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NDT Advance Access published online on January 10, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm929
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Influence of atherosclerosis on the relationship between anaemia and mortality risk in haemodialysis patients

Kiyoshi Maekawa1, Tetsuo Shoji2, Masanori Emoto2, Senji Okuno1, Tomoyuki Yamakawa1, Eiji Ishimura3, Masaaki Inaba2 and Yoshiki Nishizawa2

1 Kidney Center, Shirasagi Hospital, Osaka, Japan 2 Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan 3 Department of Nephrology, Osaka City University Graduate School of Medicine, Osaka, Japan

Correspondence and offprint requests to: Tetsuo Shoji, MD, PhD Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan. Tel: +81-6-6645-3806; Fax: +81-6-6645-3808; E-mail: t-shoji{at}med.osaka-cu.ac.jp



   Abstract
Top
 Abstract
Short summary
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Full, as compared with partial, correction of anaemia did not reduce the mortality risk in patients with chronic kidney disease (CKD), although the underlying mechanisms are unknown. Since CKD is a high-risk population for cardiovascular disease (CVD), we tested a hypothesis that the presence of atherosclerosis affects the relationship between anaemia and mortality risk.

Methods. We performed a single-centre 10-year follow-up study with an observational cohort of 505 haemodialysis patients to analyse the relationship between haematocrit and all-cause mortality. Baseline haematocrit levels did not differ between the 153 patients with CVD and the 352 patients without CVD.

Results. During the follow-up, 268 patients died. Both Kaplan–Meier and univariate Cox analyses showed that higher haematocrit levels were a significant predictor of lower risk of death in the CVD (–) group, whereas haematocrit did not predict death in the CVD (+) group. In multivariate Cox analyses, the inverse relationship between haematocrit and mortality in the CVD (–) group remained significant and independent of 14 covariates including the use of erythropoietin. In contrast, using the same Cox models, the CVD (+) group did not show such a beneficial effect of higher haematocrit. Similar observations were made when the subjects were divided based on carotid artery intima-media thickness instead of the presence of CVD.

Conclusions. These results support the hypothesis that the presence of atherosclerosis alters the relationship between anaemia and mortality risk in haemodialysis patients.

Keywords: anaemia; atherosclerosis; cardiovascular disease; haemodialysis; mortality risk



   Short summary
Top
 Abstract
 Short summary
Introduction
 Methods
 Results
 Discussion
 References
 
The relationship between haematocrit and mortality risk varies depending upon the presence or absence of cardiovascular disease/atherosclerosis in haemodialysis patients.



   Introduction
Top
 Abstract
 Short summary
 Introduction
Methods
 Results
 Discussion
 References
 
Death risk is substantially elevated in end-stage renal disease, and the cardiovascular disease is the leading cause of death in the haemodialysis population [1]. Recent studies revealed that risk of occurrence of cardiovascular disease (CVD) events [2] and risk of death after myocardial infarction [3] are both increased in a stepwise manner as the stage of chronic kidney disease (CKD) is advanced before renal replacement therapies are initiated. Arterial wall thickness [4] and stiffness [5,6] are increased in predialysis patients with CKD as well as in patients on maintenance haemodialysis [7–9]. These vascular wall changes are predictors for mortality in the haemodialysis population [10, 11].

In addition to these atherosclerotic vascular changes, anaemia is associated with poor survival in CKD patients. Anaemia is associated with impairment in quality of life [12], physical performance [13] and survival in haemodialysis patients [14,15]. Partial correction of anaemia with human recombinant erythropoietin (rHuEPO) was reported to improve physical performance [16] and left ventricular hypertrophy (LVH) [17] in haemodialysis patients, and it was also reported to retard loss of renal function in predialysis patients with chronic renal failure [18]. Clinical practice guidelines from Europe [19] and the United States [20] have recommended to achieve a haemoglobin level >11 g/dL (haematocrit higher than 33%).

Surprisingly, however, normalization of the haematocrit or haemoglobin level is not necessarily better for survival, LVH and renal function as shown in randomized controlled trials in patients with stage 5 CKD on dialysis [21,22] and in patients with stage 3–4 CKD [23,24]. A recent meta-analysis of these studies [25] showed that full, as compared with partial, correction of haemoglobin and haematocrit levels is associated with increased risk of all-cause mortality by 17%. The US Food and Drug Administration (FDA) advised physicians to monitor patients’ haemoglobin levels to ensure they do not exceed 12 g/dL [26]. The National Kidney Foundation has also updated the target haemoglobin levels generally to be in the range of 11.0–12.0 g/dL in the latest version of the KDOQI guidelines [27].

So far, however, it is unknown whether all haemodialysis patients benefit from the recommended level of anaemia correction. Lower haematocrit levels might be better for some specific groups of haemodialysis patients. A higher haematocrit directly increases oxygen content of blood on one hand, but it increases blood viscosity and reduces blood flow volume on the other hand. Accordingly, there is an optimal haematocrit level in view of oxygen delivery to tissue [28]. Since blood flow volume is affected not only by blood viscosity but blood vessel as well, it is possible that the optimal haematocrit levels for survival are different in the absence and the presence of atherosclerosis.

In the present study using a historical cohort of haemodialysis patients, we tested the above hypothesis by examining the association between haematocrit levels and mortality risk in the two groups of haemodialysis patients with and without history of CVD at baseline. Similar analyses were also performed based on carotid artery intima-media thickness (CA-IMT) at baseline, rather than history of CVD.



   Methods
Top
 Abstract
 Short summary
 Introduction
 Methods
Results
 Discussion
 References
 
Study design and subjects
This is a observational cohort study of patients on maintenance haemodialysis to analyse predictors of mortality. Baseline studies were performed in October 1996. Information was collected for pre-existing CVD, medications, body weight, height, blood pressure, haematocrit, blood chemistry and other clinical parameters. In 423 patients who agreed to perform carotid arterial echography, carotid artery intima-media thickness was also measured in the period between August and October 1996. The cohort was followed up until October 2006. They had been treated by regular haemodialysis for >1 month at Kidney Center, Shirasagi Hospital, Osaka, Japan. The 505 subjects were recruited from 508 total outpatients on haemodialysis excluding 3 with advanced malignancy at baseline. Mean (±SD) age at entry was 60.2 ± 12.5 years, and 61% of them were male. Mean Kt/V was 1.14 ± 0.23. Median (range) duration of haemodialysis before inclusion was 55 (1–312) months. They received 3–5 h of haemodialysis, three times a week, using standard bicarbonate dialysate. This study was approved by the ethics committee of the hospital, and all the subjects gave informed consent to participate in the study.

Pre-existing CVD at baseline
Pre-existence of CVD was evaluated by clinical information regarding coronary, cerebral and peripheral artery diseases and aortic aneurysm. Coronary artery disease was diagnosed when a subject had one or more of the following criteria: (1) past history of percutaneous coronary intervention or coronary artery bypass grafting, (2) presence of significant stenosis by coronary angiography, (3) presence of ST-T abnormalities on electrocardiogram associating typical symptoms attributable to angina pectoris and (4) use of one or more medications for coronary ischaemia. Seventy-seven patients were diagnosed to have coronary artery disease. Cerebrovascular disease was diagnosed by past history that had been confirmed by positive findings of infarction or bleeding by X-ray computed tomography or magnetic resonance imaging. Seventy-two patients had such past history. Peripheral artery disease was diagnosed in seventeen patients whose legs had been amputated due to angiographically demonstrated leg ischaemia. Diagnosis of aortic aneurysm was made by X-ray computed tomography in six patients. At baseline, 153 patients had one or more of the above cardiovascular complications.

Body weight and blood pressure measurements
Body weight denotes ‘dry weight’ and body mass index (BMI) was calculated by dividing dry weight (kg) by squared height (m2). Blood pressure was measured with a standard mercury sphygmomanometer and cuffs adapted to arm circumference, after the subject had rested in the supine position for at least 5 min. The systolic and diastolic blood pressure levels were taken as the points of appearance and disappearance of Korotkoff sounds, respectively. The average of three measurements was used for analysis.

Blood sampling and assays
Blood was taken just before the start of the first dialysis session of the week in a supine position, and drawn into vacuum plastic tubes. Whole blood was used for haematocrit and serum for other biochemical assays. These assays were performed without delay using an automated analyser. Intact parathyroid hormone (PTH) was determined by a two-site immunoradiometric assay (Allegro Intact PTH, Nichols Institute Diagnostics, CA, USA) [29].

Carotid artery intima-media thickness (CA-IMT)
CA-IMT was measured by high-resolution real-time ultrasonography as we previously described [7,30,31]. In this study, we used an ultrasound apparatus with a 7.5 MHz linear scanner (Aloka Model SSD 610 CL, Aloka Co. Ltd, Tokyo, Japan) [32]. The maximum value of the intima-media complex at the most advanced carotid lesion was used for analysis. The coefficient of variation (CV) of CA-IMT by this method was 3.3% for haemodialysis patients [7]. In our previous study [33], 0.94 mm was the 95th percentile level of CA-IMT among 446 healthy Japanese people.

Outcome data collection
The haemodialysis cohort was followed up to the end of September 2006 with a mean and a median (range) follow-up period of 82 and 93 (1–120) months, respectively. At the end of the follow-up, 217 patients were confirmed to be alive on haemodialysis and 269 patients to be dead. The date and cause of death were obtained by reviewing the hospital record forms. The remaining 19 out of the 505 total patients were censored during the follow-up, either at the time of renal transplantation (n = 5) or at the time of moving away from Shirasagi Hospital (n = 14).

Statistical analysis
Continuous variables were summarized as mean ± SD. Median (range) was given for duration of haemodialysis, C-reactive protein and intact PTH because of their skewed distribution. Proportion was given in percentage. Differences of mean, median and percentage between two groups were evaluated by analysis of variance, Mann–Whitney U-test or {chi}2 test, respectively. Survival curves were constructed by the Kaplan–Meier method and evaluated by the log-rank test. Prognostic variables for survival were examined using univariate Cox proportional hazards regression models, and independent predictors of death were determined by using multivariate Cox analyses. P-values <0.05 were considered significant. All these analyses were performed using statistical software (StatView 5, SAS Institute Inc., Cary, NC, USA) for Windows personal computers.



   Results
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 Abstract
 Short summary
 Introduction
 Methods
 Results
Discussion
 References
 
Baseline characteristics of the cohort
Baseline studies were performed in October 1996. Table 1 summarizes the baseline characteristics of the cohort. At baseline, 153 out of the total 505 subjects had pre-existing CVD as defined in the Methods section.


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  		Table 1 Baseline characteristics of the cohort

 
Outcomes and death rates of the cohort
For the total cohort, 268 deaths occurred during the mean follow-up of 82 months, and the crude annual mortality rate was 7.8%. This figure was lower than the mortality rate of 9.4% for the entire Japanese dialysis patients in 1996 reported by the Japanese Society for Dialysis Therapy (JSDT) but higher than the mortality rate of 6.4% for the Japanese dialysis patients participating in the DOPPS [34].

The causes of 268 deaths included 142 fatal cardiovascular events: coronary heart disease (n = 30), cerebrovascular disease (n = 36), congestive heart failure (n = 39), rupture of aortic aneurysm (n = 5), ischaemic colitis (n = 8) and sudden death (n = 24). Sudden death was defined as a witnessed death that occurred within 1 h after the onset of acute symptoms, with no evidence of accident or violence. The 126 fatal non-cardiovascular causes were infectious disease (n = 40), malignancy (n = 22), hepatic failure (n = 12), respiratory disease (n = 8), gastrointestinal disease (n = 4), bleeding (n = 4), accident (n = 4), declining of dialysis (n = 2), suicide (n = 1) and others (n = 29).

In the CVD (–) group, 139 deaths were recorded during the mean follow-up of 92 months, and the crude annual mortality rate was 5.2%. The causes of death were coronary heart disease (n = 10), cerebrovascular disease (n = 17), congestive heart failure (n = 9), rupture of aortic aneurysm (n = 1), ischaemic colitis (n = 6), sudden death (n = 15), infectious disease (n = 21), malignancy (n = 17), hepatic failure (n = 8), respiratory disease (n = 5), gastrointestinal disease (n = 3), bleeding (n = 3), accident (n = 3), declining of dialysis (n = 2) and others (n = 19).

In the CVD (+) group, 129 deaths occurred during the mean follow-up period of 59 months, and the crude annual mortality rate was 17.1%. The causes of death were coronary heart disease (n = 20), cerebrovascular disease (n = 19), congestive heart failure (n = 30), rupture of aortic aneurysm (n = 4), ischaemic colitis (n = 2), sudden death (n = 9), infectious disease (n = 19), malignancy (n = 5), hepatic failure (n = 4), respiratory disease (n = 3), gastrointestinal disease (n = 1), bleeding (n = 1), accident (n = 1), suicide (n = 1) and others (n = 10).

Mortality rates in relation to haematocrit levels in the CVD (–) and CVD (+) groups
We divided the total cohort into four categories by haematocrit levels at an interval of 3%, namely <27%, 27–30%, 30–33% and 33% or higher. The distribution of subjects among the four haematocrit categories was 99, 148, 60, 45 for the CVD (–) group and 48, 62, 19, 24 for the CVD (+) group. Then, we analysed the association between the haematocrit and mortality risk in the CVD (–) and the CVD (+) groups, respectively, by the Kaplan–Meier method (Figure 1). In the CVD (–) group, mortality rate was significantly lower in the higher levels of haematocrit. Univariate Cox analysis indicated that an increase in haematocrit (%) by 1 point was associated with a decrease in mortality by 8.1% (Table 2). In contrast, such an inverse relationship was not significant in the CVD (+) group.


Figure 1
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  		Fig. 1 Kaplan–Meier curves showing association between haematocrit and risk of all-cause mortality in haemodialysis patients with and without CVD at baseline. P-values by the log-rank test. Abbreviation: CVD, cardiovascular disease.

 

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  		Table 2 Univariate Cox analysis of predictors of all-cause mortality

 
Other univariate predictors of mortality
Other predictors of mortality were examined by univariate Cox analysis (Table 2). In the total cohort, significant predictors other than a lower haematocrit were, a higher age, a shorter duration of dialysis, the pre-existence of CVD, the presence of diabetes mellitus, a lower BMI, a lower serum albumin, a higher C-reactive protein (CRP), a lower high-density lipoprotein (HDL) cholesterol, a lower serum phosphorus and a lower serum calcium. Sex was at a borderline significance (P = 0.075), but intact PTH was not significant in univariate Cox analysis.

In the CVD (–) group, significant predictors other than a lower haematocrit were a higher age, the presence of diabetes mellitus, a lower serum albumin, a higher CRP and a lower HDL cholesterol. Other variables were not significant in univariate Cox analysis.

In the CVD (+) group, significant predictors were a higher age, the presence of diabetes mellitus, a lower serum albumin and a higher CRP. Other variables were not significant in univariate Cox analysis.

Multivariate Cox analysis in the CVD (–) and CVD (+) groups
We examined whether the inverse association between haematocrit and mortality risk in the CVD (–) group was independent of other confounding variables using multivariate Cox models (Table 3). When unadjusted for other variables, a higher haematocrit level was significantly associated with a lower risk of death (Model 1). The inverse association remained significant after adjustment for age, sex, duration of dialysis, systolic blood pressure and diabetes mellitus (Model 2). Further adjustment for CRP, serum albumin and BMI (Model 3), plus calcium and phosphorus (Model 4), plus HDL cholesterol (Model 5) did not alter the association between haematocrit and mortality. The inverse association between haematocrit and mortality risk in the CVD (–) group remained significant even after further adjustment for medications such as use of erythropoietin (Model 6), use of calcium carbonate and use of anti-hypertensive medications (Model 7).


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  		Table 3 Association of haematocrit with mortality risk in subgroups with and without CVD at baseline

 
By contrast, in the CVD (+) group, the association between haematocrit and mortality risk was consistently insignificant when adjusted for these covariates using the same models.

Analyses based on CA-IMT instead of history of CVD
To evaluate whether atherosclerotic vascular changes explain the distinct patterns of mortality in relation to haematocrit in the CVD (–) and CVD (+) groups, we analysed the data based on CA-IMT rather than history of CVD. Data of carotid artery ultrasound examinations were available in 423 out of the 505 total subjects. The 423 patients were divided into two groups having lower CA-IMT (<0.94 mm, n = 279) and higher CA-IMT (>0.94 mm, n = 144) values. The cut-off level was the 95th percentile level of 446 healthy Japanese subjects enrolled in our previous study [33]. As compared with the total cohort of the 505 patients, the 423 patients were not different in age (60.1 ± 12.6 years), sex (61% male), haematocrit (28.8 ± 3.7%) or the crude annual mortality rate (7.8%). The numbers of deaths, mean follow-up periods and crude annual mortality rates for the lower versus the higher CA-IMT groups were 110 versus 113 deaths, 91.5 versus 60.0 months and 5.2% versus 15.7%, respectively.

Table 4 gives Cox analyses performed to examine the association between haematocrit and mortality in the lower and higher CA-IMT groups separately using the same models as shown in Table 3. The lower CA-IMT group repeatedly showed significant and inverse association of haematocrit with mortality risk in these models, although it was at a borderline significance (P = 0.076) in Model 7 in which full adjustment was made for the 14 covariates. In contrast, the higher CA-IMT group consistently showed no significant association of haematocrit with mortality risk.


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  		Table 4 Association of haematocrit with mortality risk in subgroups based on CA-IMT at baseline

 


   Discussion
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 Abstract
 Short summary
 Introduction
 Methods
 Results
 Discussion
References
 
We examined whether the presence of atherosclerosis affects the association between haematocrit and mortality risk in this observational cohort study of haemodialysis patients. The patients without CVD showed an inverse association between haematocrit and mortality risk, whereas those with CVD did not show such a clear association. The distinct pattern of the haematocrit–mortality relationship between the patient groups with and without CVD was consistently found even after multivariate adjustment. Similarly, the patients having a lower CA-IMT showed an inverse association between haematocrit and mortality risk, whereas those having a higher CA-IMT did not show such an association. These data indicate that atherosclerosis is an important factor affecting the risk of death due to anaemia in haemodialysis patients.

The present study showed that a higher haematocrit level was significantly associated with a lower risk of mortality in haemodialysis patients without atherosclerosis, but that haematocrit was not significantly associated with mortality risk in the subgroup of haemodialysis patients with atherosclerosis. Although the precise mechanism is unknown, there are several explanations for this observation. First, although a higher haematocrit directly increases oxygen content of blood, it also increases blood viscosity and reduces flow volume. Therefore, oxygen delivery to vital organs may be decreased over a certain level of haematocrit as reported by Hirakata et al. [28]. Since blood flow volume is affected not only by blood viscosity but also by blood vessel properties, we speculate that such an adverse rheological impact of a higher haematocrit on tissue oxygen delivery is greater in subjects with atherosclerotic vascular changes, resulting in worse outcomes. In support of our speculation, Ruschitzka et al. [35] reported survival of transgenic mice overexpressing human erythropoietin that developed polycythaemia with haematocrit of 80%. The survival of the polycythaemic mice was not shorter due to marked increase in endothelial nitric oxide (NO) synthase, NO-mediated endothelium-dependent relaxation, and circulating and vascular tissue NO levels. Inhibition of NO synthesis by treatment with L-NAME resulted in vasoconstriction of peripheral resistance vessels, hypertension and death of the polycythaemic mice in a few days, whereas wild-type siblings did not show increased mortality despite hypertension following the same treatment. Clinically, endothelial function is impaired in patients with CVD [36], correlating closely with CA-IMT [37]. Thus, the difference in the haematocrit–mortality relationship between the CVD (–) and CVD (+) groups could be attributable at least partly to the presence of atherosclerotic vascular changes that reflect the impaired NO system in the CVD (+) group.

Second, because anaemia correction improves vitality and physical activity, the risk of cardiac events may be raised at higher haematocrit levels if the patient has advanced atherosclerosis. Such an increased risk is less likely to occur in those without atherosclerosis. Also, improved activity may increase intake of sodium and potassium, resulting in hypertension, cardiac accidents and worse outcomes.

Third, the means to achieve a higher target of haematocrit may have deleterious effects. Iron is a highly reactive metal that may increase oxidative stress if it is excessively accumulated. In dialysis patients, the regulation of intracellular iron storage is impaired and its levels in polymorphonuclear leukocytes are increased [38]. A high serum ferritin level is known as a predictor of poor survival of haemodialysis patients [39]. In addition, the use of rHuEPO may increase blood pressure [40] which could have an additional adverse impact on survival. However, we failed to show the association of the use of rHuEPO or intravenous iron injections with mortality risk in the present cohort.

Our data support the current concept that we should aim at a higher haemoglobin/haematocrit level within the range of ‘partial’ correction of anaemia. In haemodialysis patients without CVD, a higher haematocrit level was associated with better survival. Although a higher haematocrit was not associated with better survival in those with CVD, better quality of life is expected by anaemia correction [12]. Thus, haemodialysis patients would receive overall benefit from partial anaemia correction regardless of the presence of CVD.

There are limitations in this study. First, because of the observational nature of this cohort study, the associations do not necessarily indicate causality. Therefore, although the results of this study are of clinical interest, randomized controlled trials are needed to prove the hypothesis. Second, our study does not answer whether haematocrit levels higher than the recommended target are associated with worse outcome in patients with atherosclerosis. Such an analysis was difficult because the haematocrit levels were relatively low. Only 69 patients (13.6%) of the cohort exceeded a the haematocrit of 33%, the upper limit of the target range recommended by the Japanese Society for Dialysis Therapy [41], and 29 patients (5.7%) exceeded a the haematocrit of 36% that corresponds to the upper limit of the recommended haemoglobin level (12 g/dL) by the latest FDA Sounds Alert [26] and the KDOQI guidelines [27]. Third, although the cohort of this study included most of the haemodialysis patients of the hospital, there might have been some selection bias. This was a single-centre study of prevalent dialysis patients in an urban area of Osaka, Japan. Thus, generalizability should be carefully considered with regard to ethnic groups, geographic areas and prevalent versus incident dialysis patients. Fourth, we calculated the mortality risk based on the one-point measurements of haematocrit at the start of observation, not averaged values during the follow-up. Therefore, we could only show the very remote effect on mortality during a 10-year follow-up. Time-varying analysis based on sequential measurements during the follow-up may give more direct association between haematocrit and outcomes. Fifth, because many haemodialysis patients are thought to have asymptomatic coronary artery disease, such patients with advanced atherosclerosis might have been excluded from the CVD (+) group, and the association among anaemia, atherosclerosis and mortality risk might have been underestimated. This is the reason why we performed additional analysis based on CA-IMT. However, since CA-IMT could not perfectly predict asymptomatic coronary lesions, studies with coronary angiography may provide more impressive data than the current study.

In conclusion, the present observational study indicates that higher as compared to lower achieved haematocrit levels are only associated with better prognosis in patients without evidence for advanced atherosclerosis. This could imply that optimal target haemoglobin levels differ depending on cardiovascular comorbidity.

Conflict of interest statement. None declared. Part of this study was presented as a poster (SU-PO581) at Renal Week 2008 of American Society of Nephrology, San Francisco, California, and published as an abstract form (J Am Soc Nephrol 2007; 18: 711A).



   References
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 Abstract
 Short summary
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis (1998) 32:S112–S119.[Web of Science][Medline]
  2. 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) 351:1296–1305.[Abstract/Free Full Text]
  3. Anavekar NS, McMurray JJ, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med (2004) 351:1285–1295.[Abstract/Free Full Text]
  4. Shoji T, Emoto M, Tabata T, et al. Advanced atherosclerosis in predialysis patients with chronic renal failure. Kidney Int (2002) 61:2187–2192.[CrossRef][Web of Science][Medline]
  5. Shinohara K, Shoji T, Tsujimoto Y, et al. Arterial stiffness in predialysis patients with uremia. Kidney Int (2004) 65:936–943.[CrossRef][Web of Science][Medline]
  6. Kimoto E, Shoji T, Shinohara K, et al. Regional arterial stiffness in patients with type 2 diabetes and chronic kidney disease. J Am Soc Nephrol (2006) 17:2245–2252.[Abstract/Free Full Text]
  7. Kawagishi T, Nishizawa Y, Konishi T, et al. High-resolution B-mode ultrasonography in evaluation of atherosclerosis in uremia. Kidney Int (1995) 48:820–826.[Web of Science][Medline]
  8. Shoji T, Nishizawa Y, Kawagishi T, et al. Intermediate-density lipoprotein as an independent risk factor for aortic atherosclerosis in hemodialysis patients. J Am Soc Nephrol (1998) 9:1277–1284.[Abstract]
  9. London GM, Marchais SJ, Safar ME, et al. Aortic and large artery compliance in end-stage renal failure. Kidney Int (1990) 37:137–142.[Web of Science][Medline]
  10. Shoji T, Emoto M, Shinohara K, et al. Diabetes mellitus, aortic stiffness, and cardiovascular mortality in end-stage renal disease. J Am Soc Nephrol (2001) 12:2117–2124.[Abstract/Free Full Text]
  11. Nishizawa Y, Shoji T, Maekawa K, et al. Intima-media thickness of carotid artery predicts cardiovascular mortality in hemodialysis patients. Am J Kidney Dis (2003) 41:S76–S79.[CrossRef][Web of Science][Medline]
  12. Kalantar-Zadeh K, Kopple JD, Block G, et al. Association among SF36 quality of life measures and nutrition, hospitalization, and mortality in hemodialysis. J Am Soc Nephrol (2001) 12:2797–2806.[Abstract/Free Full Text]
  13. Grunze M, Kohlmann M, Mulligan M, et al. Mechanisms of improved physical performance of chronic hemodialysis patients after erythropoietin treatment. Am J Nephrol (1990) 10(Suppl_2):15–18, 18–23. discussion.[Web of Science][Medline]
  14. Foley RN, Parfrey PS, Harnett JD, et al. The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease. Am J Kidney Dis (1996) 28:53–61.[Web of Science][Medline]
  15. Locatelli F, Pisoni RL, Combe C, et al. Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant (2004) 19:121–132.[Abstract/Free Full Text]
  16. McMahon LP, McKenna MJ, Sangkabutra T, et al. Physical performance and associated electrolyte changes after haemoglobin normalization: a comparative study in haemodialysis patients. Nephrol Dial Transplant (1999) 14:1182–1187.[Abstract/Free Full Text]
  17. Pascual J, Teruel JL, Moya JL, et al. Regression of left ventricular hypertrophy after partial correction of anemia with erythropoietin in patients on hemodialysis: a prospective study. Clin Nephrol (1991) 35:280–287.[Web of Science][Medline]
  18. 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) 77:176–185.[Web of Science][Medline]
  19. Locatelli F, Aljama P, Barany P, et al. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant (2004) 19(Suppl 2):ii1–ii47.[Free Full Text]
  20. KDOQI Clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis (2006) 47:S11–S145.[CrossRef][Medline]
  21. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med (1998) 339:584–590.[Abstract/Free Full Text]
  22. Parfrey PS, Foley RN, Wittreich BH, et al. Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. J Am Soc Nephrol (2005) 16:2180–2189.[Abstract/Free Full Text]
  23. 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) 355:2071–2084.[Abstract/Free Full Text]
  24. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med (2006) 355:2085–2098.[Abstract/Free Full Text]
  25. Phrommintikul A, Haas SJ, Elsik M, et al. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet (2007) 369:381–388.[CrossRef][Web of Science][Medline]
  26. Mitka M. FDA sounds alert on anemia drugs. JAMA (2007) 297:1868–1869.[Free Full Text]
  27. KDOQI Clinical practice guideline and clinical practice recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis (2007) 50:471–530.[CrossRef][Medline]
  28. Hirakata H, Kanai H, Fukuda K, et al. Optimal hematocrit for the maximum oxygen delivery to the brain with recombinant human erythropoietin in hemodialysis patients. Clin Nephrol (2000) 53:354–361.[Web of Science][Medline]
  29. Nussbaum SR, Zahradnik RJ, Lavigne JR, et al. Highly sensitive two-site immunoradiometric assay of parathyrin, and its clinical utility in evaluating patients with hypercalcemia. Clin Chem (1987) 33:1364–1367.[Abstract/Free Full Text]
  30. Hosoi M, Nishizawa Y, Kogawa K, et al. Angiotensin-converting enzyme gene polymorphism is associated with carotid arterial wall thickness in non-insulin-dependent diabetic patients. Circulation (1996) 94:704–707.[Abstract/Free Full Text]
  31. Kogawa K, Nishizawa Y, Hosoi M, et al. Effect of polymorphism of apolipoprotein E and angiotensin-converting enzyme genes on arterial wall thickness. Diabetes (1997) 46:682–687.[Abstract]
  32. Emoto M, Nishizawa Y, Kawagishi T, et al. Stiffness indexes beta of the common carotid and femoral arteries are associated with insulin resistance in NIDDM. Diabetes Care (1998) 21:1178–1182.[Abstract]
  33. Fukumoto M, Shoji T, Emoto M, et al. Antibodies against oxidized LDL and carotid artery intima-media thickness in a healthy population. Arterioscler Thromb Vasc Biol (2000) 20:703–707.[Abstract/Free Full Text]
  34. Goodkin DA, Bragg-Gresham JL, Koenig KG, et al. Association of comorbid conditions and mortality in hemodialysis patients in Europe, Japan, and the United States: the Dialysis Outcomes and Practice Patterns Study (DOPPS). J Am Soc Nephrol (2003) 14:3270–3277.[Abstract/Free Full Text]
  35. Ruschitzka FT, Wenger RH, Stallmach T, et al. Nitric oxide prevents cardiovascular disease and determines survival in polyglobulic mice overexpressing erythropoietin. Proc Natl Acad Sci USA (2000) 97:11609–11613.[Abstract/Free Full Text]
  36. Neunteufl T, Katzenschlager R, Hassan A, et al. Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease. Atherosclerosis (1997) 129:111–118.[CrossRef][Web of Science][Medline]
  37. Kobayashi K, Akishita M, Yu W, et al. Interrelationship between non-invasive measurements of atherosclerosis: flow-mediated dilation of brachial artery, carotid intima-media thickness and pulse wave velocity. Atherosclerosis (2004) 173:13–18.[CrossRef][Web of Science][Medline]
  38. Otaki Y, Nakanishi T, Hasuike Y, et al. Defective regulation of iron transporters leading to iron excess in the polymorphonuclear leukocytes of patients on maintenance hemodialysis. Am J Kidney Dis (2004) 43:1030–1039.[CrossRef][Web of Science][Medline]
  39. Kalantar-Zadeh K, Don BR, Rodriguez RA, et al. Serum ferritin is a marker of morbidity and mortality in hemodialysis patients. Am J Kidney Dis (2001) 37:564–572.[Web of Science][Medline]
  40. Vaziri ND. Mechanism of erythropoietin-induced hypertension. Am J Kidney Dis (1999) 33:821–828.[Web of Science][Medline]
  41. Gejyo F, Saito A, Akizawa T, et al. 2004 Japanese Society for Dialysis Therapy guidelines for renal anemia in chronic hemodialysis patients. Ther Apher Dial (2004) 8:443–459.[CrossRef][Web of Science][Medline]
Received for publication: 15.10.07
Accepted in revised form: 12.12.07


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