Haematocrit and the risk of developing end-stage renal disease
Kunitoshi Iseki,
Yoshiharu Ikemiya,
Chiho Iseki and
Shuichi Takishita
Dialysis Unit and Third Department of Internal Medicine, University of The Ryukyus and Okinawa General Health Maintenance Association, Okinawa, Japan
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Abstract
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Background. Anaemia is common in patients with renal failure; however, it is not known whether haematocrit level in the general population is a predictor for developing end-stage renal disease (ESRD).
Methods. A retrospective analysis was conducted to assess the development of ESRD within a population of 71 802 subjects (37 190 men and 34 612 women), 2099 years, in Okinawa, Japan. Haematocrit data were collected between April 1983 and March 1984 and the subjects were followed forward to the year 2000 whether they were identified in the Okinawa Dialysis Study registry for identification of ESRD. Multivariate logistic analyses were performed to analyse the influence of haematocrit on the development of ESRD after adjusting for age, sex, blood pressure, body mass index, proteinuria and haematuria. In a subgroup of the cohort, similar analyses were repeated adjusting for estimated creatinine clearance by the method of Cockcroft and Gault.
Results. The mean (SD) level of haematocrit at the time of screening was 45.3% (3.3%) for men and 38.8% (3.2%) for women. During the 17-year follow-up, 269 patients (171 men and 98 women) were identified with ESRD. The mean time to onset of ESRD was 130.4 (53.6) months. The adjusted odds ratio and 95% confidence interval (CI) for the influence of haematocrit (%) on the development of ESRD was 0.991 and 0.9880.995 (P<0.0001), suggesting that the lower haematocrit, the greater was the risk of developing ESRD. This finding was repeated in the subgroup analysis that included calculated creatinine clearance (adjusted odds ratio 0.991 and 95% CI 0.9840.997, P=0.0057). In women, the adjusted odds ratio for haematocrits of 20.034.9% was 3.086 (CI 1.7705.376, P<0.0001) when compared with the reference haematocrits of 35.039.9%. In men, the adjusted odds ratio for haematocrits of 25.039.9% was 1.927 (CI 1.4182.625, P<0.0001) when compared with the reference haematocrits of 45.049.9%.
Conclusions. Subjects with low haematocrits, <40% for men and <35% for women, have a significantly increased risk of ESRD.
Keywords: anaemia; end-stage renal disease; haematocrit
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Introduction
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The number of patients with end-stage renal disease (ESRD) requiring chronic dialysis is increasing worldwide [1,2]. Patients with pre-dialysis co-morbidities, patients with diabetes mellitus, and the elderly are now accepted for treatment by dialysis; thus the clinical demographics are changing. Okinawa, Japan, is an area with high rates of dialysis treatment [1]. Early detection of individuals who are at high risk is one of the strategies used to reduce the costs of treatment of ESRD. We have reported previously the significance of conventional risk factors such as proteinuria, haematuria, blood pressure and serum creatinine on the development of ESRD [3]. However, the relation between the haematocrit level in the general population and renal outcome has not been well defined [46].
Anaemia is a known complication of renal failure that results from decreased kidney production of erythropoietin. Cardiovascular consequences of renal anaemia begin relatively early in the course of renal failure, and an increase in left ventricular mass index is closely related to the changes in haemoglobin over time [7]. Whether individuals with anaemia have an increased incidence of ESRD is not known. Therefore, the goal of this study was to examine the link between haematocrit level and the incidence of developing ESRD by using a large cohort that was screened for baseline haematocrit levels.
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Subjects and methods
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Study design
All individuals over 20 years of age who participated in the 1983 mass health screening examinations in Okinawa, Japan, were eligible for the study. Potential participants were excluded from the study if their birth date, haematocrit level or results of dipstick urinalysis were not available in the computer data file. Patients who were already on chronic dialysis were also excluded.
The Okinawa Dialysis Study (OKIDS) registry was used to identify patients who had been among the 1983 screening participants who had become dialysis patients during the study period through December 31, 2000. Each patient's identity was verified by reviewing the medical charts in the dialysis units. The cumulative incidence of ESRD and the relative risk of ESRD were determined according to the levels of haematocrit at the screening.
Mass screening
A large community-based health screening is conducted annually by the Okinawa General Health Maintenance Association under the direction of Dr Y. Ikemiya [3]. Examination includes an interview regarding health status, a physical examination, a urine test and blood tests. Blood pressure (sitting) is measured by a nurse or doctor using a standard mercury sphygmomanometer. Dipstick urinalysis (Ames dipstick) is performed using spontaneously voided fresh urine. The results of the urine test are interpreted by physicians or their assistants and recorded as -, ±, 1+, 2+, 3+ and 4+.
The database generated from the 1983 screening included health data collected from April 1, 1983 through March 31, 1984. The original data set covered a total of 107 192 participants (51 122 men and 56 070 women). According to the 1980 Census, the total population in Okinawa of persons over 15 years of age was 781 166 (377 479 men and 403 687 women). Therefore, the estimated proportion of the adult population over 18 years of age in 1983 who participated in the mass screening was
13.7% (13.6% of men and 13.9% of women). For the present study, we extracted those individuals aged 2099 years. The total number of people screened for whom haematocrit data was available was 71 802 (37 190 men and 34 612 women) (Table 1
). Data for serum creatinine was available for 10 255 (14.3%) of the people screened. Creatinine clearance was calculated by the method of CockcroftGault [8]. The institutional ethical committee approved the protocol of this study.
Dialysis registry in Okinawa
Details of this dialysis registry have been published recently [9]. All chronic dialysis patients residing in Okinawa, Japan, who survive at least 1 month on scheduled dialysis, are registered in the OKIDS registry. Pertinent clinical information for the new dialysis patients in this study was provided through collaboration with physicians who are acknowledged herein. Records were updated at least twice a year for medical events such as death, renal transplantation and patient transfer outside of Okinawa. If needed, other information was obtained through nurses, medical clerks or the patients themselves. All patients were followed up until a major medical event or to January 2001. As Okinawa is made up of subtropical islands that are separated from mainland Japan, there is little migration of patients. By the end of 2000, there were 46 dialysis units in Okinawa, nine in the public sector, 17 in private hospitals and 20 in clinics.
Statistical analysis
The unpaired t-test or the
2 test was used to analyse differences in values or ratios between groups. Multivariate logistic regression analyses were performed to examine the influence of haematocrit on the development of ESRD in the presence of variables such as age, sex, proteinuria, haematuria, blood pressure and body mass index. In a subgroup of the cohort with data of serum creatinine, similar analyses were repeated to examine the role of renal function. Haematocrit was treated as a linear variable (%) and categorical variables. Odds ratios and 95% confidence intervals (CIs) were calculated. Data are expressed as mean (SD). Statistical analyses were performed with SAS software (Cary, NC, USA). A P-value <0.05 was considered statistically significant.
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Results
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The mean haematocrit levels in the screened subjects were 45.3% (3.3%) in men and 38.8% (3.2%) in women (Table 1
). The distribution of haematocrit levels in the men and women populations is shown in Table 2
. Among the screened subjects, 269 patients (171 men and 98 women) were identified as having developed ESRD during the study period of 17 years (Table 3
). The mean haematocrit levels at the time of screening in these patients were 44.6% (4.4%) in men and 38.2% (4.5%) in women. Multivariate analysis revealed that haematocrit (%) was a significant, independent, risk factor for the development of ESRD (Table 4
). Low haematocrit increased the risk of ESRD; the adjusted odds ratio was 0.991 (CI 0.9880.995, P<0.0001) for each percent increase in haematocrit.
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Table 3. Clinical descriptive data of people screened in 1983 who eventually developed ESRD by the end of 2000 and those with total ESRD patients in the OKIDS registry [9]
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The cumulative incidence of ESRD by baseline haematocrit is shown for women and men in Figures 1
and 2
, respectively. In women, the adjusted odds ratio was 3.086 (CI 1.7705.376, P<0.0001) for haematocrits of 20.034.9% when compared with haematocrits of 35.039.9% (Table 5
). In men, the adjusted odds ratio was 1.927 (1.4182.625, P<0.0001) for the haematocrit group of 25.039.9% when compared with haematocrits of 45.049.9%.
In a subgroup of subjects who had data available on serum creatinine levels, mean levels of serum creatinine and calculated creatinine clearance were compared between haematocrit levels (Table 6
). Mean levels of serum creatinine were within normal ranges for both men and women. However, the mean levels of calculated creatinine clearance were slightly decreased for both men and women. In women, the mean level of serum creatinine was significantly, P<0.001, higher in those people screened with haematocrit
45.0% when compared with those with haematocrits of 35.039.9%. In men, the mean level of serum creatinine was significantly, P<0.001, higher in people screened with haematocrits 25.039.9% than in those screened with haematocrits of 45.049.9%. There was a significant positive correlation between creatinine clearance and haematocrit level (R2=0.0976, P<0.01). Among the subgroup of these screened, 77 patients (42 men and 35 women) were identified as having developed ESRD during the study period. The mean (SD) haematocrit in these patients was 41.6 (5.6)% at the time of screening. The cumulative incidence of ESRD in women was 0.016, 0.005, 0.005 and 0.009 for a haematocrit of 20.034.9, 35.039.9, 40.044.9 and
45.0%, and that in men was 0.038, 0.009, 0.006 and 0.021 for a haematocrit of 25.039.9, 40.044.9, 45.049.9 and
50.0%. Table 7
summarizes the results of multivariate logistic analysis when taking creatinine clearance into account. Association between the haematocrit levels and the risk of ESRD was slightly modified after the addition of creatinine clearance. However, the overall significance of haematocrit (%) was still significant; the adjusted odds ratio and its 95% CI were 0.991 and 0.9840.997 (P=0.0057). Significance of categorical variables of haematocrit is summarized in Table 8
.
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Table 7. Results of univariate and multivariate analyses on the risk of developing ESRD in a subcohort of the screening with data of serum creatinine
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Table 8. Adjusted odds ratio for the risk of developing ESRD by the baseline levels of haematocrit in a subgroup of people screened with serum creatinine
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Discussion
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This study documents the clinical influence of haematocrit on the development of ESRD. The risk of developing ESRD increased in people screened with low baseline haematocrit. However, the observations were different for men and women. Compared with men, women on average have lower haematocrits and a lower incidence of ESRD. Therefore, the sex difference in the incidence of ESRD [10] is not explained by the difference in haematocrit level.
The reasons why the incidence of ESRD is influenced by haematocrit are not clear. It could be due to exacerbation of pre-existing renal disease or due to an increased incidence of renal damage or renal disease. It is well known that hypoxia causes kidney damage [11]. Systemic hypoxia leads to a re-setting of the balance between the antidiuretic and antinatriuretic influences of the reninangiotensin system and the diuretic and natriuretic influences of atrial natriuretic peptide. Hypoxic stimulation may cause increased renal sympathetic activity [12]. Systolic and/or diastolic dysfunction can occur early on in essential hypertension [13] and renal disease [14] and congestive heart failure (CHF) can cause glomerulopathy [15]. Early detection and adequate treatment of such dysfunction may retard the progression of both renal disease and heart failure [16]. It has been shown that the development of CHF in patients with essential hypertension is one of the most powerful predictors of ESRD [17]. In patients with chronic hypoxia, an increased haematocrit is considered to be a causative factor in the pathogenesis of glomerulopathy in CHF and cor pulmonale [18]. Recently, Fine et al. [19] proposed the chronic hypoxia hypothesis: a self-perpetuating cycle of endothelial injury, hypoxia, fibrosis and microvascular obliteration in the tubulointerstitial compartment could provide a unifying explanation for the pathogenesis of glomerulopathy.
Garcia et al. [20] showed in nephrectomized rats that the prevention of anaemia led to systemic hypertension and accelerated glomerular injury. Roth et al. [21] showed that there was no adverse effect of erythropoietin on renal function in humans. However, there are several studies suggesting a beneficial effect of erythropoietin on renal function in pre-dialysis patients [2224]. The overall effect of erythropoietin in physical function, energy, cognitive function, sexual function and other parameters is an increase in health-related quality of life as for dialysis patients and pre-dialysis patients [25].
When the data were adjusted for creatinine clearance, men had a higher risk of ESRD among subjects with high haematocrits,
50.0% (Table 8
). Obstructive nephropathy is a common cause of ESRD in men. An association between polycythaemia and hydronephrosis has been reported, and, in a few instances, increased red blood cell counts decreased after surgery [26].
There are some limitations to the present study. We did not examine the causes of low and high haematocrits. It is unknown whether subjects with acute illness, liver disease and pre-existing renal disease participated in this screening programme. However, the mean haematocrit levels and the distribution of haematocrit levels were normal. The distribution of primary renal disease in this cohort was similar to that of the total OKIDS registry, other than diabetes mellitus incidence (Table 3
) [9]. The incidence of acute renal failure is very rare in the outpatients setting [27]. As shown in Table 2
, the numbers of subjects with severely low haematocrits, <25.0% for men and <20.0% for women, were very low (<0.1%). The indications for haematocrit measurements in this screening is not known, although about two-thirds of the participants underwent haematocrit determination as routine laboratory tests in the 1983 screening. Measurement of serum creatinine was performed only in about 14% of those who had measured haematocrits. It is possible that the test was ordered or the subject requested the test because of concerns about abnormal urine test (Table 1
). There was a significant positive relation between creatinine clearance and haematocrit levels (Figure 3
).

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Fig. 3. Relation between haematocrit and creatinine clearance in screened subjects in 1983. Creatinine clearance was calculated by the method of CockcroftGault [8].
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Additionally, we may not have controlled for some potential confounding factors that play a role in the association between haematocrit and progression to ESRD. Lifestyle-related variables such as smoking, alcohol intake and exercise habits were not considered [3]. Haematocrit was measured on only one occasion resulting in an underestimation of the strength of the association between ESRD and haematocrit. An average haematocrit determined from several tests should yield greater differences in the incidence of ESRD associated with lower or higher than normal ranges of haematocrits.
Geographic heterogeneity and variability in the incidence of ESRD among nations and within nations has been recognized [1,9]. We did not register subjects who died within 1 month of dialysis, as it is often difficult to differentiate acute renal failure and ESRD. The present study findings therefore need to be confirmed in other populations.
Finally, haemoglobin is a better measure than haematocrit for monitoring and managing anaemia in patients with chronic renal disease [28]. However, Hsu et al. [6] reported a similar relation between haematocrit and renal function if haematocrit is used instead of haemoglobin. Obviously, correction of anaemia is not a substitute for well-defined effective therapies such as with antihypertensives, but it seems to be an important addition to the care of these patients therapy. Anaemia and polycythaemia in men should be evaluated and normalized, if possible. Erythropoietin is effective and safe for correcting anaemia in patients with progressive renal failure if blood pressure is controlled [23,25]. Long-term, randomized controlled trials are needed to assess both the optimal timing and the target levels of haematocrit in these patients [7].
In conclusion, the present study findings suggest that mild to moderate anaemia is a significant, independent, predictor of ESRD, at least when adjusted for commonly measured variables such as blood pressure, body mass index, proteinuria and haematuria in our cohort of screening. Anaemia, therefore, should be evaluated for its underlying cause, and in association with other conventional risk factors such as hypertension, proteinuria and haematuria.
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Acknowledgments
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We are indebted to the staff of the Okinawa General Health Maintenance Association, in particular to Mr M. Itokazu and Mr K. Shiroma for retrieving data files from the 1983 health screening. The authors are grateful for the collaboration of the physicians and co-medical staff of all of the dialysis units in Okinawa. The following doctors gave invaluable advice, support, and encouragement: Drs T. Minei, T. Kowatari, K. Nishime, H. Ogimi, T. Yonaha, C. Mekaru, K. Kinjo, M. Nakayama, H. Uehara, H. Sunagawa, S. Nakasato, Y. Oshiro, N. Kuwae, T. Wake, M. Arakaki, S. Yoshi, S. Miyagi, K. Tokuyama, I. Kyan, Y. Uezu, T. Hokama, S. Kiyuna, H. Henzan, T. Asato, Y. Nakasone, Y. Shiohira, K. Higa, T. Miyagi, H. Afuso, F. Miyasato, S. Maeshiro, T. Sakuda, H. Momozono, T. Asato, M. Ikemura, T. Taminato, Y. Oshiro, M. Yamasato, T. Izumi, T. Oura, S. Toma, T. Sunagawa, T. Funakoshi, S. Terukina, T. Oyama, Y. Tinen, Y. Oshiro, K. Nakama, K. Nakao, O. Shiranezawa, K. Nagasawa, H. Uchima, T. Higa, A. Higa, K. Yoshihara, M. Maeshiro, S. Miyagi, T. Kinjo, M. Ishu, H. Yoshimura, Y. Arakaki, N. Nakamura, H. Kinjo, O. Shinjo, T. Nakanishi, I. Shiroma, S. Shiroma, K. Ishikawa, K. Nagata, K Akamine, T. Tana, S. Oshiro, N. Tomiyama, K. Kohagura, H. Muratani, Professor Y. Ogawa, ex-Prof. A. Osawa and ex-Prof. K. Fukiyama. The authors are also grateful to Dr O. Morita, who helped with the data processing and statistical analyses for this study. This study was supported in part by grants from the Ministry of Health and Welfare.
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Notes
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Correspondence and offprint requests to: Dr Kunitoshi Iseki, Dialysis Unit, University Hospital of The Ryukyus, 207-Uehara, Okinawa 903-0215, Japan. Email: chihokun{at}med.u-ryukyu.ac.jp 
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Received for publication: 12. 8.02
Accepted in revised form: 14.11.02