Correlates of Urinary Albumin Excretion in Young Adult Blacks and Whites
The Coronary Artery Risk Development in Young Adults Study
Maureen A. Murtaugh1,
David R. Jacobs, Jr.1,2 ,
Xinhua Yu1,
Myron D. Gross3 and
Michael Steffes3
1 Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, MN.
2 Institute for Nutrition Research, University of Oslo, Oslo, Norway.
3 Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, MN.
Received for publication November 20, 2002; accepted for publication April 18, 2003.
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ABSTRACT
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The rate of urinary albumin excretion is an important risk factor for kidney failure, stroke, and cardiovascular disease, perhaps because higher albumin excretion reflects endothelial cell dysfunction. The authors characterized urinary albumin excretion according to blood pressure, diabetes mellitus, and other factors in 2,582 Black and White participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study who were aged 1830 years in 19851986. Urinary albumin and creatinine concentrations were determined using single untimed samples 10 and 15 years later. The albumin:creatinine ratio was analyzed as a continuous variable and a dichotomous variable (higher albumin excretion, including microalbuminuria (25249 mg/g) and macroalbuminuria (
250 mg/g)). Seventy percent of persons with increased albumin excretion were both normoglycemic and normotensive (systolic/diastolic blood pressure <140/90 mmHg and no use of antihypertensive drugs). Even when diabetic subjects, who have greater risk, were excluded, albumin excretion rose continuously as blood pressure increased among Blacks; increases started at systolic/diastolic blood pressures of 130/85 mmHg among Whites. Furthermore, blood pressure measured up to 15 years earlier predicted incident higher albumin excretion at year 15. These findings persisted after adjustment for age, body mass index, smoking, and blood lipid and plasma insulin levels. A risk of higher urinary albumin excretion exists at blood pressure levels below those commonly regarded as hypertension, with a greater risk among Blacks than among Whites.
albuminuria; blacks; blood pressure; diabetes mellitus; whites
Abbreviations:
Abbreviations: CARDIA, Coronary Artery Risk Development in Young Adults; CI, confidence interval; OR, odds ratio; TE, technical error as a percentage of the mean.
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INTRODUCTION
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Microalbuminuria, the excretion of albumin in the urine at a level above the normal range but below the level of macroalbuminuria, is common in both hypertension and diabetes mellitus. It predicts stroke (1, 2), coronary heart disease (1, 35), and cardiovascular disease, as well as total mortality (1, 6) and end-stage renal disease (712). Even below the standard cutpoint for microalbuminuria, urinary albumin excretion at a rate regarded as high normal is associated with higher rates of all-cause death and cardiovascular disease in persons without diabetes (13). Elevations in albumin excretion may underlie the relation of renal disease to cardiovascular disease, especially in diabetic nephropathy (14). In fact, the predictive value of microalbuminuria may be a reflection of arterial endothelial cell dysfunction generally (11, 15). As a result, microalbuminuria may be of interest in itself as a subclinical marker of endothelial cell dysfunction, a condition that is believed to promote atherogenesis.
Therefore, it is important to understand how factors such as blood pressure may lead to a higher rate of urinary albumin excretion. Some studies have suggested that the association between blood pressure and albumin excretion is continuous across the range of blood pressures (1621), although other studies in Whites of European descent have not (22, 23). Only two studies have addressed the level of blood pressure at which microalbuminuria begins to increase (18, 20).
In this paper, we report on urinary albumin excretion based on the urinary albumin:creatinine ratio (24), both as a continuous variable and as the prevalence of higher albumin excretion (micro- or macroalbuminuria) in different population groups. In our analysis, we focused on the relation of albumin excretion to blood pressure, fasting glucose status, and other coronary heart disease risk factors in healthy young Black and White men and women in whom a single untimed urine sample had been obtained on two occasions, 10 and 15 years after the beginning of the study. Furthermore, we examined the utility of blood pressure measurements up to 15 years earlier in predicting the occurrence of higher albumin excretion.
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MATERIALS AND METHODS
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The Coronary Artery Risk Development in Young Adults (CARDIA) Study has as its overarching goal the description of the evolution of cardiovascular disease risk, starting in young adulthood (25). The study recruited 5,115 Black and White men and women aged 1830 years in 19851986 at four clinical centers located in Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and Oakland, California. Follow-up examinations were completed 2, 5, 7, 10, and 15 years later. Of the 3,379 persons who attended both the year 10 and the year 15 examinations, 40 were excluded because of pregnancy and 27 were excluded because of reported kidney failure, transplantation, dialysis, glomerulonephritis, or a serum creatinine level greater than or equal to 2 mg/dl at either examination. Of the 3,312 persons remaining, 2,724 had albumin values for both examinations, 231 provided urine samples only at year 10, 320 provided samples only at year 15, and 37 provided samples at neither examination. The 588 persons without albumin values for both examinations were excluded. The predominant reason for not providing a urine sample was menstruation (n = 176 at year 10 and n = 209 at year 15); the remaining cases in which albumin was not measured were cases of inability to provide a sample, refusal, or technical error, such as sample spillage. We further excluded participants whose blood pressure and fasting glucose status could not be defined because of missing values for blood pressure (n = 3) or fasting glucose (n = 36) or because the participant had fasted for less than 8 hours (n = 103). Thus, the final analytical sample included 2,582 participants.
Examinations
Information on race, sex, and age was provided by self-report. Interviews were used to obtain sociodemographic information such as education, income, medical history, and medication use. Certified technicians measured blood pressure three times after a 5-minute rest, with 1-minute intervals between measurements, using a Hawksley random-zero sphygmomanometer (W. A. Baum Company, Copaigue, New York). Blood pressure categories were defined according to the guidelines set forth by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (26): 1) hypertensive (systolic blood pressure
140 mmHg or diastolic blood pressure
90 mmHg or use of antihypertensive medication); 2) blood pressure
139/89not hypertensive but systolic pressure within 130139 mmHg or diastolic pressure within 8589 mmHg; 3) blood pressure
129/85neither of the two previous categories but systolic pressure within 120129 mmHg or diastolic pressure within 8084 mmHg; 4) blood pressure <119/79neither of the three previous categories but systolic pressure within 110119 mmHg or diastolic pressure within 7579 mmHg; and 5) blood pressure <110/75none of the previous categories but systolic pressure less than 110 mmHg and diastolic pressure less than 75 mmHg.
Blood samples were drawn from seated participants after at least 8 hours of fasting. Tourniquet use was limited to 2 minutes to prevent hemoconcentration. Blood samples were centrifuged, aliquoted, and frozen at 70°C within 90 minutes of drawing. Aliquots were stored locally for 1 month and then shipped on dry ice for analysis or long-term storage. Glucose was measured using a Cobas Mira Plus chemistry analyzer (Roche Diagnostic Systems, Inc., Montclair, New Jersey) with the hexokinase ultraviolet method at Linco, Inc. (St. Louis, Missouri) (27, 28). The classification of diabetes was assigned to persons who had a fasting serum glucose level greater than or equal to 126 mg/dl or who were using insulin or oral hypoglycemic medication in any year (29). Given that only 15 of 109 persons taking medication for diabetes (in the entire CARDIA sample) both were taking insulin and had been diagnosed before age 30 years, most diabetics in this study are likely to have had type 2 diabetes. Impaired fasting glucose was defined as a fasting serum glucose level of 110125 mg/dl in subjects who were not taking medication. Normal fasting glucose was defined as a fasting serum glucose level less than 110 mg/dl in persons who were not taking medication, according to the American Diabetes Association definition (29).
Measurement of urinary albumin and creatinine levels
A single, untimed (spot) urine sample was collected at both the year 10 and year 15 examinations when convenient during the clinic visit, usually shortly after arrival at the clinic. Albumin and creatinine levels were measured in year 10 at the Regional Kidney Disease Program Renal Laboratory, Hennepin County Medical Center, Minneapolis, Minnesota. Albumin was assessed using a nephelometric procedure with a specific anti-albumin monoclonal antibody, and creatinine was assessed using the Jaffe method. The year 15 samples were analyzed at the Northwest Lipid Research Laboratory in Seattle, Washington, using a nephelometric procedure for albumin and the Jaffe method for creatinine.
Estimation of albumin excretion rate
We estimated albumin excretion rate using the formula albumin/(k x creatinine) (denoted A/kC), where k adjusts for race and sex differences in typical daily creatinine excretion (24). For these calculations, albumin and creatinine concentrations are expressed in mg/liter and g/liter, respectively. Thus, A/kC is expressed in mg/g. Briefly, urinary creatinine concentration in men was multiplied by 0.68, which approximated the ratio of albumin:creatinine cutpoints used by Warram et al. (30) to indicate sex-specific elevated albumin excretion in type 1 diabetes mellitus. For correction of race bias, urinary creatinine concentration in Blacks was multiplied by 0.88, the average ratio of White participants to Black participants for urinary creatinine excretion (mg/24 hours) found in the CARDIA Study (24) and the study by James et al. (31). Applying these adjustments allowed the use of 25 mg/g as the A/kC cutpoint for microalbuminuria and 250 mg/g as the cutpoint for macroalbuminuria in each of the four CARDIA race-sex groups (24). In keeping with the National Kidney Foundation recommendations for assessing proteinuria (32), the first definition used in these analyses was based on the average of the year 10 A/kC and the year 15 A/kC. By averaging two observations, this definition reduced variation in the estimate of albumin excretion. In addition, we studied four aspects of appearance and disappearance of higher albumin excretion. The first included people whose higher albumin excretion did not persist at year 15 (an indicator variable for year 10 A/kC
25 mg/g, omitting those persons with year 15 A/kC
25 mg/g). The second included incident cases, people whose higher albumin excretion was first seen at year 15 (an indicator variable for year 15 A/kC
25 mg/g, omitting those persons with year 10 A/kC
25 mg/g). The third included people whose higher albumin excretion persisted at years 10 and 15 (an indicator variable for both year 10 and year 15 A/kC
25 mg/g, omitting those with only year 10 A/kC
25 mg/g and those with only year 15 A/kC
25 mg/g). Finally, the fourth aspect was the union of these indicator variables, namely people who satisfied either the year 10 A/kC
25 mg/g criterion or the year 15 A/kC
25 mg/g criterion; this variable, in effect, based the definition of higher albumin excretion on the maximum value of A/kC.
Laboratory methods and technical error
At year 10, samples were pH-adjusted in the clinic prior to freezing. The sensitivity of the albumin assay was 0.045 mg/liter; no samples had undetectable levels of albumin. A total of 406 split samples were analyzed for quality assurance; the mean difference, correlation coefficient (r), and technical error as a percentage of the mean (TE) were as follows: for albumin, 0.002 mg/liter (standard deviation, 1.1), r = 0.99, TE = 28.2 percent; for creatinine, 0.01 mg/dl (standard deviation, 25.9), r = 0.96, TE = 10.8 percent. The year 15 samples were analyzed at the Northwest Lipid Research Laboratory. Samples were pH-adjusted after thawing in the laboratory. A similar nephelometric method was used, but the assay was less sensitive. Albumin values for 353 samples with nondetectable albumin levels were set at 0.22 mg/liter. A total of 432 split samples analyzed for quality assurance showed the following mean differences, correlation coefficients, and TEs: for albumin, 0.02 mg/liter (standard deviation, 0.4), r = 0.99, TE = 16.2 percent; for creatinine, 0.6 mg/dl (standard deviation, 13.5), r = 0.99, TE = 5.9 percent. The method used at year 10 was implemented in 2002 at the Molecular Epidemiology and Biomarker Research Laboratory at the University of Minnesota, Minneapolis, Minnesota. In 10 single untimed urine samples provided by laboratory staff, A/kC ranged from 1.5 mg/g to 30.6 mg/g. Mean A/kC levels were similar regardless of whether the pH adjustment was made before freezing (8.8 mg/g) or after thawing (9.0 mg/g) (p for difference = 0.6). Therefore, from a technical perspective, we decided that we could combine the data from analyses at year 10 and year 15.
Statistical methods
We analyzed continuous A/kC values on the logarithmic scale to focus analytical attention on the central peak of the skewed distribution. For purposes of presentation, the values were transformed back to a linear scale (by exponentiation), yielding geometric means. We conducted linear regression and cross-tabulations to determine the prevalence of higher albumin excretion and its relation with blood pressure, fasting glucose status, and other covariates. With the exception of blood pressure assessments at years 0 and 7, all predictor variables were assessed at year 10. Attenuation of demographic relations was calculated as the regression coefficient for the demographic variable in the full model minus the corresponding regression coefficient in the limited model, divided by the regression coefficient in the limited model. All analyses were completed using the SAS statistical package, version 8.2 (SAS Institute, Inc., Cary, North Carolina).
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RESULTS
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General characteristics
Compared with Whites within sex, Blacks were heavier, had higher blood pressure, were more likely to be current smokers, and had lower educational attainment (table 1). Compared with women within race, men were heavier and had higher blood pressure; among Blacks, men were more likely than women to be current smokers and had lower educational attainment. White men had a higher body mass index (weight (kg)/height (m)2) than White women, but Black men had a lower body mass index than Black women.
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TABLE 1. Characteristics of participants at the year 10 examination (19951996), by sex and race, Coronary Artery Risk Development in Young Adults Study, 19851986 to 2000
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As in the previously reported data based on year 10 only (24), the geometric mean A/kC based on the average of years 10 and 15 was higher among Blacks than among Whites and higher among men than among women (9.4 mg/g in Black men, 7.2 mg/g in Black women, 6.8 mg/g in White men, and 5.8 mg/g in White women; p < 0.001 for all pairwise comparisons except the comparison of White men with Black women (p = 0.3)). After adjustment for race and sex, persons who had received no education beyond high school had a higher geometric mean A/kC (n = 673; 7.9 mg/g) than persons who had (n = 1,903; 6.8 mg/g) (p < 0.0001). Average A/kC was slightly higher among participants over 35 years of age (n = 1,524; 7.3 mg/g) than among those below age 35 years at the year 10 examination (n = 1,052; 6.7 mg/g) (p = 0.01).
Distribution of albumin excretion values
Based on A/kC at the individual examinations, 2,327 persons consistently had normoalbuminuria and 255 persons had higher albumin excretion at either examination or both examinations (table 2). Based on the average of the year 10 A/kC and the year 15 A/kC, 2,400 of the 2,582 participants included in these analyses had normal albuminuria and 182 had higher albumin excretion (table 2). Thus, 73 persons had higher albumin excretion at one examination only, but their average A/kC was below 25 mg/g.
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TABLE 2. Numbers of cases of higher urinary albumin excretion (A/kC* 25 mg/g, including microalbuminuria and macroalbuminuria) based on the year 15 measurement (19992000), according to the year 10 measurement (19951996) and the average of the year 10 and year 15 measurements, Coronary Artery Risk Development in Young Adults Study, 19851986 to 2000
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Based on the average of year 10 A/kC and year 15 A/kC, 18 participants had macroalbuminuria (A/kC
250 mg/g). An additional six participants had macroalbuminuria at year 15 but not at year 10, and one participant had macroalbuminuria at year 10 but microalbuminuria at year 15. Thus, 25 people had macroalbuminuria based on the maximum A/kC between years 10 and 15.
Associations with fasting glucose status at year 10
Fasting glucose status was a major correlate of albumin excretion after adjustment for sex, age, education, study center, and blood pressure status (table 3): The geometric mean A/kC (based on the average of the year 10 and year 15 measurements) was 25.7 mg/g among diabetic subjects (p < 0.0001 in comparison with normal fasting glucose), 10.0 mg/g among subjects with impaired fasting glucose (p = 0.007 in comparison with normal fasting glucose), and 6.9 mg/g among participants with normal fasting glucose. Relations with prevalence of higher albumin excretion paralleled those with the continuous variable A/kC. There was a nearly 11-fold increase in the odds of higher albumin excretion among diabetic participants compared with participants with normal fasting glucose (odds ratio (OR) = 10.91, 95 percent confidence interval (CI): 5.80, 20.5); the odds of higher albumin excretion among persons with impaired fasting glucose were threefold (OR = 3.05, 95 percent CI: 1.28, 7.3) those of persons with normal fasting glucose. Blacks with normal fasting glucose had a higher A/kC and a greater prevalence of higher albumin excretion than Whites with normal fasting glucose (p < 0.0001). Whites and Blacks with impaired fasting glucose and diabetes had similar A/kCs (p > 0.4), but Blacks with diabetes had a greater prevalence of higher albumin excretion (p = 0.006). Men had a higher A/kC and a greater prevalence of higher albumin excretion than women, regardless of fasting glucose status.
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TABLE 3. Geometric mean A/kC* (average of year 10 and year 15 measurements (19952000)) and prevalence of higher urinary albumin excretion (A/kC 25 mg/g, including micro- or macroalbuminuria), by fasting glucose status, Coronary Artery Risk Development in Young Adults Study, 19851986 to 2000
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Associations with blood pressure at year 10
Geometric mean A/kC (average of the year 10 and year 15 measurements) increased for each higher category of blood pressure, the increase appearing to be steeper the higher the blood pressure (p < 0.0001; table 4, figure 1), after adjustment for sex, age, education, study center, and fasting glucose status. For each standard deviation of increase in systolic and diastolic blood pressure (modeled as continuous variables), the odds of higher albumin excretion increased approximately 1.5-fold (for a 12.3-mmHg increase in systolic blood pressure, OR = 1.60, 95 percent CI: 1.38, 1.85; for a 9.9-mmHg increase in diastolic blood pressure, OR = 1.51, 95 percent CI: 1.29, 1.76). When systolic and diastolic pressure were modeled together, systolic blood pressure remained an independent predictor of higher albumin excretion (OR = 1.48, 95 percent CI: 1.19, 1.84), while diastolic blood pressure had an odds ratio of only 1.10 per standard deviation. Compared with systolic blood pressure, a one-standard-deviation increase of 8.1 mmHg pulse pressure (systolic minus diastolic) was associated with a smaller increase in risk of elevated albumin excretion (OR = 1.27, 95 percent CI: 1.10, 1.46).
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TABLE 4. Geometric mean A/kC* (average of year 10 and year 15 measurements (19952000)) and prevalence of higher albumin excretion (A/kC 25 mg/g, including micro- or macroalbuminuria), by blood pressure status, Coronary Artery Risk Development in Young Adults Study, 19851986 to 2000
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FIGURE 1. Relation of blood pressure at years 0, 7, and 10 to prevalence of higher urinary albumin excretion (UAE) (A/kC 25 mg/g, based on the average of year 10 and year 15 measurements), adjusted for year 10 age, sex, race, education, and diabetes mellitus status, Coronary Artery Risk Development in Young Adults Study, 19851986 to 2000. Blood pressure category was determined by the higher of systolic or diastolic blood pressure; for example, a person with a blood pressure of 128/78 mmHg and no use of medication was placed in the category <130/85 and 120/80. (*Odds ratios (OR) and 95% confidence intervals (CI) are for comparison with the blood pressure category 110/75 mmHg and no use of medication at year 10.)
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The tendency for men to have a higher A/kC than women was most apparent for the two highest blood pressure categories. Among hypertensive subjects, approximately 18 percent had higher albumin excretion. The quadratic pattern of relation between higher albumin excretion and blood pressure seen in figure 1 persisted among persons with normal fasting glucose (data not shown). The higher prevalence of higher albumin excretion in Blacks than in Whites in the nonhypertensive range (<140/90 mmHg and not on medication; see table 4) also persisted among persons with normal fasting glucose (data not shown).
Level of albumin excretion predicted from blood pressure measurement prior to year 10
The prevalence of higher albumin excretion was greater the higher the blood pressure, even for blood pressure measured at year 0, 10 years before urinary albumin was first assessed. In general, the shapes of the relations between blood pressure and higher albumin excretion were similar regardless of when the participant reached the level of blood pressure and regardless of whether blood pressure was modeled using the criteria of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (figure 1) (26) or separately by systolic blood pressure, diastolic blood pressure, or pulse pressure (data not shown). The relation became more stable as the prevalence of subjects in the higher blood pressure categories increased in the later years of the study. In part, the prediction from early blood pressure measurements arose from blood pressure tracking (i.e., the correlations between pairs of blood pressure measurements at years 0 and 7 versus year 10 were 0.59 and 0.70 for systolic blood pressure and 0.46 and 0.62 for diastolic blood pressure, respectively).
Most people with higher albumin excretion were normotensive and had a normal fasting glucose level at year 10. Of the 182 participants with higher albumin excretion (based on the average of the year 10 and year 15 measurements), 22 had diabetes or impaired fasting glucose but not hypertension; 24 had hypertension but not diabetes or impaired fasting glucose; and eight had both hypertension and either diabetes or impaired fasting glucose. Thus, 54 participants (30 percent) had diabetes, impaired fasting glucose, or hypertension.
Associations of higher albumin excretion with other risk factors measured at year 10
Both the continuous-measure A/kC (average of the year 10 and year 15 measurements) and the measure of prevalence of higher albumin excretion had weaker relations with other year 10 coronary heart disease risk factors than they did with blood pressure and fasting glucose status (table 5). Albumin excretion increased with plasma triglyceride level, apparently more rapidly the higher the level of triglycerides; the association was somewhat attenuated after adjustment for blood pressure and fasting glucose status. A U-shaped relation was seen with body mass index, slightly attenuated after adjustment for blood pressure and fasting glucose status. Relations with fasting plasma insulin and low density lipoprotein cholesterol lost statistical significance after adjustment for blood pressure and fasting glucose status. Albumin excretion was unrelated to high density lipoprotein cholesterol or cigarette smoking. The associations of the two measures of albumin excretion with fasting glucose status and blood pressure shown in tables 3 and 4 were little changed by further adjustment for the coronary heart disease risk factors listed in table 5 or in the subset of participants without diabetes or hypertension (data not shown).
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TABLE 5. Prevalence of higher urinary albumin excretion (A/kC 25 mg/g, including micro- or macroalbuminuria) and geometric mean A/kC* (average of year 10 and year 15 measures (19952000)), according to other coronary heart disease risk factors, Coronary Artery Risk Development in Young Adults Study, 19851986 to 2000
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Attenuation of demographic associations by risk factor adjustment
A substantial portion of the association of prevalence of higher albumin excretion with demographic factors was explained by adjustment for blood pressure group and fasting glucose status (29 percent of the race difference, 34 percent of the sex difference, 23 percent of the education difference, and 89 percent of the age difference). Nevertheless, the race, sex, and education differences remained statistically significant after this adjustment (p < 0.0006 in each case; p = 0.35 for age). Findings were similar for geometric mean A/kC.
Findings for incident higher albumin excretion and other definitions of higher albumin excretion
The associations of higher albumin excretion with year 10 blood pressure and fasting glucose status were insensitive to the way in which A/kC was combined across years 10 and 15 and, in particular, held for incident higher albumin excretion (figures 2 and 3). The associations were clearest in the analysis based on the maximum A/kC between years 10 and 15. The association of higher albumin excretion with blood pressure was least apparent in persons whose higher albumin excretion was not sustained at year 15.

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FIGURE 2. Relation of year 10 blood pressure to higher urinary albumin excretion (UAE) (A/kC 25 mg/g) according to four alternative definitions: incident, not persistent, persistent, and present at either examination (see Materials and Methods for details), Coronary Artery Risk Development in Young Adults Study, 19851986 to 2000. Data were adjusted for year 10 age, sex, race, education, and diabetes mellitus status. Blood pressure category was determined by the higher of systolic or diastolic blood pressure; for example, a person with a blood pressure of 128/78 mmHg and no use of medication was placed in the category <130/85 and 120/80.
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FIGURE 3. Relation of year 10 fasting glucose status to higher urinary albumin excretion (UAE) (A/kC 25 mg/g) according to four alternative definitions: incident, not persistent, persistent, and present at either examination (see Materials and Methods for details), Coronary Artery Risk Development in Young Adults Study, 19851986 to 2000. Data were adjusted for year 10 age, sex, race, education, and blood pressure. Note that the y-axis scale differs between figures 2 and 3.
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DISCUSSION
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The healthy young adults studied in CARDIA experienced a significant prevalence of microalbuminuria (6.4 percent) and a lower prevalence of macroalbuminuria (0.7 percent), based on the average of the A/kCs obtained at years 10 and 15. A/kC increased with both impaired fasting glucose and diabetes and with rising systolic and diastolic blood pressures, regardless of whether the higher albumin excretion outcome was incident (at year 15 only), persistent (at both year 10 and year 15), or prevalent (at either year or both years). Blood pressure was predictive of albumin excretion 1015 years later. Seventy percent of micro- and macroalbuminuria cases were among persons with both normal fasting glucose and normal blood pressure. Because higher urinary albumin excretion is a subclinical marker for endothelial cell dysfunction in the arterial system and albumin excretion rate is related to higher risk of cardiovascular disease and other chronic diseases (16, 812, 3336), the findings of this study imply a significant prognostic value of urinary albumin excretion both below and above the cutoffs used for microalbuminuria, particularly in a population where the opportunity for primary prevention of cardiovascular disease and kidney disease still exists.
There is general agreement that microalbuminuria occurs frequently in subjects with diabetes mellitus (2123, 3740). The nearly sevenfold increase in prevalence of micro- and macroalbuminuria among diabetic CARDIA subjects (41 percent) as compared with those with normal fasting glucose (7 percent) is similar to the Pima Indian experience (47 percent in diabetic subjects vs. 8 percent in those with normal glucose tolerance) (41) and agrees with the results of other studies showing an increase in the prevalence of higher albumin excretion among persons with impaired fasting glucose (39, 4143). These data support the idea that in some people, microalbuminuria may precede the onset of clinically defined diabetes (39).
We confirmed previous reports that the rise of albumin excretion began within the normal range of blood pressure values (1619, 40, 41, 4448). These data prospectively demonstrate that a rising blood pressure, even below the range recommended for treatment (26), relates prognostically to the development of higher albumin excretion. The increased prevalence of higher blood pressure and higher albumin excretion at each level of blood pressure among Black participants could be useful in focusing investigations on the disproportionate burden of kidney disease among Blacks as compared with Whites.
With the possible exception of fasting plasma triglyceride level, albumin excretion showed much stronger associations with blood pressure and fasting glucose status than with other coronary heart disease risk factors in this young, healthy cohort. These results agree with those from other reports showing inconsistent relations of age (5, 6, 13, 4043, 49, 50), smoking (19, 40, 42, 43, 49, 51), body mass index (18, 19, 21, 39, 40, 42), and triglycerides (39, 40, 42, 43, 45, 52) with albumin excretion. The modest strength of the association of these covariates with albumin excretion, differences in the types of participants studied, and different methods of assessing albumin excretion may all have contributed to these inconsistencies in the literature.
The National Kidney Foundation guidelines for assessment of proteinuria (26) recommend screening adults using the albumin:creatinine ratio or an albumin-specific dipstick in a single untimed urine sample. This is consistent with our previous report, in which we adjusted the ratio for race and sex differences in creatinine excretion (thus partially addressing differences in skeletal muscle mass) (24). Although use of the ratio A/kC is likely to misclassify some peoples urinary albumin excretion rate, timed urine samples are also subject to misclassification due to inadequate collection and inaccurate timing.
While most clinical guidelines recommend repeat testing, this is generally not possible in epidemiologic studies. To partially mimic this procedure, we focused on the average of A/kCs in two untimed urine samples separated by 5 years. Nevertheless, the similarity of findings in this study, whether based on a single untimed urine sample at year 10 only or on incident cases at year 15, implies that considerable epidemiologic information about the causes and consequences of urinary albumin excretion can be obtained in a single untimed urine sample.
In addition to diabetes and hypertension, we found that Black race, male sex, fasting serum glucose level, and blood pressure level within the normotensive range were strong correlates of high normal albumin excretion, microalbuminuria, and macroalbuminuria. Identification of other physiologic, genetic, or environmental factors affecting urinary albumin excretion in normotensive, normoglycemic persons should be a priority. Other investigators have also observed that microalbuminuria is a fairly common occurrence in people who do not have diabetes (1) or who have neither diabetes nor hypertension (49). We add to this the observation that A/kC and microalbuminuria increased at lower levels of normal blood pressure in Blacks than in Whites and that blood pressure measured 1015 years earlier predicted level of A/kC. The implications of higher A/kC and greater prevalence of micro- and macroalbuminuria in Blacks than in Whites, in men than in women, and at relatively low levels of blood pressure require more attention from both interventional (5355) and pathophysiologic perspectives.
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NOTES
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Correspondence to Dr. David R. Jacobs, Jr., Division of Epidemiology, University of Minnesota School of Public Health, 1300 South 2nd Street, Suite 300, Minneapolis, MN 55454 (e-mail: jacobs{at}epi.umn.edu). 
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