エビデンスに基づく CKD 診療ガイドライン 2009 解説 1 CKD は末期腎不全の危険因子である 1. 腎機能低下は末期腎不全の危険因子である CKD 4, 5 CKD 17 CKD 3 CKD CKD 3 8, 38 2 GFR 1 Iseki , Cr

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1 2 CKD の意義 ステートメント 1 腎機能低下と末期腎不全 1 進行した腎機能の低下 (CKD ステージ ) 1, 2) は末期腎不全の危険因子である 3-7). 2 日本人の GFR の低下速度は平均 0.36 ml/ 分 /1.73 m 2 / 年であり,40~69 歳では 50 ml/ 分 / 1.73 m 2 以下,70~79 歳では 40 ml/ 分 /1.73 m 2 以下の腎機能の場合, 腎機能低下速度が有意 に速まる 8). 2 蛋白尿と末期腎不全 1 蛋白尿およびアルブミン尿は末期腎不全の危険因子である. 蛋白尿, アルブミン尿の程度が増 すごとにリスクが高くなる 9-16). 2 治療介入による, 蛋白尿, アルブミン尿の減少の程度は, 腎機能悪化抑制と相関がある. 3 血尿と末期腎不全 血尿 ( 試験紙法 ) は, 男性において末期腎不全の危険因子であるが, その関与度は蛋白尿に比べ ると弱い. また, 尿潜血と尿蛋白の両方が陽性の場合, 末期腎不全のリスクが高い 10) 4 CKD と心血管病 (CVD) 1 腎機能の低下は心血管病 (CVD) の危険因子である 3, 17-34). 2 蛋白尿およびアルブミン尿は CVD の危険因子である. 蛋白尿, アルブミン尿の程度が増すご とに CVD のリスクが高くなる 17-20, 22, 24, 28, 30-34). 3 治療介入による, 蛋白尿 アルブミン尿の減少の程度は,CVD 発症の抑制と相関があ る 35-37). 5 日本における CKD の頻度 日本人成人における CKD 患者の頻度はステージ 1 が 0.6%, ステージ 2 が 1.7%, ステージ 3 が 10.4%, ステージ が 0.2% である. ステージ 3 ~ 5 の推計患者数は約 1,097 万人にのぼり, 総合的な CKD 対策が求められている. 17

2 エビデンスに基づく CKD 診療ガイドライン 2009 解説 1 CKD は末期腎不全の危険因子である 1. 腎機能低下は末期腎不全の危険因子である CKD 4, 5 CKD 17 CKD 3 CKD CKD 3 8, 38 2 GFR 1 Iseki , Cr 1.4 mgdl 1.2 mgdl Cr 2.0 mg dl egfr 6069 ml1.73 m 2 2 GFR ml1.73 m ml1.73 m 蛋白尿は末期腎不全の危険因子である. CKD 1 3 8, ,860 Cr Cr g CKD 1 2 ACEI 3. 血尿と末期腎不全 18

3 2.CKD の意義 10 2 CKD は CVD の危険因子である 1.CKD は CVD の危険因子であるという新しい考え CVD 17, National Kidney FoundationKidney Disease Outcomes Quality InitiativeKDOQIwork group CKD CVD American Heart AssociationAHA Kidney Disease as a Risk Factor for Development of Cardiovascular Disease Scientific Statement Kidney DiseaseImproving Global OutcomesKDIGO cardiorenal association CKD risk equivalent CKD 3 CVD CKD CVD 2. 腎機能低下は CVD の危険因子である KDOQI 19 AHA Scientific Statement 20 CVD KDOQI 19 GFR CVD CVD 1, , 23, 25 23, 25 1, 23, , 26 24, 27 CVD , 27, 28 3.アルブミン尿, 蛋白尿は CVD の危険因子である CVD , KDOQI 19 CVD CVD CVD 2 CVD 19, 20, 24, CVD 18, 22, 30 22, 31, 32, 34 CVD 17, 19, 20, 33 CVD 17, 22, 28 17, 治療介入によるアルブミン尿 蛋白尿の減少は CVD 発症の抑制を示唆する CKD CVD LDL HDL CKD CVD PREVENDIntervention Trial 35 RENAAL 19

4 エビデンスに基づく CKD 診療ガイドライン 2009 study 36 LIFE study 37 ACEI ARB CVD 5.Traditional risk factor と non-traditional risk factor について CKD CVD CKD CVD CVD CKD CKD CVD traditional CVD risk factor CVD LDL HDL CVD CKD CKD CVD CKDrelated nontraditional CVD risk factor CKD CVD CKD GFR PCa ADMA asymmetric dimethylargininefetuina 3 日本人における CKD の頻度 1. 腎機能低下に基づいた日本人における CKD の頻度 CKD NHANES egfr60 ml1.73 m % % % % 7.2% 9.4% 40 CKD GFR GFR GFR egfr60 ml 1.73 m % egfr 0.36 ml1.73 m ml1.73 m ml1.73 m 2 9 egfr mmhg 96 mmhg 1.2 egfr 本邦における検尿システムと検尿異常者の割合 CKD CKD b 20

5 2.CKD の意義 CKD 2.7% 2.0% 0.6% 0.1% 6.8% 4.5% 2.0% 0.4% 4.9% 2.7% 1.8% 0.3% 7.31% b, c 6.3% 3.9% 1.7% 0.6% 18.4% 16.0% 1.4% 0.9% b 9.1% 0.6%0.9% 0.9%0.9% 6.2%1.1% b Takahata 2, % 3 CKD % 41 50, % d %95% CI % 95% CI e 21

6 エビデンスに基づく CKD 診療ガイドライン 2009 アブストラクトテーブル 論文コード対象方法結果 1.Drey N, Am J Kidney Dis ,000 CKD Cr 1.7 mgdl 5.5 Cr 5.5 4% 69% Cr 3.57 mgdl 21% Cr 5.7 mgdl 46% 2.Kovesdy CP, Adv Chronic Kidney Dis CKD GFR MDRD GFR 20 ml 1.73 m 2 GFR4160 ml1.73 m 2 GFR 10 ml1.73 m ,000 egfr 20 ml1.73 m ml1.73 m ml 1.73 m ml1.73 m Keith DS, Arch Intern Med 2004 egfr 90 ml1.73 m 2 27,998 5 GFR MDRD 5 CKD 2 1.1% 3 1.3% % % % % Patel UD, Am J Kidney Dis 7 12,570 3 GFR MDRD 3 egfr 60 ml1.73 m egfr60 ml1.73 m egfr 4559 ml 1.73 m egfr 3044 ml1.73 m egfr 1529 ml 1.73 m egfr 15 ml 1.73 m Evans M, Am J Kidney Dis Cr 3.4 mgdl 2.8 mgdl 5579 GFR MDRD 80% % GFR Serrano A, Adv Chronic Kidney Dis 2007 CKD CKD GFR GFR MDRD egfr 15 ml 1.73 m 2 egfr15 ml1.73 m 2 GFR 1 ml1.73 m % 22

7 2.CKD の意義 論文コード対象方法結果 7.Norris KC, J Am Soc Nephrol GFR2065 ml 1.73 m 2 1, GFR 50% 25 ml 1.73 m 2 GFR 125iothalamate clearance GFR GFR 40 ml1.73 m 2 GFR 5 ml1.73 m 2 HR Imai E, Hypertens Res 2008 患者対照研究 ,727 egfr MDRD egfr 0.36 ml1.73 m 2 egfr 6069 ml1.73 m 2 2 GFR ml 1.73 m ml1.73 m 2 9.Ishani A, J Am Soc Nephrol 12,866 MRFIT 25 egfr MDRD eGFR 60 ml 1.73 m 2 75 ml1.73 m Iseki K, , Zhang Z, J Am Soc Nephrol 2 vs. Cr mgg Cr Cr mg dl1,513 RE- NAAL 1 g 24 g g Peterson JC, Ann Intern Med 1995 CKD 840 MDRD vs. 2.2 GFR 13.Lea J, Arch Intern Med GFR vs. vs ml1.73 m ,094 AASK 2 GFR 0.54 ml1.73 m 2 14.Halbesma N, J Am Soc Nephrol 8,592 PREVEND 22 factorial design 4 CVD HR 2.6HR 3.4eGFR 2.3 ml1.73 m ml1.73 m 2 15.Atkins RC, Am J Kidney Dis mg 2 Cr 3.0 mgdl 1,715 2 Cr

8 エビデンスに基づく CKD 診療ガイドライン 2009 論文コード対象方法結果 16.Jafar TH, 2001 メタ解析 ACEI 11 1,860 ACEI vs. 2.2 Cr 1 1 g RR 2.94 Cr 1 1 g RR Kannel WB, Am Heart J 1984 Framingham study 5, HR 2.995%CI %CI Damsgaard EM, BMJ1990 Fredericia HR %CI KDOQI, Am J Kidney Dis 2002 システマティックレビュー CKD CVD NKF CKD CVD 10 CKD CVD 28 CVD CKD CVD 20.Sarnak MJ, Circulation 2003 システマティックレビュー CKD CVD AHA CVD 13 CVD 21 CVD 49 CVD CKD CVD AHA 21.Ninomiya T, 2, Cox CKD coronary heart disease egfrml HR %CI ischemic stroke 1.73 m 2 60 CKD HR %CI CVD coronary heart disease ischemic strokehemorrhagic stroke 22.Nakayama M, Nephrol Dial Transplant Cox 1,977 Calculated CCr ml1.73 m CVD HR CVD HR 23.Anavekar NS, VALIANT study N Engl J Med CVD 14, ( からの観察研究 ) Cox egfr ml1.73 m CVD 24.7 GFRmL1.73 m 2 10 CVD HR % CI

9 2.CKD の意義 論文コード対象方法結果 24.Kottgen A, J Am Soc Nephrol Cox egfr 4 ml1.73 m , egfrml1.73 m HR %CI Brugts JJ, Arch Intern Med Ommoord 4, Cox CockcroftGault MDRD CockcroftGault HR %CI %CI %CI MDRD HR %CI %CI %CI Weiner DE, J Am Soc Nephrol Go AS, N Engl J Med A R I C s t u d y, CHS 20, Kaiser Permanent 1,120,295 Cox egfr ml 1.73 m 2 60 CKD CKD CKD HR %CI %CI CKD SBPmmHg HR %CI J shape 2.84 Cox RR egfrml1.73 m CVD 28.Irie F, 96, Cox CVD CVD CVD CVD CVD RR 29.Manjunath G, J Am Coll Cardiol , Cox egfrml1.73 m egfrml1.73 m 2 CVD HR CVD 30.Dinneen SF, Arch Intern Med 1997 メタ解析 NIDDM 11 2,138 HR 2.4 CVD CVD 95%CI1.33.1CVD CVD %CI Gerstein HC, JAMA HOPE study CVD ( からの観察研究 ) 5,545 CVD 3, Wachtell K, LIFE study Ann Intern Med II, III ,206 ( からの観察研究 ) , 4.5 Cox CVD 39,122 Cox Cr 10 5 CVD HR CVD1.8395%CI %CI %CI Cr 10 57%CVD 97.7% 75.2% 51% 45% 25

10 エビデンスに基づく CKD 診療ガイドライン 2009 論文コード対象方法結果 33.Hillege HL, Circulation 2002 Groningen 40, UAC CVD CVD 961 Cox UAC 4 10 mgl 1020 mgl mgl200 mgl 4 CVD CVD 34.Klausen K, Circulation The Third Copenhagen City Heart Study 2,762 CHD Cox 4 2.1g g g4.8g 4 CHD 4.8g HR CHD 2.095%CI %CI Asselbergs FW, Circulation Groningen PREVEND mg 24 hr factorial designcvd CVD 26% 40% 36.de Zeeuw D, Circulation 2004 ( からの観察研究 ) 37.Olsen MH, J Hypertens ( からの観察研究 ) RENAAL study NIDDM 0.3 g g Cr g 1,513 LIFE study ,679 Cox 6 CVD Cox 1 log Cr CVD 50% CVD 18% 27% 1 log Cr HR 1.29 per 10fold increase CVD HR 1.59, p Framingham risk score CVD 38.Eriksen BO, Tromso CKD 3 egfr ml1.73 m 2 3, GFR MDRD egfr 1.03 ml1.73 m %CKD % egfr 10 ml1.73 m Iseki K, Cr 95,255 7 CockcroftGault CCr 1, CCr CCr CCr CCr CCr CCr CCr CCr79.4 CCr 26

11 2.CKD の意義 論文コード対象方法結果 40.Coresh J, JAMA 2007 National Health and Nutrition Examination Sur veynhanes , , mgg Cr MDRD GFR CKD CKD 10.0% % % % % % % , 7.7% % % Konta T, 40 2,321 CockcroftGault CCr %1.7%4.4% CKD % 2.7% 42.Yamagata K, Nephron , % Yokoyama H, Diabetes Care Japan Diabetes Clinical Data Management Study Group 2 8,897 Cr % 95% CI %95% CI

12 エビデンスに基づく CKD 診療ガイドライン 2009 文献 1. Drey N, Roderick P, Mullee M, Rogerson M. A populationbased study of the incidence and outcomes of diagnosed chronic kidney disease. Am J Kidney Dis Kovesdy CP, Trivedi BK, Anderson JE. Association of kidney function with mortality in patients with chronic kidney disease not yet on dialysisa historical prospective cohort study. Adv Chronic Kidney Dis Keith DS, Nichols GA, Gullion CM, Brown JB, Smith DH. Longitudinal followup and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med Patel UD, Young EW, Ojo AO, Hayward RA. CKD progression and mortality among older patients with diabetes. Am J Kidney Dis Evans M, Fryzek JP, Elinder CG, Cohen SS, McLaughlin JK, Nyrén O, Fored CM. The natural history of chronic renal failureresults from an unselected, populationbased, inception cohort in Sweden. Am J Kidney Dis Serrano A, Huang J, Ghossein C, Nishi L, Gangavathi A, Madhan V, Ramadugu P, Ahya SN, Paparello J, Khosla N, Schlueter W, Batlle D. Stabilization of glomerular filtration rate in advanced chronic kidney diseasea twoyear followup of a cohort of chronic kidney disease patients stages 4 and 5. Adv Chronic Kidney Dis Norris KC, Greene T, Kopple J, Lea J, Lewis J, Lipkowitz M, Miller P, Richardson A, Rostand S, Wang X, Appel LJ. Baseline predictors of renal disease progression in the African American Study of Hypertension and Kidney Disease. J Am Soc Nephrol Imai E, Horio M, Yamagata K, Iseki K, Hara S, Ura N, Kiyohara Y, Makino H, Hishida A, Matsuo S. Slower decline of glomerular filtration rate in the Japanese general populationa longitudinal 10year followup study. Hypertens Res Ishani A, Grandits GA, Grimm RH, Svendsen KH, Collins AJ, Prineas RJ, Neaton JD. Association of single measurements of dipstick proteinuria, estimated glomerular filtration rate, and hematocrit with 25year incidence of endstage renal disease in the multiple risk factor intervention trial. J Am Soc Nephrol Iseki K, Ikemiya Y, Iseki C, Takishita S. Proteinuria and the risk of developing endstage renal disease Zhang Z, Shahinfar S, Keane WF, Ramjit D, Dickson TZ, Gleim GW, Mogensen CE, de Zeeuw D, Brenner BM, Snapinn SM. Importance of baseline distribution of proteinuria in renal outcomes trialslessons from the reduction of endpoints in NIDDM with the angiotensin II antagonist losartan RENAALstudy. J Am Soc Nephrol Peterson JC, Adler S, Burkart JM, Greene T, Hebert LA, Hunsicker LG, King AJ, Klahr S, Massry SG, Seifter JL. Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med Lea J, Greene T, Hebert L, Lipkowitz M, Massry S, Middleton J, Rostand SG, Miller E, Smith W, Bakris GL. The relationship between magnitude of proteinuria reduction and risk of endstage renal diseaseresults of the African American study of kidney disease and hypertension. Arch Intern Med Halbesma N, Kuiken DS, Brantsma AH, Bakker SJ, Wetzels JF, De Zeeuw D, De Jong PE, Gansevoort RT. Macroalbuminuria is a better risk marker than low estimated GFR to identify individuals at risk for accelerated GFR loss in population screening. J Am Soc Nephrol Atkins RC, Briganti EM, Lewis JB, Hunsicker LG, Braden G, Champion de Crespigny PJ, DeFerrari G, Drury P, Locatelli F, Wiegmann TB, Lewis EJ. Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy. Am J Kidney Dis Jafar TH, Stark PC, Schmid CH, Landa M, Maschio G, Marcantoni C, de Jong PE, de Zeeuw D, Shahinfar S, Ruggenenti P, Remuzzi G, Levey ASAIPRD Study Group. AngiotensinConverting Enzymne Inhibition and Progression of Renal Disease. Proteinuria as a modifiable risk factor for the progression of nondiabetic renal disease Kannel WB, Stampfer MJ, Castelli WP, Verter J. The prognostic significance of proteinuriathe Framingham study. Am Heart J Damsgaard EM, Froland A, Jorgensen OD, Mogensen CE. Microalbuminuria as predictor of increased mortality in elderly people. BMJ National Kidney Foundation. KDOQI clinical practice guidelines for chronic kidney diseaseevaluation, classification, and stratification. Am J Kidney Dis S Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, McCullough PA, Kasiske BL, Kelepouris E, Klag MJ, Parfrey P, Pfeffer M, Raij L, Spinosa DJ, Wilson PW. Kidney disease as a risk factor for development of cardiovascular diseasea statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation Ninomiya T, Kiyohara Y, Kubo M, Tanizaki Y, Doi Y, Okubo K, Wakugawa Y, Hata J, Oishi Y, Shikata K, Yonemoto K, Hirakata H, Iida M. Chronic kidney disease and cardiovascular disease in a general Japanese populationthe Hisayama Study Nakayama M, Metoki H, Terawaki H, Ohkubo T, Kikuya M, Sato T, Nakayama K, Asayama K, Inoue R, Hashimoto J, Totsune K, Hoshi H, Ito S, Imai Y. Kidney dysfunction as a risk factor for first symptomatic stroke events in a general Japanese populationthe Ohasama study. Nephrol Dial Transplant Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau JL, White HD, Nordlander R, Maggioni A, Dickstein K, Zelenkofske S, Leimberger JD, Califf RM, Pfeffer MA. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med

13 2.CKD の意義 24. Kottgen A, Russell SD, Loehr LR, Crainiceanu CM, Rosamond WD, Chang PP, Chambless LE, Coresh J. Reduced kidney function as a risk factor for incident heart failurethe atherosclerosis risk in communitiesaricstudy. J Am Soc Nephrol Brugts JJ, Knetsch AM, MattaceRaso FU, Hofman A, Witteman JC. Renal function and risk of myocardial infarction in an elderly populationthe Rotterdam Study. Arch Intern Med Weiner DE, Tighiouart H, Levey AS, Elsayed E, Griffith JL, Salem DN, Sarnak MJ. Lowest systolic blood pressure is associated with stroke in stages 3 to 4 chronic kidney disease. J Am Soc Nephrol Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med Irie F, Iso H, Sairenchi T, Fukasawa N, Yamagishi K, Ikehara S, Kanashiki M, Saito Y, Ota H, Nose T. The relationships of proteinuria, serum creatinine, glomerular filtration rate with cardiovascular disease mortality in Japanese general population Manjunath G, Tighiouart H, Ibrahim H, MacLeod B, Salem DN, Griffith JL, Coresh J, Levey AS, Sarnak MJ. Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol Dinneen SF, Gerstein HC. The association of microalbuminuria and mortality in noninsulindependent diabetes mellitus. A systematic overview of the literature. Arch Intern Med Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, Halle JP, Young J, Rashkow A, Joyce C, Nawaz S, Yusuf S. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA Wachtell K, Ibsen H, Olsen MH, BorchJohnsen K, Lindholm LH, Mogensen CE, Dahlof B, Devereux RB, Beevers G, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Kristianson K, LederballePedersen O, Nieminen MS, Okin PM, Omvik P, Oparil S, Wedel H, Snapinn SM, Aurup P. Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophythe LIFE study. Ann Intern Med Hillege HL, Fidler V, Diercks GF, van Gilst WH, de Zeeuw D, van Veldhuisen DJ, Gans RO, Janssen WM, Grobbee DE, de Jong PE. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation Klausen K, BorchJohnsen K, FeldtRasmussen B, Jensen G, Clausen P, Scharling H, Appleyard M, Jensen JS. Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes. Circulation Asselbergs FW, Diercks GF, Hillege HL, van Boven AJ, Janssen WM, Voors AA, de Zeeuw D, de Jong PE, van Veldhuisen DJ, van Gilst WH. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation de Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, Snapinn S, Cooper ME, Mitch WE, Brenner BM. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation Olsen MH, Wachtell K, Ibsen H, Lindholm LH, Dahlof B, Devereux RB, Kjeldsen SE, Oikarinen L, Okin PM. Reductions in albuminuria and in electrocardiographic left ventricular hypertrophy independently improve prognosis in hypertensionthe LIFE study. J Hypertens Eriksen BO, Ingebretsen OC. The progression of chronic kidney diseasea 10year populationbased study of the effects of gender and age Iseki K, Ikemiya Y, Fukiyama K. Risk factors of endstage renal disease and serum creatinine in a communitybased mass screening Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, Van Lente F, Levey AS. Prevalence of chronic kidney disease in the United States. JAMA Konta T, Hao Z, Abiko H, Nishizawa M, Takahoshi T, Ikeda A, Ichikawa A, Takasaki S, Kubota I. Prevalence and risk factor analysis of microalbuminuria in Japanese general population Yamagata K, Takahashi H, Tomida C, Yamagata Y, Koyama A. Prognosis of asymptomatic hematuria andor proteinuria in men. High prevalence of IgA nephropathy among proteinuric patients found in mass screening. Nephron Yokoyama H, Kawai K, Kobayashi M. Microalbuminuria is common in Japanese Type 2 diabetic patients. A nationwide survey from the Japan Diabetes Clinical Data Management Study Group JDDM 10. Diabetes Care 参考にしたガイドラインなど a. National Kidney Foundation. KDOQI clinical practice guidelines for chronic kidney diseaseevaluation, classification, and stratification. Am J Kidney Dis Suppl 1S1S266. b c d e ,