Abstract
Objectives. Microalbuminuria as an independent marker of cardiovascular morbidity and mortality in hypertensive individuals is under debate. The aim of this study was to study the possible associations between microalbuminuria on one hand and known cardiovascular risk factors and cardiovascular disease on the other hand, in a large, unselected population of treated hypertensives without diabetes. Design. Cross-sectional study. Setting. Participants of the HUNT Study, Norway (n = 65,258). Subjects. 5,369 individuals (≥20 years) with treated hypertension delivered three morning urine samples for microalbuminuria analysis. Main outcome measures. Microalbuminuria expressed as albumin-to-creatinine ratio, cardiovascular risk factors and cardiovascular disease. Results. Increasing age, pulse pressure (systolic blood pressure–diastolic blood pressure), s-creatinine, cigarette pack years, cardiovascular disease, antihypertensive medication group, and years with antihypertensive medication were significantly associated with microalbuminuria in men. Increasing pulse pressure, cigarette pack years, and antihypertensive medication group were associated with microalbuminuria in women, adjusted for other cardiovascular risk factors. When excluding individuals of both sexes with self-reported cardiovascular disease and blood pressure > 160/90 mm Hg, no variable associated with cardiovascular risk factors registered was statistically associated with microalbuminuria. Conclusion. The present study indicates that microalbuminuria mainly represents a mirror image of hypertension (BP > 160/90) and prior or present cardiovascular disease. We therefore question whether the treatment quality would improve if yet another risk factor, microalbuminuria, were introduced as a routine test in treated hypertensives.
Introduction
Microalbuminuria is usually defined as a urinary excretion rate of albumin between 20 and 200 µg/min. Microalbuminuria is a well-known predictor of cardiovascular morbidity, mortality, and progressive renal failure in diabetic patients Citation[1], Citation[2], and in a Swedish study of diabetic and non-diabetic hypertensives, Bog-Hansen et al. Citation[3] found that the overall mortality in men was predicted by microalbuminuria. Non-diabetic individuals with microalbuminuria have increased levels of atherogenetic risk factors and increased risk of cardiovascular disease Citation[4–7]. In non-diabetic patients with essential hypertension, microalbuminuria predicts cardiovascular events, target organ damage and early renal damage Citation[8], Citation[9]. In some cross-sectional studies in non-diabetic untreated hypertensive individuals, association between microalbuminuria and cardiovascular risk factors has been found Citation[10], Citation[11]. Most studies in non-diabetic individuals are, however, performed in rather small, untreated samples with essential hypertension Citation[9], Citation[12–14], and studies in treated hypertensives also include only relatively small samples Citation[15], Citation[16]. To our knowledge, no previous microalbuminuria study among large unselected populations of treated hypertensive patients exists.
Microalbuminuria as an independent marker of cardiovascular morbidity in hypertensive patients is under debate.
In high-risk patients (high blood pressure, high cholesterol, smoking, cardiovascular disease) microalbuminuria was clearly associated with cardiovascular risk factors.
In low-risk patients, however, no cardiovascular risk factors registered were statistically associated with microalbuminuria.
GPs can easily identify high-risk patients without measuring microalbuminuria.
The authors therefore question whether the treatment quality would improve if microalbuminuria were introduced as a routine test in treated hypertensives in primary healthcare.
In contrast to previous editions, recent guidelines recommend microalbuminuria monitoring in hypertensive patients Citation[17]. The aim of the present study was therefore to study the possible associations between microalbuminuria on one hand and known cardiovascular risk factors and disease on the other hand, in a large, unselected group of treated non-diabetic hypertensive patients of both sexes in a wide age range. We especially wanted to study which additional information microalbuminuria could provide in monitoring this group of patients.
Material and methods
A health survey was conducted in Nord-Trøndelag County, Norway, during 1995–97. All residents in the county aged ≥ 20 years were invited, and a total of 65,258 (70.4%) participated Citation[18]. The present study was limited to the non-diabetic participants who answered “yes” to the question: “Do you take antihypertensive medication now?” Three consecutive first-morning urine samples for microalbuminuria analyses were delivered by 5755 participants (response rate: 89.4%). The participants who answered “yes” to one or more questions about urinary tract infection in the previous week, persistent haematuria in the previous year or menstruation at collection time, individuals with non-fasting serum (s)-glucose > 11.1 mmol/l, individuals with macroalbuminuria (albumin-to-creatinine ratio > 30 mg/mmol), and three with missing registrations were excluded, leaving a total of 2307 men and 3062 women for the final analyses. Details of the microalbuminuria study have been published previously Citation[19].
Clinical examination
The clinical examination included standardized measurements of height, weight, and blood pressure (diastolic and systolic). After a minimum of two minutes’ rest, three sitting consecutive standardized blood pressure measurements were recorded at one-minute intervals. The measurements were performed using an automatic oscillometric method (Dinamap 845XT; ®Criticon, Tampa, FL, US).
Urine sampling
The microalbuminuria screening participants received a unit containing three plastic receptacles for three first-morning urine samples, three transport tubes, and a pre-stamped envelope for mailing back to the laboratory. The unit also contained written instructions on how to collect urine samples and a questionnaire concerning urinary tract infection the week before urine collections, persistent haematuria in the last year and menstruation at the time of collection.
Blood sampling, laboratory procedures
Blood sampling was non-fasting. Urine albumin and creatinine were measured by an immunoturbidimetric method Citation[20] (anti-human serum albumin from Dako Norway, Oslo) and Jaffé method Citation[21] respectively. In this paper, urinary albumin excretion is expressed as albumin-to-creatinine ratio Citation[22]. Details of laboratory methods have been published previously Citation[19].
Statistical analysis
In this study, microalbuminuria is defined as albumin-to-creatinine ratio ≥ 2.5 mg/mmol. Systolic and diastolic blood pressure and pulse pressure (systolic blood pressure–diastolic blood pressure) were calculated as the mean of the second and third of three measurements. Body mass index (BMI) was defined as weight in kilograms divided by height in metres squared. Cigarette pack years were calculated as the product of number of cigarettes smoked daily and the number of years of daily smoking divided by 20. Pearson's chi-squared test was used when comparing prevalences.
In the general linear model analyses, data for men and women were analysed separately, because of multiple interactions between the sex variable and the other independent variables. To achieve normal distributed residuals, the urine albumin-to-creatinine ratio variable was log (ln-)-transformed. All statistical analyses were performed using SPSS, version 11.01.
Consent
Attendance was voluntary, and each participant signed a written consent. The HUNT Study was approved by the Norwegian Data Inspectorate and recommended by the Regional Committee for Ethics in Medical Research.
Results
A larger proportion of women than men were treated for hypertension and they had a higher prevalence of blood pressure > 140/90 mmHg (). Women had higher mean age, systolic blood pressure, pulse pressure, years of antihypertensive medication, BMI, total cholesterol, HDL, and triclycerides than men. Men had higher mean urine albumin-to-creatinine ratio, diastolic blood pressure, waist–hip ratio, cigarette pack years, total cholesterol/HDL ratio, and s-creatinine than women.
Table I. Cardiovascular risk factors and disease in men and women with treated hypertension in the Nord-Trøndelag Health Study (HUNT). Values are mean of all in sex, and standard deviation (SD) unless otherwise indicated.
The prevalence of urine albumin-to-creatinine ratio ≥ 2.5 mg/mmol increased with age in both sexes (), in men from the youngest age group and in women from the age group 50–59. In the age groups under 60 there were no sex differences, but in the two oldest age groups (60–69 and 70 + ) the prevalences were higher in men than in women. In men with blood pressure > 160/90 mmHg, the prevalence was 20.2%, compared with 12.4% in those with blood pressure ≤ 160/90 mmHg. In women the corresponding prevalences were 14.8% and 7.8% (). After further exclusion of individuals with cardiovascular diseases, the prevalence was reduced by only 0.4% in women and 1.4% in men (calculated from ).
Table II. Prevalence (%) of microalbuminuria (albumin–creatinine ratio > 2.5 mg mmol−1, mean of three samples) in treated hypertensives, by sex and age groups.
Mean urine albumin-to-creatinine ratio was higher in men than in women, and increased with increasing age, pulse pressure, years of antihypertensive medication, blood pressure > 140/90 mmHg, blood pressure > 160/90 mmHg, cardiovascular disease, and daily smoking in both sexes (). Mean urine albumin-to-creatinine ratio also increased significantly with increasing cigarette pack years, and was especially high in the highest cigarette pack year quartile. In women mean urine albumin-to-creatinine ratio was significantly higher in the fourth quartile of cholesterol/HDL ratio compared with the first quartile, but in men there was no significant difference. Mean urine albumin-to-creatinine ratio showed a U-shaped association with BMI in both sexes, with lowest level of urine albumin-to-creatinine ratio in the second and third quartile. In both sexes mean urine albumin-to-creatinine ratio was significantly higher in the highest quartile of s-creatinine compared with the lowest quartile. In women mean urine albumin-to-creatinine ratio decreased with increasing level of education, but in men there was a U-shaped association between mean urine albumin-to-creatinine ratio and levels of education.
Table III. Sex differences in mean urine albumin–creatinine ratio (95% CI) by various age groups. Sex specific quartiles and no/yes groups.
In total, 59.0% reported single antihypertensive drug treatment (). Beta-blocking agents and calcium-channel-blocking agents were the most often used single drugs (16.9% and 16.0% respectively), while only 9.0% used diuretics as single drug.
Table IV. HUNT 2: Self reported antihypertensive medication group (ATC code): Mean urine albumin–creatinine ratio.
When applying a general linear model with ln transformed (ln-) urine-albumin-to-creatinine ratio as the dependent variable and antihypertensive medication group as the fixed factor, the population was subdivided into four categories according to assumed cardiovascular risk: (1) all in the sex (men/women), (2) blood pressure ≤ 160/90 mm Hg, (3) without cardiovascular disease, and (4) blood pressure ≤ 160/90 mmHg and without cardiovascular disease. In men () ln-urine-albumin-to-creatinine ratio was positively associated with age, s-creatinine, pulse pressure, cigarette pack years, cardiovascular disease, years of antihypertensive medication, and antihypertensive medication group. In category 2, ln-urine-albumin-to-creatinine ratio was positively associated with BMI in addition to age and cardiovascular disease, and in category 3, ln-urine-albumin-to-creatinine ratio was positively associated with pulse pressure, s-creatinine, and antihypertensive medication group. In the low risk group (category 4), ln-urine-albumin-to-creatinine ratio was not significantly associated with any independent variable. In women () in category 1, ln-urine-albumin-to-creatinine ratio was positively associated with cigarette pack years and pulse pressure. There was also a positive association with antihypertensive medication group in categories 1 and 2 (blood pressure ≤ 160/90, with cardiovascular disease). In the low-risk group (category 4), ln-urine-albumin-to-creatinine ratio was not significantly associated with any independent variable.
Table Va. General linear model with ln urine–albumin–creatinine ratio (mg mmol−1) as the dependent variable.
Table Vb. General linear model with ln urine–albumin–creatinine ratio (mg mmol−1) as the dependent variable.
Discussion
The main finding in this study of the large population of treated hypertensive individuals was that the association between microalbuminuria on one hand and cardiovascular risk factors on the other was obvious in high-risk patients (high blood pressure, high cholesterol, smoking, cardiovascular disease), but was not present in low-risk patients.
Another finding was that the prevalence of microalbuminuria increased with age in both sexes. Due to various definitions of microalbuminuria, different blood pressure cut-offs and different age groups, comparisons with other studies are difficult. Cuspidi et al. Citation[15] reported a prevalence of 5.1% in individuals (mean age 53 years) with blood pressure ≤ 140/90 mm Hg, compared with 9.1% in the similar blood pressure group in the present study (at mean age 62 years). As demonstrated in studies of other hypertensive samples Citation[23], Citation[24], the present treated hypertensive population also had poor blood pressure control, indicating an unfavourable cardiovascular risk profile.
In these data the sex differences were obvious. In univariate analysis (see ) all registered variables except non-fasting s-glucose showed significant sex difference. Similar sex-specific prevalences have been reported from other studies of essential hypertensives Citation[11] and in general populations Citation[25].
Microalbuminuria was associated with cardiovascular disease and a number of cardiovascular risk factors routinely monitored in hypertensive patients. When restricting the groups into individuals with lower blood pressure and lower cardiovascular risk (blood pressure ≤ 160/90 and no cardiovascular disease), the association with microalbuminuria vanished in both sexes, indicating that microalbuminuria was mainly associated with the cardiovascular risk.
In women, the bivariate significance of cardiovascular disease was eliminated by age (data not shown), when the general linear model was applied, indicating that there was no association between microalbuminuria and cardiovascular disease when adjusting for age. In men, cardiovascular disease and age were independently associated with microalbuminuria (in groups with cardiovascular disease). This is in accordance with other studies Citation[10], Citation[19], Citation[26].
Antihypertensive medication group was independently associated with microalbuminuria in men with blood pressure > 160/90 mmHg, with and without cardiovascular disease (see ). A similar association occurred in women with cardiovascular disease included (see ). However, due to the study design we cannot conclude on cause–effect relationships between specific drugs and microalbuminuria.
A strength of this study is the large unselected population of treated hypertensive patients recruited from a general health survey with a high participation rate. Another strength is the standardized measurements. When measuring microalbuminuria, 24 h urine collection is usually regarded as the gold standard. In population health surveys, however, morning spot urine albumin-to-creatinine ratio is considered sufficient Citation[22], Citation[27]. To compensate for day-to-day variation, the mean of three morning samples was used. One limitation of the study is that the cross-sectional design does not allow assumptions of cause and effect relations.
Previous clinical guidelines did not recommend microalbuminuria as a routine test in hypertensive patients. Recent guidelines, however Citation[26], Citation[28], Citation[29], advocate that microalbuminuria should be a routine test in hypertensive patients. The 2003 European Society of Hypertension – European Society of Cardiology guidelines for the management of arterial hypertension Citation[17] also include microalbuminuria as a recommended test. When monitoring an unselected hypertensive population with relatively poorly controlled blood pressure Citation[30], as in the present study, it is necessary to ask what additional information the routine microalbuminuria measurement could provide to achieve adequate cardiovascular risk control. In studies investigating the obstacles to high-quality treatment in general practice Citation[31], clinical guidelines have demonstrated a sparse impact. A number of factors may explain this, such as doctors’ lack of time and insufficient training, poor patient compliance, and patients’ autonomy Citation[31], Citation[32]. Routinely, blood pressure, lipids, and cardiovascular disease occurrence are monitored in these patients, and it is reasonable to assume that physicians are fully aware of the poor compliance with international clinical guidelines without measuring microalbuminuria. We therefore question whether the treatment quality would improve if yet another risk factor, microalbuminuria, were introduced as a routine test. Before microalbuminuria is fully included in clinical guidelines for hypertension, the poor compliance with international clinical guidelines should be properly addressed.
Conclusions
The present study indicates that microalbuminuria mainly represents a mirror image of hypertension (BP > 160/90) and prior or present cardiovascular disease. We therefore question whether the treatment quality would improve if yet another risk factor, microalbuminuria, were introduced as a routine test in treated hypertensives.
The Nord-Trøndelag Health Study (The HUNT Study) is a collaboration between the HUNT Research Centre, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Verdal, Norwegian Institute of Public Health, Nord-Trøndelag County Council and the Nord-Trøndelag Hospital Trust. The Microalbuminuria Study was financially supported by the National Health Association, Norway and MSD. The present study was supported by a scholarship from the Faculty of Medicine, Norwegian University of Science and Technology and the Mid-Norway Hospital Trust. The authors especially thank the municipality health service and the people of Nord-Trøndelag County for their endurance and participation.
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