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(Circulation. 2001;103:3057.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Excessive Urinary Albumin Levels Are Associated With Future Cardiovascular Mortality in Postmenopausal Women

Mark Roest, PhD; Jan Dirk Banga, MD, PhD; Wilbert M. T. Janssen, MD, PhD; Diederick E. Grobbee, MD, PhD; Jan J. Sixma, MD, PhD; Paul E. de Jong, MD, PhD; Dick de Zeeuw, MD, PhD; Yvonne T. van der Schouw, PhD

From the Julius Center for Patient Oriented Research (M.R., D.E.G., Y.T.v.d.S.), the Department of Hematology (M.R., J.D.B.), Graduate School of Biomembranes, and the Department of Internal Medicine (M.R., J.J.S.), Utrecht University Medical School, Utrecht, the Netherlands, and the Department of Internal Medicine (W.M.T.J., P.E.d.J.), Division of Nephrology, and the Department of Clinical Pharmacology (W.M.T.J., D.d.Z.), University Hospital Groningen, Groningen, the Netherlands.

Correspondence to Mark Roest, PhD, Julius Center for General Practice and Patient Oriented Research, D01-335, Utrecht University Medical School, PO Box 85500, 3508 GA Utrecht, Netherlands. E-mail M.Roest{at}LAB.AZU.NL

	Abstract

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Background—Microalbuminuria is an early predictor of cardiovascular morbidity and mortality, in both diabetic patients and hypertensive patients. Little is known about the relation of microalbuminuria to cardiovascular disease in women of the general population.

Methods and Results—We have studied the relation of urinary albumin levels to cardiovascular mortality in a cohort study of 12 239 postmenopausal women living in Utrecht, the Netherlands. The initial age was between 52 and 67 years. Women were followed on vital status between 1976 and 1995 (168 513 women-years). Albumin was determined in the urine of 561 cases and 557 controls. Data were analyzed by using a nested case-control design. The cardiovascular mortality rate (95% CI) for women who were in the highest quintile of urinary albumin levels was 13.2/1000 years (8.1 to 20.9) compared with 2.6/1000 years (2.3 to 3.1) in women without detectable urinary albumin. The age-adjusted rate ratio (95% CI) between these groups was 4.4 (2.6 to 7.6).

Conclusions—This is the first large cohort study that confirms a predictive role of urinary albumin for the risk of future cardiovascular mortality independent of hypertension and diabetes. Our findings support the hypothesis that microalbuminuria is a reflection of vascular damage and a marker of early arterial disease in women from the general population.

Key Words: follow-up studies • mortality • myocardial infarction • women

	Introduction

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Microalbuminuria is associated with increased risk of renal and cardiovascular morbidity and mortality in diabetes and hypertension.^{1 2 3 4 5 6 7 8 9 10 11} To date, little is known about the mechanism linking microalbuminuria to cardiovascular disease. There is growing support for the view that microalbuminuria is a reflection of a generalized arterial process affecting the glomeruli, the retina, and the intima of large vessels simultaneously.^{12 13 14 15} Therefore, leakage of albumin through the glomerular membrane may be a marker of preclinical atherosclerosis.

At present, it is not known whether microalbuminuria is an intermediate marker of arterial disease in subjects with hypertension and diabetes only or whether it is a general marker of arterial disease in any subject. Findings from small studies have suggested a relationship between microalbuminuria and cardiovascular disease incidence in the normal population,^{16 17 18 19} but large cohort studies remain to be performed. Very little is known about the importance of microalbuminuria in cardiovascular disease in women. We studied the relation of urinary albumin excretion to cardiovascular mortality in a population-based study among 12 239 women followed up for a maximum of 18 years (168 513 person-years).^{20 21}

	Methods

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Population
A total of 20 555 women born between 1911 and 1925 and residing in the city of Utrecht, the Netherlands, were asked to participate in an experimental breast cancer–screening program "Doorlopend Onderzoek Morbiditeit/Mortaliteit (DOM)" between December 1974 and October 1980.^{20 21} They were subsequently invited for repeat examinations. For the present study, we selected the 12 239 (60%) women who underwent a second examination (1976 to 1978), because this included a questionnaire on smoking at baseline. The women were followed with regard to vital status until December 31, 1995. The total follow-up time for the present analysis was 168 513 person-years. All participants gave oral informed consent for the use of their urine samples in future scientific research. These samples were stored at -20°C. The study was approved by the Institutional Review Board of the University Hospital Utrecht, Utrecht, the Netherlands.

Design
Full cohort analysis on the relationship between urinary albumin/creatinine ratio and cardiovascular mortality would be both expensive and labor intensive. Therefore, we used the nested case-control approach, which takes full advantage of the cohort information and has the cost-effectiveness of conventional case-control studies.^{22 23} The case group was composed of 608 women who died of cardiovascular disease, and the control group was composed of a random sample of 618 of 11 631 women who did not die of cardiovascular disease (sampling fraction 1:18.8). Urine samples of 59 cardiovascular mortality cases and of 49 women of the control group were not collected at baseline or were not retrieved. Therefore, these women were excluded from the present study. The final study group was composed of 549 cardiovascular mortality cases and 569 women of the control group.

Risk Factors
Each woman completed a questionnaire at baseline, with regard to medication, prescribed diets, history and presence of cardiovascular disease, and smoking. Blood pressure, height (m), and weight (kg) were also measured at that time. Overnight urine samples of each participant were stored at -20°C during follow-up. The women were classified as having diabetes mellitus if they used either insulin or oral blood glucose–lowering drugs or if they were on a diabetes diet. They were defined as smokers if they smoked at baseline. Body mass index (BMI, kg/m²) was calculated as weight (kg) divided by height squared (m²). Obesity was defined as BMI 30. Hypertension was defined as systolic blood pressure >160 mm Hg and/or diastolic blood pressure >90 mm Hg and/or the use of antihypertensive medication.

End Points
Municipal registries provided information on a regular basis to the Department of Epidemiology (currently the Julius Center for General Practice and Patient Oriented Research) regarding the migration and/or mortality of the DOM cohort members. General practitioners provided information from their records, including specialists’ reports. Mortality was coded according to the International Classification of Diseases, Ninth Revision (ICD-9): mortality from myocardial infarction was defined as ICD-9 410 to 414; cerebrovascular mortality, as ICD-9 430 to 439; and other cardiovascular mortality, as all remaining ICD-9 codes between 390 and 460. A total of 1447 women (12.3%) had moved outside the recruitment area and had a median follow-up of 10 years, with a maximum of 18 years; those subjects were withdrawn from the study at the time point that they were lost. The 9062 surviving women had a median follow-up time of 17 years, with a maximum of 18 years. The number of deaths during follow-up (168 513 women-years) totaled 1714: 608 were from cardiovascular disease (ICD-9 390 to 459), 601 were from neoplasms (ICD-9 140 to 239), 299 were from other causes, and 206 were from unknown causes.

Urinary Albumin and Creatinine Measurements
Urinary albumin concentration was determined by a commercial immunoturbidimetry assay with sensitivity of 2.3 mg/L and interassay and intra-assay coefficients of variation of 4.4% and 4.3%, respectively (Dade Behring Diagnostica). Microalbuminuria was defined as the highest quintile of albumin excretion. Urinary creatinine concentration was measured by using a colorimetric assay (Merck). The collection time of overnight urine samples was not registered; therefore, we adjusted all albumin concentrations for creatinine levels. In 658 of the 1118 urine samples, the albumin concentration was below the detection limit. The 460 women with measurable quantities of albumin in their urine were assigned to quintiles, according to their urinary albumin/creatinine ratio.

Data Analysis
Means and proportions of baseline cardiovascular risk factors were computed for subgroups according to urinary albumin/creatinine ratios. Difference in means was tested by ANOVA, whereas differences in proportions were tested by ² statistics.

The nested case-referent approach enabled us to study mortality rates of cardiovascular disease according to urinary albumin/creatinine ratios.^{22 23} Rate ratios were estimated for each quintile in relation to women without albumin in their urine. The control group was a random sample of the total cohort of noncases. Therefore, we could estimate the person-years in the cohort as all person-years of the cases, while giving the person-years of the control group a weight of 18.8 (the inverse of the sampling fraction). Poisson regression was used to estimate mortality rates and risk ratios; 95% CIs were calculated with the method of Huber.²⁴ Similarly, crude relative risks, mortality rates, and rate ratios were estimated for women with myocardial infarction (ICD 410 to 414), cerebrovascular disease (ICD 430 to 438), and other cardiovascular disease (all remaining ICD codes between 390 and 459), separately.

The potential effect of age, history of cardiovascular disease, smoking, obesity, diabetes, and hypertension on the relationship between microalbuminuria and cardiovascular mortality was analyzed in a multivariate model. Effect modification was studied by subgroup analyses on age (above or below the median), obesity (yes/no), diabetes (yes/no), hypertension (yes/no), and smoking (yes/no). The significance of possible effect modification was tested with interaction terms, which were added to the multivariate model containing individual factors.

	Results

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A total of 460 urine samples contained detectable quantities of albumin, whereas the other 658 urine samples did not contain detectable quantities of albumin. The 460 women with detectable quantities of albumin in their urine were assigned to quintiles, and the 658 women without detectable quantities of albumin were defined as not detectable. Age at entry, BMI, and smoking were not associated with urinary albumin levels (Table 1). The percentage of hypertensive patients was higher in women in the highest quintile than it was in women in the lower quintiles and in the not-detectable group. The number of subjects with diabetes mellitus and history of cardiovascular disease was too low to reliably estimate the prevalence in each quintile.

View this table: [in this window] [in a new window]   Table 1. Baseline Measurements According to Subgroups of Urinary Albumin/Creatinine Values

The cardiovascular mortality rate was expressed as the number of cases per 1000 follow-up years. In quintiles 1 through 3, the cardiovascular mortality rate was similar to that in the not-detectable group; the mortality rates were 2.8, 3.3, and 2.9, respectively (Table 2). However, in the fourth and the fifth quintiles, the cardiovascular mortality rates were higher: 4.5 and 13.2, respectively. The rate ratios (95% CI) were 1.8 (1.2 to 2.8) and 4.9 (2.9 to 8.3), respectively (Table 2). The increased risk of cardiovascular disease in relation to increased urinary albumin levels was consistent for myocardial infarction, cerebrovascular mortality, and all other forms of cardiovascular mortality (Table 2). The survival curves of cardiovascular mortality, according to the quintiles of urinary albumin excretion, are shown in the Figure.

View this table: [in this window] [in a new window]   Table 2. Cardiovascular Mortality Rate (Incidence/1000 y) and Rate Ratios According to Urinary Albumin/Creatinine Values

View larger version (13K): [in this window] [in a new window]   Figure 1. Survival curves for cardiovascular mortality in relation to urinary albumin excretion.

Adjustment for age and diabetes attenuated the rate ratios between the fifth quintile and not-detectable group slightly (rate ratio 3.65, 95% CI 2.14 to 6.25; Table 3). Further adjustment for blood pressure, history of cardiovascular disease, smoking, and BMI did not affect the risk estimates.

View this table: [in this window] [in a new window]   Table 3. Cardiovascular Mortality Rate Ratios in Quintiles of Urinary Albumin/Creatinine Values Relative to Nonexcreters and Influence of Age, Diabetes, Hypertension, Smoking, and BMI on Relationship

Subgroup analysis of the relationship between albumin and cardiovascular mortality according to hypertension is presented in Table 4. The age-adjusted risk ratio (95% CI) between the fifth quintile and not-detectable group was 4.3 (2.3 to 8.1) in hypertensive women and 3.3 (1.2 to 8.8) in nonhypertensive women; this difference did not reach statistical significance. There was also no indication for effect modification by smoking, diabetes, obesity, or age.

View this table: [in this window] [in a new window]   Table 4. Cardiovascular Mortality Rate (/1000 y) According to Urinary Albumin Excretion and Hypertension

	Discussion

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We found a relationship between urinary albumin excretion and an increased risk of cardiovascular mortality in postmenopausal women of the general population. The cardiovascular mortality rate (95% CI) for women who were in the highest quintile of the urinary albumin/creatinine ratio was 13.2 (8.1 to 20.9) per 1000 follow-up years compared with 2.6 (2.3 to 3.1) per 1000 follow-up years in women without detectable quantities of urinary albumin.

To appreciate our findings, some characteristics of the present study need to be addressed. Our data were obtained from a large cohort study and, therefore, are not subject to any form of bias that can be introduced by the investigator, because case definition was based on the occurrence of disease during follow-up and because the exposure took place before the cases were defined. The prospective collection of urine samples enabled us to investigate cardiovascular mortality, whereas conventional case-control studies commonly rely on retrospectively collected data and, therefore, are limited to morbidity or to intermediate markers of disease.

It should be noted that the present study was conducted among nonhospitalized subjects, and data on cardiovascular end points were obtained from hospital records or general practitioner diagnosis. We expect a certain degree of misclassification of cardiovascular end points. Because this misclassification is not expected to be related to the albumin excretion at baseline, it will be random misclassification. In general, this will only lead to a dilution of the risk estimates toward the null.

A disadvantage of conventional full-cohort analysis is the large number of biological samples to be screened on biomarkers. This was solved by adopting a nested case-control approach: urine samples of all 549 women who died of cardiovascular disease were analyzed together with samples of 569 women who did not die of cardiovascular disease who were selected at random from the remainder of the cohort. Nested case-control analysis takes full advantage of a cohort study, but it has the efficiency of a case-control study.^{21 22} A potential disadvantage of nested case-control analysis compared with full-cohort analysis is that some power may be lost to measure a weak relationship between rare determinants.

Albumin levels were determined in urine samples after 20 years of storage at -20°C. It should be considered that absolute urinary albumin levels may decline during freezer storage.^{25 26 27 28} However, it is not expected that freezer storage will have major consequences for ranking into quintiles, and it is very unlikely that freezer instability of albumin could induce a relationship between urinary albumin excretion and cardiovascular mortality. If anything, freezer instability of albumin may lead to a certain degree of misclassification into the quintiles, which may attenuate the risk ratios.

However, freezer storage might explain why the number of samples in which albumin was not detectable was slightly higher than that expected in fresh samples. As a consequence, the absolute urinary albumin values in the whole population may be lower than those expected from albumin measurements in fresh urine samples. In addition, some women with traces of albumin in their urine may have been classified in the not-detectable group because their urinary albumin levels had decreased to below the detection limit because of storage; therefore, our risk ratios may provide an underestimation of true risk ratios. We do not expect selection bias by our measurements because there was no difference in storage and handling conditions between urine samples of cases and the rest of the cohort, and ranking is expected to be preserved. Observer bias was excluded by coding the urine samples and blinding the investigator to case or control status.

Blood pressure was measured at baseline for the entire cohort according to a standardized protocol. Diastolic and systolic blood pressure measurements were not higher than those expected from this elderly population. The high prevalence of hypertension may partly be due to conventional cutoff values for systolic and diastolic blood pressure in the definition of hypertension.

Our findings of a relationship between microalbuminuria and cardiovascular mortality in normal subjects support the view that microalbuminuria is a reflection of cardiovascular disease not only in diabetic and/or hypertensive subjects but also in postmenopausal women from the general population. This is further illustrated by our findings that stratification according to hypertension (yes/no) and diabetes (yes/no) had no influence on the relative risk between urinary albumin excreters and the not-detectable group.

This is the first large cohort study on the relationship between urinary albumin levels and cardiovascular mortality in postmenopausal women. Our findings confirm the findings of some small studies on microalbuminuria and cardiovascular disease incidence and fit in the hypothesis that microalbuminuria is an important marker of early generalized arterial dysfunction.^{16 17 18 19} Microalbuminuria may be used as an intermediate point of subclinical arterial damage. Further studies on the pathophysiological mechanism linking microalbuminuria to cardiovascular disease are indicated.

	Acknowledgments

 
This study was supported by the Netherlands Heart foundation (NHS 96-165).

Received December 29, 2000; revision received March 30, 2001; accepted April 5, 2001.

	References

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				M. J. Sarnak, A. S. Levey, A. C. Schoolwerth, J. Coresh, B. Culleton, L. L. Hamm, P. A. McCullough, B. L. Kasiske, E. Kelepouris, M. J. Klag, et al. Kidney Disease as a Risk Factor for Development of Cardiovascular Disease: A Statement From the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention Circulation, October 28, 2003; 108(17): 2154 - 2169. [Full Text] [PDF]

				M. A. Murtaugh, D. R. Jacobs Jr., X. Yu, M. D. Gross, and M. Steffes Correlates of Urinary Albumin Excretion in Young Adult Blacks and Whites: The Coronary Artery Risk Development in Young Adults Study Am. J. Epidemiol., October 1, 2003; 158(7): 676 - 686. [Abstract] [Full Text] [PDF]

				S. P. McDonald, G. P. Maguire, and W. E. Hoy Renal function and cardiovascular risk markers in a remote Australian Aboriginal community Nephrol. Dial. Transplant., August 1, 2003; 18(8): 1555 - 1561. [Abstract] [Full Text] [PDF]

				J. E. Liu, D. C. Robbins, V. Palmieri, J. N. Bella, M. J. Roman, R. Fabsitz, B. V. Howard, T. K. Welty, E. T. Lee, and R. B. Devereux Association of albuminuria with systolic and diastolic left ventricular dysfunction in type 2 diabetes: The Strong Heart Study J. Am. Coll. Cardiol., June 4, 2003; 41(11): 2022 - 2028. [Abstract] [Full Text] [PDF]

				F. C. Luft Pre-eclampsia and the maternal cardiovascular risk Nephrol. Dial. Transplant., May 1, 2003; 18(5): 860 - 861. [Full Text] [PDF]

				H. L. Hillege, V. Fidler, G. F.H. Diercks, W. H. van Gilst, D. de Zeeuw, D. J. van Veldhuisen, R. O.B. Gans, W. M.T. Janssen, D. E. Grobbee, P. E. de Jong, et al. Urinary Albumin Excretion Predicts Cardiovascular and Noncardiovascular Mortality in General Population Circulation, October 1, 2002; 106(14): 1777 - 1782. [Abstract] [Full Text] [PDF]

				J. Redon, E. Rovira, A. Miralles, R. Julve, and J. M. Pascual Factors Related to the Occurrence of Microalbuminuria During Antihypertensive Treatment in Essential Hypertension Hypertension, March 1, 2002; 39(3): 794 - 798. [Abstract] [Full Text] [PDF]

R. Pedrinelli, G. Dell'Omo, G. Penno, and M. Mariani Non-diabetic microalbuminuria, endothelial dysfunction and cardiovascular disease Vascular Medicine, November 1, 2001; 6(4): 257 - 264. [Abstract] [PDF]