90 (GFR<30 ml/min) 10 g/dl 0.2 [2,3] [1] (nephron) ( ) (angiotensin converting enzyme inhibitors, ACEI) (angiotensin receptor blockers, ARB)

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1 * * [1] (angiotensin converting enzyme inhibitors, ACEI) (angiotensin receptor blockers, ARB) (Hemoglobin, Hgb) 13 g/dl 12 g/dl 90 (GFR<30 ml/min) 10 g/dl [2,3] (nephron) ( ) ( 1.) (glomerulosclerosis)

2 (interstitial fibrosis) (interstitial fibrosis) (hypoxia) (matrix) (profibrotic) transforming growth factor- (TGF- ) endothelin-1 (fibroblastic cells) (atubular glomeruli) (reactive oxygen species) (oxidative stress) (proinflammatory) monocyte chemotactic protein-1 TGF- 1 (erythropoietin, EPO) (antiapoptotic properties) (interstitial capillary network) [4] superoxide dismutase, catalase, glutathione peroxidase (reactive oxygen species) C E coenzyme Q Glutathione reductase glutathione (angiogenesis) (proangiogenic effect) Bahlmann

3 Garcia 1988 [5] 5/ % 33% 1980 RENAAL losartan [6] 11.2 g/dl 13.8 g/dl (60% vs 20%) Roth 1994 [7] mg/dl 43 rhu-epo 50 U/kg EPO (hematocrit, Hct) (glomerular filtration rate, GFR) EPO ml/min ml/min p = EPO ( 16 Hct > 35%) GFR 3 ( GFR ml/min/month vs. GFR ml/min/ month, P = 0.05) Kuriyama 1997 EPO [8]

4 2-4 mg/dl 31 (Hct < 30%) EPO 42 (Hct < 30%) EPO 35 (Hct > 30%) EPO ACEI (primary end point) (serum creatinine doubling) 26 (84%) 22 (52%) 21 (60%) (P < ) EPO Jungers 2001 [9] ( Ccr) EPO µmol/l Ccr 15 ml/ min/1.73 m 2 43 rhuepo T 0 T 0 24 T 0 Ccr T 0 Ccr EPO Ccr ml/min/1.73 m 2 EPO Ccr ml/min/1.73 m 2 P 0.05 EPO EPO (P < 0.01) Teplan 2003 (keto acids, KA) (low protein diet, LPD) [10] ml/min LPD + EPO + KA LPD + EPO LPD Tapolyai 2003 [11] 18 EPO 12 EPO 12 EPO mg/dl 30% EPO 33-37% % % EPO 1/creatinine (non-parametric Wilcoxon matched pairs signed rank sum test: Z value: -2.91; P = 0.004) EPO 12 5/18 EPO 2004 Gouva [12] mg/dl, Hgb g/dl EPO 13 g/ dl 9 g/dl EPO 8 mg/dl (renal replacement) 22.5 EPO

5 12 EPO 2001 ECAP (The Effect of Early Correction of Anaemia on the Progression of Chronic Kidney Disease Study) EPO GFR ml/min 13 g/dl 12.5 g/dl EPO g/dl 11 g/dl EPO (pure red cell aplasia, PRCA) epoetin GFR (0.058 vs ml/min/1.73 m 2 /month) [13] 2007 [14] EPO EPO g/dl g/dl EPO g/dl PRCA GFR ml/min/1.73 m g/dl (Hgb g/dl) EPO (Hgb g/dl) GFR [15] 2006 CHOIR [16] 1432 (GFR ml/min/1.73 m2) 11 g/dl 13.5 g/dl 11.3 g/ dl 12.6 g/dl 11.3 g/dl 16 CREATE [17] 603 (GFR ml/min/1.73 m 2 ) (Hgb g/dl) (Hgb g/dl) 8 (transient ischemic accident) Phrommintikul [18] meta-analysis

6 ( 1.17, P = 0.031) ( 1.16, P = ) DOQI 13 g/dl 1. Meguid El, Nahas A, Bello AK: Chronic kidney disease: The global challenge. Lancet 2005; 365: Sarnak MJ, Tighiouart H, Manjunath G, MacLeod B, Griffith J, Salem D, Levey AS, et al: Anemia as a risk factor for cardiovascular disease in The Atherosclerosis Risk in Communities (ARIC) study. J Am Coll Cardiol 2003; 40: McClellan WM; Flanders WD; Langston RD; Jurkovitz C; Presley R, et al: Anemia and renal insufficiency are independent risk factors for death among patients with congestive heart failure admitted to community hospitals: a population-based study. J Am Soc Nephrol 2002; 13: Rossert J, Froissart M, Jacquot C: Anemia management and chronic renal failure progression. Kidney Int 2005; 68 (suppl 99): S Garcia DL, Anderson S, Rennke HG, Brenner BM: Anemia lessens and its prevention with recombinant human erythropoietin worsens glomerular injury and hypertension in rats with reduced renal mass. Proc Natl Acad Sci USA 1988; 85: Keane WF, Brenner BM, de Zeeuw D, et al: The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy: The RENAAL study. Kidney Int 2003; 63: Roth D, Smith RD, Schulman G, et al: Effects of recombinant human erythropoietin on renal function in chronic renal failure predialysis patients. Am J Kidney Dis 1994; 24: Kuriyama S, Tomonari H, Yoshida H, et al: Reversal of anemia by erythropoietin therapy retards the progression of chronic renal failure, especially in nondiabetic patients. Nephron 1997; 77: Jungers P, Choukroun G, Oualim Z, et al: Beneficial influence of recombinant human erythropoietin therapy on the rate of progression of chronic renal failure in predialysis patients. Nephrol Dial Transplant 2001; 16: Teplan V, Schuck O, Knotek A, Hajny J, Horackova M, Kvapil M: Enhanced metabolic effect of erythropoietin and keto acids in CRF patients on low-protein diet: Czech multicenter study. Am J Kidney Dis 2003; 41 (suppl 1): S Tapolyai M, Kadomatsu S, Perera-Chong M: r.hu- Erythropoietin (EPO) treatment of pre-esrd patients slows the rate of progression of renal decline. BMC Nephrology 2003; 4: Gouva C, Nikolopoulos P, Ioannidis JP, Siamopoulos KC: Treating anemia early in renal failure patients slows the decline of renal function: A randomized controlled trial. Kidney Int 2004; 66: Rossert J, Levin A, Roger SD, et al: Effect of early correction of anemia on the progression of CKD. Am J Kidney Dis 2006; 47: Macdougall IC, Mark Temple R, Kwan JTC, on behalf of the EPO-GBR-2 Study Group: Is early treatment of anaemia with epoetin- beneficial to pre-dialysis chronic kidney disease patients? Results of a multicentre, open-label, prospective, randomized, comparative group trial. Nephrol Dial Transplant 2007; 22: Villar E, Lievre M, Labeeuw M, Pouteil-Noble C: [The NEPHRODIAB2 randomized trial.] Nephrologie 2003; 24: (French) 16. Singh AK, Szczech L, Tang KL. et al: Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355: Drueke TB, Locatelli F, Clyne N, et al: Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006; 355: Phrommintikul A, Haas SJ, Elsik M, Krum H: Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a metaanalysis. Lancet 2007; 369: