ACEIs / ARBs NDHP dihydropyridine ( DHP ) ACEIs ARBs ACEIs ARBs NDHP. ( GFR ) 60 ml/min/1.73m ( chronic kidney disease, CKD )

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1 ( chronic kidney disease, CKD ) 003 ( end-stage renal disease, ESRD ) Angiotensin-converting enzyme inhibitors ( ) angiotensin receptor blockers ( ) nondihydropyridine ( NDHP ) / NDHP dihydropyridine ( DHP ) NDHP ( Calcium channel blockers, ) ( Angiotensin-converting enzyme inhibitors, ) (Angiotensin receptor blockers, ) ( Chronic kidney disease, CKD ) ( Diabetic nephropathy ) ( Renoprotection ) 003 ( chronic kidney disease, CKD ) ( GFR ) 60 ml/min/1.73m 3 ( damage markers ) 701

2 176 80% 50% 85% 63% 00 mmhg ( end-stage renal disease, ESRD ) 10 mmhg mmhg ESRD 70 mmhg 30.9 ESRD ( intraglomerular pressure ) ( glomerular capillary hypertension ) 3 40% ( stroke ) 0-5% 50 % 7 00 ( National Kidney Foundation, NKF ) 1 135/85 mmhg 1 15/75 mmhg ( interstitium ) ( mesangial cells ) NF B ( nuclear factor kappa B) ET-1 ( endothelin-i ) NF B ( vascular smooth muscle cells ) MCP-1 ( monocyte chemoattractant protein-1 ) cytokine cell adhesion molecular ( mesangial inflammation ) ( mesangial cell hyperplasia ) ET-1 ( mesangial matrix ) ( angiotensin-converting enzyme inhibitors ) ( angiotensin receptor blockers ) ( calcium channel blockers, ) 003 JNC VII ( The Seventh Report of the Joint National Committee ) 130/80 mmhg ( American Diabetes Association, ADA ) 130/80 mmhg RAAs ( renin-angiotensin-aldosterone system ) angiotensin II NF B TGF- 1 ( transforming growth factor 1) 8 ( ) 3-6 angiotensin-ii ( ) ) ( 6 ( renoprotection )

3 177 (permeability) 1 ( renal autoregulation ) dihydropyridine ( dihydropyridine calcium channel blockers, ) nifedipine nicardipine amlodipine nondihydropyridine ( nondihydropyridine calcium channel blockers, NDHP ) verapamil diltiazem 9 L-type T- 9 ( 10 mmhg ) N 9,11,13,15-16 lercanidipine lercanidipine lercanidipine lercanidipine 17 type (afferent arterioles) L-type T-type (efferent arterioles) T-type L-type 9,10 DHP NDHP N N ( mesagial volume ) 10 6 ( 5 ) ( creatinine clearance, ClCr ) 63 ml/min/1.73m g/day diltiazem verapamil lisinopril atenolol ClCr diltiazem verapamil lisinopril ClCr ( P=0.36 ) 1.6 ml/min ( GFR 1 ml/min ) atenolol ClCr 3.4 ml/min ( P < ) Diltiazem verapamil lisinopril atenolol irbesartan 300 mg amlodipine 10mg ( serum creatinine, SCr ) ESRD irbesartan 0 ( P=0.0 ) irbesartan amlodipine irbesartan amlodipine 3 ( P=0.006 ) amlodipine 18

4 178 ( P= 0.69 ) (African American ) ( randomized, openlabel ) ( non-diabetic hypertensive renal disease ) ( GFR ) 0-65 ml/min/ 1.73m ramipril.5-10 mg amlodipine 5-10 mg metoprolol mg urine protein/cr 0. ramipril metoprolol amlodipine GFR ( P< 0.05 ) Ramipril metoprolol amlodipine 49% ( P< 0.01 ) 4%( P< 0.03 ) ESRD 0 N 39% ( 95% CI, 19%-63%, P = 0.00 ) N NDHP ACEI ARB DHP ( ) ( ) ( GFR ) DHP N ( Systematic review ) N Bakris GL ( systematic review ) 15 DHP N 6 ( endpoint ) ( randomized clinical trials ) ( sample zize) ( study length ) ( baseline value ) (1) N ( -13 %, -18.5%, P = 0.8 ) % N 30% ( 95% CI, 10%-54%, P = 0.01 ) () % Bakris GL 37 ( SCr ) mg/dl g/day (randomized, open-label ) verapamil trandolapril verapamil trandolapril verapamil trandolapril (P<0.001 ) 1 Herlitz H 167 ( GFR 3-55 ml/min/1.73m ) felodipine ramipril felodipine ramipril ramipril ( GFR ) ( P> 0.0 ) felodipine ( P < 0.05 ) N N,6,8,15,1,

5 179 N ( lack data ) ( baseline data ) 15 N N NDHP N N NDHP 1. G, Levin N, Bailie G, et al. K/DOQI clinical practice guidelines for chronic. kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 00; 39: S Ljutic D, Kes P. The role of arterial hypertension in the progression of non- diabetic glomerular diseases. Nephrol Dial Transplant 003; 18: Mailloux LU, Levey AS. Hypertension in patients with chronic renal disease. Am J Kidney Dis 1998; 3: S Remuzzi G, Ruggenenti P, Benigni A. Understanding the nature of renal disease progression. Kidney Int 1997; 51: Hebert LA, Wilmer WA, Falkenhain ME, et al. Renoprotection: one or many therapy? Kidney Int 001; 59: 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 003; 89: Molitch MF, DeFronzo RA, Franz MJ, et al. Nephropathy in diabetes. Diabetes Care 004; 7: S Hayashi K, Ozawa Y, Fujiwara K, Wakino S, Kumagai H. Role of actions of calcium antagonists on efferent arterioles-with special references to glomerular hypertension. Am J Nephrol 003; 3: Tarif N, Bakris GL. Preservation of renal function : the spectrum of effects by calcium-channel blockers. Nephrol Dial Transplant 1997; 1: Anderson S. Nifedipine versus fosinopril in uninephrectomized diabetic rats. Kidney Int 199; 41: Smith AC, Toto R, Bakris GL. Differential effects of calcium channel blockers on size selectivity of proteinuria in diabetic glomerulopathy. Kidney Int 1998; 54: Brown SA, Walton CL, Crawford P, Bakris GL. Long-term effects of antihypertensive regimens on renal hemodynamics and proteinuria. Kidney Int 1993; 43: Gaber L, Walton C, Brown S, Bakris G. Effects of different antihypertensive treatments on morphologic progression of diabetic nephropathy in uninephrectomized dogs. Kidney Int 1994; 46: Bakris GL, Weir MR, Secic M, Campbell B. Differential effects of calcium antagonist subclasses on markers of nephropathy progression. Kidney Int 004; 65: August P, Lenz T, Laragh JH. Comparative renal hemodynamic effects of lisinopril, verapamil, and amlodipine in patients with chronic renal failure. Am J Hypertens 1993; 6: 148S-54S. 17.Sabbatini M, Vitaioli L, Baldoni E, Amenta F. Nephroprotective effect of treatment with with calcium channel blockers in spontaneously hypertensive rats. J Pharmacol Exp Ther 000; 94: Bakris GL, Copley JB, Vicknair N, Sadler R, Leurgans S. Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int 1996; 50: Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type diabetes. N Engl J Med 001; 345:

6 180 0.Wright JT, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease. JAMA 00; 88: Bakris GL, Weir MR, DeQuattro V, McMahon FG. Effect of an ACE inhibitor / calcium antagonist combination on proteinuria in diabetic nephropathy. Kidney Int 1998; 54: Herlitz H, Harris K, Risler T, et al. The effects of an ACE inhibitor and a calcium antagonist on the progression of renal disease: the Nephros Study. Nephrol Dial Transplant 001; 16: The Role of Calcium Channel Blockers in Chronic Kidney Disease Hsiao-Lin Chang, Yea-Huei Kao, Shu-Min Kao 1 Ming-Cheng Wang, and Chin-Chung Tseng Institute of Clinical Pharmacy, National Cheng Kung University 1 Department of Pharmacy, National Cheng Kung University Medical Center Department of Internal Medicine, Division of Nephrology, National Cheng Kung University Medical Center Chronic kidney disease (CKD) is a progressive renal disease. According to the data of Department of Health, Executive Yuan, CKD was the eighth leading cause of death in Taiwan in 003. How to delay the progression of CKD to end-stage renal disease (ESRD) is an important issue. Angiotensin-converting enzyme inhibitors () or angiotensin receptor blockers () are the first choice for the treatment in CKD patients with hypertension. Are there alternative drugs to or for renoprotection? Animal studies and clinical trials demonstrated that nondihydropyridine calcium channel blockers (N), in addition to blood pressure control, could reduce the proteinuria in the presence or absence of diabetes. In the patients unable to tolerate and/or, we can consider the use of N for the management of blood pressure and renoprotection. Dihydropyridine calcium channel blockers () in CKD should be restricted to further lower blood pressure in patients unsatisfactory with or. The combination of or and N is more favorable in alleviating proteinuria and has better blood pressure control than monotherapy. ( J Intern Med Taiwan 005; 16: )

Management of Hypertensive Chronic Kidney Disease: Role of Calcium Channel Blockers. Robert D. Toto, MD

R e v i e w P a p e r Management of Hypertensive Chronic Kidney Disease: Role of Calcium Channel Blockers Robert D. Toto, MD Both the prevalence and incidence of end-stage renal disease have been increasing