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2 Maintenance hematocrit levels and mortality in hemodialysis patients with renal anemia receiving recombinant human erythropoietin (rhuepo) treatment (rhuepo survey) Yoshihei Hirasawa*1, Masashi Suzuki*1, Noritomo Itami*2, Seiji Ohira*3, Tsuguo Mizuno*4, Kentaro Mera*5, Yoshiharu Haga*5, Hironobu Kawai*6, Keiichi Mashimo*6, Isahiro Obara*7, Norio Kurosawa*7, Yasushi Nakamoto*8, Kazuo Numazawa*8, Mitsuyoshi Furuhashi*9, Yukitaka Maruyama*9, Ryuji Miki*10, Shigefumi Koike*10, Hachiro Seno*11, Hirohisa Kawahara*11, Hiroyuki Kobayashi*12, Toshihiko Ono*12, Senji Okuno*13, Masao Kim *13, Ryoichi Miyazaki*14, Yasushi Saika*15, Yoshihiro Motomiya*16, Kazuhi Taniai*17, Koji Usui*18, Kenichiro Shigemoto*19, Takashi Mizuguchi*20, Shu Kawashima*21, Kenji Yuasa*22, Kazumichi Ohta*22, Takashi Sato*23, Kenichi Fukunari*24, Yuzo Kimura*25, Hisashi Takahashi*26, Kougi Yuu*26 Department of Internal Medicine, Shinrakuen Hospital*1; Nikko Memorial Hospital*2; Nikko Memorial Hospital (Sapporo Kita Clinic)*3; Sanai Hospital*4; Nitto Hospital*5; Saiseikai Maebashi Hospital*6; Sakura Memorial Hospital*7; Kichijoji Asahi Hospital*8; Maruyama Hospital*9; Toyohashi Mates Clinic*10; Nagoya Kyoritsu Hospital, Kaikoukai Central Clinic*11; Tojinkai Hospital*12; Kidney Center, Shirasagi Hospital*13; Fujita Memorial Hospital*14; Ryoshukai Fujii Hospital Fujii Shinryosho*15; Suiyukai Clinic*16; Okayama Central Hospital*17; Ichiyokai Clinic*18; Ichiyokai Harada Hospital*19; Kamojima Kawashima Clinic*20; Kawashima Hospital*21; Kochi-Takasu Hospital*22; Koga Clinic*23; Koga Hospital 21*24; Kimura Clinic*25; Takahashi Naika Clinic*26 A total of 2,654 maintenance hemodialysis patients with at feast 6 months history of dialysis, who had been continuously treated with recombinant human erythropoietin (rhuepo) over 6 months, were included in this study. The association between maintenance hematocrit levels and patient mortality was retrospectively studied. A Cox regression analysis was performed to evaluate mortality risks. Patients with hematocrit values of 30% to <33% exhibited significantly lower 1-year mortality risk (0.447 [95% confidence intervals (CI): `0.689] p=0.0003), when compared to patients with the reference hematocrit range, 27% to <30% (reference group) [Relative Risk (RR): 1.000]. However, there was no significant difference in the 1-year mortality risk between patients with hematocrit values of 33% to <36% (0.605 [95% CI: `1.146] p= ) and the reference group. On the other hand, compared to the reference group, patients with hematocrit values of <27% exhibited significantly higher risk of death during the 1-year follow-up period (1.657 [95% CI: `2.367] p=0.0054). A similar pattern was observed for 3-year mortality risks. Compared to the reference group, patients with hematocrit values of 30% to <33% exhibited significantly lower 3-year mortality risk (0.677 [95% CI: `0.855] p=0.0010). However, there was no significant difference in 3-year mortality risk between patients with hematocrit values of 33% to <36% (1.111 [95% CI: `1.514] p=0.5036) and the reference group. Compared to the reference group, patients with hematocrit values of <27% exhibited significantly higher risk of death during the 3-year follow-up period (1.604 [95% CI: `2.019] p<0.0001). These observations demonstrate that patients with hematocrit values of 30% to less than 33% have significantly lower risk for 1-year and 3-year mortality, when compared to patients with hematocrit values of 27% to <30%. Based on mortality, our findings suggest that the maintenance hematocrit level of 30% to less than 33% is favorable for hemodialysis patients with rhuepo treatment. Though there were few patients with hematocrit values of 33% or higher, these patients exhibited lower risk of death during the 1-year follow-up period. Further study is needed to clarify the benefit of these high hematocrit levels.

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4 Clinical characteristics of the study population Survival rates of the hematocrit groups (first year and third year)

5 Patient characteristics and survival rates for all hematocrit groups combined (first year and third year) The impact of hematocrit and patient characteristics on mortality (first year and third year)

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8 1) Working party for European best practice guide lines for the management of anaemia in patients with chronic renal failure: European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant 14 (Suppl 5): 1-50, ) National Kidney Foundation anemia working group: NKF-K/DOQI Clinical Practice Guidelines for the Treatment of Anemia of Chronic Renal Failure. Am J Kidney Dis 30 (Suppl 3): S192-S240, ) National Kidney Foundation anemia working group: NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease, Am J Kidney Dis 37 (Suppl 1): S182-S238, ) Ma JZ, Ebben J, Xia H, Collins AJ: Hematocrit Level and Associated Mortality in Hemodialysis Patients. J Am Soc Nephrol 10: , ) Xia H, Ebben J, Ma JZ, Collins AJ: Hematocrit Levels and Hospitalization Risks in Hemodialysis Patients. J Am Soc Nephrol 10: , ) Collins AJ, Li S, St Peter W, Ebben J, Roberts T, Ma JZ, Manning W: Death, Hospitalization, and Economic Associations among Incident Hemodialy sis Patients with Hematocrit Values of 36 to 39%. J Am Soc Nephrol 12: , ) Inagaki H, Kuroda M, Watanabe S, Hamazaki T: Changes in major blood components after adopting the supine position during haemodialysis. Nephrol Dial Transplant 16: , ) Britten GM, Brecher G, Johnson CA, Elashoff RM: Stability of blood in commonly used anticoagulants. Am J Clin Pathol 52: ,

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