( 1) Framingham Heart

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1 ( 1) ( 1) Framingham Heart Study [1] 1. (Am J Kidney Dis. 45: , 2005)

2 Framingham Heart Study ( 1) American Heart Association (1) (2) (3) (4) [2] (GFR) [3] ARIC [4] Cardiovascular Health Study [5] Hoorn study [6] (GFR) GFR [7] NHANES II Mortality Study GFR 70 ml/min [8] GFR Aspirin beta blocker Angiotensionconverting enzyme (ACE) inhibitor (microalbuminuria) K/DOQI guidelines mg 3 mg/dl mg/g 1. (Homocysteine) Lipoprotein(a) and apolipoprotein(a) isoforms LDL Lipoprotein remnants (C-reactive protein) (malnutrition) Thrombogenic factors Nitric oxide/endothelin Am J Kidney Dis. 45: ,

3 mg/g [9] ( 2) (sarcomeres) eccentric hypertrophy ( 45%) concentric hypertrophy ( 45%) 30% stage 3 4 [10] 55% GFR 59 ml/min [11] [12] ARIC stage 3 low GFR [13] 2. (Kidney Int 68: , 2005)

4 (artherosclerotic plaque) (collagen) (arteriosclerosis) arterial stiffening stage 5 53% ( 50% ) [14] (inflammation) (oxidative stress) (hyperhomocysteinemia) (metabolic syndrome) (abnormal calcium and phosphate metabolism) (endothelial cell dysfunction and injury) 1. (inflammation) C (C-reactive protein) CRP MDRD CRP Interleukin-6 Interleukin-10 tumor necrosis factor (TNF) receptor I and II TNF-α fibrinogen [15-16] 2. (oxidative stress) (reactive oxygen species, ROS) (proinflammatory cytokine) [17] (insulin resistance) [18] (Lipid peroxidation products plasma F2-isoprostanes, malonyldialdehyde) advanced oxidation protein products (LDL) reduced glutathione E Heart Outcomes and Protection (HOPE) E [19] Secondary Prevention with Antioxidants of Cardiovascular Disease in End- Stage Renal Disease(SPACE) E [20] 3. (metabolic syndrome) 2005 (International Diabetes Federation) mg/dl 40 mg/dl 50 mg/dl 100 mg/dl 130/85 mmhg adiponectin adiponectin adiponectin [21] hypoadiponectinemia [22] 4. (hyperhomocysteinemia)

5 [23] (Homocysteine) GFR [24] stage 3 4 GFR [25] B6 B12 [26] 5. ( e n d o t h e l i a l c e l l dysfunction and injury) brachial artery reactivity Aymmetric dimethylarginine (ADMA) ADMA ADMA [27] ADMA left ventricular mass index [28] ADMA ADMA 1. Wilson PW, D Agostino RB, Levy D, et al: Prediction of coronary heart disease using risk factor categories. Circulation 1998; 97: Appel LJ: Beyond (or back to) traditional risk factors: Preventing cardiovascular disease in patients with chronic kidney disease. Ann Intern Med 2004; 140: Go AS, Chertow GM, Fan D, et al: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351: Manjunath G, Tighiouart H, Ibrahim H, et al: Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J AmColl Cardiol 2003; 41: Fried LF, Shlipak MG, Crump C, et al: Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals. J Am Coll Cardiol 2003; 41: Henry RM, Kostense PJ, Bos G, et al: Mild renal insufficiency is associated with increased cardiovascular mortality: The Hoorn Study. Kidney Int 2002; 62: Weiner DE, Tighiouart H, Amin MG, et al: Chronic kidney disease as a risk factor for cardiovascular disease and allcause mortality: A pooled analysis of community-based studies. J Am Soc Nephrol 2004; 15: Muntner P, He J, Hamm L, Loria C, Whelton PK: Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States. J Am Soc Nephrol 2002; 13: Wachtell K, Ibsen H, Olsen MH, et al: Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: The LIFE Study. Ann Intern Med 2003; 139: Mcmahon LP, Roger SD, Levin A: Development, prevention, and potential reversal of left ventricular hypertrophy in chronic kidney disease. J AmSoc Nephrol 2004; 15: Mcalister FA, Ezekowitz J, Tonelli M, et al: Renal insufficiency and heart failure: Prognostic and therapeutic implications from a prospective cohort study. Circulation 2004; 109: Levin A, Singer J, Thompson CR, et al: Prevalent left ventricular hypertrophy in the predialysis population: Identifying opportunities for intervention. Am J Kidney Dis 1996; 27: Astor BC, Arnett DK, Brown A, et al: Association of kidney function and hemoglobin with left ventricular morphology among African Americans: The Atherosclerosis Risk in Communities (ARIC) study. Am J Kidney Dis 2004; 43: Ohtake T, et al: High Prevalence of Occult Coronary Artery Stenosis in Patients with Chronic Kidney Disease at the Initiation of Renal Replacement Therapy: An Angiographic Examination. J Am Soc Nephrol 2005; 9: Menon V, Greene T, Wang X, et al: C-reactive protein and serum albumin as predictors of all-cause and cardiovascular mortality in patients with chronic kidney disease. Kidney Int 2005; 68: Descamps-Latscha B, Witko-Sarsat V, Nguyen-Khoa T, et al: Advanced oxidation protein products as risk factors

6 for atherosclerotic cardiovascular events in nondiabetic predialysis patients. Am J Kidney Dis 2005; 45: Gordon CA, Himmelfarb J: Antioxidant therapy in uremia: Evidence-based medicine? Semin Dial 2004; 17: Himmelfarb J, Stenvinkel P, Ikizler TA, et al: The elephant in uremia: Oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int 2002; 62: Mann JF, Lonn EM, Yi Q, et al: Effects of vitamin E on cardiovascular outcomes in people with mild-to-moderate renal insufficiency: results of the HOPE study. Kidney Int 2004; 65: Boaz M, Smetana S,Weinstein T, et al: Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): Randomised placebo-controlled trial. Lancet 2000; 356: Zoccali C, Mallamaci F, Tripepi G, et al: Adiponectin, metabolic risk factors, and cardiovascular events among patients with endstage renal disease. J AmSoc Nephrol 2002; 13: Iwashima Y, Ogihara T, et al: Adiponectin and renal function, and implication as a risk of cardiovascular disease. Am J Cardiol Dec 15; 98(12): Epub 2006 Oct Welch GN, Loscalzo J: Homocysteine and atherothrombosis. N Engl J Med 1998; 338: Mallamaci F, Zoccal C, Tripepi G, et al: Hyperhomocysteinemia predicts cardiovascular outcomes in hemodialysis patients. Kidney Int 2002; 61: Menon V, Sarnak MJ, Greene T, et al: Relationship between homocysteine and mortality in chronic kidney disease. Circulation 2006; 113: Wrone EM, Hornberger JM, Zehnder JL, et al: Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease. J AmSoc Nephrol 2004; 15: Valkonen VP, Paiva H, Salonen JT, et al: Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine. Lancet 2001; 358: Zoccali C, Mallamaci F, Maas R, et al: Left ventricular hypertrophy, cardiac remodeling and asymmetric dimethylarginine (ADMA) in hemodialysis patients. Kidney Int 2002; 62: