENT ISH subset) LVH กก enalapril (The LIVE study) 25, microalbuminuria type II diabetes ก enalapril (The NESTOR study) 26 indapamide SR metabolic 6.2 Metalozone thiazides ก ก ก distal convoluted tubule ก proximal tubule metolazone 6.3 Torasemide loop diuretics ก ก 12 ก ก HT tarasemide ก 1. Yusuf S, Reddy S, Ounpuu S, et al. Global burden of cardiovascular diseases. Part 1: General considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation 2001; 104: World Health Organization. The Word Health Report 2002: Risks to Health Geneva. World Health Organization. 3. Perera G. Hypertensive vascular disease. J Chornic Dis 1955; 1: Blumenfeld JD, Laragh JH. Essential hypertension. In The Kidney, Brenner BM, editor. Chapter 45. Seventh edition. Philadelphia, USA. Saunders 2004: pp Kaplan NM, Rose BD. Thiazide versus loop diuretics in treatment of hypertension. Up To Date 2006 version Kaplan NM, Rose BD. Mechanism of antihypertensive effect of diuretics. Up To Date 2006 version Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. JAMA 1967; 202:

22 8. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. JAMA 1970; 213: Multiple Risk Factor Intervention Trial Research Group: Mortality after 10 years for hypertensive partici pants in the Multiple Risk Factor Intervention Trial Circulation 1990; 82: Psaty BM, Lumley T, Furberg CD. Meta-analysis of health outcomes of chlorthalidone-based vs nonchlorthalidone-based low-dose diuretic therapies. JAMA 292; 2004: Blood Pressure Lowering Treatment Trialists Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively designed overviews of randomized trials. Lancet 2000; 356: ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: Wing LM, Reid CM, Ryan P, et al. A comparison of outcomes with angiotesin-converting enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003; 348: Blood Pressure Lowering Treatment Trialists Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomized trials. Lancet 2003; 362: Dobbie H, Capasso, Unwin R. Diuretics and b blockers. In Therapy in Nephrology and Hypertension. Brady HR, Wilcox CS, editors. Chapter 54. Second edition. London Saunders 2003: pp Salvetti A, Ghiadoni L. Thiazide diuretics in the treatment of hypertension: An update. J Am Soc Nephrol 2006; 17: S25-S Kaplan NM, Rose BD. Thiazide dosage in essential hypertension. Up To Date 2006 version Chobaman 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: Guidelines Commttee 2003 European Society of Hypertension-European Society of Cardiology Guidelines for the management of arterial hypertension. J Hypertens 2003; 21: World Health Organization, International Society of Hypetension Writing Group 2003 WHO/ISH statement on management of hypertension. J Hypertens 2003; 21: William B, Poulter NR, Brown MJ, et al. British Hypertension Society guidelines for hypertension management 2004 (BHS-IV): summary. BMJ 2004; 328: Nolan CR. The patient with hypertension. In. Manual of Nephrology Schrier RW, editor. Sixth edition. Philadelphia. Lippincott Williams & Wilkins 2005: pp Sassard J, Bataillard A, McIntyre H. An overview the pharmacology and clinical efficacy of indapamide sustained release. Fund Clin Pharmacol 2005; 19: London G, Schmieder R, Calvo C, et al. Indapamide SR versus Candesartan and Amlodipine in Hypertension: The X-CELLENT Study. Am J Hypertens 2006; 19: Gosse P, Sheridan DJ, Zannad F, et al. Regression of Left ventricular hypertrophy. In hypertensive patients treated with indapamide SR 1.5 Versus Enalapril 20 : the LIVE study. J Hypertens 2000; 18: Marre M, Garcia-Puig J, Kokot F, et al. Equivalence of indapamine SR and enalapril on microalbuminuria reduction hypertensive patients with type 2 diabetic : the NESTOR study. J Hypertens 2004; 22:

23 Target Organs Damage in Hypertensive Patients and Role of New Generation Calcium Channel Blocker Sarana Boonbaichaiyapruck,MD Division of Cardiology Ramathibodi Hospital Calcium channel blockers are an important component of hypertension treatment. Introduced in the 1960s, Dihydropyridines calcium channel blockers have been among the most widely used drugs for the management of cardiovascular disease. The first-generation agents (e.g., nifedipine) have proven efficacy in correcting hypertension. However, because of their short duration and rapid onset of vasodilator action, these drugs were associated with adverse effects especially ankle edema that later limited their use. By design, the slow-release preparation of the short-acting calcium channel blockers became the second generation agents (e.g., nifedipine GITS, felodipine SR) and that allowed better control of the therapeutic effect with reduction in some adverse effects. Pharmacodynamic innovation with regard to the dihydropyridines began with the third-generation agents (amlodipine, nitrendipine) with a long duration of action related to prolonged plasma half-life. The fourth generation dihydropyridines are now available (e.g., lercanidipine, lacidipine). This new type, possess a chemical structure that allows the molecule to be held in the cell membrane in order to block the calcium channel receptor. They smoothly and permanently reduce blood pressure over 24 h than other old dihydropyridines, a positive prognostic feature related to the end-organ damage of hypertension. This new class CCB also overall lower the incidence of side effects - ankle edema, flushing and headache compared to the older generations. They have been evidence in experimental and clinical settings that the drug reduce the progression of atherogenic lesions in blood vessels, pathology of which are related to cardiovascular complication of hypertension. Indeed, we have witnessed the evolution of CCB. The fourth generation drug is the new attractive alternative drug for treatment of hypertension, heart failure and angina pectoris. 23

24 Target organ protection of Newer CCB ก ก ก ก Hypertension is one of the most significant cardiovascular risk factor for coronary heart disease, stroke, chronic kidney disease and peripheral arterial disease. Optimal control of hypertension is the best way to prevent target organ damage secondary to uncontrolled HT. Untreated HT has resulted in increase of CAD mortality (50%), stroke (33%) and renal failure (10-15%). However, to achieve the target blood pressure (less than 140/90 mmhg for normal population, less than 130/85 mmhg for DM and 125/75 mmhg for chronic kidney disease), it needs not only the potent antihypertensive drugs but also a combination of drugs. Calcium channel blockers (CCB) are ones of the most popular and higher effective antihypertensive drugs. From the Syst-Eur (Systolic hypertension-europe) trial, nitrendipine therapy (10-40 mg/day) reduced the rate of cardiovascular complications (26% reduction) and CVA in patients older than 60 years old with isolated systolic HT. From Meta analysis by McMahon et al, The Blood Pressure Trialists group showed that CCB reduce major cardiovascular events by 28% and stroke by 39% when compared with placebo. ALLHAT (Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial) told us that in patients with HT, amlodipine, lisinopril and chlorthalidone all had similar effects on CAD deaths and nonfatal MI but CCB treatment had significantly lower non cardiovascular complications than the other 2 groups. From the HOT (Hypertension Optimal Trial), felodipine reduced major cardiovascular events by 51% in 1,501 patients with diabetes subgroup.the renal function test assessed by preservation of estimated GFR was better in the amlodipine group than chlorthalidone and lisinopril groups. However, angiotensin receptor blocker (ARB), valsartan was more effective than amlodipine in decreasing urine albumin excretion and re-establishing normal albuminuric status in type 2 DM with microalbuminuria irrespective of the decrease in blood pressure.jnc-7 guidelines recommended CCB for HT patients with compelling conditions such as high coronary disease risk and diabetes. Long acting CCB esp. dihydropiridines (DHDP) are preferred than short acting ones because it can control blood pressure at peak and trough period. There are 3 groups of long-acting dihydropiridines including firstly; nifedipine in a long-acting gastrointestinal transport system (GITS), secondly; dihydropiridines with long plasma half life (amlodipine and felodipine) and thirdly; those with strong membrane binding and slow release to calcium channel (lacidipine and lercanidipine) 24

25 The newer long-acting third to fourth-generation DHDP CCBs, lercanidipine significantly inhibit angiotensin I-mediated protein kinases c (PKC) -alpha and delta in vivo and vitro in a double-transgenic rat model with over expression of human rennin and angiotensinogen genes, so it prevents tissue injury and can prevent endothelial dysfunction and target organ damage. Lercanidipine has higher partition coefficient, lipophilic activity, high affinity to vascular cell membrane, high vascular selectivity and no negative inotropic activity. Lercanidipine has slower onset of action comparing with amlodipine and nifedipine (time to 90% maximal action; lercanidipine 99 min, amlodipine 60 min and nifedipine 11 min.). There were many studies to compare between the antihypertensive efficacy of lercanidipine and other antihypertensive drugs such as losartan, irbesartan, telmisartan, felodipine, nifedipine GTS, amlodipine and lacidipine. Most reports revealed the more potency of lercanidipine over other drugs. There was also a double-blind, randomized trial called COHORT trial, comparing the efficacy and tolerability of lercanidipine to amlodipine and lacidipine in 828 HT older patients (e 60 years old) in Italy. The efficacy is comparable in the 3 groups with 30 mmhg reduction of systolic blood pressure and 15 mm hg reduction of diastolic blood pressure.discontinuiation rate due to edema was highest in the amlodipine groups (9%) comparing with 2% of lercanidipine group and 1% of lacidipine group. Left ventricular hypertrophy regression in hypertensive patients was induced by lercanidipine at more degree than losartan and hydrochlorothiazide. In the DIAL study, the reduction of microalbuminuria more than 50% of baseline in diabetic patients with moderate HT was found more in the lercanidipine group than in the ramipril group. The newer CCB drugs, lercanidipine was one of the most effective antihypertensive drugs with less pedal edema and good tolerability when comparing with amlodipnine and lacidipine. It can be used as a monotherapy or combination therapy.it can also improve endothelial dysfunction and prevent target organ damages such as left ventricular hypertrophy and microalbuminuria. 25

26 Medical Treatment for Renovascular Disease ก ก ก ก ก ก (Renovascular hypertension, RVH) Secondary hypertension ก ก 1 % ก % refractory ก atherosclerosis (80 90 %) fibromuscular dysplasias (10 20 %) ก ก ก screening ก ก ก 1. ก ก > 160/100 mmhg (JNC VII classification ) ก กก ก 3.1. Accelerated hypertension 3.2. Resistant hypertension 3.3. Malignant hypertension 4. ก Acute renal failure ก ACE inhibitor angiotensin receptor blocking 5. atrophic kidney ก กก ก flash pulmonary edema renal failure ก ก (Gold standard) ก Renal Arteriography ก invasive ก ก noninvasive ก Magnetic resonance angiography (MRA), Computed tomographic angiography (CTA) Duplex Doppler Ultrasound ก sensitivity specificity ก IVP, plasma renin activity captopril renogram ก ACEI scan ก hemodynamic ก ก ก ก ก 3 ก ก ก ก (Medical Treatment) ก ก percutaneous renal angioplasty (PTRA) ก ก ก ก ก 130/ 80 mmhg ก ก 26 ก ก Renovascular hypertension ก ก Fibromuscular dysplasia ก ก ก กก ก Renin Angiotensin aldosterone

27 system (RAS) RVH ก ACEI ARB ก ก hyperkalemia ARF ก ก 90 % ACEI ก diuretic thiazide ก ก ARB, calcium channel blocker beta blocker ก ก ก ก ก ก ก ก ก ก renal revascularization ก กก ก ก renal revascularization ก ก ก ก revascularization ก ก ก Atherosclerosis renal artery stenosis ก ก Atherosclerosis ก ก (Bilateral) ก ก ก ก ก (Ischemic Nephropathy) ก ก ก ก revascularization ก ก ก ก fibromuscular dysplasia ก ก ก กก revascularization ก Resistance index (RI) Duplex Doppler Ultrasound RI กก 0.8 ก ก ก revascularization ก ก ก ก ก ก ACEI ARB ก revascularization resistant hypertension, recurrent flash pulmonary edema ก ก ก systemic atherosclerosis ก ก ก ก ก LDL ก กก ก ก 27

28 Renal arterial Disease: Renal stenting Renal artery stenosis (RAS) 6.8% ก ก 65 กก screening renal duplex ultrasound (1) ก 30% cardiac catheterization screening renal angiography (2-4) ก ก ก peripheral arterial disease 22% - 59% (5-15) Atherosclerotic RAS ก 7% (16) ก ก ก กก ก RAS กก 75% 40% 5 (17) Clinical clues ก RAS 1. onset hypertension ก onset severe hypertension Accelerated hypertension 4. Resistant hypertension ( full doses 3-drug regimen diuretics ก 5. Malignant hypertension hypertension ก acute end organ damage 6. new azotemia worsening renal function ACEI ARB 7. unexplained atrophic kidney 2 ก ก ก 1.5 cm 8. unexplained, sudden pulmonary edema (Flash pulmonary edema) unexplained renal failure ก RAS ก Duplex Ultrasonography, CT angiography MRA ก ก ก ก ก ก catheter angiography ก ก ก ก RAS multivessel coronary artery disease, PAD, unexplained congestive heart failure refractory angina atherosclerosis RAS 90% (18) ก aorto ostium proximal 1 cm main renal artery ก Fibromuscular dysplasia 2 RAS ก ก involve middle distal 2/3 main artery involve branch (19-22) 28 1 Renovascular disease - Atherosclerosis - Fibromuscular dysplasia - Renal artery aneurysm - Takayasu s arteritis - atheroemboli - thromboemboli - William s syndrome

29 - Neurofibromatosis - Spontaneous renal artery dissection - Arteriovenous malformations or fistulas - trauma - prior abdominal radiation therapy - retroperitoneal fibrosis ก ก RAS ก ก ก, ก ก ก cardiovascular events ก ก ก กก ก ก ACEI Calcium channel blockers ก ก progression renal disease unilateral renal artery stenosis (23-27) ก ก ก beta blockers, hydralazine chlorothiazide ก ก RAS ก progression renal disease ก ก กก กก, ก ก ก aspirin Revascularization Indication (figure 1) 1. Asymptomatic hemodynamically significant RAS 2. Hypertension 3. Preservation of renal function 4. Congestive heart failure and unstable angina 29

30 Asymptomatic hemodynamically significant RAS RAS end organ dysfunction ก a) diameter stenosis ก 50 70% ก peak gradient 20 mmhg mean gradient 10 mmhg b) Diameter stenosis กก 70% ก visual estimation ก intravascular ultrasound Incidental RAS กก screen renal angiography ก coronary peripheral angiography ก กก 30% ก severe RAS ก ก ก ก ก RCTs ก ก revascularization ก ก expert opinion ก Hypertension ก ก ก atherosclerosis RAS the most common form correctable hypertension ก ก DRASTIC medical therapy ก percutaneous transluminal renal angioplasty ก ก PTA 3 1 ก ก ก crossover ก medical therapy PTA 40% ก ก ก ก ก stent (28) stent ก re-intervention ก 48% 14% (29) ก ก ก renal stenting ก ก bilateral RAS (30) ก ก RAS ก revascularization 20% 70% ก Preservation of Renal function Atherosclerotic RAS renal failure ก survival rate 56% 2 (31) ก ก ก renal stenting bilateral RAS unilateral solitary RAS ก progression renal function preserve renal mass (32) ก ก proteinuria กก 1 gram, renal atrophy, severe renal parenchymal disease, severe diffuse intrarenal arteriolar disease, stable renal function ก ก ก ก ก revascularization ก ก ก renal atheroembolization ก กก ก ก กก embolic protection device ก ก ก ก atheroembolization ก (33) ก ก ก ก ก ก Congestive heart failure and unstable angina significant RAS coronary ischemia congestive heart failure ก ก peripheral vasoconstriction, direct effects angiotensin II myocardium volume overload coronary artery disease RAS ก renal stenting ก angina 88% (34,35) 30 Guideline recommendation (36) 1. Renal stent atherosclerotic RAS

31 2. Balloon angioplasty with bailout stenting Fibromuscular dysplasia 3. Vascular surgical reconstruction Fibromuscular dysplasia segmental arteries macroaneusysms, atherosclerotic RAS multiple small renal arteries early primary branching main renal artery ก aortic aneurysm aortoiliac occlusive disease References. 1. Hansen KJ, Edwards MS, Craven TE, et al. Prevalence of renovascular disease in the elderly: a population-based study. J Vasc Surg 2002;36: Harding MB, Smith LR, Himmelstein SI, et al. Renal artery stenosis: prevalence and associated risk factors in patients undergoing reassess routine cardiac catheterization. J Am Soc Nephrol 1992;2: Weber-Mzell D, Kotanko P, Schumacher M, et al. Coronary anatomy predicts presence or absence of renal artery stenosis: a prospective study in patients undergoing cardiac catheterization for suspected coronary artery disease. Eur Heart J 2002; 23: Jean WJ, al-bitar I, Zwicke DL, et al. High incidence of renal artery stenosis in patients with coronary artery disease. Cathet Cardiovasc Diagn 1994;32: Wilms G, Marchal G, Peene P, et al. The angiographic incidence of renal artery stenosis in the arteriosclerotic population. Eur J Radiol 1990;10: Choudhri AH, Cleland JG, Rowlands PC, et al. Unsuspected renal artery stenosis in peripheral vascular disease. BMJ 1990; 301: Swartbol P, Thorvinger BO, Parsson H, et al. Renal artery stenosis in patients with peripheral vascular disease and its correlation to hypertension: a retrospective study. Int Angiol 1992;11: Missouris CG, Papavassiliou MB, Khaw K, et al. High prevalence of carotid artery disease in patients with atheromatous renal artery stenosis. Nephrol Dial Transplant 1998;13: Missouris CG, Buckenham T, Cappuccio FP, et al. Renal artery stenosis: a common and important problem in patients with peripheral vascular disease. Am J Med 1994;96: Olin JW, Melia M, Young JR, et al. Prevalence of atherosclerotic renal artery stenosis in patients with atherosclerosis elsewhere. Am J Med 1990;88(1N):46N-51N. 11. Louie J, Isaacson JA, Zierler RE, et al. Prevalence of carotid and lower extremity arterial disease in patients with renal artery stenosis. Am J Hypertens 1994;7: Zierler RE, Bergelin RO, Polissar NL, et al. Carotid and lower extremity arterial disease in patients with renal artery atherosclerosis. Arch Intern Med 1998;158: Rossi GP, Rossi A, Zanin L, et al. Excess prevalence of extracranial carotid artery lesions in renovascular hypertension. Am J Hypertens 1992;5: Metcalfe W, Reid AW, Geddes CC. Prevalence of angiographic atherosclerotic renal artery disease and its relationship to the anatomical extent of peripheral vascular atherosclerosis. Nephrol Dial Transplant 1999;14: Valentine RJ, Clagett GP, Miller GL, et al. The coronary risk of unsuspected renal artery stenosis. J Vasc Surg 1993;18:433-9; discussion Caps MT, Perissinotto C, Zierler RE, et al. Prospective study of atherosclerotic disease progression in the renal artery. Circulation 1998;98: Schreiber MJ, Pohl MA, Novick AC. The natural history of atherosclerotic and fibrous renal artery disease. Urol Clin North Am 1984;11: Safian RD, Textor SC. Renal-artery stenosis. N Engl J Med 2001;344:

32 19. Luscher TF, Keller HM, Imhof HG, et al. Fibromuscular hyperplasia: extension of the disease and therapeutic outcome: results of the University Hospital Zurich Cooperative Study on Fibromuscular Hyperplasia. Nephron 1986;44 suppl 1: Archibald GR, Beckmann CF, Libertino JA. Focal renal artery stenosis caused by fibromuscular dysplasia: treatment by percutaneous transluminal angioplasty. AJR Am J Roentgenol 1988;151: Cluzel P, Raynaud A, Beyssen B, et al. Stenoses of renal branch arteries in fibromuscular dysplasia: results of percutaneous transluminal angioplasty. Radiology 1994;193: Mounier-Vehier C, Haulon S, Devos P, et al. Renal atrophy outcome after revascularization in fibromuscular dysplasia disease. J Endovasc Ther 2002;9: Plouin PF, Chatellier G, Darne B, et al. Blood pressure outcome of angioplasty in atherosclerotic renal artery stenosis: a randomized trial. Essai Multicentrique Medicaments vs Angioplastie (EMMA) Study Group. Hypertension 1998;31: Webster J, Marshall F, Abdalla M, et al. Randomised comparison of percutaneous angioplasty vs continued medical therapy for hypertensive patients with atheromatous renal artery stenosis. Scottish and Newcastle Renal Artery Stenosis Collaborative Group. J Hum Hypertens 1998;12: Nordmann AJ, Woo K, Parkes R, et al. Balloon angioplasty or medical therapy for hypertensive patients with atherosclerotic renal artery stenosis? A meta-analysis of randomized controlled trials. Am J Med 2003;114: Plouin PF. Stable patients with atherosclerotic renal artery stenosis should be treated first with medical management. Am J Kidney Dis 2003;42: Hollenberg NK. Medical therapy of renovascular hypertension: efficacy and safety of captopril in 269 patients. Cardiovasc Rev Repl 1983;4: van Jaarsveld BC, Krijnen P, Pieterman H, et al. The effect of balloon angioplasty on hypertension in atherosclerotic renalartery stenosis. Dutch Renal Artery Stenosis Intervention Cooperative Study Group. N Engl J Med 2000;342: van de Ven PJ, Kaatee R, Beutler JJ, et al. Arterial stenting and balloon angioplasty in ostial atherosclerotic renovascular disease: a randomised trial. Lancet 1999;353: Rocha-Singh KJ, Mishkel GJ, Katholi RE, et al. Clinical predictors of improved long-term blood pressure control after successful stenting of hypertensive patients with obstructive renal artery atherosclerosis. Catheter Cardiovasc Interv 1999;47: Mailloux LU, Napolitano B, Bellucci AG, et al. Renal vascular disease causing end-stage renal disease, incidence, clinical correlates, and outcomes: a 20-year clinical experience. Am J Kidney Dis 1994;24: Watson PS, Hadjipetrou P, Cox SV, et al. Effect of renal artery stenting on renal function and size in patients with atherosclerotic renovascular disease. Circulation 2000;102: Henry M, Klonaris C, Henry I, et al. Protected renal stenting with the PercuSurge GuardWire device: a pilot study. J Endovasc Ther 2001;8: Bloch MJ, Trost DW, Pickering TG, et al. Prevention of recurrent pulmonary edema in patients with bilateral renovascular disease through renal artery stent placement. Am J Hypertens 1999;12(1 pt 1): Khosla S, White CJ, Collins TJ, et al. Effects of renal artery stent implantation in patients with renovascular hypertension presenting with unstable angina or congestive heart failure. Am J Cardiol 1997;80: Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, Hiratzka LF, Murphy WRC, Olin JW, Puschett JB, Rosenfield KA, Sacks D, Stanley JC, Taylor LM Jr, White CJ, White J, White RA. ACC/AHA Guidelines for the Management of Patients with Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic): A Collaborative Report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society for Vascular Medicine and Biology, and the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease 32

33 Nonpharmacologic Treatment of Hypertension in CKD ก ก (chronic kidney disease, CKD) ก ก ก (end-stage renal disease, ESRD) ก ก ก ก ก 26 1 ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก (lifestyle modification) ก ก ก ก ก ก ก (practice guideline) ก ก ก กก nonpharmacologic treatment ก ก ก (lifestyle modification) ก ก ก ก ก ก 1. ก ก (body mass index, BMI > 30 กก./..) 2 2 ก 3 ก obstructive sleep apnea ก ก ก ก ก ก ก activity sympathetic hyperinsulinemia ก ก ก high-normal ก 4-5 ก ก ก ideal body weight ก ก ก ก 3 2. ก กก ก ก กก ก ก ก ก ก ก ก กก กก ก ก 70 ก ก กก ก ก 33

34 ก ก ก กก ก ก 30 5 ก ก กก ก ก ก ก ก ก ก ก ก biphasic ก ก ก ก ก ก ก sympathetic ก ก ก ก ก ก stroke ก 30 ก ethanol 4. ก ก ก ก ก ก ก ก ก ก ก ก ก ก 8 ก ก ก threshold ก ก ก ก ก ก กก 120 ก Intersalt study ก 9 ( ก ) ก ก ก ก ก ก ก salt sensitive salt resistant ก sodium sensitive ก ก ก ก salt sensitive ก ก 1 ก ก ก microalbuminuria ก ก salt sensitive ก ก ก 1) ก ก ก ก atrial natri-uretic peptide, kallikrein, prostaglandins, nitric oxide 10 2) ก alpha-adrenergic ก beta-adrener-gic ก vasoconstriction ก ก ก cathecho- lamine adrenergic receptor binding 3) renin ก ก ก renin aldosterone ก renin ก ก extracellular fluid sodium sensitivity 4) ก ก ก ก salt sensitive ( ก ) กก 45 ก ก DASH trial high normal (135/85 139/89. ) stage 1 hypertension (140/90 159/99. JNC7) ก ก ก ก ก ก DASH diet 13 ก ก ก ก 150, ก ก- ก 150/ /80. JNC 7 ก 100 ( ก Na 2.4 ก ก 6 ก ) 15 34

35 ก ก ก ก ก ก ก ก ก ก ก ก Nonpharmacologic treatment practice guideline ก ก ก nonpharmacologic treatment ก ก (lifestyle modification) ก ก ก ก ก 1. ก ก ก JNC 7 ก ก ก ก JNC 7 15 ก ก ก ก ก ก ก 1.1 ก ก ก ก ก ก (BMI < 25 ก ก /. ) ก ก DASH (Dietary Approaches to Stop Hypertension) ก ก ก 100 ( 2.4 ก / ) 1.4 ก กก ก ก ก ก ก ( < 2 ก, < 1 ก ) ก ก ก NKF-K/DOQI ก ก ก ก ก 2.1 ก ก ก 100 ( 2.4 ก / ) 2.2 ก 2.3 ก ก ก ก 2.4 ก ก ก ก ก ก ก ก ก 1. ก ก ก ก ก sodium handling ก CKD 17 ก ก ก extracellular fluid (ECF) ก ก ก ECF volume expansion กก ก DASH DASH-Sodium Trial 13 CKD ก ก ก 100 ( ก 2.4 ก ) ก ก 50 (1.2 ก ) ก ก CKD saltwasting nephropathy ก ก ก ก 2. DASH diet ก K/DOQI guideline DASH diet ก CKD 1-2 CKD 3-4 ก DASH diet ก กก ก CKD 3-4 ก DASH diet ก 35

36 ( 1.4 ก /ก ก / ) ก ก (0.80 ก /ก ก / ) ก CKD 3 (0.75 ก /ก ก / ) CKD 4 (0.60 ก / ก ก / ) 18 ก ก ก ก ก MDRD ก ก ก CKD DASH diet CKD GFR < 60./ /1.73. ก ก 3. CKD ก ก hyperkalemia ก ก DASH diet ก 4,500 ก./ ( meq ) ก 1,700 ก./ ( meq ) ก ก CKD 3 ก ACE inhibitors, ARBs potassium-sparing diuretics ก hyperkalemia ก ก salt substitute ก ก CKD ก phosphorus ก ก ก ก ก calcium-phosphate ก ก soft tissue DASH diet 1.7 ก ก (700 ก./ ) ก ก CKD 3 16 ก ก ก ก ก ก ก ก ก ก ก (lifestyle modification) ก ก ก ก ก (staging) GFR ก 30./ Reference: 1. Thailand Renal Replacement Therapy Registry 2003 Report. 2. Bender R, Jockel KH, Richter B, Spraul M, Berger M. Body weight, blood pressure,a and mortality in a cohort of obese patients. Am J Epidemiol 2002; 156: Trials of Hypertension Prevention Collaboration Research Group. The effects of nonpharmacologic intervention on blood pressure of persons with high normal levels. JAMA 1992; 267: Stewart KJ. Exercise training and the cardiovascular consequences of type 2 diabetes and hypertension: Plausible mechanisms for improving cardiovascular health. JAMA 2002; 288: Summary of Revisions for the 2004 Clinical Practice Recommendations. Diabetes Care 2004; 27 (Suppl):S1-S Knowler WC, Barrette-Conner E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: MacGregor GA. Sodium is more important than calcium in essential hypertension. Hypertension. 1985; 7: Prior IAM, Evans JG, Harvey HB, et al. Sodium intake and blood pressure in two Polynesian population. N Engl J 36

37 Med 1968; 279: Weinberger MH. Salt sensitivity of blood pressure in humans. Hypertension 1996; 27: Midgley JP, Mathew AG, Greenwood CM, Logan AG. Effect of reduced dietary sodium on blood pressure. JAMA 1996; 275: Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med 1997; 336: Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med 2001; 344: Conlin PR, Chow D, Miller ER, et al. The effect of dietary patterns on blood pressure control in hypertensive patients: results from the Dietary Approaches to Stop Hypertension (DASH) trial. Am J Hypertens 2000; 13: Chobanian AV, Bakris GL, Black HR, et al. and the National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 2003; 289: K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease. Am J Kidney Dis 2004; 43(Suppl 1):S1-S Johnson RJ, Herrera-Acosta J, Schreiner GF, et al. Mechanisms of disease: Subtle acquired renal injury as a mechanism of salt-sensitive hypertension. N Engl J Med 2002; 346: Clinical Practice Guideliones for Nutrition in Chronic Renal Failure. K/DOQI, National Kidney Foundation. Am J Kidney Dis 2000; 35 (Suppl 3):S1-S Level AS, Greene T, Beck GJ, et al. Dietary protein restriction and the progression of chronic renal disease: What have all of the results of the MDRD study shown? Modification of Diet in Renal Disease Study group. J Am Soc Nephrol 1999; 10:

38 Renin angiotensin aldosterone system (RAAS) ก Angiotensin converting enzyme inhibitors (ACEIs) Angiotensin receptor blockers (ARBs) ก ก ก ก กก intraglomerular pressure ก efferent arteriole non-hemodynamic effects ก ก ACEIs ARBs RAAS ก ก ก ก ก ACEIs Angiotensin converting enzyme (ACE) ก Angiotensin II (AII) ก Angiotensin I ACEIs ก AII ก ก ก AII (Alternative pathway Non-ACE pathway) ก ก ACE ก bradykinin ก ACE ACEI bradykinin bradykinin ก ก ก bradykinin ACEIs ก ARBs ก bradykinin ก ก ก ACEIs ก ARBs ก Angiotensin receptor type 1 (AT1R) Angiotensin II (AII) ก ACEIs ก AII ก กก ก AT1R ก ก ARBs AT1R ก ก Angiotensin receptor ก ก Angiotensin receptor ก ก AT1R ก ก ก ก ก ก ก ก ก ก ก ก ACEIs ก ก ก ก ก ACEIs (Non diabetes mellitus) ก ก AIPRI (ACEI In Progressive Renal Insufficiency study), REIN (Ramipril Efficacy In Renal study) AASK (African American Study of Kidney disease and hypertension) ก ก ก ก ก ก ARBs ก ก ก Captopril collaborative study (Lewis study) meta-analysis ACEI in DN trialist group ก ACEIs 1 ก ก ก ก (End stage renal disease, ESRD) ก 1 ACEIs ก 2 ก ก BENEDICT (BErgamo NEphrologic DIabetic Complications Trial) ก (Normoalbuminuria) ACEI ก ก microalbuminuria ก ก MicroHOPE (MIcroalbuminuria, Cardiovascular and Renal Outcomes in the Heart Outcomes Prevention Evaluation) 38 Angiotensin Converting Enzyme Inhibitors (ACEIs) versus Angiotensin Receptor Blockers (ARBs) in Chronic Kidney Disease ก ก ก ก ก ก ก ก ก ก

39 ก ก ก ก ก ACEI microalbuminuria ก overt proteinuria 2 MARVAL (Microalbuminuria Reduction with Valsartan) IRMAII (Irbesartan Reduce MicroAlbuminuria in type 2 diabetes) ก ก ARBs 2 microalbuminuria ก ก ก overt proteinuria ก ก ก ก ACEIs ก ก ก ก ก (ESRD) 2 ก ก ARBs 2 overt proteinuria ก ก ก IDNT (Irbesartan Diabetic Nephropathy Trial) RENAAL (Reduction of Endpoint in NIDDM with the Angiotensin II Antagonist Losartan) ก ARBs ก ก ESRD 2 ก ก ก ก ACEIs ARBs ก ก Diabetics Exposed to Telmisartan And enalapril (DETAIL) ก ก ก ก 2 ก 5 ก (glomerular filtration rate, GFR) ก ก ก ก ก ก ก ก COOPERATE (Combination treatment of angiotensin-ii receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease) ก ACEI ARB ก ก ก ACEI ARB ก ก ก ESRD ก ก ก ก ก ก ก ACEIs ARBs ก ก ARBs ACEIs ก ก กก ACEIs ก ก ก ACEIs ARBs ก ก ก ก ก ก ก ก ก ก ARBs ก ACEIs ก ARBs ก ก ACEIs ก ARBs ก ก ก ACEIs ก ก ก (GFR) ก ACEIs ARBs ก ก (hypotension), ก GFR, ก, ก, ก ก ก ( 1) ก ก ACEIs ก ACEIs/ARBs ก ก ก hyperkalemia ACEIs ARBs ก ก ก GFR ก 30% ก ก 4 ( 2) serum potassium ก 5.5 meq/l. ก ก ACEIs ARBs ก ก ก ก ก, GFR, K ก ก ก ก ก ก ก ก ก ก ก hyperkalemia ก ก ก ก 39

40 1 ก, GFR ก ACE Inhibitors ARB ก (. ) > 120 < 120 GFR (./ /1.73.) > 60 < 60 GFR ก (%) < 15 > 15 (meq/l) < 4.5 > 4.5 ก ก ก 4 2 ก BP ก ก ก กก GFR ก ก ACE-I ARB GFR 0-15% 15-30% 30-50% >50% ก ACEI ARB GFR ก GFR % ก, GFR ก 5-7 ก GFR ก 30 % ก ก 5-7 ก GFR ก 15 % ก GFR ( ) 40

41 Hypertension in Hemodialysis ก ก 1 (end-stage renal disease, ESRD) กก 80 2 ก ก 1 ก ก systolic hypertension ก pulse pressure ก (arterial stiffness) กก diffuse arteriosclerosis ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก 4 ก hyperparathyroidism, (vascular calcification) ก กก calcium x phosphorus product, ก endothelin, sympathetic activation vascular inflammation ก ก ก intravascular volume angitotension II ก vascular compliance ก ก ก ก pressure overload ก (left ventricular hypertrophy, LVH) diastolic dysfunction 4 ก ก coronary perfusion ก (congestive heart failure) (coronary artery disease) ก ก ก pressure overload ก ก ก ก (volume overload) ก กก ก arterovenous fistula ก ก ก ก end diastolic volume (myocardial wall tension) ก ก ก ก ก wall tension ก atherosclerosis ก ก ก ก myocardial ischemia ก systolic dysfunction ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก (pre-dialysis BP) ก ก (post-dialysis BP) ก ก ก ก 5 ก ก ambulatory blood pressure 41

42 monitoring (ABPM) ก ก ก ก ก ก pre-dialysis BP post-dialysis BP ก inter-dialytic systolic BP 10 inter-dialytic diastolic BP 7 ก ABPM ก ก systolic BP load ก ก LVH nocturnal hypertension (non-dipping) ก ก ABPM ก ก ก ABPM nocturnal hypertension ก ก Zoccali 6 pre-dialysis BP ก ก ก LVH ก post-dialytic BP predialysis BP ( ก ก 12 ) ก ก ก LVH ABPM ก ก pre-dialysis BP standardized protocol ก 7 (home BP) ก ก white coat hypertension ก ก ก ก ก ก U/J shape ก predialysis systolic BP < 110 ก ก Zager 6 ก >5,000 ก pre-dialysis systolic BP ก diastolic < 70 ก ก ก ก (USRDS) pulse pressure ก ก ก 5 ก ก ก case-mix ( significant systolic dysfunction left ventricular dilatation) ก ก ก level A ก ก ก 2 8 1) ก classic systolic-diastolic hypertension pre-dialysis BP <140/90 ก isolated systolic hypertension pulse pressure ( ก ) pre-dialysis BP / ) ก ก systolic BP < 140 ก (acceptable well being) ก ก ก ก ก 2 ก CREED study 9 ก ก systolic BP > 125 ( ก previous cardiovascular complications, diastolic BP, diabetes, left ventricular mass, ejection fraction) ก ก ก ก ก ก ก ก ก กก ก ก ก vascular calcification (parathyroid hormone, calcium, phosphorus) ก ก ก ก ก ก ก ก ก ก ก ( 85-90) ก กก ก ก ก ก ก ก ก (dry weight) ก ก ก ก ก ก ก 4 ก ก ESRD ก ก ก ก standard hemodialysis 42

43 ก ก ก ก 6-7 ก ก ก (8-10 ) (nocturnal daily hemodialysis) ก ก Tassin ก 3 / 8 ก ก (>90%) ก ก ก ก ก ก standard hemodialysis ก ก nocturnal daily hemodialysis ก total peripheral resistance cardiac output ก ก norepinephrine endothelial function ก ก ก ก ก ก ก ก ก (volume-independent mechanism) ก ก daily dialysis sleep apnea 10 ก ก ก ก (comorbidity) ก ก ก ก ก ก ก ก ก ก ก calcium channel blocker (CCB) ก ก (volume expansion) ก LVH, diastolic dysfunction, stable angina pectoris ก non-dihydropyridine CCB negative inotropic negative chronotopic ก congestive heart failure ก ก b- blocker ก CCB ก ก ก ก ก ก angiotensin-converting enzyme (ACE) inhibitor ก LVH, systolic dysfunction ก ก ก erythropoietin ก ก AN69 dialyzer ก ก ก anaphylactoid ก ก ESRD ก ก ก ก angiotension II receptor blocker (ARB) ก ACE inhibitor ก ก ก ก ก ARB ก ก ก ก 5 ก b-blocker ก ก ก myocardial infraction ก ก b1-selective blocker ก non-selective b-blocker ก ( bradycardia, bronchospasm, peripheral vascular disease ) carvedilol b-blocker ก ก dilated cardiomyopathy ก ก ก ก methyldopa, clonidine, guanfacine ก ก ก ก ก orthostatic hypotension minoxidil ( ก./ ) resistant hypertension ก b-blocker ก tachycardia ก ESRD ก extracellular volume ก 43

44 1 ก ก - Extracellular fluid volume expansion - Activation of the renin-angiotensin aldosterone system - Increased activity of the sympathetic nervous system - Increased endogenous vasoconstrictors (endothelin-1, Na-K-ATPase inhibitors, adrenomedulin) and decreased vasodilator (nitric oxide, prostaglandins/bradykinins) compounds - Obesity / metabolic syndrome - Renal vascular disease and renal artery stenosis - Erythropoietin administration - Parathyroid hormone secretion / increased intracellular calcium / hypercalcemia - Calcification of arterial tree, arterial stiffness - Essential hypertension - Sleep apnea References: 1. Rido N, Luno, Garcia d, et al. Prevalence of hypertension in renal disease. Nephrol Dial Transplant 2001;16 (suppl 1): Agarwal R, Nissenson AR, Batlle D, et al. Prevalence, treatment, and control of hypertension in chronic hemodialsyis patients in the United States. Am J Med 2003;115: Sarnak MJ, Levey AS: Cardiovascular disease and chronic renal disease: a new paradigm. Am J Kidney Dis 2000;35:S117-S Agarwal R. Systolic hypertension in hemodilaysis patients. Semin Dial 2003;16: Kiss I, Fasang C, Rodicio JL. Treatment of hypertension in dialysis patients. J hypertens 2005;23: Zoccali C. Cardiovascular risk in uraemic patients-is it fully explained y classical risk factors? Nephrol Dial Transplant 2000;15: Lazar AE, Smith MC, Rahman M. Blood pressure measurement in hemodialysis patients. Semin Dial 2004;17(4): Locatelli F, Covic A, Chazot C, Leunissen K, Luno J, Yaqoob M. Hypertension and cardiovascular risk assessment in dialysis patients. Nephrol dial Transplant 2004;19: Zoccali C, Mallamaci F, Tripepi G et al. Prediction of left ventricular geometry by clinic, pre-dialysis and 24-h ambulatory BP monitoring in hemodialysis patients: CREED investigators. J Hypertens 1999;17: Santos SF, Peixoto AJ. Hypertension in dialysis. Curr Opin Nephrol Hypertens 2005;14:

45 Exhibition List Name Booth No. * Abbott Laboratiories Limited 23 * AstraZeneca (Thailand) Limited 14 * Astellas Pharma (Thailand) Co., Ltd. 17 * Aventis Pharma Co., Ltd. 13 * Bayer (Thai)Co., Ltd. 15 * BJC TradingCo., Ltd. 18 * Boehringer Ingellheim (Thai) Ltd. 12 * E for L International Co., Ltd. 25 * GlaxoSmithKline (Thailand) Ltd. 11 * Great Eastern Drug Co., Ltd. 22 * Jack Chia Industries (Thailand) Public Co., Ltd. 1 * Jassen-Cilag Limited 29 * Merck Limited 21 * Novartis Thailand Limited (Sandoz) 6 * Novartis Thailand Limited 3 * MSD (Thailand) Ltd. 24 * Olic (Thailand) Limited 28 * Pfizer (Thailand)Co., Ltd. Zone A * Roche Thailand Co., Ltd. 4-5 * Schering-Plough Limited 2 * Sanofi-AventisCo., Ltd * Servier (Thailand) Ltd. 26 * Solvay Pharma (Thailand) Ltd. 27 * Solvay Pharma (Thailand) Ltd. Zone B * Takeda (Thailand) Limited * Wellchem Pharmaceutical Co., Ltd

46 Other sponsors * Pfizer (Thailand) Co., Ltd ก Breakfast symposium, ก ก ก ก * Solvay Pharma (Thailand) Ltd ก Luncheon symposium * AstraZeneca (Thailand) Limited ก ก 46

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