1 Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.
2 Dunn Human Nutrition Unit, Medical Research Council, Cambridge, United Kingdom.
Received for publication June 2, 2003; accepted for publication July 31, 2003.
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ABSTRACT |
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albuminuria; cardiovascular diseases; coronary disease; diabetes mellitus; hypertension; proteinuria; risk factors
Abbreviations: Abbreviations: CHD, coronary heart disease; CI, confidence interval; EPIC, European Prospective Investigation into Cancer and Nutrition.
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INTRODUCTION |
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Microalbuminuria is associated with an increased risk of cardiovascular and renal disease in patients with diabetes mellitus (3, 4) and hypertension (5, 6). Although the role microalbuminuria plays in the general population is less well known, studies have shown that it is independently associated with prevalent cardiovascular disease in the general population (7, 8) and that it predicts all-cause and cardiovascular disease mortality in the general population and in nondiabetic persons (7, 912). Although the significance of albuminuria as a possible predictor of CHD in persons without diabetes has been suggested (1315), there has not been a report from a large population-based cohort study of albuminuria and incident CHD. The prognostic significance of albuminuria in persons with baseline CHD in the general population is also unknown. Therefore, we undertook this study to examine the etiologic significance of microalbuminuria for incident primary CHD and its prognostic significance among persons with established CHD in a British population.
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MATERIALS AND METHODS |
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Recruitment into EPIC-Norfolk began in March 1993 and was completed at the end of 1997. Participants were followed until March 31, 2002. Male and female residents of Norfolk aged 4079 years were recruited using general-practice age-sex registers. Of the 77,630 mailed invitations, 30,447 persons consented to participate and completed a detailed baseline health and lifestyle questionnaire, and 25,633 underwent a health examination conducted by trained nurses using a standard protocol. A random spot urine sample was collected during the clinic visit, and urinary albumin:creatinine ratio was later determined.
A total of 25,112 persons who completed the health and lifestyle questionnaire, were examined by the nurses, and had their albumin:creatinine ratio calculated constituted our study population. We excluded participants with dipstick hematuria or leukocyturia (n = 1,148); this left 23,964 participants for our analyses. Of these, 1,596 persons had a baseline history of CHD and were used for prognostic analyses, while the remaining 22,368 persons without baseline CHD (12,216 women and 10,152 men) constituted the study population for incident primary CHD events. Ethical approval for this study was obtained from the Norwich District Ethics Committee.
Study design
Information on smoking status, prevalent physician-diagnosed diabetes, hypertension treatment, hyperlipidemia, CHD, and family history of CHD was obtained from a baseline health and lifestyle questionnaire that contained a section of the Rose angina questionnaire (17). Body mass index was calculated as weight in kilograms divided by height in meters squared, with height measured using a free-standing stadiometer and weight measured using digital scales (Salter, Tonbridge, United Kingdom). Blood pressure was measured using an Accutorr sphygmomanometer (Datascope Medical Company Ltd., Huntingdon, United Kingdom). Hypertension was defined as physician-diagnosed hypertension, systolic blood pressure 140 mmHg, or diastolic blood pressure
90 mmHg.
Nonfasting serum total cholesterol, high density lipoprotein cholesterol, and triglyceride levels were measured with an RA 1,000 Technicon analyzer (Bayer Diagnostics, Basingstoke, United Kingdom), and low density lipoprotein cholesterol level was calculated using the Friedewald formula (18). Dyslipidemia was defined as baseline treatment for hypercholesterolemia or a total cholesterol level 6.2 mmol/liter. Urinary albumin concentration (mg/liter) was measured by immunonephelometry (19) using the Dade Behring Nephelometer II analyzer (Dade Behring Ltd., Milton Keynes, United Kingdom). Urinary creatinine concentration (mmol/liter) was measured by colorimetry (20) using the Dade-Behring Dimension AR analyzer (Dade Behring Ltd.). Urinary albumin:creatinine ratio (mg/mmol) was calculated. The use of urinary albumin:creatinine ratio (in random spot urine collection) as a measure of albuminuria has been validated against the "gold standard" of urinary albumin excretion rate measured in timed urine collections. In these studies, the correlation between the two methods has ranged from 0.81 to 0.99 (2125). The sensitivity for detection of albuminuria has ranged from 77 percent to 100 percent, with specificity ranging from 80 percent to 100 percent. Dipstick urinalysis was undertaken with the Multistix (Bayer Corporation, Newbury, United Kingdom) to detect hematuria and leukocyturia.
Endpoints
We identified incident fatal and nonfatal CHD events occurring between baseline and follow-up through March 31, 2002. Data on fatal endpoints were obtained from the Office for National Statistics. Data on nonfatal events were obtained from the National Health Service health district database of all hospital admissions for EPIC participants, using record linkage with the EPIC-Norfolk database. For these analyses, fatal CHD events were defined as deaths with an underlying cause of death coded 410414 according to the International Classification of Diseases, Ninth Revision, or coded I20I25 according to the International Classification of Diseases, Tenth Revision. For nonfatal events, we used the hospital codes for CHD hospital admissions, which were clinically defined by the attending consultant.
Statistical analyses
Normoalbuminuria was defined as an albumin:creatinine ratio less than 2.5 mg/mmol, microalbuminuria as an albumin:creatinine ratio of 2.525 mg/mmol, and macroalbuminuria (proteinuria) as an albumin:creatinine ratio greater than 25 mg/mmol (26). Persons with normoalbuminuria were further divided into tertiles, giving us five ordered categories of albuminuria. The normoalbuminuric population was not neatly divisible into tertiles because of the large numbers within each 0.1-mg/mmol increment of albumin:creatinine ratio. Testing for linear trends in continuous and categorical data across ordered categories of albuminuria was conducted by means of the nonparametric Cusick test and the 2 test for trend with 1 df, respectively. Multivariate Cox regression analysis was used to determine the relation between CHD and albuminuria. Data on albumin:creatinine ratio were log-transformed to base 2 before we conducted any analyses involving the use of albumin:creatinine ratio as a continuous variable, because the distribution of values for the ratio was highly positively skewed. Kaplan-Meier estimates of survival for the three major categories of albuminuria were compared by means of the
2 test for CHD survival trend. Statistical analyses were undertaken with Stata for Windows, version 7.0 (Stata Corporation, College Station, Texas), and GENSTAT 5 (Numerical Algorithms Group, Oxford, United Kingdom).
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RESULTS |
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Recurrent CHD events and prognostic significance of microalbuminuria
In the 1,596 participants who were excluded from the original analysis because they had baseline CHD, microalbuminuria and proteinuria independently predicted secondary coronary events, with hazard ratios of 1.40 (95 percent CI: 1.13, 1.74) and 1.84 (95 percent CI: 1.16, 2.92), respectively, in men and women combined. There were 604 recurrent events altogether among participants with a baseline history of CHD, with an incidence of 65.8 per 1,000 person-years in all men and women. Therefore, the absolute risk of recurrent CHD events was very high in this group. To investigate the prognostic significance of albuminuria in the group with baseline CHD events, we calculated the multivariate adjusted hazard ratios for total mortality at follow-up and found them to be 1.61 (95 percent CI: 1.19, 2.07) for microalbuminuria and 1.73 (95 percent CI: 1.20, 2.81) for macroalbuminuria.
CHD-free survival
Figure 2 shows the Kaplan-Meier CHD-free survival curves by category of baseline albuminuria in women and men. There was a significant decreasing trend in CHD-free survival with increasing albuminuria in men and women (p for trend < 0.001).
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DISCUSSION |
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In the EPIC-Norfolk Study, only single random spot urine collections were made at baseline. Given the considerable day-to-day intraindividual variation in urinary albumin excretion when repeated measurements are made (28), it is possible that there might have been random misclassification in the different albuminuria categories. Collected urine specimens in the EPIC-Norfolk Study were stored at 20°C for 48 years before albumin and creatinine were assayed. Some studies have suggested that measurement of albumin concentration in frozen urine samples after long-term storage at 20°C results in underestimation of actual albumin values in comparison with storage at 4°C for up to 12 weeks prior to measurement or long-term storage at 70°C, and therefore limits the ability to diagnose borderline cases of microalbuminuria and macroalbuminuria (29). However, a few studies have found no difference (30). These random measurement errors in characterizing urinary albumin in an individual would tend to lead to regression dilution bias and underestimation of the size of the association between microalbuminuria and CHD incidence.
CHD was ascertained using death certification and hospital admission data, and it is possible that we may have missed nonfatal CHD events, including unrecognized (silent or atypical) myocardial infarction occurring in the community and not resulting in hospital admission. However, it is very unlikely that there was any systematic difference in the accession of CHD events occurring in the community with respect to albuminuria status.
The EPIC-Norfolk Study was designed as a prospective study, which required persons who were willing to participate and be followed up over the long term rather than a representative population sample. Nevertheless, comparison of the EPIC-Norfolk population with the population of the Health Survey for England suggests that this cohort was similar to the general population of England in terms of anthropometric measures, blood pressure, and serum lipid levels, though with fewer current smokers than the general population (16).
We did not measure blood glucose in this study, and cases of diabetes were defined according to clinical criteria using multiple sources of ascertainment. It is possible that persons with undiagnosed but biochemically prevalent diabetes would have been misclassified, given that approximately half of those with type 2 diabetes are undiagnosed in the general population (31). Therefore, residual confounding by diabetes is possible.
The prevalence of microalbuminuria was higher among women than among men in EPIC-Norfolk. This may be explained by the fact that urinary creatinine levels are higher in men than in women (32, 33), and therefore the albumin:creatinine ratio may be higher in women than in men with similar urinary albumin concentrations (26, 34). Because of this, it has been suggested that a higher threshold cutoff point (3.5 mg/mmol) be used to define microalbuminuria in women instead of 2.5 mg/mmol (26, 35). If women with normoalbuminuria were misclassified as having microalbuminuria because of the use of a lower cutpoint (2.5 mg/mmol instead of 3.5 mg/mmol), we would expect the hazard ratios for CHD in women to be biased towards the null. In EPIC-Norfolk, sex was not an effect modifier of the association between albuminuria and CHD.
Microalbuminuria is an independent predictor of all-cause mortality and cardiovascular disease endpoints in patients with diabetes (3, 4) and hypertension (5, 6). The possible predictive role of microalbuminuria in the general population, especially with regard to CHD, has not been well examined. Cross-sectional and case-control studies in the general population have found that microalbuminuria is independently associated with prevalent cardiovascular disease (8). Cross-sectional and case-control studies suffer from many potential biases, including biases associated with prevalent disease and their inability to define a temporal relation between an exposure and an outcome, as well as bias in selection of cases and controls. Investigators in prospective studies have observed that microalbuminuria predicts all-cause and cardiovascular disease mortality in the general population or in nondiabetic or elderly persons (7, 912). However, most of these studies either had small sample sizes (7, 9, 11), were conducted among persons with prevalent cardiovascular disease or at high risk of cardiovascular disease (10), or were limited by a high potential for residual confounding from inadequately measured covariates (12). Although the significance of microalbuminuria as a possible predictor of CHD in persons without diabetes has been suggested (1315), there has not been a report from a large general-population cohort study of microalbuminuria and incident CHD. For example, it has recently been suggested that an albumin:creatinine ratio above the 90th percentile of the distribution (>0.65 mg/mmol) predicts CHD in the Danish component of the MONICA Study, a population-based study of nondiabetic persons (13). This observation, which is consistent with the findings of an earlier population-based study of elderly nondiabetic persons in Kuopio, Finland (14), and a nested case-control analysis of postmenopausal women in the DOM Study, the Netherlands (15), underlines the significant role urinary albumin excretion might play in the estimation of CHD risk in the community. However, the use of nonconventional cutpoints for the definition of microalbuminuria in those studies limits the direct application of those findings in clinical settings. Depending on the units used, consensus conferences (26, 36) have defined microalbuminuria as a urinary albumin excretion rate 20 µg/minute and <200 µg/minute in timed urine collection; a urinary albumin:creatinine ratio
2.5 mg/mmol and <25 mg/mmol in spot urine collection; a 24-hour urinary albumin excretion rate
30 mg/24 hours and <300 mg/24 hours; or a urinary albumin concentration
30 mg/liter and <300 mg/liter. However, some authors have argued that this definition is too diabetes-focused and that cutpoints for nondiabetic persons should be lower, given the extension of cardiovascular disease risk down to high-normal levels of albuminuria (6, 10, 13). Therefore, to our knowledge, the EPIC-Norfolk Study is the first large study to have examined the predictive effect of microalbuminuria on incident CHD in the general population using the standard definition of microalbuminuria and including sex-stratified and subgroup analyses of other risk factors. In our data, the risk of CHD appeared to increase even below levels considered cutpoints for microalbuminuria, as has been observed by others (10).
The prognostic significance of microalbuminuria for early mortality after acute myocardial infarction in clinic-based patients has been demonstrated (27). Investigators in the HOPE Study made a similar observation in the general population (10), and the finding in EPIC-Norfolk that albuminuria is predictive of both recurrent CHD events and total mortality among persons with baseline CHD in the community adds to this. Randomized placebo-controlled trials such as the HOPE Study and the MicroHOPE substudy have shown that treatment of persons with baseline cardiovascular disease or persons at significant absolute risk of cardiovascular disease, based on a constellation of risk factors including microalbuminuria, offers significant primary and secondary prevention against cardiovascular disease (37, 38).
The underlying mechanism of the association between microalbuminuria and cardiovascular disease risk is unclear. A pathophysiologic link between microalbuminuria and atherosclerosis may be mediated through an increased generalized transvascular leakage of albumin. It is hypothesized that the systemic transvascular leakiness may also include lipoproteins, thus allowing for increased lipid penetration into the vessel walls (39). The leakiness might be due to hemodynamic factors or structural or functional perturbations of the endothelium or the intracellular matrix beneath (39).
In subgroup analyses of established cardiovascular disease risk factors, the CHD risk associated with microalbuminuria was highest among persons with established cardiovascular disease risk factors (sex, diabetes, hypertension, smoking, and dyslipidemia) in comparison with those without them, although there were non-statistically-significant interactions. Besides age and sex, the strongest correlates of microalbuminuria in the general population are hypertension, diabetes, and smoking (40). Regardless of whether microalbuminuria is a sensitive indicator of damage resulting from other CHD risk factors, our results suggest that microalbuminuria might be useful for identifying persons at increased risk of CHD who might benefit the most from treatment. However, given the low sensitivity and low positive predictive value of combined microalbuminuria and macroalbuminuria for CHD risk, albuminuria cannot be used in isolation to identify persons at increased risk. Development of new scores for prediction of absolute risk of primary CHD events along the lines of the Framingham Score (41), with the inclusion of microalbuminuria as one of the easily measured risk factors, might have clinical utility. Multiple-risk-factor assessment equations for primary prevention of CHD in the general population have been developed (41, 42), and it has been proposed that microalbuminuria status be included in these absolute risk equations among diabetic persons (43). Recently, in the Steno Diabetes Centre, it was shown that multifactorial intervention, including behavior modification and pharmacologic therapy that targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria in patients with diabetes and microalbuminuria, significantly lowered the risk of cardiovascular disease by more than 50 percent (44).
In this British population, the incidence of CHD increased significantly across categories of albuminuria, with microalbuminuria being independently associated with an approximately 40 percent increased risk of CHD in comparison with normoalbuminuria. Therefore, microalbuminuria may be a useful indicator, in addition to conventional risk factors such as smoking, dyslipidemia, hypertension, and diabetes, in identifying persons in the community who are at increased risk of primary CHD and subsequent mortality.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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