NDT Advance Access first published online on October 23, 2007
This version published online on January 17, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm705
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Integrated therapies including erythropoietin decrease the incidence of dialysis: lessons from mapping the incidence of end-stage renal disease in Japan
1 Department of Nephrology, Osaka University Graduate School of Medicine, 2–2 Yamadaoka, Suita-city, Osaka, Japan 2 Department of Nephrology and Hypertension, Osaka General Medical Center, 3–1-56 Bandai-Higashi, Sumiyoshi, Osaka-city, Osaka, Japan
Correspondence and offprint requests to: Enyu Imai, MD, Department of Nephrology, Osaka University Graduate School of Medicine, 2–2 Yamadaoka (A8), Suita-city, Osaka 565–0871, Japan. Tel: +81–6-6879–3632; Fax: +81–6-6879–3639; E-mail: imai{at}medone.med.osaka-u.ac.jp
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Abstract |
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Background. Erythropoietin (EPO) has been reported to slow the decline of renal function in predialysis chronic kidney disease (CKD) patients. On the contrary, in the recent large-scale randomized controlled trial (RCT), CREATE and CHOIR, which aimed to keep a higher haemoglobin (Hb) level than former trials, the renoprotective effect of EPO was not observed. Today, the renoprotective effect of EPO has become controversial. In order to test the hypothesis that the usage of EPO in predialysis CKD patients may ameliorate the progression of renal disease, we conducted a macro-level observational study dealing with all Japanese predialysis CKD patients.
Methods. Annually since 1982, the Japanese Society for Dialysis Therapy reports the number of patients that have entered maintenance dialysis in each prefecture of Japan. Based on the 2002–2004 data, we calculated the annual incidence of end-stage renal disease (ESRD) in each of the 47 prefectures. The annual amounts paid for EPO by each prefecture, presumably corresponding to the amounts used, corrected for the estimated predialysis CKD patients, were calculated. We examined the relationship between the incidence of new dialysis and the usage of EPO in each prefecture. Furthermore, the usage of EPO was compared with that of antihypertensive agents including angiotensin converting enzyme inhibitor (ACE-I), and that of statin.
Results. There were prefectural differences in the annual incidence of ESRD from 2002 to 2004. We also found prefectural differences in the usage of EPO for the three consecutive years. The usage of EPO in predialysis patients was negatively correlated with the incidence of ESRD on linear and multiple regression analyses. At the same time, the usage of EPO had strong positive correlations with the usage of antihypertensive agents including ACE-I and with that of statin.
Conclusion. Our nationwide epidemiologic study revealed that a higher use of EPO was associated with a decreased incidence of new dialysis in daily clinical practice. In addi- tion, there were strong correlations among the usage of EPO, antihypertensive agents and statin. These data are supportive of, but do not prove, the hypothesis that EPO may be renoprotective, when used in combination with other strategies.
Keywords: ACE-I; anaemia; chronic kidney disease; end-stage renal disease; erythropoietin; integrated therapy
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Introduction |
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The usage of erythropoietin (EPO) has been reported to protect the renal function in predialysis patients [1–8]. Subanalysis of RENAAL suggested that anaemia was a predictor of the development of end-stage renal disease (ESRD) [9]. The same relationship between anaemia and ESRD was also reported in a Japanese population [10].
On the contrary, in the recent large-scale randomized controlled trial (RCT); CREATE [11] and CHOIR [12], which aimed to keep a higher haemoglobin (Hb) level than former trials, the renoprotective effect of EPO was not observed. Today, the renoprotective effect of EPO has become controversial [11–13].
In daily clinical practice, however, few can maintain an Hb level of 11 g/dl, much less 13 g/dl [14], especially in Japan [15] because Japanese health insurance limits the usage of EPO up to 24 000 units/ month for predialysis patients. These actual low Hb levels mean that the results of these RCTs are not always applicable to patients in daily clinical practice; the problem lies in the relatively low outer validity of RCTs [16]. In order to test the renoprotective effect of EPO in daily practice, a macrolevel observational study, which intrinsically has less selection bias, is needed.
As a good model of macro level observational study dealing with ESRD incidence, Usami et al. reported regional variations in the incidence of ESRD in Japan, which is ethnically homogeneous [17]. Based on these regional variations of incidence and regional variations in the consumption of angiotensin converting enzyme inhibitors (ACE-I) in Japan, it was concluded that the usage of ACE-I might slow the progression of ESRD [18]. Using the same method, the renoprotective action of statin was identified based on mapping renal failure in Japan [19]. Usami et al. proposed that mapping the incidence of renal failure to develop strategies for eliminating the risk factors for ESRD [20]. In order to validate the hypothesis that EPO can ameliorate the progression of renal disease in daily practice, we investigated the relationship between the incidence of new dialysis patients and the consumption of EPO in each prefecture of Japan.
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Methods |
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The number of patients with ESRD entering maintenance dialysis therapy, either haemodialysis or peritoneal dialysis in each prefecture, was obtained from the reports of the Japanese Society for Dialysis Therapy [21–23]. We used data from the most recent three years, i.e. from 2002 to 2004. Japanese medical insurance covers the use of EPO for renal anaemia (Hb < 10g/dl) up to 24 000 units per month in nondialysis patients.
In Japan, EPO is exclusively sold by two companies (Chugai Pharmaceutical Co. Ltd and Kirin Pharma Co. Ltd). The annual amount of money paid for EPO in each of the 47 prefectures of Japan was obtained by pharmaceutical market research.
The two pharmaceutical companies in Japan that market EPO provide seven EPO doses. 750, 1500 and 3000 units of EPO are mainly used for maintenance haemodialysis patients. 24 000 units of EPO are limited only for autologous blood transfusion. The rest of the 6000, 9000 and 12 000 units of EPO are mainly used for predialysis patients. Although the same EPO doses are used for peritoneal dialysis patients, the amounts of EPO used for peritoneal dialysis patients are negligible, because peritoneal dialysis patients account for less than 5% of all the dialysis patients in Japan [24]. Therefore, we used the total amounts of 6000, 9000 and 12 000 units of EPO as the total EPO given to predialysis patients with renal anaemia.
It is difficult to figure out the precise "number" of predialysis patients. However, the "ratio" of CKD patients among prefectures can be assumed to be almost the same as the "ratio" of new dialysis patients among prefectures. On the premise of this assumption, the ratio of EPO use per predialysis CKD patients is almost equal to the ratio of EPO per new dialysis patients.
Possible factors for prefectural differences in ESRD
We examined the factors that might contribute to prefectural differences in ESRD dynamics, including average age; the percentage of people 65 years old or older; percentage of males; average income [25]; and the number of nephrologists [26]. The amounts of money spent for antihypertensives and statins were extracted from the previous papers [18,19]. When comparing the correlations between EPO and antihypertensives or statins, we converted the EPO usage data of the 47 prefectures into the 11 regions that were used in their papers. In their examinations, data were not provided as the amounts per predialysis patients but as the amounts per population.
Statistical analysis
The normality of the data was first assessed using the Shapiro–Wilks test. One-way analysis of variance (ANOVA) was used to compare the incidence of ESRD, usage of EPO and other factors among the different prefectures. Variables with skewed distribution were entered to univariate and multivariate regression models after log-transformation. Correlation between two variables was examined by linear regression analysis. For the simple correlation studies, correlation coefficients were calculated using Pearson's method. Multiple regression analysis was used to identify independent factors for prefectural differences in the incidence of ESRD. For the multiple (stepwise forward) regression studies, factors were included as potential explanatory factors when P values were less than 0.10. For factors without colinearity (r < 0.60), the interaction terms were analyzed. All statistical analyses were performed using JMP software (SAS institute Inc., Cary, NC, USA) for WindowsTM (Microsoft Co., Redmond, WA, USA). Values are expressed as mean ± SEM. A level of P < 0.05 was considered to be statistically significant.
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Results |
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Annual ESRD incidence
We examined prefectural differences in the annual ESRD incidence for three years (2002–2004) as shown in Table 1. On ANOVA, the differences among the 47 prefectures were significant (P < 0.0001). The amounts of EPO used and the incidence of ESRD are shown in Figure 1; the highest 10 prefectures are shown in black, and the lowest 10 prefectures are shown in white.
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Usage of EPO and prefectural differences in ESRD incidence
The usage of EPO per estimated predialysis patient from 2002 to 2004 based on the amount of EPO purchased was significantly different among the 47 prefectures (P < 0.0001) (Table 1; Figure 1). Linear regression analysis showed that the usage of EPO in each prefecture had negative relationships with the annual incidence of ESRD for the three consecutive years (r = –0.33, P = 0.022 in 2002, r = –0.37, P = 0.010 in 2003, r = –0.41, P = 0.004 in 2004) (Figure 2; Table 2). Moreover, even though EPO is paid for by public medical insurance in Japan, there was a difference of more than three times in the usage of EPO among the prefectures; twice the amount of EPO use was associated with a decrease of more than 20% in new dialysis patients (Figure 2).
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Other factors correlated with prefectural differences in ESRD incidence
On linear regression analysis, the average age of the population and the percentage of the aged population were not correlated with the annual incidence of ESRD for the three years (Table 2). The percentage of males in each prefecture had negative correlations with the annual incidence of ESRD (r = –0.39, P = 0.007 in 2002, r = –0.46, P = 0.001 in 2003, r = –0.44, P = 0.002 in 2004) (Table 2). Of note, the percentage of males had strong correlations with; the average age (r = –0.71, P < 0.0001 in 2002, r = –0.71, P < 0.0001 in 2003, r = –0.71, P < 0.0001 in 2004); the aged population (r = –0.77, P < 0.0001 in 2002, r = –0.77, P < 0.0001 in 2003, r = –0.77, P < 0.0001 in 2004); and the average income (r = 0.71, P < 0.0001 in 2002, r = 0.68, P < 0.0001 in 2003, r = 0.68, P < 0.0001 in 2004). The average income (log-transformed) was negatively correlated with the incidence of ESRD in 2003 (r = –0.35, P = 0.015), but neither in 2002 (r = –0.26, P = 0.073) nor in 2004 (r = –0.26, P = 0.074) (Table 2). Parameters about the distribution of nephrologists (log-transformed) were, in part, negatively correlated with the incidence of ESRD.
Other factors correlated with prefectural differences in the usage of EPO
Linear regression analysis showed that the average age had positive correlations with EPO use (r = 0.51, P = 0.0003 in 2002, r = 0.55, P < 0.0001 in 2003, r = 0.49, P = 0.0005 in 2004). The percentage of the elderly population also had positive correlations with EPO use (r = 0.47, P = 0.0008 in 2002, r = 0.50, P = 0.0003 in 2003, r = 0.46, P = 0.001 in 2004). None of the percentage of males, the average income and the number of nephrologists per population had correlations with EPO use.
Multiple regression analysis to identify the factors independently affecting prefectural differences in ESRD incidence
On multiple (stepwise forward) regression analysis, EPO use and the percentage of males were independent factors associated with the reduction in ESRD incidence for the three consecutive years (Table 3). No other factors including interaction terms proved to be independent factors affecting ESRD incidence.
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Correlation between the usage of EPO and antihypertensives
In order to control the elevated blood pressure caused by EPO, it is necessary to start or to increase antihypertensive drugs. Thus, in daily practice, it is impossible to assess separately the beneficial effect of EPO and antihypertensives. In this study, we found strong correlations between the usage of EPO and total antihypertensive drugs (r = 0.69, P = 0.0020 in 2002, r = 0.68, P = 0.0020 in 2003, r = 0.72, P = 0.012 in 2004). At the same time, ACE-I and calcium channel-blocker (CCB) had strong positive correlations with the usage of EPO (Figure 3).
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Correlation between the usage of EPO and statin
In order to treat CKD patients comprehensively, it is not enough just to control anaemia and blood pressure. Integrated therapies for CKD are important; control of dislipidaemia consists of the strategies. In our examination, there were strong positive correlations between the usage of EPO and statin for each year (Figure 3).
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Discussion |
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The present study showed marked prefectural differences both in the annual incidence of ESRD and in the usage of EPO during the most recent three years. And a higher use of EPO was associated with a decreased incidence of new patients starting dialysis (Table 1; Figure 1). In addition, the usage of EPO was correlated with the usage of antihypertensives including ACE-Is and CCBs and with that of statin, which indicated that integrated therapies could slow down the progression of renal disease.
The usage of EPO has been considered to be one of the most promising interventions to slow down the progression of renal disease [1–8]. However, after the publication of CREATE and CHOIR studies, the beneficial effects of EPO became controversial. Then, in this study, we examined the relationship between the prefectural differences in the incidence of ESRD and EPO use. As a result, on both linear and multiple regression analyses, the usage of EPO was identified as a significant factor that was related to the reduction in ESRD incidence (Figure 2). This correlation is shown in Figure 1; most of the prefectures with high EPO use in Figure 1B corresponded to those with a low ESRD incidence in Figure 1A.
There are several mechanisms by which the treatment of EPO ameliorates the incidence of ESRD. Treatment of anaemia improves cardiac function [27,28] and hypoxia in the kidney [29–31]; breaking out of the vicious cycle of "cardio-renal anaemia syndrome" [32,33]. In addition, EPO administration requires frequent hospital visits, which might result in better blood pressure control and better compliance with treatment [34].
The male gender is generally assumed to be one of the risk factors for progression of renal failure [35]. However, our results did not support this assumption (Table 2). One possible reason for this discrepancy may be the correlation between age and gender in our study. The life expectancy of females is 8 years longer than that of males in Japan. The percentage of males in each prefecture was negatively correlated with both the average age of the population and the percentage of the aged population (data shown in the results section); this indicates that in the prefectures where the percentage of males is high, the residents are younger. Meanwhile, there was no correlation between the EPO use and the percentage of males (r = –0.27, P = 0.06 in 2002, r = –0.27, P = 0.06 in 2003, r = –0.24, P = 0.10 in 2004).
There are other potential confounding factors that might affect the EPO use or the incidence of ESRD: the average income, the distribution of nephrologists, the usage of antihypertensives and the usage of statin.
As a representative factor of the socio-economical state (SES), the average income was analyzed. On linear regression analysis, the average income (log-transformed) was correlated with the incidence of ESRD only in 2003 but not in 2002 and 2004 (Table 2). On multiple regression analysis, the average income was no longer proved to be a significant factor for three years. This could be attributable to Japanese governmental medical insurance that covers all Japanese poor or rich alike and which pays about more than 70% of the costs.
Distribution of nephrologists might have some effect on the incidence of ESRD because one of the parameters had a correlation with the ESRD incidence on univariate regression analysis, though not on multivariate regression analysis. Further investigation about contributions of nephrologists would be necessary.
We investigated whether the usage of antihypertensive agents, including ACE-Is, was related to EPO use, since ACE-Is have a proven beneficial effect in various studies and in the ACE-I consumption map study [18]. There were strong correlations between EPO use and ACE-Is, CCBs and total usage of antihypertensive drugs for each year (Figure 3). These strong correlations might suggest that patients treated with higher dosages of EPO received more intensive blood pressure control. Such a combined modality therapy might ameliorate the progression of renal dysfunction. In order to determine which treatment is more renoprotective, EPO or antihypertensive agents, it is preferable to put both EPO and antihypertensives into multivariate regression models or to examine interaction terms. However, we could not do so because their consumption data did not correspond to the data of 47 prefectures but of 11 regions that are statistically underpowered. Thus, a further analysis is required.
With respect to the usage of statin, there were also strong positive correlations with the usage of EPO (Figure 3). Recently, two meta-analyses [36,37] reported that statin seemed to be renoprotective in general, but not in patients with diabetic or hypertensive kidney disease or glomerulonephritis. At present, the existing data cannot fully support the putative renal benefits of statin alone [38]. Alternatively, strong correlations among EPO, antihypertensives and statin might suggest that combined therapy for renal anaemia, hypertension and dislipidaemia may ameliorate the progression of CKD.
This study had several limitations. First, we used the ratio of new dialysis patients among prefectures as the estimated ratio of predialysis patients among prefectures, since the precise number of predialysis patients is not available. However, as Usami et al. estimated [17–19], these uncertain factors could partly be cancelled out by the conspicuously large sample size. Second, not all predialysis patients suffer from renal anaemia. In fact, the precise distribution of renal anaemia in predialysis patients and the treatment of renal anaemia have not been reported. Third, there was no data on the haemoglobin level when dialysis started. Fourth, it is difficult to determine which treatment is more renoprotective – correction of renal anaemia by EPO or blood pressure control by antihypertensive or dislipidaemia treatment by statin. In terms of target patients, EPO is used only for CKD patients, while antihypertensives and statin are prescribed widely to patients in the general population. Judging from the specificity of the treatment target, the specific use of EPO for predialysis patients in our study could be highly estimated in renoprotective effect than the wide use of antihypertensives and statin for general population in the previous report [18,19].
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Conclusions |
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In conclusion, a nationwide macrolevel epidemiologic study revealed that a higher use of EPO was associated with a decreased incidence of new dialysis in daily clinical practice. In addition, there were strong correlations among the usage of EPO, antihypertensive agents and statin. These data are supportive of, but do not prove, the hypothesis that EPO may be renoprotective, when used in combination with other strategies.
Conflict of interest statement. None declared.
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References |
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Accepted in revised form: 11. 9.07
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