Microalbuminuria and concentrations of antioxidants among US adults

ORIGINAL INVESTIGATIONS Pathogenesis and Treatment of Kidney Disease and Hypertension

Microalbuminuria and Concentrations of Antioxidants Among US Adults Earl S. Ford, MD, Wayne H. Giles, MD, Ali H. Mokdad, PhD, and Umed A. Ajani, MBBS, MPH ● Background: Microalbuminuria may increase the risk for cardiovascular disease. Increased oxidative stress, which may be important in the pathophysiological process of cardiovascular disease, occurs frequently in people with microalbuminuria and could depress their antioxidant concentrations, which then could contribute to end-organ damage associated with microalbuminuria. Methods: We examined associations between microalbuminuria and circulating concentrations of vitamins A, C, and E and carotenoids in 9,575 US adults aged 20 years or older who participated in the Third National Health and Nutrition Examination Survey (1988 to 1994). Results: After adjustment for age, sex, race or ethnicity, education, smoking status, cotinine concentration, physical activity, alcohol use, fruit and vegetable intake, vitamin or mineral use during the past 24 hours, body mass index, systolic blood pressure, and total cholesterol, triglyceride, glucose, insulin, and C-reactive protein concentrations, concentrations of ␤-cryptoxanthin (odds ratio for quartile of highest concentration compared with quartile of lowest concentration, 0.56; 95% confidence interval, 0.38 to 0.82), lutein/zeaxanthin (odds ratio, 0.59; 95% confidence interval, 0.37 to 0.94), lycopene (odds ratio, 0.64; 95% confidence interval, 0.46 to 0.89), and total carotenoids (odds ratio, 0.54; 95% confidence interval, 0.38 to 0.75) were associated inversely with microalbuminuria. Vitamin C, vitamin E, and selenium concentrations were not significantly associated with microalbuminuria. Conclusion: People with microalbuminuria may have reduced concentrations of selected antioxidants. Additional research is needed to examine the relationships between microalbuminuria and antioxidant status, mechanisms for depletion of antioxidants, and possible benefits from increased intake of antioxidants through dietary change or the use of supplements in people with microalbuminuria. Am J Kidney Dis 45:248-255. © 2004 by the National Kidney Foundation, Inc. INDEX WORDS: Albuminuria; antioxidants; ascorbic acid; carotenoids; health surveys; selenium; vitamin E.

I

NCREASED URINARY excretion of albumin has been linked to a greater risk for future cardiovascular and renal disease.1-7 Excess albumin excretion in urine commonly is divided into microalbuminuria and macroalbuminuria. Microalbuminuria is relatively common in the US population. Approximately 10% of US adults were found to have microalbuminuria, defined from the urinary albumin-creatinine ratio (UACR).8 The condition is especially frequent in people with diabetes and hypertension. Mechanisms through which microalbuminuria increases risk for cardiovascular disease and other conditions are incompletely understood. In addition, the relationships between classic risk factors for cardiovascular disease, endothelial dysfunction, inflammation, and microalbuminuria are complex.9 Although numerous studies have examined the associations among various measures of albuminuria and a host of risk factors for cardiovascular disease in a wide variety of populations, more needs to be learned about the relationships of microalbuminuria to other processes that may be involved in the pathogenesis of cardiovascular disease, renal disease, and other 248

conditions. Understanding the determinants of microalbuminuria is useful for several reasons. First, the determinants can be used to assist in the timely identification of people who are likely to have microalbuminuria, allowing treatment to be initiated earlier. Second, identifying modifiable correlates of microalbuminuria may open new approaches to preventing or mitigating its complications. Finally, a thorough understanding of the correlates of microalbuminuria helps researchers control for potential confounders.

From the Division of Adult and Community Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA. Received August 17, 2004; accepted in revised form September 28, 2004. Originally published online as doi:10.1053/j.ajkd.2004.09.024 on December 10, 2004. Address reprint requests to Earl Ford, MD, Centers for Disease Control and Prevention, 4770 Buford Hwy, MS K66, Atlanta, GA 30341. E-mail: [email protected] © 2004 by the National Kidney Foundation, Inc. 0272-6386/04/4502-0002$30.00/0 doi:10.1053/j.ajkd.2004.09.024

American Journal of Kidney Diseases, Vol 45, No 2 (February), 2005: pp 248-255

MICROALBUMINURIA AND ANTIOXIDANTS

Microalbuminuria has been characterized as a marker of generalized vascular damage, which has been implicated in the pathophysiological states of various conditions.10,11 Healthy functioning of the endothelium is disrupted by numerous factors, including hypertension, insulin resistance, inflammation, and obesity.9,12,13 In addition, oxidative stress, which occurs with increased frequency in people with microalbuminuria, can cause endothelial dysfunction.14 Conversely, antioxidants can help maintain endothelial health. Because oxidative stress can deplete antioxidant reserves, one could expect to find an inverse association between albuminuria and antioxidant concentrations. Microalbuminuria was inversely associated with ␣-carotene, ␤-carotene, cryptoxanthin, and lycopene concentrations in a recent Australian study.15 Because this study was conducted in a special population, the generalizability of these reported associations to other populations remains to be established. Therefore, the purpose of this report is to examine associations between microalbuminuria and circulating concentrations of vitamins A, C, and E and carotenoids in a representative sample of US adults. METHODS The Third National Health and Nutrition Examination Survey (NHANES III) was carried out from 1988 to 1994. Using a multistage stratified sampling design, a representative sample of the civilian noninstitutionalized population was recruited into the survey. After an interview in the home, participants were invited to attend 1 of 3 examination sessions: morning, afternoon, or evening. Some participants unable to attend the examination because of health reasons received a limited examination at home. Details about the survey and its methods have been published.16-18 Urinary albumin was measured by using a fluorescent immunoassay on a Sequoia-Turner Fluoremeter (SequoiaTurner Corp, Mountain View, CA). Urinary creatinine was measured by means of the rate of color formation on a Beckman Synchron AS/ASTRA clinical analyzer (Beckman Instruments Inc, Brea, CA) after creatinine reacted with picrate. Microalbuminuria is defined as a UACR of 30 mg/g or greater, but less than 300 mg/g. Participants with a UACR less than 30 mg/g are defined as not having albuminuria (normoalbuminuria), and those with a UACR of 300 mg/g or greater are considered to have macroalbuminuria. Concentrations of retinol and retinyl esters, vitamin E, and 5 carotenoids (␣- and ␤-carotene, ␤-cryptoxanthin, lutein/zeaxanthin, and lycopene) were measured in serum by using isocratic reverse-phase high-performance liquid chromatography, with detection at 325, 300, and 450 nm, respec-

249

tively. Selenium concentration was measured in serum by using graphite furnace atomic absorption spectroscopy. After reviewing more than 60 studies that had information about correlates of albuminuria or microalbuminuria, we included the following variables in our analyses: age, sex, race or ethnicity, education, smoking status, serum cotinine concentration, body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, glucose concentration, insulin concentration, white blood cell count, C-reactive protein concentration, leisure-time physical activity, total cholesterol concentration, triglyceride concentration, high-density lipoprotein cholesterol concentration, non– high-density lipoprotein cholesterol concentration, vitamin or mineral use during the previous 24 hours or 30 days, and intake of fruits and vegetables. Serum cotinine concentration was determined by using high-performance liquid chromatography atmosphericpressure chemical ionization tandem mass spectrometry. Body mass index was calculated from measured weight and height (weight in kilograms divided by height in meters squared). Waist circumference was measured using a steel tape to the nearest 0.1 cm at the high point of the iliac crest at minimal respiration. Three blood pressure readings were obtained in the mobile examination center: averages of the second and third systolic and diastolic readings were used in analyses. Plasma glucose concentration was measured by using an enzymatic reaction (Cobas Mira assay; Roche Diagnostic Systems, Inc., Montclair, NJ). Serum insulin was measured by means of radioimmunoassay using the Pharmacia Insulin RIA Kit (Pharmacia Diagnostics AB, Uppsala, Sweden). White blood cell count was determined on a Coulter Counter Model S-PLUS JR (Coulter Electronics, Hialeah, FL). C-Reactive protein was measured at the University of Washington Department of Laboratory Medicine by using latex-enhanced nephelometry. Three levels of physical activity were defined: vigorously or moderately active, lightly active, and sedentary. Vigorously active is defined as participating 3 or more times per week in an activity with a metabolic equivalent level of 6 or greater for participants 60 years or older and 7 metabolic equivalents or greater for participants younger than 60 years. One metabolic equivalent is the energy expenditure of approximately 3.5 mL of oxygen per kilogram of body weight per minute or 1 kcal/kg of body weight per hour. Moderately active is defined as participating 5 or more times per week in activities of which no more than 2 could be considered vigorous activities. Lightly active is defined as participation that was not vigorous or moderate. Sedentary is defined as engaging in no leisure-time physical activity. Serum total cholesterol concentrations were measured enzymatically with a Hitachi 704 Analyzer (Boehringer Mannheim Diagnostics, Indianapolis, IN). High-density lipoprotein cholesterol was measured after the precipitation of other lipoproteins with a heparin-manganese chloride mixture on a Hitachi 704 Analyzer. We calculated non–highdensity lipoprotein cholesterol concentration by subtracting the concentration of high-density lipoprotein cholesterol from that of total cholesterol. Serum triglycerides were measured enzymatically after hydrolyzation to glycerol on a Hitachi 704 Analyzer.

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Participants were asked about their use of vitamins or minerals with 2 questions: “Have you taken any vitamins or minerals during the past 24 hours?” and “Have you taken any vitamins or minerals in the past month?” To estimate the number of monthly fruit and vegetable servings, we summed responses to 21 items on the NHANES III food frequency questionnaire. In addition, we adjusted for serum creatinine concentration or glomerular filtration rate in various analyses. Creatinine was measured on a Hitachi 737 autoanalyzer (Boehringer Mannheim Diagnostics). Glomerular filtration rate was estimated by using the formula19: Estimated glomerular filtration rate (mL ⁄ min ⁄ 1.73 m2) ⫽ 186 ⫻ (serum creatinine in mg ⁄ dL)⫺1.154 ⫻ (age in years)⫺0.203 ⫻ (0.742 if female) ⫻ (1.21 if African American) We limited our analyses to participants aged 20 years or older who had fasted for 8 hours or longer. We excluded pregnant women. When age adjustment was performed, data were adjusted to the 2000 US population aged 20 years or older by using the direct method.16 We used a test for linear trend to assess trends in means or percentages of covariates across 3 levels of UACR (normoalbuminuria, microalbuminuria, and macroalbuminuria). Pearson’s correlation coefficients between UACR and antioxidant concentrations were calculated after log-transformation of UACR. In addition, associations between log UACR and antioxidant concentrations were examined by using multiple linear regression analysis. We also examined associations of microalbuminuria by using logistic regression analysis. To account for the complex survey design, we used the statistical software SUDAAN (Research Triangle Institute, Research Triangle Park, NC) and the medical examination clinic sampling weights to produce our weighted estimates and SEs.

RESULTS

A total of 9,805 men and nonpregnant women aged 20 years or older attended the mobile examination center and fasted for 8 hours or longer. A UACR value was available for 9,575 of them. With increasing degrees of albuminuria, decreases were observed for the percentage of participants who were white, mean years of education, and percentage engaged in moderate or vigorous physical activity, whereas increases were seen for body mass index, waist circumference, systolic and diastolic blood pressure, glucose concentration, insulin concentration, white blood cell count, elevated Creactive protein concentration, and triglyceride concentration (Table 1). For antioxidants, retinol concentration increased as albuminuria increased, whereas vitamin C, ␣-carotene,

␤-carotene, lycopene, and total carotenoids concentrations decreased. No significant linear trends were observed for vitamin E, cryptoxanthin, or lutein/zeaxanthin. Of covariates included in the fully adjusted linear and logistic regression models, age, sex, body mass index, systolic blood pressure, glucose concentration, elevated C-reactive protein concentration, and physical activity were significantly associated with either log-transformed UACR or the presence of microalbuminuria (Table 2). In addition, insulin concentration was significantly associated with log-transformed UACR, whereas alcohol intake was significantly associated with the presence of microalbuminuria. In linear regression analyses that included the study covariates, retinol concentration was related positively to log-transformed UACR (Table 3). ␤-Cryptoxanthin, lutein/zeaxanthin, lycopene, and total carotenoid concentrations were inversely related to UACR. Vitamin C, vitamin E, ␣-carotene, and ␤-carotene concentrations were not significantly related to UACR. Additional adjustment for serum creatinine concentration or glomerular filtration rate did not materially affect results from the regression analyses, with the exception of models for vitamin A. Retinol concentration was positively associated with microalbuminuria after adjustment for the study covariates (Table 4). In addition, ␤-cryptoxanthin, lutein/zeaxanthin, lycopene, and total carotenoid concentrations were inversely associated with microalbuminuria. Repeating the analyses after excluding users of vitamin and mineral supplements did not change the associations. Similar findings were observed after excluding participants with selfreported diabetes or a fasting blood glucose concentration of 126 mg/dL or greater (ⱖ7.0 mmol/L). DISCUSSION

In this study, participants with microalbuminuria were more likely to have antioxidant deficits than participants with normoalbuminuria. In particular, ␤-cryptoxanthin, lutein/zeaxanthin, and lycopene concentrations were lower in participants with microalbuminuria. Vitamin C, ␣-carotene, and ␤-carotene concentra-

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251

Table 1. Age-Adjusted Baseline Characteristics by Albuminuria Status Among Adults Aged 20 Years or Older in the NHANES III, 1988 to 1994 Albuminuria (mg/g) ⬍30

N

Age (y)* Men* (%) White* (%) Education (y) Serum cotinine (ng/mL) Body mass index (kg/m2) Waist circumference (cm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Glucose (mg/dL) Serum insulin (␮U/mL) White blood cell count (⫻ 103/mL) C-reactive protein ⬎3 mg/L (%) Moderately or vigorously active (%) Total cholesterol concentration (mg/dL) High-density lipoprotein (mg/dL) Non–high-density lipoprotein cholesterol (mg/dL) Triglyceride (mg/dL) Retinol (␮g/dL) Vitamin C (mg/dL) Vitamin E (␮g/dL) Vitamin E/cholesterol (␮g/mg) ␣-Carotene (␮g/dL) ␤-Carotene (␮g/dL) ␤-Cryptoxanthin (␮g/dL) Lutein/zeaxanthin (␮g/dL) Lycopene (␮g/dL) Total carotenoids (␮mol/L) Selenium (ng/mL) Vitamin or mineral use during previous 24 h (%) Vitamin or mineral use during past mo (%) Fruit and vegetable intake (times per mo)

30–⬍300

ⱖ300

P for Trend

0.001 0.783 0.028 0.027 0.139 0.007 0.036 ⬍0.001 0.006 0.010 0.027 0.013 0.001 0.030

9,575 9,575 9,575 9,522 9,165 9,558 9,269 9,237 9,225 9,370 9,296 9,308 9,193 9,575

42.9 (0.4) 50.1 (0.7) 76.1 (1.4) 12.3 (0.1) 75.5 (3.0) 26.6 (0.1) 92.2 (0.2) 119.2 (0.3) 72.8 (0.3) 98.0 (0.3) 10.2 (0.2) 6.9 (0.1) 24.4 (1.1) 41.6 (1.4)

55.0 (1.0) 40.2 (3.1) 72.3 (2.3) 11.9 (0.2) 80.9 (10.3) 26.9 (0.4) 92.5 (1.1) 126.9 (1.2) 76.1 (0.7) 114.1 (3.6) 12.0 (0.6) 7.3 (0.1) 39.4 (2.9) 31.2 (3.4)

61.0 (2.0) 52.2 (7.4) 63.1 (5.6) 11.3 (0.4) 57.3 (11.9) 30.9 (1.5) 102.2 (4.6) 133.8 (2.6) 78.9 (2.1) 117.8 (7.5) 18.9 (3.8) 7.6 (0.3) 48.9 (6.8) 23.4 (7.6)

9,266 9,217

204.7 (0.8) 50.3 (0.4)

210.7 (2.6) 51.7 (1.2)

212.6 (4.7) 51.1 (2.7)

0.092 0.776

9,212 9,243 9,209 8,942 9,209 9,195 9,209 9,209 9,209 9,209 9,209 9,209 9,092

154.3 (1.0) 134.8 (2.4) 58.9 (0.4) 0.7 (⬍0.1) 1,155.3 (10.4) 5.6 (0.1) 4.8 (0.1) 20.6 (0.4) 9.2 (0.2) 22.0 (0.3) 23.4 (0.3) 1.46 (0.01) 125.7 (1.0)

158.0 (2.9) 187.4 (24.9) 60.2 (1.2) 0.7 (⬍0.1) 1,204.7 (42.9) 5.6 (0.1) 4.1 (0.3) 17.2 (1.0) 8.1 (0.4) 21.5 (1.3) 21.7 (0.8) 1.33 (0.05) 125.1 (1.5)

161.5 (5.3) 183.2 (16.9) 64.0 (2.4) 0.6 (0.1) 1,153.7 (47.3) 5.4 (0.2) 3.5 (0.5) 15.5 (1.8) 9.1 (0.9) 21.7 (1.4) 19.7 (1.2) 1.26 (0.08) 123.8 (1.4)

0.173 0.005 0.039 0.012 0.972 0.313 0.015 0.007 0.933 0.783 0.003 0.017 0.226

9,363

23.2 (1.0)

22.3 (2.5)

12.7 (3.1)

0.003

9,568

41.4 (1.1)

37.1 (3.5)

43.0 (7.3)

0.826

9,574

64.6 (0.9)

64.2 (2.9)

62.6 (6.3)

0.773

NOTE. To convert serum cotinine in ng/mL to nmol/L, multiply by 5.68; glucose in mg/dL to mmol/L, multiply by 0.05551; serum insulin in ␮U/mL to pmol/L, multiply by 7.175; white blood cell count in 103/␮L to 109/L, multiply by 1.0; cholesterol, high-density lipoprotein cholesterol, or non– high-density lipoprotein cholesterol in mg/dL to mmol/L, multiply by 0.02586; triglycerides in mg/dL to mmol/L, multiply by 0.01129; retinol in ␮g/dL to ␮mol/L, multiply by 0.0349; vitamin C in mg/dL to mmol/L, multiply by 56.78; vitamin E in ␮g/dL to ␮mol/L, multiply by 0.02322; ␣-carotene, ␤-carotene, or lycopene in ␮g/dL to ␮mol/L, multiply by 0.01863; ␤-cryptoxanthin in ␮g/dL to ␮mol/L, multiply by 0.01809; lutein/zeaxanthin in ␮g/dL to ␮mol/L, multiply by 0.01758; selenium in ng/mL to nmol/L, multiply by 12.66. *Unadjusted.

tions had a weak inverse association with microalbuminuria in some analyses. Conversely, vitamin E and selenium concentrations were not associated with microalbuminuria in this study.

Few other studies have reported on the relations between circulating concentrations of antioxidants and microalbuminuria. In a recent study of 698 indigenous people aged 15 years or older from remote areas in Australia, ␣-caro-

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Table 2. Linear and Logistic Regression Results of Covariates on Log-Transformed UACR and the Presence of Microalbuminuria in US Adults Aged 20 Years or Older, NHANES III, 1988 to 1994, Respectively Log(UACR) (N ⫽ 8,475) Regression Coefficient (SE)

Age (y) Sex M F (reference) Race/ethnicity White (reference) African American Mexican American Other Education (y) Serum cotinine (ng/mL) Body mass index Systolic blood pressure (mm Hg) Plasma glucose (mg/dL) Serum insulin (␮U/mL) C-reactive protein (mg/L) ⬎3 ⱕ3 (reference) Physical activity Moderate/vigorous None/light (reference) Alcohol use (times/mo) ⱖ61 1–60 0 (reference) Serum cholesterol (mg/dL) Serum triglycerides (mg/dL) Vitamin or mineral use during previous 24 h Yes No (reference) Fruit and vegetable intake (times/mo) ⱖ150 ⬍150 (reference)

0.0078 (0.0016) ⫺0.3855 (0.0391) —

Presence of Microalbuminuria (N ⫽ 8,265)

Wald F-Test P

Odds Ratio (95% Confidence Interval)

⬍0.001 ⬍0.001

1.02 (1.01, 1.03)

0.208 0.112 ⬍0.001 ⬍0.001 ⬍0.001 0.030 0.010

0.1283 (0.0478) —

0.306 — 1.31 (0.98, 1.75) 1.18 (0.79, 1.77) 1.40 (0.79, 2.48) 1.00 (0.95, 1.04) 1.00 (1.00, 1.00) 0.95 (0.91, 0.98) 1.03 (1.02, 1.03) 1.01 (1.01, 1.01) 1.01 (1.00, 1.03)

0.031

0.007 0.64 (0.47, 0.89) —

0.702

0.062 0.333 0.928

⫺0.0035 (0.0387) —

0.004 0.48 (0.31, 0.76) 0.56 (0.34, 0.92) — 1.00 (1.00, 1.00) 1.00 (1.00, 1.00)

0.362 0.055 0.633

1.08 (0.78, 1.49) — 0.886

⫺0.0045 (0.0312) —

0.896 0.807 0.002 ⬍0.001 ⬍0.001 0.137 ⬍0.001

1.73 (1.30, 2.32) —

⫺0.0794 (0.0356) ⫺0.0920 (0.1365) ⫺0.1111 (0.1383) — ⫺0.0009 (0.0004) 0.0002 (0.0002)

0.001 0.003

0.60 (0.43, 0.84) — 0.008

— ⫺0.1517 (0.0537) ⫺0.1012 (0.0571) ⫺0.1938 (0.0823) ⫺0.0098 (0.0077) 0.0002 (0.0001) ⫺0.0272 (0.0040) 0.0148 (0.0010) 0.0064 (0.0007) 0.0092 (0.0041)

Wald Chi-Square P

0.396 1.12 (0.86, 1.45) —

NOTE. To convert serum cotinine in ng/mL to nmol/L, multiply by 5.68; glucose in mg/dL to mmol/L, multiply by 0.05551; serum insulin in ␮U/mL to pmol/L, multiply by 7.175; cholesterol in mg/dL to mmol/L, multiply by 0.02586; triglycerides in mg/dL to mmol/L, multiply by 0.01129.

tene, ␤-carotene, cryptoxanthin, and lycopene concentrations were lower in people with microalbuminuria than in those without this condition after adjustment for age, sex, body mass index, diabetes, smoking status, cholesterol and triglyceride concentrations, and blood pressure.15 Low concentrations of antioxidants could be attributed to low intake, high utilization, or increased excretion of antioxidants. Little is known about how intake of antioxidants, whether from diet or supplements, varies by

microalbuminuria status. NHANES III data indicate that fruit and vegetable intake was not significantly associated with UACR or microalbuminuria status. Although participants with normoalbuminuria were more likely to use vitamin or mineral supplements during the previous 24 hours than those with microalbuminuria, the 2 groups were about equally likely to have used such a supplement during the prior month. Oxidative stress may be increased in people with microalbuminuria.20 Accordingly, people

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253

Table 3. Linear Regression Results of Circulating Concentrations of Antioxidants on Log-Transformed UACR in US Adults Aged 20 Years or Older, NHANES III, 1988 to 1994 Model 1*

Retinol (␮g/mL) Vitamin C (mg/mL) Vitamin E (␮g/mL) ␣-Carotene (␮g/mL) ␤-Carotene (␮g/mL) ␤-Cryptoxanthin (␮g/mL) Lutein/zeaxanthin (␮g/mL) Lycopene (␮g/mL) Total carotenoids (␮mol/L) Selenium (ng/mL)

Model 2†

Model 3‡

N

Regression Coefficient*

SE

P

Regression Coefficient†

SE

P

Regression Coefficient‡

SE

P

8,381 8,206 8,381 8,381 8,381

0.0026 ⫺0.0518 ⫺0.0001 ⫺0.0045 ⫺0.0012

0.0013 0.0403 0.0001 0.0037 0.0008

0.045 0.205 0.827 0.226 0.124

0.0019 ⫺0.0458 ⫺0.0001 ⫺0.0046 ⫺0.0013

0.0012 0.0404 0.0001 0.0037 0.0008

0.137 0.262 0.785 0.221 0.110

0.0034 ⫺0.0564 ⫺0.0001 ⫺0.0043 ⫺0.0012

0.0012 0.0398 0.0001 0.0036 0.0008

0.007 0.163 0.855 0.245 0.132

8,381

⫺0.0059

0.0024

0.017

⫺0.0059

0.0024

0.017

⫺0.0059

0.0024

0.017

8,381 8,381

⫺0.0031 ⫺0.0058

0.0016 0.0020

0.053 0.005

⫺0.0030 ⫺0.0058

0.0016 0.0020

0.063 0.005

⫺0.0032 ⫺0.0058

0.0016 0.0019

0.048 0.005

8,381 8,350

⫺0.0840 0.0011

0.0256 0.0012

0.002 0.348

⫺0.0845 0.0011

0.0259 0.0012

0.002 0.371

⫺0.0833 0.0012

0.0253 0.0011

0.002 0.308

NOTE. To convert retinol in ␮g/dL to ␮mol/L, multiply by 0.0349; vitamin C in mg/dL to mmol/L, multiply by 56.78; vitamin E in ␮g/dL to ␮mol/L, multiply by 0.02322; ␣-carotene, ␤-carotene, or lycopene in ␮g/dL to ␮mol/L, multiply by 0.01863; ␤-cryptoxanthin in ␮g/dL to ␮mol/L, multiply by 0.01809; lutein/zeaxanthin in ␮g/dL to ␮mol/L, multiply by 0.01758; selenium in ng/mL to nmol/L, multiply by 12.66. *Model 1 adjusted for age, sex, race or ethnicity, education, cotinine concentration, physical activity, alcohol use, fruit and vegetable intake, vitamin or mineral use during past 24 hours, body mass index, systolic blood pressure, total cholesterol concentration, triglycerides concentration, glucose concentration, insulin concentration, and C-reactive protein concentration. †Model 2 adjusted for factors in model 1 plus serum concentration of creatinine. ‡Model 3 adjusted for factors in model 1 plus estimated glomerular filtration rate.

with microalbuminuria may have an increased need for antioxidants to buttress their increased oxidative stress. Therefore, increased utilization of antioxidants without adequate replenishment could account for the reduced concentrations of antioxidants observed in this study. Excretion of some antioxidants may be related to degree of albuminuria,21 but it is unknown whether increased excretion of carotenoids or their metabolites occurs in people with microalbuminuria. The metabolism of carotenoids is incompletely characterized at present.22 Carotenoids are cleaved into aldehyde, acid, alcohol, and epoxide derivatives, which can undergo additional metabolization. Bile and urine are thought to be the major routes of excretion. Little is known about how retinol concentration may be related to microalbuminuria. The positive association in our analysis may have been a spurious finding. In a previous study, no significant association was found.15

Because this is a cross-sectional analysis, the directionality of the association between microalbuminuria and antioxidant concentrations is uncertain. As such, our findings should be regarded as hypothesis generating. At least 2 interpretations of the results merit consideration. First, lower antioxidant concentrations in people with microalbuminuria could contribute to the excess morbidity and mortality associated with microalbuminuria. By protecting endothelial function, antioxidants could help mitigate the negative health consequences of microalbuminuria. Second, low antioxidant concentrations could have a role in the development of microalbuminuria or albuminuria. Risk factors for cardiovascular disease, such as excess weight and poor glycemic control, lead to endothelial dysfunction and an increase in inflammation,9 factors that predict the development of microalbuminuria.3,9 Excess weight, poor glycemic control, and inflammation are all characterized by increased oxidative stress and decreased antioxidant concentrations.

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Table 4. Adjusted Odds Ratios From Multiple Logistic Regression Representing Associations Between Quartiles of Antioxidant Concentration and the Presence of Microalbuminuria in US Adults Aged 20 Years or Older, NHANES III, 1988 to 1994

N

1

2

3

4

P Wald ChiSquare

8,234 8,234 8,234

1.00 1.00 1.00

0.78 (0.52,1.18) 0.77 (0.51,1.17) 0.77 (0.51,1.18)

0.89 (0.61,1.31) 0.85 (0.57,1.27) 0.88 (0.58,1.32)

1.32 (0.92,1.90) 1.17 (0.79,1.75) 1.27 (0.86,1.88)

0.002 0.013 0.004

1.01 (1.01,1.02) 1.01 (1.00,1.02) 1.01 (1.01,1.02)

⬍0.001 0.002 ⬍0.001

8,065 8,065 8,065

1.00 1.00 1.00

0.86 (0.64,1.16) 0.86 (0.64,1.16) 0.86 (0.64,1.16)

0.68 (0.46,1.00) 0.69 (0.47,1.02) 0.68 (0.46,1.01)

0.80 (0.52,1.21) 0.82 (0.54,1.26) 0.81 (0.53,1.23)

0.260 0.307 0.277

0.72 (0.52,1.01) 0.75 (0.53,1.05) 0.73 (0.52,1.03)

0.056 0.090 0.070

8,234 8,234 8,234

1.00 1.00 1.00

0.91 (0.55,1.50) 0.90 (0.54,1.49) 0.89 (0.53,1.49)

1.01 (0.65,1.56) 1.00 (0.65,1.54) 1.00 (0.64,1.54)

0.92 (0.52,1.60) 0.91 (0.52,1.60) 0.90 (0.51,1.58)

0.918 0.920 0.912

1.00 (1.00,1.00) 1.00 (1.00,1.00) 1.00 (1.00,1.00)

0.200 0.166 0.187

8,234 8,234 8,234

1.00 1.00 1.00

0.71 (0.46,1.09) 0.70 (0.45,1.09) 0.70 (0.45,1.09)

0.86 (0.59,1.25) 0.87 (0.59,1.26) 0.85 (0.58,1.24)

0.61 (0.40,0.92) 0.60 (0.39,0.92) 0.60 (0.39,0.92)

0.092 0.078 0.083

1.00 (0.95,1.04) 1.00 (0.95,1.04) 1.00 (0.95,1.04)

0.849 0.846 0.835

8,234 8,234 8,234

1.00 1.00 1.00

0.88 (0.60,1.28) 0.87 (0.60,1.27) 0.87 (0.60,1.27)

0.75 (0.58,0.96) 0.72 (0.56,0.94) 0.74 (0.58,0.95)

0.72 (0.51,1.01) 0.72 (0.51,1.01) 0.72 (0.51,1.01)

0.088 0.069 0.073

0.99 (0.98,1.00) 0.99 (0.98,1.00) 0.99 (0.98,1.00)

0.158 0.153 0.155

8,234 8,234 8,234

1.00 1.00 1.00

0.69 (0.46,1.04) 0.69 (0.46,1.04) 0.69 (0.46,1.04)

0.57 (0.39,0.83) 0.57 (0.39,0.83) 0.57 (0.39,0.83)

0.56 (0.38,0.82) 0.55 (0.37,0.82) 0.56 (0.38,0.82)

0.005 0.005 0.005

0.97 (0.95,0.99) 0.97 (0.95,0.99) 0.97 (0.95,0.99)

0.006 0.006 0.006

8,234 8,234 8,234

1.00 1.00 1.00

0.62 (0.42,0.92) 0.62 (0.42,0.91) 0.62 (0.42,0.91)

0.68 (0.48,0.96) 0.67 (0.47,0.95) 0.67 (0.48,0.95)

0.59 (0.37,0.94) 0.59 (0.37,0.95) 0.59 (0.37,0.94)

0.049 0.046 0.046

0.98 (0.97,0.99) 0.98 (0.97,0.99) 0.98 (0.97,0.99)

⬍0.001 ⬍0.001 ⬍0.001

8,234 8,234 8,234

1.00 1.00 1.00

1.03 (0.78,1.37) 1.06 (0.80,1.40) 1.04 (0.79,1.38)

0.77 (0.53,1.11) 0.77 (0.54,1.11) 0.77 (0.54,1.11)

0.64 (0.46,0.89) 0.64 (0.46,0.89) 0.64 (0.46,0.89)

0.021 0.016 0.018

0.99 (0.98,0.99) 0.99 (0.98,0.99) 0.99 (0.98,0.99)

0.002 0.003 0.002

8,234 8,234 8,234

1.00 1.00 1.00

0.97 (0.70,1.34) 0.96 (0.69,1.33) 0.96 (0.70,1.34)

0.70 (0.50,0.98) 0.70 (0.50,0.98) 0.70 (0.50,0.98)

0.54 (0.38,0.75) 0.53 (0.38,0.75) 0.53 (0.38,0.75)

0.001 0.001 0.001

0.71 (0.57,0.89) 0.71 (0.57,0.89) 0.71 (0.57,0.89)

0.004 0.004 0.004

8,206 8,206 8,206

1.00 1.00 1.00

0.95 (0.68,1.33) 0.94 (0.67,1.32) 0.95 (0.67,1.33)

0.97 (0.70,1.33) 0.95 (0.69,1.31) 0.96 (0.69,1.32)

1.03 (0.76,1.39) 1.02 (0.75,1.38) 1.02 (0.75,1.38)

0.967 0.960 0.965

1.00 (0.99,1.01) 1.00 (0.99,1.01) 1.00 (0.99,1.01)

0.973 0.972 1.000

Quartiles of Vitamins and Carotenoids*

Retinol (␮g/mL) Model 1† Model 2‡ Model 3§ Vitamin C (mg/dL) Model 1† Model 2‡ Model 3§ Vitamin E (␮g/mL) Model 1† Model 2‡ Model 3§ ␣-Carotene (␮g/mL) Model 1† Model 2‡ Model 3§ ␤-Carotene (␮g/mL) Model 1† Model 2‡ Model 3§ ␤-Cryptoxanthin (␮g/mL) Model 1† Model 2‡ Model 3§ Lutein/zeaxanthin (␮g/mL) Model 1† Model 2‡ Model 3§ Lycopene (␮g/mL) Model 1† Model 2‡ Model 3§ Total carotenoids (␮mol/L) Model 1† Model 2‡ Model 3§ Selenium (ng/mL) Model 1† Model 2‡ Model 3§

Continuous

P

NOTE. Values expressed as odds ratios with 95% confidence limits. To convert vitamin C in mg/dL to mmol/L, multiply by 56.78; vitamin E in ␮g/dL to ␮mol/L, multiply by 0.02322; ␣-carotene, ␤-carotene, or lycopene in ␮g/dL to ␮mol/L, multiply by 0.01863; ␤-cryptoxanthin in ␮g/dL to ␮mol/L, multiply by 0.01809; lutein/zeaxanthin in ␮g/dL to ␮mol/L, multiply by 0.01758; selenium in ng/mL to nmol/L, multiply by 12.66. Retinol quartile 1, 11 to ⬍48; quartile 2, 48 to ⬍57; quartile 3, 57 to ⬍68; quartile 4, 68 to 179 ␮g/mL. Vitamin C quartile 1, 0 to ⬍0.36; quartile 2, 0.36 to ⬍0.72; quartile 3, 0.72 to ⬍1.00; quartile 4, 1.00 to 4.07 mg/dL. Vitamin E quartile 1, 137 to ⬍847; quartile 2, 847 to ⬍1,028; quartile 3, 1,028 to ⬍1,285; quartile 4, 1,285 to 6,843 ␮g/mL. ␣-Carotene quartile 1, 0 to ⬍2; quartile 2, 2 to ⬍4; quartile 3, 4 to ⬍6; quartile 4, 6 to 161 ␮g/mL. ␤-Carotene quartile 1, 0 to ⬍9; quartile 2, 9 to ⬍15; quartile 3, 15 to ⬍24; quartile 4, 24 to 674 ␮g/mL. ␤-Cryptoxanthin quartile 1, 0 to ⬍5; quartile 2, 5 to ⬍7; quartile 3, 7 to ⬍11; quartile 4, 11 to 139 ␮g/mL. Lutein/zeaxanthin quartile 1, 0 to ⬍14; quartile 2, 14 to ⬍19; quartile 3, 19 to ⬍26; quartile 4, 26 to 253 ␮g/mL. Lycopene quartile 1, 0 to ⬍15; quartile 2, 15 to ⬍23; quartile 3, 23 to ⬍31; quartile 4, 31 to 124 ␮g/mL. Selenium quartile 1, 63 to ⬍115; quartile 2, 115 to ⬍125; quartile 3, 125 to ⬍135; quartile 4, 135 to 425 ng/mL.

*

†Adjusted for age, sex, race or ethnicity, education, cotinine concentration, physical activity, alcohol use, fruit and vegetable intake, vitamin or mineral use during past 24 hours, body mass index, systolic blood pressure, total cholesterol concentration, triglyceride concentration, glucose concentration, insulin concentration, and C-reactive protein concentration. ‡Adjusted for factors in model 1 plus serum concentration of creatinine. §Adjusted for factors in model 1 plus estimated glomerular filtration rate.

MICROALBUMINURIA AND ANTIOXIDANTS

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