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*Renal Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Division of Nephrology, University of California, San Francisco, California; and Department of Medicine and Channing Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts.
Correspondence to: Dr. Holly J. Mattix, 100 Charles River Plaza, 5th Floor, Boston, MA 02114. Phone: 617-726-7598; Fax: 617-228-7491; E-mail: hmattix{at}partners.org
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Abstract |
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30 µg/mg) and sex-specific cutpoints (17 µg/mg in men and 25 µg/mg in women) measured in spot urine specimens. Mean urine albumin concentrations were not significantly different between men and women, but urine creatinine concentrations were significantly higher (P < 0.0001). Compared with non-Hispanic whites, urine creatinine concentrations were significantly higher in non-Hispanic blacks (NHB) and Mexican Americans, whereas urine albumin concentrations were significantly higher in NHB (P < 0.0001) but not Mexican Americans. When a single ACR is used, the prevalence of microalbuminuria was significantly lower among the men compared with women (6.0 versus 9.2%; P < 0.0001) and among non-Hispanic whites compared with NHB (7.2 versus 10.2%; P < 0.0001). No significant difference in the prevalence of microalbuminuria between men and women was noted when sex-specific ACR cutpoints were used. In the multivariate adjusted model, female sex (odds ratio, 1.62; 95% confidence interval, 1.29 to 2.05) and NHB race/ethnicity (odds ratio, 1.34; 95% confidence interval, 1.12 to 1.61) were independently associated with microalbuminuria when a single ACR threshold was used. When a sex-specific ACR was used, NHB race/ethnicity remained significantly associated with microalbuminuria but sex did not. The use of one ACR value to define microalbuminuria may underestimate microalbuminuria in subjects with higher muscle mass (men) and possibly members of certain racial/ethnic groups. |
Introduction |
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The ADA and the National Kidney Foundation define microalbuminuria as an ACR between 30 to 300 µg/mg in both men and women (3,4). These guidelines do not take into account sex differences in creatinine excretion, and several researchers have advocated sex-specific cutpoints of the ACR to define microalbuminuria (5,6). However, no published studies have demonstrated how the use of a single ACR cutpoint versus sex-specific ACR cutpoints measured in random urine samples affects the estimated prevalence of microalbuminuria in a nationally representative sample of US subjects.
The current definition of microalbuminuria as measured by the ACR in a random urine specimen also does not account for racial differences in creatinine excretion. Previous studies have reported urine creatinine excretion rates to be 5 to 30% higher in black subjects compared with white subjects, even after adjusting for weight (7,8). However, the number of subjects in these studies was small, and they were not representative of the entire US population.
Therefore, we examined the distribution of urine albumin and creatinine concentrations and ACR measured in spot urine specimens in a nationally representative sample of men and women and non-Hispanic whites (NHW), non-Hispanic blacks (NHB), and Mexican Americans (MA). Moreover, we evaluated the association between sex and race/ethnicity and microalbuminuria using the currently recommended ACR value (30 µg/mg) and a definition using sex-specific ACR cutpoints (17 µg/mg in men and 25 µg/mg in women).
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Materials and Methods |
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There were 17,030 men and women 20 yr and older who completed both the interview and the physical examination. Of these subjects, we excluded 457 subjects with missing data on urine specimens (181 men and 276 women) and 288 women who were pregnant at the time of the urine collection. For the analysis of the whole population, we excluded subjects with macroalbuminuria as defined by the ADA (ACR 300 µg/mg) (186 men and 165 women) (4). In all analyses that used sex-specific ACR cutpoints, 207 men and 139 women with macroalbuminuria (ACR 250 in men and 355 in women) were excluded. Thus, there were 15,934 people who were 20 yr and older at the time of the home interview who were eligible for the analysis that used ACR 30 µg/mg to define microalbuminuria, and there were 15,939 subjects who were eligible for the analyses that used the sex-specific ACR cutpoints.
Exposure
Medical and nutritional history and medication use were collected during a standardized home interview, and a detailed physical examination was completed. Age was defined as the age at the time of the interview, and race/ethnicity was self-reported as NHW, NHB, and, MA. Other race/ethnicities were grouped into the category "other." BP was determined by the average of six readings, three measured during the home interview and three during the physical examination. Diabetes mellitus (DM) was self-reported as being previously diagnosed with DM by a doctor (except during pregnancy) or the current or past use of insulin or diabetes pills. Body mass index (BMI; kg/m2) was calculated from the weight and height measured during the physical examination.
Microalbuminuria
Solid-phase fluorescence immunoassay was used to measure urinary albumin with a sensitivity level of 0.05 mg/dl. The coefficient of variation for urinary albumin measurement varied from 4.8 to 16.1% over the 6 yr of the study (10). Urine creatinine was measured with the Jaffé rate reaction (Beckman Astra, Brea, CA), and the coefficient of variation ranged from 1.5 to 7.7% throughout the study (10). Spot urine ACR ratios were calculated for all subjects.
To define microalbuminuria in random urine specimens, we used the ACR cutpoint recommended by the ADA (4) and the National Kidney Foundation (3) (ACR 30 µg/mg). We also used sex-specific ACR cutpoints as proposed by Warram et al. (5), 17 and 25 µg/mg for men and women, respectively. These sex-specific ACR cutpoints were determined by comparing the ACR in spot urine samples to albumin excretion rates collected from timed urine specimens. The ACR values 17 to 250 µg/mg in men and 25 to 355 µg/mg in women corresponded to 30 to 300 µg/min of urine albumin excretion measured in a timed urine specimen, respectively. These sex-specific ACR cutpoints, 17 and 25 µg/mg, were the 95th percentile ACR values among 218 nondiabetic, healthy men and women, respectively (5). The units of urine albumin (µg/ml), creatinine concentration (mg/dl), and ACR (µg/mg) correlate with the numeric values of albumin excretion rates (µg/min). Dividing the ACR by 8.84 converts the units (from µg/mg to mg/mmol).
Statistical Analyses
All statistical analyses, including frequencies, t tests, multivariate adjusted odds ratios (OR), and 95% confidence intervals (CI), were completed with SAS-callable SUDAAN (Research Triangle Institute, Research Triangle Park, NC) to incorporate sample weights and to adjust for the clusters and strata of the complex sample design and provide prevalence estimates, which reflect the entire US population. The NHANES III data are weighted to account for the probability of selection and to adjust for nonresponse to the interview and physical examination. Categorical variables were compared by the Wald 
2 test, and mean values of continuous variables were compared between groups by the unpaired t test.
Logistic regression was used to calculate odd ratios for microalbuminuria after controlling for multiple covariates simultaneously. The following covariates, selected from previously published reports (1,5,6), were included in the logistic model: age, sex, race/ethnicity, SBP, diastolic BP (DBP), BMI, history of DM, and current smoking. Age was categorized into decades. Race/ethnicity was categorized as NHW, NHB, MA, and other. The sample size of the "other" category was too small to be used analytically, and results from this group are not shown. SBP was categorized into 6 groups: <120, 120 to 130, 131 to 140, 141 to 150, 151 to 160, and >160 mmHg. DBP was categorized into 5 groups: <70, 70 to 80, 81 to 90, 91 to 100, >100 mmHg. BMI was divided into 4 categories on the basis of the criteria of the International Obesity Task Force (11): <18.5, 18.5 to 24.9, 25 to 30, and >30 kg/m2. Smoking was categorized as current smoker (yes/no).
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Results |
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17 µg/mg for men and 25 µg/mg for women). Thus, the use of sex-specific ACR cutpoints increased the total estimate of people in the US population with microalbuminuria from 12.9 million to 18.4 million, with approximately 1.2 million more women with microalbuminuria than men (8.6 million men and 9.8 million women).
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MA did not have significantly different urine albumin concentrations compared with NHW, but urine creatinine concentrations were significantly higher (139.0 versus 123.1 µg/mg; P < 0.0001). The frequency of microalbuminuria as defined by an ACR 30 µg/mg or by sex-specific cutpoints was not statistically different between MA and NHW.
The age-adjusted and the multivariate adjusted OR by sex and race/ethnicity are listed in Table 4. In the age-adjusted model with microalbuminuria as defined by ACR 30 µg/mg, female sex was significantly associated with microalbuminuria (OR, 1.47; 95% CI, 1.18 to 1.82). The association was slightly increased after adjusting for race/ethnicity, DM, SBP, DBP, BMI, and smoking, (OR, 1.62; 95% CI, 1.29 to 2.05). However, there was no association between sex and microalbuminuria in the age-adjusted or multivariate models when the sex-specific ACR cutpoints (ACR 17 µg/mg in men and 25 µg/mg in women) were used.
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30 µg/mg. In the multivariate model, NHB race/ethnicity remained significant (OR, 1.34; 95% CI, 1.12 to 1.61), but MA race/ethnicity (OR, 1.24; 95% CI, 0.99 to 1.54) did not. Similar results were noted when sex-specific ACR cutpoints were used to define microalbuminuria within the racial groups, but the CI for MA race/ethnicity did not include 1.0. |
Discussion |
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In this study, the higher frequency of microalbuminuria among women, defined by an ACR 30 µg/mg, was in part due to lower urine creatinine concentrations and not a higher urine albumin concentration. Creatinine is a metabolic byproduct of skeletal muscle creatine and phosphocreatine metabolism and is thus lower in subjects with lower muscle mass such as women or the elderly (7). We found significantly higher levels of urine creatinine in men but no significant differences in urine albumin concentration. Because the denominator in the ACR ratio was significantly lower in women, the multivariate adjusted OR for microalbuminuria in women, defined by an ACR 30, was 50% higher compared with men.
Several investigators have previously advocated using separate ACR cutpoints for the detection of microalbuminuria in men and women (5–6). Warram et al. (5) determined sex-specific ACR values by comparing the ACR in spot urine samples to albumin excretion rates measured in timed urine specimens. The ACR values 17 µg/mg in men and 25 µg/mg in women corresponded to 30 and 31 µg/min of urine albumin excretion, respectively. These ACR cutpoints were also the 95th percentile values among 218 nondiabetic healthy men and women. Similarly, Connell et al. (6) collected timed overnight urine samples in 187 diabetic and 105 control subjects and found that an ACR of 4.0 mg/mmol (
22 µg/mg) correlated with an albumin excretion rate of 35 µg/min in men and 23 µg/min in women.
We demonstrated significant differences in urine creatinine concentrations between NHW, NHB, and MA, as noted by previous researchers (7,8). In addition, the ratio urinary creatinine concentration/BMI was significantly higher among NHB compared with NHW. These findings are consistent with previous studies, which demonstrated higher 24-h urinary creatinine excretion per kilogram in black subjects compared with nonblack subjects (7,8). Differences in creatinine excretion are likely in part due to differences in muscle mass; some researchers have demonstrated higher skeletal muscle mass in NHB men and women compared with whites (16,17). Although urine creatinine concentrations in NHB and MA were higher than NHW (which would decrease the ACR), the frequency of microalbuminuria in these groups was significantly higher. Thus, the frequency of microalbuminuria in NHB and MA may have been underestimated. To our knowledge, no previous studies have compared individual 24-h urine collections and spot urine specimens in various race/ethnicity groups to determine appropriate ACR thresholds for different race/ethnicity groups such as NHB. Future studies should investigate appropriate ACR thresholds for different racial/ethnic groups.
Additionally, we found NHB race/ethnicity was independently associated with microalbuminuria when one ACR threshold or sex-specific ACR cutpoints was used. Savage et al. (15) noted a higher prevalence of microalbuminuria in NHB with type 2 DM. However, after adjusting for hypertension, age, and other risk factors, race/ethnicity was no longer independently associated with microalbuminuria in that study (15). In other investigations, the association between race and microalbuminuria was not assessed because of the homogenous population, which did not reflect the demographics of the United States (18,19), or it was not reported (13). In our study, NHB race/ethnicity remained independently associated with microalbuminuria even after adjusting for other risk factors, including age, DM, SBP, DBP, BMI, and smoking.
NHB had higher SBP and DBP compared with NHW, and previous reports have linked elevated SBP and DBP with microalbuminuria (6,20,21). Although we controlled for SBP and DBP in our model, we did not have information on 24-h BP measurements, which may be a more accurate measure of racial differences in terms of BP (22). The prevalence of DM was also significantly higher among NHB compared with NHW. Although we adjusted for DM in the multivariate model, we did not adjust for undiagnosed diabetes, which may partially account for the higher prevalence of microalbuminuria in this group.
In summary, urine creatinine concentrations differ between men and women and between different racial/ethnic groups. Therefore, standardizing urine albumin concentrations to creatinine (i.e., ACR) may underestimate microalbuminuria in subjects with higher muscle mass (men) and possibly in certain racial/ethnic groups, such as NHB, or overestimate it in subjects with lower muscle mass (women). Future research studies that use the ACR to define microalbuminuria should use sex-specific ACR cutpoints to help avoid the potential problems of underestimating microalbuminuria in subjects with high urine creatinine excretion (e.g., men) and overestimating microalbuminuria in subjects with low urine creatinine excretion (e.g., women). Results from prospective studies should be used to define risk of abnormal urine albumin excretion at different levels of ACR. Studies are also needed to determine appropriate ACR thresholds for different race/ethnicity groups.
NHB race/ethnicity was independently associated with microalbuminuria despite having higher urine creatinine concentrations. Because NHB have been identified as a high risk group for the association between microalbuminuria and increased cardiovascular and renal disease (1), detecting microalbuminuria in these individuals is critical so that preventive measures may be implemented early (1). The statistically significant association between race/ethnicity and microalbuminuria found in this study highlights the importance of race as an independent risk factor for both kidney and cardiovascular disease. [Printer: References (9,24) are cited here for parsing. Please delete this parenthetical information.]
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Acknowledgments |
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