- Email: [email protected]
High-normal blood pressure and microalbuminuria
High-Normal Blood Pressure and Microalbuminuria Eric L. Knight, MD, MPH, Holly M. Kramer, MD, MPH, and Gary C. Curhan, MD, ScD ● Background: High-normal blood pressure (BP) is associated with increased cardiovascular risk compared with optimal BP, but no study has specifically examined the association between high-normal BP and microalbuminuria, an established predictor of future cardiovascular events. Methods: This was a cross-sectional study of normotensive (systolic BP [SBP] < 140 mm Hg, diastolic BP [DBP] < 90 mm Hg) individuals without diabetes with no hypertension history enrolled in the Third National Health and Nutrition Examination Survey. BP was categorized as high normal (SBP, 130 to 139 mm Hg or DBP, 85 to 89 mm Hg), normal (SBP, 120 to 129 mm Hg or DBP, 80 to 84 mm Hg), and optimal (SBP < 120 mm Hg and DBP < 80 mm Hg). We also separately examined SBP, DBP, mean arterial pressure (MAP), and pulse pressure. Microalbuminuria was defined using sex-specific cutoff values (urine albumin-creatinine ratio > 17 and < 250 g/mg [>1.0 and <28 mg/mmol] for men and > 25 and < 355 g/mg for women [>3 and <40 mg/mmol]). We used multivariate logistic regression to analyze the association between different BP measurements and microalbuminuria. Results: Compared with optimal BP, high-normal BP was significantly associated with increased odds of microalbuminuria (odds ratio [OR], 2.13; 95% confidence interval [CI], 1.51 to 3.01). Similarly, MAP (OR, 1.41; 95% CI, 1.15 to 1.74 per 10-mm Hg increment), SBP (OR, 1.27; 95% CI, 1.09 to 1.48 per 10-mm Hg increment), and DBP (OR, 1.29; 95% CI, 1.06 to 1.57 per 10-mm Hg increment) were significantly associated with microalbuminuria. Conclusion: High-normal BP is significantly associated with microalbuminuria compared with optimal BP and may be a biomarker of the increased cardiovascular risk observed in this population. Am J Kidney Dis 41:588-595. © 2003 by the National Kidney Foundation, Inc. INDEX WORDS: High-normal blood pressure (BP); normal blood pressure (BP); blood pressure (BP); albuminuria; microalbuminuria; urinary protein.
H
YPERTENSION has been associated with microalbuminuria in multiple studies,1-8 but there is no study specifically examining the association between high-normal blood pressure (BP) and microalbuminuria. This relationship is important because of the high prevalence of high-normal BP and because microalbuminuria has been associated with left ventricular diastolic dysfunction9 and left ventricular hypertrophy10 in individuals with hypertension. In addition, microalbuminuria has been associated with increased cardiovascular mortality and all-cause mortality in individuals at increased risk for cardiovascular disease11 and in a general population from The Netherlands.12 Therefore, if microalbuminuria is more common in patients with From the Renal Unit, Department of Medicine, Massachusetts General Hospital; and Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. Received September 25, 2002; accepted in revised form November 14, 2002. Supported in part by grants no. T32DK0740-16, T32DK07791, and DK52866 from The National Institutes of Health. H.M.K. was an American Kidney Foundation Clinical Scientist in Nephrology Fellow from 2001 to 2002. Address reprint requests to Eric L. Knight, MD, Channing Laboratory, Nurses’ Health Study, 3rd Floor, 181 Longwood Ave, Boston, MA 02115. E-mail: [email protected] © 2003 by the National Kidney Foundation, Inc. 0272-6386/03/4103-0007$30.00/0 doi:10.1053/ajkd.2003.50120 588
high-normal BP, then microalbuminuria may be a useful biological marker of the increased cardiovascular risk observed in this population.13 To study the association between high-normal BP and microalbuminuria, we used data from the Third National Health and Nutrition Examination Survey (NHANES III).14 This enabled us to evaluate 9,462 normotensive individuals without diabetes, each with multiple BP measurements and one measurement of urinary albumin and creatinine. METHODS
Study Population The NHANES III was designed to be a probability sample of the total US civilian noninstitutionalized population aged 2 months or older and collected health, nutritional, and laboratory data for 33,994 men, women, and children from 1988 to 1994.14 Certain subgroups were oversampled, such as young children, older persons, blacks, and Mexican Americans. Details of the survey design can be found in the NHANES III operations manual.14 There were 16,573 men and women aged 20 years and older who had an interview and were examined. Of these, we excluded the following people: 5,325 persons with a diagnosis of hypertension, administered prescription medication for high BP, and/or a systolic BP (SBP) of 140 mm Hg or greater or a diastolic BP (DBP) of 90 mm Hg or greater; 1,265 persons with self-reported diabetes, 247 pregnant women, 234 persons with information missing on urine albumin or creatinine level, and 40 persons with macroalbuminuria (discussed later). This left 9,462 individuals for our primary analyses. For analyses of levels of albuminuria less than the traditional microalbuminuria threshold, we ex-
American Journal of Kidney Diseases, Vol 41, No 3 (March), 2003: pp 588-595
HIGH-NORMAL BP AND MICROALBUMINURIA
cluded an additional 711 people who met sex-specific criteria for microalbuminuria. This left 8,751 individuals for this analysis.
Assessment of BP BP was determined by the average of six readings. We separately examined SBP, DBP, pulse pressure (PP; defined as SBP ⫺ DBP), and mean arterial pressure (MAP; defined as [SBP ⫹ DBP * 2]/3. We also categorized BP into three prespecified categories based on the classification approaches of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure15 and the World Health Organization and International Society of Hypertension.16 BP categories were high-normal (SBP, 130 to 139 mm Hg or DBP, 85 to 89 mm Hg), normal (SBP, 120 to 129 mm Hg or DBP, 80 to 84 mm Hg), and optimal (SBP ⬍ 120 mm Hg and DBP ⬍ 80 mm Hg). If either SBP or DBP fell into different categories, the individual was assigned to the higher category. For example, a BP of 132/82 mm Hg would be assigned to the high-normal category.
Assessment of Outcome of Albuminuria A solid-phase fluorescent immunoassay with a sensitivity level of 0.05 mg/dL was used to measure urinary albumin, and the coefficient of variation ranged from 4.8% to 16.1% during the 6 years of the study.17 Urine creatinine was measured with the Jaffe´ rate reaction (Beckman ASTRA, Brea, CA), and the coefficient of variation ranged from 1.5% to 7.7%.17 Spot urine albumin (in micrograms per milliliter) to creatinine (in milligrams per milliliter) ratios (ACRs) were calculated for all subjects. To define microalbuminuria in random urine specimens, we used sex-specific ACR cutoff values of 17 g/mg or greater (ⱖ1.9 mg/mmol) and 250 g/mg or less (ⱕ28 mg/mmol) for men and 25 g/mg or greater (ⱖ2.8 mg/ mmol) and 355 g/mg or less (ⱕ40 mg/mmol) for women.18 These cutoff values were determined by comparing the ACR in spot urine samples with albumin excretion rates collected from timed urine specimens and correspond to 30 to 300 g/min of urine albumin excretion and the 95th percentile of ACR values for 218 healthy men and women.18,19 We also examined sex-specific levels of albuminuria that were less than the traditional microalbuminuria threshold. The two chosen categories of ACR were 8 g/mg or less (ⱕ0.9 mg/mmol) for men and 12 g/mg or less (ⱕ1.4 mg/mmol) for women and 9 to 16 g/mg (1.0 to 1.8 mg/mmol) for men and 13 to 24 g/mg (1.5 to 2.7 mg/ mmol) for women. These cutoff values represent the midpoint of the distribution of albuminuria less than the traditional microalbuminuria threshold, and the high category represents 13% of this subpopulation.
Assessment of Other Covariates A detailed medical history was obtained during the standardized home interview. Age is defined as age at the time of the home interview, and race/ethnicity were self-reported as non-Hispanic white, non-Hispanic black, Mexican American, or other. History of myocardial infarction (MI) or diabetes is defined as “being told by a doctor that you had
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previously had a heart attack or diabetes,” respectively. Current cigarette smoking is defined based on self-report. Body mass index (BMI; in kilograms per meter squared) was calculated from the weight and height measured during the physical examination. Total cholesterol, high-density lipoprotein (HDL), triglyceride, and C-reactive protein (CRP) levels were measured from the blood sample obtained at the time of the physical examination.
Statistical Analyses All statistical analyses were performed using SAScallable SUDAAN (Software for the Statistical Analysis of Correlated Data, release 8.00; Research Triangle Institute, Durham, NC) to incorporate sample weights, adjust for clusters, and provide prevalence estimates for the US population. NHANES data are weighted to account for the probability of selection, and adjust for nonresponse to the interview and physical examination in order to be representative of the entire US population. For the primary analyses, we used logistic regression to calculate the odds ratio (OR) for microalbuminuria compared with no microalbuminuria, while simultaneously adjusting for multiple covariates. For secondary analyses, we used logistic regression to assess the odds of being in the high category of albuminuria below the sex-specific microalbuminuria threshold compared with the low category below this threshold. All multivariate analyses were adjusted for covariates stated previously. Age was categorized by decade; race was categorized as non-Hispanic white, nonHispanic black, Mexican-American, and other; and BMI and cholesterol, HDL, triglyceride, and CRP levels were included as continuous variables. History of MI and current smoking were classified as yes or no. We also examined interactions between BP category and age (decades) and BP category and race (non-Hispanic white, non-Hispanic black, and Mexican American).
RESULTS
Overall, an estimated 7.2 million Americans (6.4%) without diabetes or hypertension have microalbuminuria. Of those with optimal BP, 6% (4 million) had microalbuminuria compared with 7% (1.8 million) of those with normal BP and 10% (1.4 million) of those with high-normal BP. An additional estimated 13.1 million Americans without diabetes or hypertension had high levels of albuminuria below the traditional microalbuminuria threshold. Of those with optimal BP, 11% (7.8 million) had high levels of albuminuria compared with 13% (3.3 million) of those with normal BP and 17% (2 million) of those with high-normal BP. Descriptive characteristics of the population categorized by the presence or absence of microalbuminuria are listed in Table 1, and descriptive characteristics of those with high levels of
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KNIGHT, KRAMER, AND CURHAN Table 1.
Demographic, Clinical, and Laboratory Variables Categorized by the Presence or Absence of Microalbuminuria
Variable
Albuminuria ⬍ the Microalbuminuria Threshold (N ⫽ 8,751)
Age (y) Men (%) Race (%) Non-Hispanic white Non-Hispanic black Mexican-American BP High-normal (%) Normal (%) Optimal (%) SBP (mm Hg) DBP (mm Hg) MAP (mm Hg) PP (mm Hg) BMI (kg/m2) Total cholesterol (mg/dL) HDL (mg/dL) Triglycerides (mg/dL) CRP (mg/dL) History of MI (%) Current cigarette smoker (%)
Microalbuminuria* (N ⫽ 711)
39 (38-40) 49 (48-50)
41 (39-43) 40 (34-46)
76 (73-79) 10 (9-11) 6 (4-6)
72 (68-76) 11 (9-13) 6 (4-6)
11 (10-12) 24 (22-26) 65 (63-67) 115 (114-115) 71 (71-72) 86 (85-86) 43 (43-44) 25 (25-26) 201 (199-203) 51 (50-52) 124 (120-128) 0.35 (0.33-0.37) 1 (0-1) 31 (29-33)
19 (14-24) 25 (19-30) 56 (50-62) 117 (115-118) 72 (71-73) 87 (86-88) 45 (43-46) 25 (25-26) 206 (201-210) 52 (50-54) 140 (127-153) 0.51 (0.41-0.62) 3 (1-5) 34 (27-41)
NOTE. Results expressed as mean (95% CI) for continuous variables. To convert cholesterol to mmol/L, multiply by 0.0259, to convert HDL to mmol/L, multiply by 0.0259; to convert triglycerides to mmol/L, multiply by 0.0113; to convert CRP to mg/L, multiply by 10. *Microalbuminuria is defined as a urine albumin-to-creatinine ratio (ACR) of 17 g/mg or greater (ⱖ2 mg/mmol) and 250 g/mg or less (ⱕ28 mg/mmol) in men and 25 g/mg or greater (ⱖ2.8 mg/mmol) and 355 g/mg or less (ⱕ40 mg/mmol) for women.18
albuminuria below the traditional microalbuminuria threshold categorized by urinary albumin excretion level are listed in Table 2. Multivariate logistic regression results for microalbuminuria according to BP category are listed in Table 3. Those in the high-normal BP category had twice the odds of microalbuminuria as those in the optimal category. Multivariate logistic regression results for high albuminuria below the traditional albuminuria threshold for each 10-mm Hg increase in SBP, DBP, MAP, and PP are listed in Table 4. Multivariate logistic regression results for the association between BP category and high albuminuria level below the traditional microalbuminuria threshold are listed in Table 5. High-normal BP was significantly associated with increased odds of high levels of albuminuria below the traditional microalbuminuria threshold. We also examined the multivariate odds of high albuminuria level below the traditional albuminuria
threshold for each 10-mm Hg increase in SBP, DBP, MAP, and PP (Table 6). On multivariate analysis, in terms of racial differences in albuminuria in this population, blacks had significantly greater odds of microalbuminuria (Table 3) compared with whites, but did not have significantly greater odds of high albuminuria levels below the traditional microalbuminuria threshold (Table 5). MexicanAmericans did not have significantly greater odds of microalbuminuria (Table 3) or significantly greater odds of high albuminuria levels below the traditional microalbuminuria threshold (Table 5). We found a significant interaction between age and high-normal BP for the outcome of microalbuminuria (P ⫽ 0.004). Specifically, the odds of microalbuminuria associated with highnormal BP were greater in older individuals after adjusting for BP category and age in the model. However, we did not observe a significant interaction between age and normal BP for the out-
HIGH-NORMAL BP AND MICROALBUMINURIA Table 2.
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Demographic, Clinical, and Laboratory Variables Categorized by ACR Below the Microalbuminuria Threshold ACR ⱕ 8 g/mg (0.9 mg/mmol) for Men and ⱕ 12 g/mg (1.4 mg/mmol) for Women (N ⫽ 7,579)
Variable
Age (y) Men (%) Race (%) Non-Hispanic white Non-Hispanic black Mexican-American BP High-normal (%) Normal (%) Optimal (%) SBP (mm Hg) DBP (mm Hg) MAP (mm Hg) PP (mm Hg) BMI (kg/m2) Total cholesterol (mg/dL) HDL (mg/dL) Triglycerides (mg/dL) CRP (mg/dL) History of MI (%) Cigarette smoker (%)
ACR 9-16 g/mg (1.0-1.8 mg/mmol) for Men and 13-24 g/mg (1.5-2.7 mg/mmol) for Women (N ⫽ 1,172)
39 (38-39) 49 (48-50)
42 (41-44) 52 (49-55)
76 (73-79) 10 (9-77) 6 (5-7)
78 (74-82) 8 (7-9) 6 (5-7)
11 (10-12) 26 (24-28) 65 (63-67) 114 (114-115) 71 (71-72) 86 (85-86) 43 (42-43) 25 (25-26) 200 (198-202) 51 (50-52) 123 (118-127) 0.34 (0.32-0.36) 1 (0-1) 30 (28-32)
15 (12-18) 28 (24-32) 57 (52-62) 117 (116-117) 72 (86-87) 45 (44-46) 25 (24-25) 203 (199-201) 51 (49-53) 132 (124-142) 0.41 (0.34-0.47) 3 (2-4) 37 (35-39)
NOTE. Results expressed as means (95% CI) for continuous variables. To convert cholesterol to mmol/L, multiply by 0.0259; to convert HDL to mmol/L, multiply by 0.0259; to convert triglycerides to mmol/L, multiply by 0.0113; to convert CRP to mg/L, multiply by 10.
come of microalbuminuria or between age and BP category for the outcome of high albuminuria levels below the traditional microalbuminuria threshold. We did not observe an interaction between race and BP category. DISCUSSION
High-normal BP was significantly associated with increased odds of microalbuminuria compared with optimal BP in individuals with an SBP less than 140 mm Hg and a DBP less than 90 mm Hg. In addition, among these individuals, high-normal BP was associated with increased odds of high albuminuria levels below the traditional microalbuminuria threshold. We also observed a positive interaction between age and high-normal BP for the outcome of microalbuminuria. The prevalence of microalbuminuria and high levels below this threshold increased in a graded fashion with increase in BP, and the overall prevalence of microalbuminuria was similar to that described in a large cross-sectional
study of individuals without diabetes or diagnosed hypertension from The Netherlands.20 The pathophysiological association between microalbuminuria and high-normal BP is complex. Higher BP may cause microalbuminuria by increasing glomerular filtration pressure and subsequent renal damage. It also is possible that a longer duration of high-normal BP and associated increased glomerular filtration pressure could explain the positive interaction we observed between age and high-normal BP. Alternatively, microalbuminuria may be a marker of endothelial dysfunction21 and inflammation22 associated with high-normal BP. Interestingly, when we attempted to adjust for inflammation using CRP level, we did not see a substantial change in our results. There also may be common genetic factors that predispose to both higher BP and microalbuminuria. For example, parents of individuals with type 1 diabetes and macroalbuminuria have greater rates of hypertension than parents of individuals with type 1 diabetes without macroalbuminuria,23,24 and more re-
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KNIGHT, KRAMER, AND CURHAN Table 3.
Multivariate Odds Ratios (ORs) With 95% Confidence Intervals (CIs) and Chi-Square Values for Microalbuminuria Adjusted for All Variables in the Table
Variable
Multivariate OR (95% CI)
Chi-Square
2.13 (1.51-3.01) 1.34 (0.91-1.98) 1.00 (referent)
19.6 2.3 — 21.0†
BP category* High-normal Normal Optimal Age (y) ⱖ80 70-79 60-69 50-59 40-49 30-39 20-29 Female sex (referent ⫽ male) Race Non-Hispanic black Mexican-American Non-Hispanic white BMI (per 1 䡠 kg/m2) Total cholesterol level (per 50 mg/dL) HDL level (per 10 mg/dL) Triglyceride level (per 50 mg/dL) CRP level (per 0.5 mg/dL) History of MI Current cigarette smoker
1.84 (1.08-3.15) 1.12 (0.63-2.00) 0.81 (0.49-1.34) 0.71 (0.40-1.25) 0.66 (0.44-0.98) 0.91 (0.60-1.38) 1.00 (referent) 1.56 (1.16-2.10)
9.1
1.30 (1.04-1.64) 1.16 (0.90-1.51) 1.00 (referent) 0.97 (0.94-1.00) 1.07 (0.87-1.31) 1.03 (0.94-1.04) 1.09 (1.02-1.16) 1.17 (1.09-1.25) 2.03 (1.06-3.87) 1.16 (0.81-1.67)
5.5 1.3 — 4.5 0.4 0.5 7.9 18.1 4.8 0.7
NOTE. To convert cholesterol to mmol/L, multiply by 0.0259; to convert HDL to mmol/L, multiply by 0.0259; to convert triglycerides to mmol/L, multiply by 0.0113; to convert CRP to mg/L, multiply by 10. Microalbuminuria is defined as a urine ACR of 17 g/mg or greater (ⱖ1.9 mg/mmol) and 250 g/mg or less (ⱕ28 mg/mmol) in men and 25 g/mg or greater (ⱖ3 mg/mmol) and 355 g/mg or less (ⱕ40 mg/mmol) for women. *High-normal is SBP of 130 to 139 mm Hg or DBP of 85 to 89 mm Hg, normal is SBP of 120 to 129 mm Hg or DBP of 80 to 84 mm Hg, and optimal is SBP less than 120 mm Hg and DBP less than 80 mm Hg. †Six degrees of freedom.
cently, specific genetic differences in the angiotensin-converting enzyme gene have been identified that are associated with hypertension and microalbuminuria.25 The relationship between hypertension and microalbuminuria has been shown previously in persons without diabetes,1-8 but there are limited Table 4.
and inconsistent data on the association between high-normal BP and albuminuria in these individuals. A small population-based study of 199 patients (171 patients, BP ⬍ 140/90 mm Hg) from the United Kingdom showed no significant correlation between BP less than 140/90 mm Hg and albumin excretion rate, but showed a signifi-
Age- and Sex-Adjusted and Multivariate ORs With 95% CIs for Microalbuminuria for Each 10-mm Hg Increment in the Specified BP Measurement
BP Measurement*
SBP DBP MAP PP
Age- and Sex-Adjusted OR (95% CI)
Multivariate OR* (95% CI)
1.28 (1.11-1.47) 1.29 (1.08-1.53) 1.40 (1.17-1.68) 1.08 (0.93-1.24)
1.27 (1.09-1.48) 1.29 (1.06-1.57) 1.41 (1.15-1.74) 1.06 (0.92-1.23)
NOTE. Microalbuminuria is defined as a urine ACR 17 g/mg or greater (ⱖ1.9 mg/mmol) and 250 g/mg or less (ⱕ28 mg/mmol) in men and 25 g/mg or greater (ⱖ3 mg/mmol) and 355 g/mg or less (ⱕ40 mg/mmol) for women. *Adjusted for age, sex, race, BMI, total cholesterol, HDL, triglycerides, CRP, history of MI, and current cigarette smoking.
HIGH-NORMAL BP AND MICROALBUMINURIA Table 5.
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Multivariate ORs With 95% CIs and Chi-Square Values for High ACR Levels Below the Microalbuminuria Threshold
Variable
Multivariate OR (95% CI)
BP category* High-normal Normal Optimal Age (y) ⱖ80 70-79 60-69 50-59 40-49 30-39 20-29 Female sex (referent ⫽ male) Race Non-Hispanic black Mexican American Non-Hispanic white BMI (per 1 kg/m2) Total cholesterol level (per 50 mg/dL) HDL level (per 10 mg/dL) Triglyceride level (per 50 mg/dL) CRP level (per 0.5 mg/dL) History of MI Current cigarette smoker
1.38 (1.03-1.85) 1.20 (0.89-1.62) 1.00 (referent)
Chi-Square
4.9 1.5 — 119†
4.63 (2.94-7.28) 2.87 (1.87-4.39) 1.93 (1.23-3.03) 1.00 (0.65-1.54) 0.83 (0.56-1.24) 0.96 (0.70-1.33) 1.00 (referent) 0.96 (0.76-1.22)
0.1
0.89 (0.73-1.08) 1.16 (0.96-1.39) 1.00 (referent) 0.95 (0.93-0.97) 0.96 (0.82-1.13) 1.02 (0.95-1.10) 1.08 (1.02-1.14) 1.11 (1.02-1.20) 1.37 (0.73-2.56) 1.42 (1.16-1.74)
1.4 2.6 — 20.0 0.21 0.4 6.8 6.2 1.0 12.3
NOTE. ORs adjusted for all variables in the table. High ACR is defined as 9 to 16 g/mg (1.0 to 1.8 mg/mmol) for men and 13 to 24 g/mg (1.5 to 2.7 mg/mmol) for women, and the referent group is 8 g/mg or less (ⱕ0.9 mg/mmol) for men and 12 g/mg or less (ⱕ1.4 mg/mmol) for women. To convert cholesterol to mmol/L, multiply by 0.0259; to convert HDL to mmol/L, multiply by 0.0259; to convert triglycerides to mmol/L, multiply by 0.0113; to convert CRP to mg/L, multiply by 10. *High-normal is SBP of 130 to 139 mm Hg or DBP of 85 to 89 mm Hg, normal is SBP less of 120 to 129 mm Hg or DBP 80 to 84 mm Hg, and optimal is SBP less than 120 mm Hg and DBP less than 80 mm Hg. †Six degrees of freedom.
Table 6. Age- and Sex-Adjusted and Multivariate ORs With 95% CIs for High ACR Levels Below the Microalbuminuria Threshold for Each 10-mm Hg Increment in the Specified BP Measurement BP Measurement
SBP DBP MAP PP
Age- and Sex-Adjusted OR (95% CI)
Multivariate OR* (95% CI)
1.12 (1.02-1.22) 1.08 (0.95-1.22) 1.12 (0.99-1.28) 1.07 (0.97-1.18)
1.20 (1.08-1.34) 1.18 (1.04-1.33) 1.27 (1.11-1.45) 1.08 (0.97-1.20)
NOTE. High ACR level is defined as 9 to 16 g/mg (1.0 to 1.8 mg/mmol) for men and 13 to 24 g/mg (1.5 to 2.7 mg/mmol) for women and the referent group is 8 g/mg or less (ⱕ0.9 mg/mmol) for men and 12 g/mg or less (ⱕ1.4 mg/mmol) for women. *Adjusted for age, sex, race, BMI, total cholesterol, HDL, triglycerides, CRP, history of MI, and current cigarette smoking.
cant correlation between albumin excretion and MAP in patients with an SBP and/or DBP of 140/90 mm Hg or greater.26 A larger study of very low levels of albuminuria (mean ACR, 2.4 ⫾ 9.8 g/mg [0.27 ⫾ 1.1 mg/mmol]) in young adults (N ⫽ 1,131) found no significant association between BP and albuminuria in whites (OR, 0.9; 95% confidence interval [CI], 0.5 to 2.2 for the odds of being in the ⱖ90th percentile of urinary albumin excretion for the highest quartile of SBP compared with the lowest quartile), but found a significant association between BP and albuminuria in blacks (OR, 7.1; 95% CI, 2.0 to 25.8).27 A study by Goetz et al5 found a significant difference in albuminuria as a continuous variable between individuals with an SBP of 140 mm Hg or greater and those with an SBP less than 125 mm Hg, but there was overlap in CIs be-
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tween those with an SBP of 125 to 139 mm Hg and those with an SBP less than 125 mm Hg (P for comparison not reported).5 Similarly, Cirillo et al7 reported a continuous relationship between SBP and albuminuria, but the majority of these patients were hypertensive, and no data were reported on the association between lower BP levels and albuminuria. Finally, a recent large (N ⫽ 2,091) study by Romunstad et al28 of individuals without diabetes or treated hypertension found a significant association between BP and microalbuminuria, but these investigators included a large number of subjects with elevated BP (SBP ⱖ 150 mm Hg; N ⫽ 467; DBP ⱖ 90 mm Hg; N ⫽ 393), and they observed no statistically significant difference in albuminuria between normotensive individuals with an SBP of 120 to 134 mm Hg compared with an SBP less than 120 mm Hg and between normotensive individuals with a DBP of 80 to 89 mm Hg compared with a DBP less than 80 mm Hg.28 The current study is unique in that we examined the association between BP and microalbuminuria in a large population of normotensive individuals, we examined BP in different ways (eg, specific BP categories, SBP, DBP, MAP, and PP), and we examined levels of albuminuria below the microalbuminuria threshold that have been specifically associated with increased cardiovascular risk.11 In addition, this study has the advantage of being representative of the entire normotensive nondiabetic adult US population. Also, because of the size of this study, we had greater power than previous studies to detect differences in albuminuria between different categories of normal BP. This study has limitations that deserve mention. This was a cross-sectional study; therefore, we were unable to examine the impact of BP over time. Also, although we had multiple measurements of BP, we only had one measurement of urinary albumin and creatinine, and these measurements are subject to both intra-assay and intraperson variation. Ideally, to reduce intraperson variability, we would have multiple measurements of urinary albumin. It also is possible that we did not adequately adjust for all important confounders. Nonetheless, we included detailed information on potential confounders and excluded patients with diabetes and hypertension,
KNIGHT, KRAMER, AND CURHAN
conditions associated with increased albuminuria. However, it is possible we may have included some individuals with undiagnosed diabetes. Overall, these results demonstrate that highnormal BP is significantly associated with microalbuminuria in a large diverse population representative of the normotensive nondiabetic adult US population. In addition, within the normal BP range, higher SBP, DBP, and MAP were associated with increased odds of microalbuminuria. We also demonstrated that individuals with highnormal BP had increased odds of having high levels of albuminuria below the traditional microalbuminuria threshold. Therefore, because high-normal BP is associated with increased albuminuria relative to optimal BP, and high levels of albuminuria are associated with increased cardiovascular risk in high-risk individuals, this study suggests that albuminuria may be a biomarker of the increased cardiovascular risk observed in this population. However, prospective studies are needed to quantify the cardiovascular risk associated with different degrees of albuminuria in normotensive nondiabetic individuals. ACKNOWLEDGMENT The authors thank Melissa Francis for assistance with manuscript preparation.
REFERENCES 1. Parving HH, Mogensen CE, Jensen HA, Evrin PE: Increased urinary albumin-excretion rate in benign essential hypertension. Lancet 1:1190-1192, 1974 2. Metcalf P, Baker J, Scott A, Wild C, Scragg R, Dryson E: Albuminuria in people at least 40 years old: Effect of obesity, hypertension, and hyperlipidemia. Clin Chem 38: 1802-1808, 1992 3. Winocour PH, Harland JO, Millar JP, Laker MF, Alberti KG: Microalbuminuria and associated cardiovascular risk factors in the community. Atherosclerosis 93:71-81, 1992 4. Palatini P, Graniero GR, Mormino P, et al: Prevalence and clinical correlates of microalbuminuria in stage I hypertension. Results from the Hypertension and Ambulatory Recording Venetia Study (HARVEST Study). Am J Hypertens 9:334-341, 1996 5. Goetz FC, Jacobs DR Jr, Chavers B, Roel J, Yelle M, Sprafka JM: Risk factors for kidney damage in the adult population of Wadena, Minnesota. A prospective study. Am J Epidemiol 145:91-102, 1997 6. Pontremoli R, Sofia A, Ravera M, et al: Prevalence and clinical correlates of microalbuminuria in essential hypertension: The MAGIC Study. Microalbuminuria: A Genoa Investigation on Complications. Hypertension 30:1135-1143, 1997
HIGH-NORMAL BP AND MICROALBUMINURIA
7. Cirillo M, Senigalliesi L, Laurenzi M, et al: Microalbuminuria in nondiabetic adults: Relation of blood pressure, body mass index, plasma cholesterol levels, and smoking: The Gubbio Population Study. Arch Intern Med 158:19331939, 1998 8. Martinez MA, Moreno A, Aguirre de Carcer A, et al: Frequency and determinants of microalbuminuria in mild hypertension: A primary-care-based study. J Hypertens 19: 319-326, 2001 9. Grandi AM, Santillo R, Bertolini A, et al: Microalbuminuria as a marker of preclinical diastolic dysfunction in never-treated essential hypertensives. Am J Hypertens 14: 644-648, 2001 10. Wachtell K, Palmieri V, Olsen MH, et al: Urine albumin/creatinine ratio and echocardiographic left ventricular structure and function in hypertensive patients with electrocardiographic left ventricular hypertrophy: The LIFE study. Losartan Intervention for Endpoint Reduction. Am Heart J 143:319-326, 2002 11. Gerstein HC, Mann JF, Yi Q, et al: Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 286:421-426, 2001 12. Hillege HL, Fidler V, Diercks GF, et al: Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation 106:17771782, 2002 13. Vasan RS, Larson MG, Leip EP, et al: Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med 345:1291-1297, 2001 14. National Center for Health Statistics: Survey Design of the Third National Health and Nutrition Examination Survey, 1988-1994. Hyattsville, MD, Centers for Disease Control and Prevention, 1996 15. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 157:2413-2446, 1997 16. Subcommittee G: 1999 World Health OrganizationInternational Society of Hypertension guidelines for the management of hypertension. J Hypertens 17:151-183, 1999 17. National Center for Health Statistics: Third National Health and Nutrition Examination Survey, 1988-1994, Reference Manuals and Reports: Manual for Medical Technicians and Laboratory Procedures Used for NHANES III. Hyattsville, MD, Centers for Disease Control and Prevention, 1996, pp 591-617
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18. Warram JH, Gearin G, Laffel L, Krolewski AS: Effect of duration of type I diabetes on the prevalence of stages of diabetic nephropathy defined by urinary albumin/creatinine ratio. J Am Soc Nephrol 7:930-937, 1996 19. Mattix HJ, Hsu CY, Shaykevich S, Curhan G: Use of the albumin/creatinine ratio to detect microalbuminuria: Implications of sex and race. J Am Soc Nephrol 13:10341039, 2002 20. Hillege HL, Janssen WM, Bak AA, et al: Microalbuminuria is common, also in a nondiabetic, nonhypertensive population, and an independent indicator of cardiovascular risk factors and cardiovascular morbidity. J Intern Med 249:519-526, 2001 21. Pedrinelli R, Giampietro O, Carmassi F, et al: Microalbuminuria and endothelial dysfunction in essential hypertension. Lancet 344:14-18, 1994 22. Festa A, D’Agostino R, Howard G, Mykkanen L, Tracy RP, Haffner SM: Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: The Insulin Resistance Atherosclerosis Study. Kidney Int 58:1703-1710, 2000 23. Viberti GC, Keen H, Wiseman MJ: Raised arterial pressure in parents of proteinuric insulin dependent diabetics. Br Med J (Clin Res Ed) 295:515-517, 1987 24. Krolewski AS, Canessa M, Warram JH, et al: Predisposition to hypertension and susceptibility to renal disease in insulin-dependent diabetes mellitus. N Engl J Med 318:140145, 1988 25. Pontremoli R, Ravera M, Viazzi F, et al: Genetic polymorphism of the renin-angiotensin system and organ damage in essential hypertension. Kidney Int 57:561-569, 2000 26. Gosling P, Beevers DG: Urinary albumin excretion and blood pressure in the general population. Clin Sci (Colch) 76:39-42, 1989 27. Jiang X, Srinivasan SR, Radhakrishnamurthy B, Dalferes ER Jr, Bao W, Berenson GS: Microalbuminuria in young adults related to blood pressure in a biracial (blackwhite) population. The Bogalusa Heart Study. Am J Hypertens 7:794-800, 1994 28. Romundstad S, Holmen J, Hallan H, Kvenild K, Kruger O, Midthjell K: Microalbuminuria, cardiovascular disease and risk factors in a nondiabetic/nonhypertensive population. The Nord-Trondelag Health Study (HUNT, 199597), Norway. J Intern Med 252:164-172, 2002
H
YPERTENSION has been associated with microalbuminuria in multiple studies,1-8 but there is no study specifically examining the association between high-normal blood pressure (BP) and microalbuminuria. This relationship is important because of the high prevalence of high-normal BP and because microalbuminuria has been associated with left ventricular diastolic dysfunction9 and left ventricular hypertrophy10 in individuals with hypertension. In addition, microalbuminuria has been associated with increased cardiovascular mortality and all-cause mortality in individuals at increased risk for cardiovascular disease11 and in a general population from The Netherlands.12 Therefore, if microalbuminuria is more common in patients with From the Renal Unit, Department of Medicine, Massachusetts General Hospital; and Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. Received September 25, 2002; accepted in revised form November 14, 2002. Supported in part by grants no. T32DK0740-16, T32DK07791, and DK52866 from The National Institutes of Health. H.M.K. was an American Kidney Foundation Clinical Scientist in Nephrology Fellow from 2001 to 2002. Address reprint requests to Eric L. Knight, MD, Channing Laboratory, Nurses’ Health Study, 3rd Floor, 181 Longwood Ave, Boston, MA 02115. E-mail: [email protected] © 2003 by the National Kidney Foundation, Inc. 0272-6386/03/4103-0007$30.00/0 doi:10.1053/ajkd.2003.50120 588
high-normal BP, then microalbuminuria may be a useful biological marker of the increased cardiovascular risk observed in this population.13 To study the association between high-normal BP and microalbuminuria, we used data from the Third National Health and Nutrition Examination Survey (NHANES III).14 This enabled us to evaluate 9,462 normotensive individuals without diabetes, each with multiple BP measurements and one measurement of urinary albumin and creatinine. METHODS
Study Population The NHANES III was designed to be a probability sample of the total US civilian noninstitutionalized population aged 2 months or older and collected health, nutritional, and laboratory data for 33,994 men, women, and children from 1988 to 1994.14 Certain subgroups were oversampled, such as young children, older persons, blacks, and Mexican Americans. Details of the survey design can be found in the NHANES III operations manual.14 There were 16,573 men and women aged 20 years and older who had an interview and were examined. Of these, we excluded the following people: 5,325 persons with a diagnosis of hypertension, administered prescription medication for high BP, and/or a systolic BP (SBP) of 140 mm Hg or greater or a diastolic BP (DBP) of 90 mm Hg or greater; 1,265 persons with self-reported diabetes, 247 pregnant women, 234 persons with information missing on urine albumin or creatinine level, and 40 persons with macroalbuminuria (discussed later). This left 9,462 individuals for our primary analyses. For analyses of levels of albuminuria less than the traditional microalbuminuria threshold, we ex-
American Journal of Kidney Diseases, Vol 41, No 3 (March), 2003: pp 588-595
HIGH-NORMAL BP AND MICROALBUMINURIA
cluded an additional 711 people who met sex-specific criteria for microalbuminuria. This left 8,751 individuals for this analysis.
Assessment of BP BP was determined by the average of six readings. We separately examined SBP, DBP, pulse pressure (PP; defined as SBP ⫺ DBP), and mean arterial pressure (MAP; defined as [SBP ⫹ DBP * 2]/3. We also categorized BP into three prespecified categories based on the classification approaches of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure15 and the World Health Organization and International Society of Hypertension.16 BP categories were high-normal (SBP, 130 to 139 mm Hg or DBP, 85 to 89 mm Hg), normal (SBP, 120 to 129 mm Hg or DBP, 80 to 84 mm Hg), and optimal (SBP ⬍ 120 mm Hg and DBP ⬍ 80 mm Hg). If either SBP or DBP fell into different categories, the individual was assigned to the higher category. For example, a BP of 132/82 mm Hg would be assigned to the high-normal category.
Assessment of Outcome of Albuminuria A solid-phase fluorescent immunoassay with a sensitivity level of 0.05 mg/dL was used to measure urinary albumin, and the coefficient of variation ranged from 4.8% to 16.1% during the 6 years of the study.17 Urine creatinine was measured with the Jaffe´ rate reaction (Beckman ASTRA, Brea, CA), and the coefficient of variation ranged from 1.5% to 7.7%.17 Spot urine albumin (in micrograms per milliliter) to creatinine (in milligrams per milliliter) ratios (ACRs) were calculated for all subjects. To define microalbuminuria in random urine specimens, we used sex-specific ACR cutoff values of 17 g/mg or greater (ⱖ1.9 mg/mmol) and 250 g/mg or less (ⱕ28 mg/mmol) for men and 25 g/mg or greater (ⱖ2.8 mg/ mmol) and 355 g/mg or less (ⱕ40 mg/mmol) for women.18 These cutoff values were determined by comparing the ACR in spot urine samples with albumin excretion rates collected from timed urine specimens and correspond to 30 to 300 g/min of urine albumin excretion and the 95th percentile of ACR values for 218 healthy men and women.18,19 We also examined sex-specific levels of albuminuria that were less than the traditional microalbuminuria threshold. The two chosen categories of ACR were 8 g/mg or less (ⱕ0.9 mg/mmol) for men and 12 g/mg or less (ⱕ1.4 mg/mmol) for women and 9 to 16 g/mg (1.0 to 1.8 mg/mmol) for men and 13 to 24 g/mg (1.5 to 2.7 mg/ mmol) for women. These cutoff values represent the midpoint of the distribution of albuminuria less than the traditional microalbuminuria threshold, and the high category represents 13% of this subpopulation.
Assessment of Other Covariates A detailed medical history was obtained during the standardized home interview. Age is defined as age at the time of the home interview, and race/ethnicity were self-reported as non-Hispanic white, non-Hispanic black, Mexican American, or other. History of myocardial infarction (MI) or diabetes is defined as “being told by a doctor that you had
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previously had a heart attack or diabetes,” respectively. Current cigarette smoking is defined based on self-report. Body mass index (BMI; in kilograms per meter squared) was calculated from the weight and height measured during the physical examination. Total cholesterol, high-density lipoprotein (HDL), triglyceride, and C-reactive protein (CRP) levels were measured from the blood sample obtained at the time of the physical examination.
Statistical Analyses All statistical analyses were performed using SAScallable SUDAAN (Software for the Statistical Analysis of Correlated Data, release 8.00; Research Triangle Institute, Durham, NC) to incorporate sample weights, adjust for clusters, and provide prevalence estimates for the US population. NHANES data are weighted to account for the probability of selection, and adjust for nonresponse to the interview and physical examination in order to be representative of the entire US population. For the primary analyses, we used logistic regression to calculate the odds ratio (OR) for microalbuminuria compared with no microalbuminuria, while simultaneously adjusting for multiple covariates. For secondary analyses, we used logistic regression to assess the odds of being in the high category of albuminuria below the sex-specific microalbuminuria threshold compared with the low category below this threshold. All multivariate analyses were adjusted for covariates stated previously. Age was categorized by decade; race was categorized as non-Hispanic white, nonHispanic black, Mexican-American, and other; and BMI and cholesterol, HDL, triglyceride, and CRP levels were included as continuous variables. History of MI and current smoking were classified as yes or no. We also examined interactions between BP category and age (decades) and BP category and race (non-Hispanic white, non-Hispanic black, and Mexican American).
RESULTS
Overall, an estimated 7.2 million Americans (6.4%) without diabetes or hypertension have microalbuminuria. Of those with optimal BP, 6% (4 million) had microalbuminuria compared with 7% (1.8 million) of those with normal BP and 10% (1.4 million) of those with high-normal BP. An additional estimated 13.1 million Americans without diabetes or hypertension had high levels of albuminuria below the traditional microalbuminuria threshold. Of those with optimal BP, 11% (7.8 million) had high levels of albuminuria compared with 13% (3.3 million) of those with normal BP and 17% (2 million) of those with high-normal BP. Descriptive characteristics of the population categorized by the presence or absence of microalbuminuria are listed in Table 1, and descriptive characteristics of those with high levels of
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KNIGHT, KRAMER, AND CURHAN Table 1.
Demographic, Clinical, and Laboratory Variables Categorized by the Presence or Absence of Microalbuminuria
Variable
Albuminuria ⬍ the Microalbuminuria Threshold (N ⫽ 8,751)
Age (y) Men (%) Race (%) Non-Hispanic white Non-Hispanic black Mexican-American BP High-normal (%) Normal (%) Optimal (%) SBP (mm Hg) DBP (mm Hg) MAP (mm Hg) PP (mm Hg) BMI (kg/m2) Total cholesterol (mg/dL) HDL (mg/dL) Triglycerides (mg/dL) CRP (mg/dL) History of MI (%) Current cigarette smoker (%)
Microalbuminuria* (N ⫽ 711)
39 (38-40) 49 (48-50)
41 (39-43) 40 (34-46)
76 (73-79) 10 (9-11) 6 (4-6)
72 (68-76) 11 (9-13) 6 (4-6)
11 (10-12) 24 (22-26) 65 (63-67) 115 (114-115) 71 (71-72) 86 (85-86) 43 (43-44) 25 (25-26) 201 (199-203) 51 (50-52) 124 (120-128) 0.35 (0.33-0.37) 1 (0-1) 31 (29-33)
19 (14-24) 25 (19-30) 56 (50-62) 117 (115-118) 72 (71-73) 87 (86-88) 45 (43-46) 25 (25-26) 206 (201-210) 52 (50-54) 140 (127-153) 0.51 (0.41-0.62) 3 (1-5) 34 (27-41)
NOTE. Results expressed as mean (95% CI) for continuous variables. To convert cholesterol to mmol/L, multiply by 0.0259, to convert HDL to mmol/L, multiply by 0.0259; to convert triglycerides to mmol/L, multiply by 0.0113; to convert CRP to mg/L, multiply by 10. *Microalbuminuria is defined as a urine albumin-to-creatinine ratio (ACR) of 17 g/mg or greater (ⱖ2 mg/mmol) and 250 g/mg or less (ⱕ28 mg/mmol) in men and 25 g/mg or greater (ⱖ2.8 mg/mmol) and 355 g/mg or less (ⱕ40 mg/mmol) for women.18
albuminuria below the traditional microalbuminuria threshold categorized by urinary albumin excretion level are listed in Table 2. Multivariate logistic regression results for microalbuminuria according to BP category are listed in Table 3. Those in the high-normal BP category had twice the odds of microalbuminuria as those in the optimal category. Multivariate logistic regression results for high albuminuria below the traditional albuminuria threshold for each 10-mm Hg increase in SBP, DBP, MAP, and PP are listed in Table 4. Multivariate logistic regression results for the association between BP category and high albuminuria level below the traditional microalbuminuria threshold are listed in Table 5. High-normal BP was significantly associated with increased odds of high levels of albuminuria below the traditional microalbuminuria threshold. We also examined the multivariate odds of high albuminuria level below the traditional albuminuria
threshold for each 10-mm Hg increase in SBP, DBP, MAP, and PP (Table 6). On multivariate analysis, in terms of racial differences in albuminuria in this population, blacks had significantly greater odds of microalbuminuria (Table 3) compared with whites, but did not have significantly greater odds of high albuminuria levels below the traditional microalbuminuria threshold (Table 5). MexicanAmericans did not have significantly greater odds of microalbuminuria (Table 3) or significantly greater odds of high albuminuria levels below the traditional microalbuminuria threshold (Table 5). We found a significant interaction between age and high-normal BP for the outcome of microalbuminuria (P ⫽ 0.004). Specifically, the odds of microalbuminuria associated with highnormal BP were greater in older individuals after adjusting for BP category and age in the model. However, we did not observe a significant interaction between age and normal BP for the out-
HIGH-NORMAL BP AND MICROALBUMINURIA Table 2.
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Demographic, Clinical, and Laboratory Variables Categorized by ACR Below the Microalbuminuria Threshold ACR ⱕ 8 g/mg (0.9 mg/mmol) for Men and ⱕ 12 g/mg (1.4 mg/mmol) for Women (N ⫽ 7,579)
Variable
Age (y) Men (%) Race (%) Non-Hispanic white Non-Hispanic black Mexican-American BP High-normal (%) Normal (%) Optimal (%) SBP (mm Hg) DBP (mm Hg) MAP (mm Hg) PP (mm Hg) BMI (kg/m2) Total cholesterol (mg/dL) HDL (mg/dL) Triglycerides (mg/dL) CRP (mg/dL) History of MI (%) Cigarette smoker (%)
ACR 9-16 g/mg (1.0-1.8 mg/mmol) for Men and 13-24 g/mg (1.5-2.7 mg/mmol) for Women (N ⫽ 1,172)
39 (38-39) 49 (48-50)
42 (41-44) 52 (49-55)
76 (73-79) 10 (9-77) 6 (5-7)
78 (74-82) 8 (7-9) 6 (5-7)
11 (10-12) 26 (24-28) 65 (63-67) 114 (114-115) 71 (71-72) 86 (85-86) 43 (42-43) 25 (25-26) 200 (198-202) 51 (50-52) 123 (118-127) 0.34 (0.32-0.36) 1 (0-1) 30 (28-32)
15 (12-18) 28 (24-32) 57 (52-62) 117 (116-117) 72 (86-87) 45 (44-46) 25 (24-25) 203 (199-201) 51 (49-53) 132 (124-142) 0.41 (0.34-0.47) 3 (2-4) 37 (35-39)
NOTE. Results expressed as means (95% CI) for continuous variables. To convert cholesterol to mmol/L, multiply by 0.0259; to convert HDL to mmol/L, multiply by 0.0259; to convert triglycerides to mmol/L, multiply by 0.0113; to convert CRP to mg/L, multiply by 10.
come of microalbuminuria or between age and BP category for the outcome of high albuminuria levels below the traditional microalbuminuria threshold. We did not observe an interaction between race and BP category. DISCUSSION
High-normal BP was significantly associated with increased odds of microalbuminuria compared with optimal BP in individuals with an SBP less than 140 mm Hg and a DBP less than 90 mm Hg. In addition, among these individuals, high-normal BP was associated with increased odds of high albuminuria levels below the traditional microalbuminuria threshold. We also observed a positive interaction between age and high-normal BP for the outcome of microalbuminuria. The prevalence of microalbuminuria and high levels below this threshold increased in a graded fashion with increase in BP, and the overall prevalence of microalbuminuria was similar to that described in a large cross-sectional
study of individuals without diabetes or diagnosed hypertension from The Netherlands.20 The pathophysiological association between microalbuminuria and high-normal BP is complex. Higher BP may cause microalbuminuria by increasing glomerular filtration pressure and subsequent renal damage. It also is possible that a longer duration of high-normal BP and associated increased glomerular filtration pressure could explain the positive interaction we observed between age and high-normal BP. Alternatively, microalbuminuria may be a marker of endothelial dysfunction21 and inflammation22 associated with high-normal BP. Interestingly, when we attempted to adjust for inflammation using CRP level, we did not see a substantial change in our results. There also may be common genetic factors that predispose to both higher BP and microalbuminuria. For example, parents of individuals with type 1 diabetes and macroalbuminuria have greater rates of hypertension than parents of individuals with type 1 diabetes without macroalbuminuria,23,24 and more re-
592
KNIGHT, KRAMER, AND CURHAN Table 3.
Multivariate Odds Ratios (ORs) With 95% Confidence Intervals (CIs) and Chi-Square Values for Microalbuminuria Adjusted for All Variables in the Table
Variable
Multivariate OR (95% CI)
Chi-Square
2.13 (1.51-3.01) 1.34 (0.91-1.98) 1.00 (referent)
19.6 2.3 — 21.0†
BP category* High-normal Normal Optimal Age (y) ⱖ80 70-79 60-69 50-59 40-49 30-39 20-29 Female sex (referent ⫽ male) Race Non-Hispanic black Mexican-American Non-Hispanic white BMI (per 1 䡠 kg/m2) Total cholesterol level (per 50 mg/dL) HDL level (per 10 mg/dL) Triglyceride level (per 50 mg/dL) CRP level (per 0.5 mg/dL) History of MI Current cigarette smoker
1.84 (1.08-3.15) 1.12 (0.63-2.00) 0.81 (0.49-1.34) 0.71 (0.40-1.25) 0.66 (0.44-0.98) 0.91 (0.60-1.38) 1.00 (referent) 1.56 (1.16-2.10)
9.1
1.30 (1.04-1.64) 1.16 (0.90-1.51) 1.00 (referent) 0.97 (0.94-1.00) 1.07 (0.87-1.31) 1.03 (0.94-1.04) 1.09 (1.02-1.16) 1.17 (1.09-1.25) 2.03 (1.06-3.87) 1.16 (0.81-1.67)
5.5 1.3 — 4.5 0.4 0.5 7.9 18.1 4.8 0.7
NOTE. To convert cholesterol to mmol/L, multiply by 0.0259; to convert HDL to mmol/L, multiply by 0.0259; to convert triglycerides to mmol/L, multiply by 0.0113; to convert CRP to mg/L, multiply by 10. Microalbuminuria is defined as a urine ACR of 17 g/mg or greater (ⱖ1.9 mg/mmol) and 250 g/mg or less (ⱕ28 mg/mmol) in men and 25 g/mg or greater (ⱖ3 mg/mmol) and 355 g/mg or less (ⱕ40 mg/mmol) for women. *High-normal is SBP of 130 to 139 mm Hg or DBP of 85 to 89 mm Hg, normal is SBP of 120 to 129 mm Hg or DBP of 80 to 84 mm Hg, and optimal is SBP less than 120 mm Hg and DBP less than 80 mm Hg. †Six degrees of freedom.
cently, specific genetic differences in the angiotensin-converting enzyme gene have been identified that are associated with hypertension and microalbuminuria.25 The relationship between hypertension and microalbuminuria has been shown previously in persons without diabetes,1-8 but there are limited Table 4.
and inconsistent data on the association between high-normal BP and albuminuria in these individuals. A small population-based study of 199 patients (171 patients, BP ⬍ 140/90 mm Hg) from the United Kingdom showed no significant correlation between BP less than 140/90 mm Hg and albumin excretion rate, but showed a signifi-
Age- and Sex-Adjusted and Multivariate ORs With 95% CIs for Microalbuminuria for Each 10-mm Hg Increment in the Specified BP Measurement
BP Measurement*
SBP DBP MAP PP
Age- and Sex-Adjusted OR (95% CI)
Multivariate OR* (95% CI)
1.28 (1.11-1.47) 1.29 (1.08-1.53) 1.40 (1.17-1.68) 1.08 (0.93-1.24)
1.27 (1.09-1.48) 1.29 (1.06-1.57) 1.41 (1.15-1.74) 1.06 (0.92-1.23)
NOTE. Microalbuminuria is defined as a urine ACR 17 g/mg or greater (ⱖ1.9 mg/mmol) and 250 g/mg or less (ⱕ28 mg/mmol) in men and 25 g/mg or greater (ⱖ3 mg/mmol) and 355 g/mg or less (ⱕ40 mg/mmol) for women. *Adjusted for age, sex, race, BMI, total cholesterol, HDL, triglycerides, CRP, history of MI, and current cigarette smoking.
HIGH-NORMAL BP AND MICROALBUMINURIA Table 5.
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Multivariate ORs With 95% CIs and Chi-Square Values for High ACR Levels Below the Microalbuminuria Threshold
Variable
Multivariate OR (95% CI)
BP category* High-normal Normal Optimal Age (y) ⱖ80 70-79 60-69 50-59 40-49 30-39 20-29 Female sex (referent ⫽ male) Race Non-Hispanic black Mexican American Non-Hispanic white BMI (per 1 kg/m2) Total cholesterol level (per 50 mg/dL) HDL level (per 10 mg/dL) Triglyceride level (per 50 mg/dL) CRP level (per 0.5 mg/dL) History of MI Current cigarette smoker
1.38 (1.03-1.85) 1.20 (0.89-1.62) 1.00 (referent)
Chi-Square
4.9 1.5 — 119†
4.63 (2.94-7.28) 2.87 (1.87-4.39) 1.93 (1.23-3.03) 1.00 (0.65-1.54) 0.83 (0.56-1.24) 0.96 (0.70-1.33) 1.00 (referent) 0.96 (0.76-1.22)
0.1
0.89 (0.73-1.08) 1.16 (0.96-1.39) 1.00 (referent) 0.95 (0.93-0.97) 0.96 (0.82-1.13) 1.02 (0.95-1.10) 1.08 (1.02-1.14) 1.11 (1.02-1.20) 1.37 (0.73-2.56) 1.42 (1.16-1.74)
1.4 2.6 — 20.0 0.21 0.4 6.8 6.2 1.0 12.3
NOTE. ORs adjusted for all variables in the table. High ACR is defined as 9 to 16 g/mg (1.0 to 1.8 mg/mmol) for men and 13 to 24 g/mg (1.5 to 2.7 mg/mmol) for women, and the referent group is 8 g/mg or less (ⱕ0.9 mg/mmol) for men and 12 g/mg or less (ⱕ1.4 mg/mmol) for women. To convert cholesterol to mmol/L, multiply by 0.0259; to convert HDL to mmol/L, multiply by 0.0259; to convert triglycerides to mmol/L, multiply by 0.0113; to convert CRP to mg/L, multiply by 10. *High-normal is SBP of 130 to 139 mm Hg or DBP of 85 to 89 mm Hg, normal is SBP less of 120 to 129 mm Hg or DBP 80 to 84 mm Hg, and optimal is SBP less than 120 mm Hg and DBP less than 80 mm Hg. †Six degrees of freedom.
Table 6. Age- and Sex-Adjusted and Multivariate ORs With 95% CIs for High ACR Levels Below the Microalbuminuria Threshold for Each 10-mm Hg Increment in the Specified BP Measurement BP Measurement
SBP DBP MAP PP
Age- and Sex-Adjusted OR (95% CI)
Multivariate OR* (95% CI)
1.12 (1.02-1.22) 1.08 (0.95-1.22) 1.12 (0.99-1.28) 1.07 (0.97-1.18)
1.20 (1.08-1.34) 1.18 (1.04-1.33) 1.27 (1.11-1.45) 1.08 (0.97-1.20)
NOTE. High ACR level is defined as 9 to 16 g/mg (1.0 to 1.8 mg/mmol) for men and 13 to 24 g/mg (1.5 to 2.7 mg/mmol) for women and the referent group is 8 g/mg or less (ⱕ0.9 mg/mmol) for men and 12 g/mg or less (ⱕ1.4 mg/mmol) for women. *Adjusted for age, sex, race, BMI, total cholesterol, HDL, triglycerides, CRP, history of MI, and current cigarette smoking.
cant correlation between albumin excretion and MAP in patients with an SBP and/or DBP of 140/90 mm Hg or greater.26 A larger study of very low levels of albuminuria (mean ACR, 2.4 ⫾ 9.8 g/mg [0.27 ⫾ 1.1 mg/mmol]) in young adults (N ⫽ 1,131) found no significant association between BP and albuminuria in whites (OR, 0.9; 95% confidence interval [CI], 0.5 to 2.2 for the odds of being in the ⱖ90th percentile of urinary albumin excretion for the highest quartile of SBP compared with the lowest quartile), but found a significant association between BP and albuminuria in blacks (OR, 7.1; 95% CI, 2.0 to 25.8).27 A study by Goetz et al5 found a significant difference in albuminuria as a continuous variable between individuals with an SBP of 140 mm Hg or greater and those with an SBP less than 125 mm Hg, but there was overlap in CIs be-
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tween those with an SBP of 125 to 139 mm Hg and those with an SBP less than 125 mm Hg (P for comparison not reported).5 Similarly, Cirillo et al7 reported a continuous relationship between SBP and albuminuria, but the majority of these patients were hypertensive, and no data were reported on the association between lower BP levels and albuminuria. Finally, a recent large (N ⫽ 2,091) study by Romunstad et al28 of individuals without diabetes or treated hypertension found a significant association between BP and microalbuminuria, but these investigators included a large number of subjects with elevated BP (SBP ⱖ 150 mm Hg; N ⫽ 467; DBP ⱖ 90 mm Hg; N ⫽ 393), and they observed no statistically significant difference in albuminuria between normotensive individuals with an SBP of 120 to 134 mm Hg compared with an SBP less than 120 mm Hg and between normotensive individuals with a DBP of 80 to 89 mm Hg compared with a DBP less than 80 mm Hg.28 The current study is unique in that we examined the association between BP and microalbuminuria in a large population of normotensive individuals, we examined BP in different ways (eg, specific BP categories, SBP, DBP, MAP, and PP), and we examined levels of albuminuria below the microalbuminuria threshold that have been specifically associated with increased cardiovascular risk.11 In addition, this study has the advantage of being representative of the entire normotensive nondiabetic adult US population. Also, because of the size of this study, we had greater power than previous studies to detect differences in albuminuria between different categories of normal BP. This study has limitations that deserve mention. This was a cross-sectional study; therefore, we were unable to examine the impact of BP over time. Also, although we had multiple measurements of BP, we only had one measurement of urinary albumin and creatinine, and these measurements are subject to both intra-assay and intraperson variation. Ideally, to reduce intraperson variability, we would have multiple measurements of urinary albumin. It also is possible that we did not adequately adjust for all important confounders. Nonetheless, we included detailed information on potential confounders and excluded patients with diabetes and hypertension,
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conditions associated with increased albuminuria. However, it is possible we may have included some individuals with undiagnosed diabetes. Overall, these results demonstrate that highnormal BP is significantly associated with microalbuminuria in a large diverse population representative of the normotensive nondiabetic adult US population. In addition, within the normal BP range, higher SBP, DBP, and MAP were associated with increased odds of microalbuminuria. We also demonstrated that individuals with highnormal BP had increased odds of having high levels of albuminuria below the traditional microalbuminuria threshold. Therefore, because high-normal BP is associated with increased albuminuria relative to optimal BP, and high levels of albuminuria are associated with increased cardiovascular risk in high-risk individuals, this study suggests that albuminuria may be a biomarker of the increased cardiovascular risk observed in this population. However, prospective studies are needed to quantify the cardiovascular risk associated with different degrees of albuminuria in normotensive nondiabetic individuals. ACKNOWLEDGMENT The authors thank Melissa Francis for assistance with manuscript preparation.
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