Q J Med 2001; 94: 541-550
© 2001 Association of Physicians
Factors affecting renal function in 119 985 adults over three years
1 From the Ibaraki Kidney Foundation, 2 Ibaraki Health Science Center, 3 Ibaraki Health Service Association, 4 Institute of Community Medicine and 5 Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan
Received 8 November 2000 and in revised form
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Blood pressure, proteinuria and serum creatinine (SCr) were examined in 119 985 adults, aged 40 years and older, who attended annual health examinations both in 1993 and 3 years later. Renal function was assessed from SCr; changes in individuals' renal function were estimated using the slope of the regression line for the reciprocal of the SCr level vs. time (slope of rSCr) over the 3-year period. Age-dependent SCr concentration increments were observed; however, there was no significant age-dependent change in the slope of rSCr. SCr in hypertensives on anti-hypertensive medication was significantly higher than that in untreated hypertensives, borderline hypertensives and normotensives. The slopes of rSCr in hypertensives (treated, untreated and borderline) were steeper than normotensives in males, and that in untreated hypertensives was steeper than other groups in females. In hypertensives with proteinuria, SCr was higher and renal function deteriorated more rapidly, compared with hypertensives without proteinuria. Hypertension with proteinuria appears to be an important indicator for progressive decline in renal function, this trend being more obvious in males. Renal function decreases with age; however, the rate of decline is constant. The influences of proteinuria and blood pressure on renal function are different in males and females.
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Introduction |
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At the end of 1997 in Japan, 175 988 patients were receiving dialysis treatment, and a further 28 000 patients are estimated to begin dialysis each year.1 To prevent progressive deterioration of renal function, early detection of renal insufficiency is necessary. Since 1983, Japan has had a legal requirement for adults over the age of 40 years to have an annual health examination. To screen for renal disease, annual urinalysis was started in 1983, and annual measurement of serum creatinine (SCr) in 1992.
Aging, high blood pressure, extent of proteinuria and male gender are recognized as risk factors for a progressive loss in renal function.2–4 However, there have been few detailed studies of large populations concerning the influence of these factors; in particular, how these factors relate to each other, and whether blood pressure treatment has an influence. In the present study, we clarify changes in renal function and their association with aging, proteinuria and hypertension from a mass screening of approximately 120 000 adults.
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Methods |
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The subjects were 119 985 (male 37 513, female 82 472) adults aged 40 or over, who underwent an annual health examination in the Ibaraki prefecture in 1993 (at baseline) and again three years later in 1996 (Table 1
). At the initial screening in 1993, a total of 198 136 adults aged 40 or over, were examined. Those individuals who did not attend the second health examination were excluded. All subjects were interviewed to obtain information regarding their use of anti-hypertensive medications. Blood pressure was measured, after several minutes’ rest, in a sitting position with a mercury sphygmomanometer or automatic device. Blood pressure measurement was repeated if the first reading was outside the normal range.
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The subjects were divided into four groups according to WHO blood pressure criteria and their use of anti-hypertensive medications in 1993: (1) subjects with anti-hypertensive medications at baseline were defined as treated hypertensive subjects; (2) normotensive subjects were defined as those having systolic blood pressure
140 mmHg and diastolic blood pressure 90 mmHg; (3) untreated hypertensive subjects as having systolic blood pressure 
160 mmHg or diastolic blood pressure 95 mmHg, without anti-hypertensive medication; and (4) patients with systolic blood pressure 141–159 or diastolic blood pressure 91–94 mmHg were defined as borderline hypertensive subjects. Proteinuria was tested using dipsticks (Ames Hemacombisticks, Bayer-Sankyo). Trace positive samples of proteinuria were re-examined using the sulphosalicylic acid test, and they were divided into four groups (0, 1+, 2+, 3+). A test result of 1+ or more was defined as positive. Serum creatinine concentration was measured by Jaffe's method (creatinine HR, Wako Pure Chemicals Industries) using an autoanalyser (Hitachi 7350, Hitachi or RX-20, JEOL). Changes in renal function were estimated by the slope of the regression line for the reciprocal of SCr (rSCr) vs. time for each subject. rSCr has a rectilinear relation to glomerular filtration rate (GFR). Measurements for glycosuria and blood glucose were incomplete, and therefore these analyses were not included in the present study.
Statistical analysis examined the influence of blood pressure, age and proteinuria on renal function. Subjects were stratified for each gender into (i) five age groups: 40–49; 50–59; 60–69; 70–79; and 80–89, (ii) four blood pressure groups: normotensive group; borderline hypertensive group; untreated hypertensive group; and treated hypertensive group, and (iii) two proteinuria groups: (a) either ‘0’ or ‘+’ for analysis of variance (ANOVA) or (b) four proteinuria groups (0, 1+, 2+, 3+) for Jonckheere-Terpstra test.5 Three-way ANOVA using age, blood pressure and proteinuria as independent variables was used to determine their respective influence on initial SCr and the slope of rSCr as the dependent variables. Interactions between age, proteinuria and blood pressure were also analysed. If ANOVA was significant (p<0.05), multiple comparisons were made for each group. The differences were considered significant below a level of 0.05. All values are presented as means±SE. All analyses were performed using SAS software (SAS Institute).
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Results |
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Baseline distribution of serum creatinine concentration
The baseline distribution of SCr by age is shown in Figure 1
. The mode of the serum creatinine concentration was 1.0 mg/dl in males, and 0.8 mg/dl in females among all age groups. There was a tendency towards an increase in the serum creatinine concentration with increasing age.
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Demographic changes to hypertensive groups during the 3-year period (1993–96)
In the treated hypertensive group, nearly 90% were still receiving anti-hypertensive therapy after 3 years follow-up (Table 2). Of the 3322 males in the untreated hypertensive group at baseline, after 3 years follow-up, 26.6% had changed to the treated hypertensive group, 14.9% were normotensive, and 28.3% remained in the untreated hypertensive group in 1996. Of the 4293 females in the untreated hypertensive group at baseline, 32.2% had changed to the treated hypertensive group, 16.2% were moved into the normotensive group and 23.6% remained in the untreated hypertensive group.
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Initial and final blood pressures are shown in Table 3
. Significant differences (p<0.01) between initial and final blood pressure were present among all groups in both males and females. At baseline, both systolic and diastolic blood pressures were significantly higher in all three hypertensive groups compared with those in the normotensive group. In all three hypertensive groups, the average blood pressure was reduced after 3 years compared with the baseline level. At the 3-year follow-up, systolic and diastolic blood pressures were still significantly higher in the hypertensive groups compared with those in the normotensive group.
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Effect of aging
Baseline mean SCr by age group is shown in Figure 2a. Mean SCr showed significant age-dependent increases in both males and females. Significant differences in SCr were present between all age groups (p<0.001) except for the 40s and 50s age groups in males. Comparisons of the mean slope of rSCr for the 3-year period among the five age groups are shown in Figure 2b. There was no significant difference in the average slope among the five age groups in either males or females.
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Effect of blood pressure
The effect of blood pressure on SCr and the average slope of rSCr for 3 years were analysed (Figure 3a and b). The highest mean SCr was found in the treated hypertensive group. There was a trend of lower SCr values in the normotensive groups compared with the hypertensive group. Mean SCr in the treated hypertensive group was significantly higher than that in the other three groups in both males and females (p<0.05).
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The rates of decline of renal function (slope of rSCr) in borderline, untreated and treated hypertensives were significantly faster than that in the normotensive group in males (p<0.01). In females, the rate of decline in the untreated hypertensive group was significantly faster than the other three groups (p<0.05) (Figure 3b
).
Effect of proteinuria
The effect of proteinuria on SCr was analysed (Figure 4a). Mean SCr showed a significant proteinuria-dependent increase in both males and females (p<0.01, Jonckheere-Terpstra test). Significant differences in SCr were present between each of the four proteinuria groups (p<0.0001–0.02). Comparisons of the mean slope of rSCr for the 3-year period among the four proteinuria groups are shown in Figure 4b. There was also a significant proteinuria-dependent decrease in the average slope of rSCr in both males and females (p<0.01, Jonckheere-Terpstra test).
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Interactions between aging, blood pressure and proteinuria
To determine both the effects and interactions of age, blood pressure and proteinuria on the changes in SCr, we performed three-way ANOVA (Table 4). In both males and females, baseline SCr was significantly dependent upon age, blood pressure and proteinuria. In males, there were significant interactions between age, blood pressure and proteinuria. In females, however, there was no interaction with SCr, between proteinuria and blood pressure. This indicates that the presence of proteinuria as well as degree of blood pressure were independent determinants for the increase in SCr in females (Table 4a).
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The slope of rSCr over the 3-year period was significantly dependent on blood pressure and proteinuria in both males and females. Age alone was not a significant factor in either gender. In males, there were significant interactions between age and blood pressure, proteinuria and blood pressure, and all three factors, but not between age and proteinuria. However, in females none of these interactions were significant (Table 4b
).
The highest mean SCr was found in the treated hypertensive group, for all age groups. The trend in lower blood pressure from the hypertensive to normotensive groups was associated with a similar trend in lower SCr values. Mean SCr in the treated hypertensive group was significantly higher than that in the other three hypertensive groups in both males and females (p<0.01). In each age group, the findings showed the same tendency (Figure 5a). The mean slopes of rSCr with the untreated hypertensive group in the 50s and 70s age decades were significantly negative compared to those in other blood pressure groups in males (p<0.05). In untreated hypertensive females, the same tendency was observed in all age groups except for the 40s. In contrast, in treated hypertensive subjects in the 50s, 70s, and 80s age decades in males and in all age groups except for the 40s in females, there was slower deterioration of renal function (Figure 5b).
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In males with proteinuria, SCr was significantly higher in the treated hypertensive groups than in other hypertensive groups (p<0.001); however, this trend was less in females. (Figure 6a
).
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The mean slope of rSCr in all subjects with proteinuria was steeper than in those without proteinuria, except for the normotensive groups (Figure 6b
). In males, the rates of decline in both untreated and treated hypertensive groups with proteinuria were significantly faster than that in the normotensive group with or without proteinuria (p<0.05). In females, however, only in the untreated hypertensive group with proteinuria was the rate of decline significantly faster than that in the normotensive group, with or without proteinuria (p<0.05).
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Discussion |
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We have shown that SCr is related to age, blood pressure and proteinuria, and that the rate of loss of renal function is accelerated in hypertensive subjects, in those with proteinuria, and especially in those in whom both are present. Our subjects were a large group of individuals who underwent annual health examinations under the auspices of local government and the Ministry of Health and Welfare. Although people with renal diseases may have been included, as in other studies,4 the present findings must be valuable because this is one of the largest study groups that have been reported.
In the present study, we used SCr as a marker of renal function because it was available from mass screening of large populations. The rate of creatinine production is dependent on muscle mass and is constant. With increasing age, SCr in elderly individuals sometimes fails to increase despite a decrease in GFR, because muscle mass decreases with age.6 In a previous study, the SCr, corrected for body surface area was found to rise significantly with age, although the actual SCr increased only slightly.7 In the present study, some subjects lost muscle mass during the observation period, and therefore their renal function might be under-estimated; however, because of the large numbers of community-based relatively healthy subjects, it is apparent that the baseline SCr increased with age. Thus, we have assumed that the actual SCr, not corrected for body surface area, is valid as a measure of renal function.
It has been reported that GFR remains within the normal range in the majority of healthy elderly people.8 We found that the mean SCr in the elderly groups, although significantly increased, also remained within the normal range. We examined the relationship between SCr and blood pressure in all age groups. SCr was higher in hypertensive groups compared with normotensives in each age group (Figure 5a), which suggests the presence of hypertension-related renal impairment in the elderly. In treated hypertensives, who were already on treatment at entry into the study in 1993, SCr was higher than in untreated hypertensives in each age group. The untreated hypertensives were considered newly diagnosed, while, in contrast, the treated hypertensives were assumed to have had a relatively longer duration of hypertension. In both males and females, proteinuria was tested using ANOVA as an independent factor for renal function. SCr was significantly higher in the presence of proteinuria, which indicates that proteinuria is an independent determinant of SCr, as previously reported.9
To estimate the rate of decline of renal function, we used the slope of rSCr over the 3-year period. Most previous studies have reported that the rate of decline in renal function accelerates with aging.10–12 However, in our study, ANOVA showed no significant differences in the slope of rSCr among the five age groups. Our findings suggest that the rate of decline in renal function is constant after the age of 40 years.
Higher blood pressure was associated with a more negative slope of rSCr vs. time in males (Figure 3b). Thus, blood pressure is a relevant factor in impairment of renal function, especially in males. Other studies have demonstrated a similar detrimental effect of increased blood pressure on renal function.12–16 Klag et al. reported that higher blood pressure, as measured carefully on a single occasion, was a strong independent risk factor for end-stage renal disease in men during an average of 16 years follow-up.15 The subjects of this study were also divided into four blood pressure groups using a single measurement of blood pressure in 1993. Even in borderline hypertensive subjects, renal function deteriorated more rapidly than normotensive subjects, which agreed with previous results,15 but this effect was not observed in females.
In treated hypertensive subjects in their 50s, 70s, and 80s (males), and in all age groups except the 40s (females), there was a slower deterioration of renal function (Figure 5b). However, some studies have failed to detect a relationship between the treatment of blood pressure and renal function in hypertensive subjects,17,18 perhaps related to the duration of the follow-up, occult renal diseases, blood pressure goal level or hypertensive medications. Recently, strict blood pressure controls were recommended for patients with renal insufficiency.3,19,20 If treated hypertensive subjects received strict blood pressure controls, decline of renal function might be slower than in this study. Further, a protective effect of anti-hypertensive medications on renal function has been documented in hypertensive patients,21–24 patients with non-diabetic renal insufficiency25 and diabetic nephropathy.26,27 The present findings confirm that proteinuria is one of the most important risk factors for decline in renal function.28–30 Especially in men, there was a significant interaction between blood pressure and proteinuria. The present study could not determine whether proteinuria in hypertensives was the consequence of a long-standing advanced hypertension or due to pre-existing intrinsic renal disease, and we did not evaluate the effects of specific classes of anti-hypertensive medications on renal function. However, several studies have suggested that taking angiotensin-converting-enzyme inhibitors or angiotensin-2 receptor blockers has benefits not only for controlling blood pressure but also in reducing proteinuria.31,32 Recent treatment recommendations for hypertension with renal insufficiency might improve the slope of rSCr in these subjects.
In summary, in a mass screening of approximately 120 000 adults, SCr was related to age, blood pressure and proteinuria. The rate of decline in renal function was accelerated in those with hypertension or proteinuria, and especially when both were present. These effects were more obvious in men. Blood pressure treatment with anti-hypertensive drugs was associated with a slower reduction in renal function. Early detection of hypertension and urinary protein, and adequate control of blood pressure in hypertensive individuals are thus potentially effective ways to reduce the deterioration of renal function with aging.
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Acknowledgments |
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We are grateful to Professor Guy Neild and Dr Robin Woolfson, of Middlesex Hospital, London, University College London Medical School, who provided invaluable guidance, encouragement and support. This investigation was supported in part by a Research Grant from the ‘Disease Control Division’, Health Service Bureau, Ministry of Health and Welfare, Japan.
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Notes |
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Address correspondence to Dr A. Koyama, Institute of Clinical Medicine, University of Tsukuba, 1–1–1 Ten-oudai, Tsukuba, Ibaraki 305-8575, Japan. e-mail: kidney{at}md.tsukuba.ac.jp
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