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(Hypertension. 1997;30:1135-1143.)
© 1997 American Heart Association, Inc.
Articles |
Prevalence and Clinical Correlates of Microalbuminuria in Essential Hypertension
The MAGIC Study
From the Department of Internal Medicine (R.P., A.S., M.R., C.N., F.V., A.T., N.R., C.T., G.D.) and the Institute of General Pathology (G.S.), University of Genoa; and the Division of Medicine, Galliera (C.C.) and S. Martino (G.G.) Hospitals, Genoa, Italy.
Correspondence to Giacomo Deferrari, MD, Department of Internal Medicine, University of Genoa, Viale Benedetto XV, 6-16132 Genoa, Italy. E-mail dimi-dir{at}unige.it
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionAppendix 1References |
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Abstract The prevalence of microalbuminuria and its relationship with several cardiovascular risk factors and target organ damage were evaluated in a cohort of 787 untreated patients with essential hypertension. Albuminuria was measured as the albumin-to-creatinine ratio in three nonconsecutive, first morning urine samples. The prevalence of microalbuminuria was 6.7%. Albuminuric patients were more likely to be men and to be characterized by higher blood pressure, body mass index, and uric acid levels and lower HDL cholesterol and HDL cholesterol-to-LDL cholesterol ratio. Piecewise linear regression analysis demonstrated that uric acid and diastolic blood pressure significantly influence albuminuria and together account for a large part of its variations. K-means cluster analysis performed on the entire cohort of patients confirmed that microalbuminuria is associated with a worse cardiovascular risk profile. Furthermore, microalbuminuria was associated with the presence of target organ damage (eg, electrocardiographic [ECG] abnormalities and retinal vascular changes). Age and the presence of microalbuminuria act as independent risk factors for the development of ECG abnormalities and retinal vascular changes. Cluster analysis allowed us to identify three subgroups of patients who differed in the presence or absence of microalbuminuria, retinopathy, and ECG abnormalities. We conclude that the prevalence of microalbuminuria in essential hypertension is lower than previously reported. Increased urinary albumin excretion is associated with a worse cardiovascular risk profile and is a concomitant indicator of early target organ damage.
Key Words: albuminuria • hypertension, essential • cardiovascular damage • risk factors
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Increased urinary excretion of albumin ranging between 30 and 300 mg/d (ie, microalbuminuria) has been found in a relatively large number of patients with essential hypertension.1 2 3 4 5 6 7 8 9 10 Variations in the prevalence of microalbuminuria between 10% and 40% that have been reported in other studies are likely due to differences in the selection criteria, to the techniques used for the detection of microalbuminuria, and, in some cases, to the small number of patients studied. Recently, a large clinical trial that involved patients with mild and moderate essential hypertension showed a 6.1% prevalence of microalbuminuria, which is a considerably lower value than previously reported.11
Currently, the pathophysiological mechanisms leading to the development of microalbuminuria are not fully understood. This may be the result of altered intrarenal hemodynamics and may represent, as in insulin-dependent diabetes mellitus, an early feature of renal impairment, or it may be simply a marker of capillary leakiness at the glomerular level and thus reflect generalized atherosclerotic vascular damage.12 13 The latter hypothesis is supported by several epidemiological studies that show an association between microalbuminuria and increased morbidity and mortality, especially that caused by cardiovascular disease1 2 14 independently of other risk factors. Recently, interest in the study of microalbuminuria has grown because it may represent a useful and relatively inexpensive clinical tool for the identification of hypertensive patients at higher risk for cardiovascular damage.
The present study was initiated to investigate the prevalence of microalbuminuria and its relationship with several clinical and biochemical variables and target organ damage in a large population of patients with mild or moderate essential hypertension.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Selection of Patients
Since June 1993, several hypertension clinics in the Genoa area (see "Appendix" for detailed list of participating centers) were asked to take part in a large clinical trial (Microalbuminuria: A Genoa Investigation on Complications [MAGIC]) approved by the Ethics Committee of our Institution. The selection criteria for the study led to the exclusion of 257 patients as follows: age <18 or >72 years (104 patients); the presence of neoplastic (5 patients), hepatic (3 patients), and/or renal disease (16 patients); chronic heart failure (NYHA class III and IV) (13 patients); diabetes mellitus (defined as a blood glucose level
6.66 mmol/L [120 mg/dL] on two separate
occasions; 46 patients); severe obesity (defined as body weight >150%
of ideal body weight; 26 patients); severe hypertension (42 patients);
and disabling diseases such as dementia or the inability of the patient
to cooperate (2 patients). More than 90% of the remaining patients
(n=966; 528 men, 438 women) agreed to participate in the study.Written
or oral informed consent was obtained from each patient. Diagnosis of
essential hypertension was made by the attending physician after
complete medical history, physical examination, and routine biochemical
analyses of blood and urine were obtained from every patient.
Further investigation was carried out only when abnormalities were
found in these analyses or when other symptoms or signs of
secondary hypertension were present. Hypertension was defined
according to JNC-V criteria as an average BP 140/90 mm Hg on at
least three different occasions or by the presence of antihypertensive
treatment. No patients showed evidence or history of congestive heart
failure or advanced chronic obstructive pulmonary disease. None
of the patients were on medication at the time of the study. They
either had never been treated for hypertension or had been taken off
therapy at least 4 weeks before the study. On the study day, height and
weight were measured, and then venous blood was drawn after an
overnight fast in preparation for laboratory examinations. Data on the
patients (n=172; 86 men, 86 women) who either did not comply with
washout instructions (52 patients), failed to collect urine samples
properly (65 patients), or had to resume treatment because of severe
hypertension during the washout period (55 patients) were excluded from
analysis. Seven patients (4 men, 3 women) were excluded because
of hypokalemia (serum K <3.5 mmol/L). Data obtained from
the remaining 787 patients (438 men, 349 women; all European whites)
form the basis of the present report.
BP Measurements
With the patient in a seated position and after a 5-minute rest,
BP was measured on the right arm with a mercury sphygmomanometer (cuff
size, 12.5x40 cm) by a physician or trained nurse. The
systolic pressure and DBP were read to the nearest 2
mm Hg. Disappearance of Korotkoff's sounds (phase V) was the
criterion for DBP. The lowest of three consecutive readings was
recorded. BMI was calculated with the following formula: BMI=weight
(kg)/height (m)2. Twenty-four-hour urinary collection was
obtained from each patient on the day before the study for the
assessment of dietary sodium intake. Creatinine, blood urea
nitrogen, electrolytes, uric acid, triglycerides, total
cholesterol and HDL-C, and other standard chemistry
evaluations were performed on the serum in accordance with routine
methods. LDL-C was calculated with the Friedewald
formula.15 Family history and lifestyle habits were
assessed by means of a standardized questionnaire. Smoking was graded
with a five-point scale: nonsmoker, ex-smoker, smoking 1 to 14
g/d, smoking 15 to 25 g/d, or smoking more than 25
g/d (1 cigarette=1 g). The amount of usual physical activity was
estimated as follows: mild (infrequent running, swimming, sports, etc),
moderate (1 to 2 times per week running, swimming, sports, etc), and
vigorous (3 or more times per week running, swimming, sports, etc).
Information regarding usual alcohol intake was collected, and the
number of alcohol units per week was recorded (1 alcohol unit=300
mL of beer, 100 mL of wine, or 30 mL of liquor).
Albuminuria
At the end of the washout period, if any, the presence of
microalbuminuria was evaluated in each patient by
measurement of the ACR on three nonconsecutive, first morning urine
samples. Patients were instructed to freeze each urine sample directly
after collection and to keep it frozen until their next visit to the
clinic. Only samples from patients with a negative urine culture were
collected. When a positive urine culture was found, urine samples were
discarded, appropriate antibacterial treatment was instituted, and
urine collection for albuminuria was repeated only after a
second culture tested negative. The ACR was calculated as follows:
urinary albumin concentration (milligram per liter)/urinary
creatinine concentration (millimole per liter). Serum and
urine creatinine levels were determined by the routine
Jaffe reaction. Urine albumin concentration was measured by a
commercially available radioimmunoassay kit (Sclavo, Cinisello). Normal
values of albumin excretion as previously defined in our
laboratory were obtained by measurement of both AER and ACR in timed
overnight urine collections in a group of 63 normal subjects (30 men,
33 women; age, 50±0.8 years, mean±SEM) recruited among the staff of
our hospital (AER, 3.5±0.27 µg/min; range, 1 to 8
µg/min; ACR, 0.46±0.3; mean±SEM). The intra-assay and
interassay variabilities of the method used in our laboratory were
4.5% and 6.1%, respectively. The average (arithmetic mean) of the
three ACRs from each patient was used to categorize patients. To
account for differences in basal creatinine excretion rates
and BMI, different criteria were used to define
microalbuminuria in men (ACR between 2.38 and 19) and women
(ACR between 2.96 and 20). These criteria proved to have good
sensitivity and specificity for the detection of an AER between 20 and
200 µg/min.16 An ACR between 1.2 and 2.37 (for
men) and between 1.52 and 2.95 (for women) was used to define
borderline microalbuminuria. The average of each patient's
three ACRs was used to indicate the level of albumin excretion.
Results were transformed logarithmically because the AER followed a
log-normal distribution.
ECG Abnormalities
Standard ECGs (12 leads) were recorded and coded according
to the MC.17 With the criteria of the US Pooling
Project,18 which were slightly modified according to
the MC, major ECG abnormalities were defined as having Q waves (MC1-1:
1 to 2), ST depression (MC4: 1 to 2), T-wave inversion (MC5: 1 to 2),
complete or second-order atrioventricular block (MC6: 1
to 22), complete left or right bundle branch block or
intraventricular block (MC7: 1 to 2 or 4), frequent
ectopic ventricular beats (MC8: 1), or atrial fibrillation
(MC8: 3). Left ventricular hypertrophy was
defined as increased voltage (MC3: 1 or MC3: 3) plus ST or T-wave
changes (MC4: 1 to 3, or MC5: 1 to 3).
Retinopathy
The presence, type, and extent of hypertensive
retinopathy were investigated in a darkened room and
under pupil dilatation. Direct ophthalmoscopy was carried out with a
halogen ophthalmoscope; the first arteriovenous crossing at least one
disc diameter from the disc in each quadrant was selected and assessed.
Each quadrant of the fundus was photographed by means of a Zeiss fundus
camera with a 30° field. Photographic slides were projected and
evaluated by a team of two ophthalmologists who were unaware of the
patients' clinical data. Retinal features sought were venule nicking,
venule deviation, and light reflex change at all clearly visualized
crossings with comparably sized arterioles at least one disc diameter
from the disc. The mean ratio of diameters of equivalent order
arterioles and venules in each quadrant was measured, and the presence
of focal arteriolar narrowing, hemorrhages, exudates, and
papilledema was sought. Retinal lesions were classified according to
the Keith-Wagener-Barker classification.19
Statistical Analysis
All data are expressed as mean±SEM. Differences between
variables were assessed with the appropriate statistical test based
on the underlying distribution of the variables. ANOVA with
multiple comparison posttest was used to analyze data from
patients grouped according to sex, different degrees of
albuminuria, and the presence or absence of target organ
damage. Either a nonparametric (Welch's t test)
or a parametric (Student's t test) test was used to
assess differences between variables. ANCOVA was used to
analyze differences between continuous variables adjusted
for age and BMI. Pearson correlation tests were used to study the
linear relationship between the log of ACR and other continuous
variables. Differences between prevalences were assessed by
2 test or Fisher's exact test as appropriate.
The calculation of OR was performed to provide an estimate of the
relative risk of microalbuminuria,
retinopathy, and ECG abnormalities in groups of
patients with or without end-organ damage.20 Piecewise
linear regression analysis was performed to assess the
contribution of several variables on albumin excretion.
This analysis may provide better assessment of data when the
nature of the relationship between one or more independent
variables and a dependent variable changes over the range of
the dependent variable. It also allows us to identify where
discontinuity in the regression line occurs (ie, the regression break
point).21 Multiple logistic regression analyses
were performed to assess the independent contribution of several
variables to the presence of retinopathy and ECG
abnormalities. Retinopathy (0, absent; 1, grade I; 2,
grade II) and ECG abnormalities (0, normal; 1, present) were
considered class level information.
K-means cluster analyses were performed on the entire cohort of patients to identify different subgroups of patients according to the severity of the cardiovascular risk profile, target organ damage, and different degrees of albuminuria. The appropriateness of the classification was assessed with a standard between-group ANOVA for each variable.22 All statistical analyses were performed with SAS (SAS Institute) software.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Characteristics of the Population
The main clinical characteristics of the study subjects grouped according to sex are reported in Table 1
.
On the average, women were older than men and had a longer duration of
disease and a somewhat better biochemical risk profile (ie, lower uric
acid, triglycerides, and HDL-C to LDL-C ratio). ACR was
significantly higher in men, even after adjustment for age as shown by
ANOVA of the log of ACR by sex with age as a covariant (main
effect, sex; F, 4.047; P<.05; covariate, age; F, 6.633;
P<.01). There was no difference in BP levels, family
history for hypertension, and retinal and ECG changes. As expected, BMI
and serum creatinine were higher in men.
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Prevalence of Microalbuminuria
The distribution of ACR in the entire population showed a positive
skew (Fig 1).
Microalbuminuria was present in 53 subjects (6.7%). In
61 subjects (7.8%), ACR was between 1.2 and 2.37 (men) and between
1.52 and 2.95 (women) (ie, borderline microalbuminuria). In
663 individuals (84.2%), the ACR was between 0 and 1.2 (men) and
between 0 and 1.52 (women) (ie, normoalbuminuria). However,
10 subjects (1.3%) showed ACR levels >19 (men) or >20 (women) (ie,
macroalbuminuria). The prevalence of
microalbuminuria was higher in men than in women, both when
defined as an ACR above 1.2 (men) and 1.5 (women), as shown in Table 1
,
as well as when a cutoff level of 2.38 (men) and 2.96 (women) was used
(10% in men versus 5.4% in women, P<.05, data not shown).
This held true even when identical cutoffs in ACR levels were used to
define microalbuminuria.
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Clinical Characteristics According to Albumin
Excretion Levels
Table 2 shows the main clinical
characteristics of the patients with normal albuminuria,
borderline microalbuminuria, and
microalbuminuria. The three groups were
homogeneous for age, duration of disease, family history of
hypertension, smoking habits, and alcohol intake. There was a trend
toward a higher men to women ratio in patients with increased
albuminuria. Both groups with microalbuminuria
exhibited higher BP levels, as well as a more atherogenic serum profile
(ie, higher uric acid and lower HDL-C and HDL-C to LDL-C ratio compared
with the normoalbuminuric group). No significant difference was
found in the prevalence of ECG and retinal changes among the three
groups of patients; however, a significantly higher prevalence of ECG
abnormalities was present in the two groups with
microalbuminuria combined compared with
normoalbuminuric patients (OR, 1.675; 95% CI, 1.058 to 2.947;
P=.039; data not shown).
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Urinary Albumin Excretion Levels According to Family
History of Hypertension and Lifestyle Factors
Urinary albumin excretion was similar in patients with a
negative and positive family history for hypertension. Smoking habits,
alcohol intake, and the amount of physical activity do not seem to
affect the AER. There was a tendency toward higher BMI in patients with
greater AER (P<.01, Table 2).
Univariate Correlations Between Log of ACR (n=787) and
Selected Clinical Variables
Univariate correlation coefficients between the
logarithm of ACR and various clinical parameters are shown
in Table 3. The log of ACR showed a
positive although weak correlation with age and a stronger correlation
with BP (DBP and mean BP), but it was unrelated to BMI and the duration
of hypertension. This held true when the correlation was made with men
and women separated. A negative correlation was present between the
log of ACR and HDL-C and HDL-C to LDL-C ratio. This held true for men
but not for women when analyzed separately (data not
shown).
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Determinants of Albuminuria
A piecewise linear regression analysis was performed among
the entire cohort of patients to identify factors that independently
influence ACR. A two-slope linear model was identified with a break
point value of 2.3, which is almost identical to the one predefined to
indicate the passage from normoalbuminuria to
microalbuminuria. DBP and uric acid significantly
influenced ACR levels and together accounted for 
60% of the
variations in albumin excretion (Table 4).
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Characteristics of Patients According to Target Organ
Damage
Clinical characteristics of patients grouped according to the
presence or absence of cardiac damage are shown in Table 5. Patients with major ECG changes were
more likely to have microalbuminuria (OR, 1.76; 95% CI,
1.06 to 2.95; P<.04) and showed higher levels of
albuminuria and BP, older age, and a longer duration of
hypertension compared with patients with normal ECGs.
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Furthermore, patients with ECG abnormalities were more likely to show signs of retinal vascular damage (OR, 2.59; 95% CI, 1.43 to 4.68; P<.001). This held true even when men (OR, 2.6; 95% CI, 1.20 to 5.60; P<.02) and women (OR, 2.6; 95% CI, 1.02 to 6.60; P<.05) were analyzed separately.
Patients with retinal vascular changes were more often men and on the average older and with a longer duration of hypertension and a lower glomerular filtration rate as indicated by creatinine clearance. Furthermore, they were more likely to show ECG abnormalities (OR, 2.6; 95% CI, 1.44 to 4.68; P<.001). This held true even when men (OR, 2.6; 95% CI, 1.20 to 5.60; P<.02) and women (OR, 2.6; 95% CI, 1.02 to 6.56; P<.05) were analyzed separately. Overall, there was no difference in ACR or in the prevalence of microalbuminuria on the basis of the presence of retinal vascular changes. This held true when women were analyzed separately, whereas men with retinopathy showed higher levels of ACR compared with those without retinopathy.
There was a significant trend for a higher prevalence of ECG
abnormalities in patients with more severe degrees of
retinopathy (P<.005; Table 5). Moreover,
there was a significant trend for men (P<.03), older age
(P<.0001), and a longer known duration of disease
(P<.004) as well as for a higher prevalence of ECG
abnormalities (P<.005) in patients with more severe degrees
of retinopathy (data not shown). Furthermore, patients
with grades I and II retinopathy had a twofold higher
risk of left ventricular hypertrophy (OR, 2.6;
95% CI, 1.43 to 4.68; P<.002; data not shown).
Determinants of Target Organ Damage
By use of multiple logistic regression analysis, we
investigated the relationship between several variables that
included albuminuria and the presence of organ damage,
specifically ECG abnormalities and retinal vascular changes. Age,
microalbuminuria, and the presence of
retinopathy were significantly related to the presence
of ECG changes independently of other variables as shown in Table 6 (ECG abnormalities). Furthermore, age
as well as the presence of microalbuminuria and ECG
abnormalities were found to be independently associated with the
presence of retinal vascular changes at fundoscopy (Table 6,
Retinopathy).
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Cluster Analyses
K-means cluster analysis of the entire cohort of patients
allowed us to identify three subgroups that differed significantly in
the severity of cardiovascular risk profile and also
showed different degrees of albuminuria (F, 205.509 for
age; F, 98.060 for log of ACR; F, 28.617 for BMI; F, 123.702 for DBP;
and F, 89.071 for LDL-C; df, 2 to 486; P<.001
for each one of the variables examined by multimethod,
between-group ANOVA, and contrast analysis; Fig 2), whereas no difference was indicated
for other clinical and biochemical parameters. Patients in
cluster 2 (n=175) showed normal albumin excretion levels and
were characterized by low cardiovascular risk profiles
(ie, lower values of DBP, LDL-C, lower BMI, and younger age). Patients
in cluster 3 (n=188) showed less favorable risk profiles and were older
on average compared with those in cluster 2. Finally, patients in
cluster 1 (n=126) were characterized by worse
cardiovascular risk profiles (ie, older age and higher
levels of DBP, LDL-C, and BMI) and showed significantly higher levels
of albuminuria compared with the other groups. Therefore,
higher levels of albuminuria tended to cluster with several
cardiovascular risk factors in patients with essential
hypertension.
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A separate K-means cluster analysis was performed on the entire cohort of patients to identify subgroups on the basis of the presence or absence of organ damage. Again, three subsets of patients were identified, with each one differing significantly for the presence or absence of retinal vascular changes (df, 2 to 521; F, 705.461; P<.001), ECG abnormalities (df, 2 to 521; F, 219.074; P<.001), and the level of ACR (df, 2 to 521; F, 78.527; P<.001). Interestingly, the presence of microalbuminuria proved to be associated with the presence of cardiovascular damage.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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The present study reports a 6.7% prevalence of microalbuminuria in untreated patients with mild to moderate essential hypertension. This figure differs from those of several previously published reports that indicate a variable but considerably higher prevalence of microalbuminuria.1 2 3 4 5 6 7 8 9 10 11 These discrepancies are mostlikely due to different criteria in patient selection (ie, the severity of hypertension, age, race, coexistence of renal disease, and the techniques used for the detection of albuminuria).
Therefore, Agewall et al5 reported an 23% prevalence
of microalbuminuria in a population of hypertensive
patients who were selected as at high risk for
cardiovascular disease. Unfortunately, the study was
conducted when patients were receiving antihypertensive drug treatment;
therefore, the results of the study were even more difficult to
interpret. In the present study, however, great care was taken to
exclude patients who were obese, diabetic, or had a history or signs of
primary renal disease. When necessary, adequate pharmacological washout
was performed before urinary albumin excretion was evaluated.
Although the strict enforcement of our selection protocol led to the
exclusion of patients who did not complete the washout period or did
not properly collect urine samples and therefore introduced a potential
source of error, it allowed us to screen carefully for comorbid
conditions, which might have influenced microalbuminuria,
and to study a fairly homogeneous cohort of patients with
mild and moderate hypertension. Age and race seem to exert a
significant influence on urinary albumin excretion and may
account for some of the variability reported in the literature. In
fact, Damsgaard et al2 reported a relatively high
prevalence of microalbuminuria in a group of 216 elderly
hypertensive patients, and Summerson et al10 found a 32%
prevalence in a group of black hypertensive subjects, a population
known for its susceptibility to developing hypertensive organ damage.
In the latter study, a much lower prevalence of
microalbuminuria (14%) was reported in a group of white
patients with mild or moderate essential hypertension. A significant
part of the variability in the prevalence of
microalbuminuria is certainly attributable to different
values used to define it, as well as to the techniques and protocols
used to evaluate it. The use of 24-hour urine collection, for example,
is likely to yield higher values than overnight collection because of
the influence of food and physical activity on urinary albumin
excretion. Accordingly, with the use of a 24-hour urine collection
procedure, Bigazzi et al4 reported a high prevalence of
microalbuminuria (40%) in a group of 123 unselected
patients with essential hypertension. The measurement of the ACR on
first voided morning samples used in the present study was
previously shown to be an accurate and reproducible predictor of the
AER, perhaps because of the relative stability of renal
hemodynamics during night rest. Furthermore, the high
day-to-day variability of albumin excretion may have impaired
an accurate estimate of persisting microalbuminuria in
studies in which only one urinary sample was obtained from each
patient.3 7 In the present study, this disadvantage
was overcome by the collection of three different samples on
nonconsecutive days and by the rigorous exclusion of other factors,
such as the presence of urinary tract infection, that are known to
influence urinary albumin excretion. Finally, many studies may
have been limited by the small number of patients
examined.3 8 9 The only large cross-sectional study that
has been published that concerns patients with mild or moderate
essential hypertension11 indicates a 6.1% prevalence rate
of microalbuminuria; this percentage is almost identical to
the one reported in the present study. The relatively low
prevalence of microalbuminuria in our study population is
still significantly higher than that found in a well-matched group of
225 (115 men, 110 women; 50±9 years; BMI, 26.1±3.4; mean±SD)
normotensive, nondiabetic, healthy subjects with comparable dietary
habits and living in a nearby area that has environmental
characteristics similar to the Genoa area.23
The prevalence of macroalbuminuria reported in the present study is lower than that generally reported in patients with essential hypertension.24 However, the possibility must be considered that patients with a previous history or evidence of renal disease (eg, the presence of significant abnormalities in urinalysis) were excluded on the basis of our study protocol. Because many so-called essential hypertensive patients with clinical proteinuria may have some underlying renal disease, we believe that caution should be taken when these data are compared with data previously reported in the literature.
The second important finding of the present study is the
association between microalbuminuria and a number of
metabolic and nonmetabolic
cardiovascular risk factors. Albuminuric
patients were more likely to be men and to have higher BMI, uric acid,
and BP levels as well as lower ratios of HDL to LDL (Table 2). A
similar cluster of metabolic abnormalities was previously
reported in association with microalbuminuria, both in
nondiabetic normotensive subjects25 26 27 and hypertensive
patients28 and resembles the one occurring secondarily to
insulin resistance and commonly known as syndrome X.29
Among the many risk factors reported in association with
microalbuminuria in our study population, an increased
serum uric acid level appears to have special relevance because this
abnormality with DBP level accounted for a large part of the variation
in urinary albumin excretion, as indicated by piecewise linear
regression analysis (Table 4). Because of this, it should be
noted that decreased urinary uric acid clearance and a subsequent
increase in serum uric acid concentration have beenpreviously
demonstrated in association with insulin resistance, thus suggesting a
role for hyperinsulinemia in the promotion of an
increase in renal uric acid reabsorption.30 Whereas the
present study does not allow us to speculate on the mechanism
underlying these associations, other studies have previously shown that
hyperinsulinemia and peripheral
resistance to insulin-mediated glucose uptake are present in
hypertensive patients with microalbuminuria.31
Moreover, higher levels of circulating von Willebrand factor
antigen, an indicator of endothelial damage, were found
in microalbuminuric patients compared with well-matched
normoalbuminuric patients with essential
hypertension,32 thus supporting a link between increased
albumin excretion and the development of
endothelial dysfunction, which may lead to the
development of atherosclerosis. In addition to
metabolic abnormalities, the present study shows also
that microalbuminuric patients are characterized by higher BP
levels. This is in agreement with several previously published studies
showing that the degree and the prevalence of
microalbuminuria correlate with the height of BP when
considering office measurements and, even more so, 24-hour ambulatory
BP monitoring.33 The clustering of
microalbuminuria with several other risk factors is
confirmed in the present study by the results of
multivariate statistical analysis (Fig 2).
K-means cluster analysis that was performed on the entire
cohort of patients allowed us to identify three subgroups that differed
significantly from each other for age, albumin excretion, BMI,
DBP, and LDL-C levels. Patients in the high-risk group (cluster 1)
share a cluster of abnormalities that suggest an unfavorable risk
profile, whereas patients in cluster 2 show a better risk profile
together with lower levels of albuminuria. These data
suggest that microalbuminuria could be the reflection of
diffuse atherosclerotic vascular changes, which also involve renal
vasculature, thus determining the urinary leakage of
albumin.
Major ECG abnormalities and vascular retinal changes are thought to
reflect pressure overload and atherosclerotic vascular damage in
patients with essential hypertension and thereby are considered
predictors of future vascular events.34 35 36 37 An association
between microalbuminuria and target organ damage has been
reported previously.38 By means of
echocardiographic examination, Redon et
al33 found that patients with microalbuminuria
show a larger left ventricular mass and a higher degree of
left ventricular hypertrophy, thus confirming
data reported by Cerasola et al,39 who also described a
positive correlation between microalbuminuria and greater
glomerular filtration rate in a group of 47 patients with
essential hypertension. Biesenbach et al40 described a
higher prevalence of coronary artery disease and hypertensive
retinopathy in a group of hypertensive patients with
persistent microalbuminuria despite effective
antihypertensive treatment. Moreover, in a relatively small group of
patients with essential hypertension and microalbuminuria,
Bigazzi et al41 reported an increased thickness of the
intima and media layers of the common carotid artery, therefore
suggesting a greater degree of vascular remodeling. These data are in
agreement with those reported by Del Sette et al,42 who
also measured carotid intima-media thickness in a group of
microalbuminuric hypertensive subjects compared with a group of
normoalbuminuric subjects matched for age, sex, BMI, and
duration of hypertension. Data from the present study confirm that
patients with microalbuminuria are characterized by signs
of diffuse vascular and organ damage (ie, a higher incidence of major
ECG abnormalities and vascular retinal changes [Table 2]). The
statistical analysis of data presented here provides
further evidence of an association between microalbuminuria
and hypertensive organ damage. In fact, the three subgroups of patients
identified on the basis of their cardiovascular risk
profile (Fig 2) differ also for the prevalence of ECG abnormalities
(2, 8.520, P<.02;
2 for trend, 8.500; P<.01) and
retinopathy (2, 12.366;
P<.01; 2 for trend, 10.626;
P<.002, data not shown). In a separate cluster
analysis (Fig 3) also performed
on the entire cohort of patients, three distinct subgroups were
identified according to the presence or absence of
microalbuminuria, retinopathy, and ECG
abnormalities. Furthermore, multiple logistic regression
analyses showed a significant and independent role of
microalbuminuria in the presence of ECG abnormalities and
vascular retinal changes (Table 6). Together, these data support the
conclusion that microalbuminuria is a marker of early
end-organ and cardiovascular damage in patients with
essential hypertension.
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Although the consideration of mechanisms responsible for the development of increased urinary albumin excretion is beyond the scope of the present cross-sectional study, the data presented here seem to indicate that both higher BP levels and diffuse atherosclerotic vascular changes may have a role in the pathogenesis of microalbuminuria.
In conclusion, this study confirms that increased urinary albumin excretion is associated with a worse pattern of cardiovascular risk factors and is a marker of concomitant cardiovascular damage in essential hypertension. Microalbuminuria can therefore be regarded as a useful, relatively inexpensive, integrated marker to help identify patients at higher cardiovascular risk for whom more aggressive preventive strategies and/or additional treatment measures may be advisable. Long-term studies are required to determine whether it also represents an initial sign of renal damage and a prognostic indicator of progressive renal disease.
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Selected Abbreviations and Acronyms |
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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The following is a list of centers and research personnel who participated in the MAGIC Study.
La Spezia, Division of Medicine: Carlo Del Prato; Sestri Levante, Division of Medicine: Nicola Acquarone; Recco, Division of Medicine: Antonio Pompei; Genova, S. Martino Hospital, I Division of Medicine: Giuliano Grillo, Domenico Bessarione, Paolo Trombino; Genova, S. Martino Hospital, Emergency Medicine: Paolo Moscatelli; Genova, S. Martino Hospital, Cardiology: Ubaldo Martini; Genova, DIMI, Cardiology: Salvatore Caponnetto, Claudio Brunelli, Gian Marco Rosa; Genova, DIMI, Nephrology: Roberto Pontremoli, Antonella Sofia, Angelito Tirotta, Maura Ravera, Clizia Nicolella, Francesca Viazzi, Valeria Berruti; Genova, DIMI, Chair of Medical Therapy: Giacomo Deferrari; Genova, Galliera Hospital, Division of Medicine: Cristoforo Castello, Gian Carlo Antonucci; Pietra Ligure, S. Corona Hospital, II Division of Medicine: Alberto Artom, Donatella Mela; Savona, Cardiology: Emilio Martinengo, Sebastiano Gandolfo; Imperia, Nephrology: Fosco Cavatorta.
Steering Comittee: Patrizio Odetti, Valeria Cheli, Raffaella Lotti, Gian Paolo Bezante, Lorenzo Derchi, Massimo Del Sette.
President: Giacomo Deferrari.
Received March 3, 1997; first decision March 25, 1997; accepted April 10, 1997.
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References |
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|---|
- Yudkin JS, Forrest RD, Jackson C. Microalbuminuria as predictor of vascular disease in non diabetic subjects. Lancet. 1988;2:530-533.[Medline] [Order article via Infotrieve]
- Damsgaard EM, Froland A, Jorgensen OD, Mogensen CE. Microalbuminuria as predictor of increased mortality in elderly people. Br Med J. 1990;300:297-300.
- West JNW, Gosling P, Dimmitt SB, Littler WA. Non diabetic microalbuminuria in clinical practice and its relationship to posture, exercise and blood pressure. Clin Sci. 1991;81:101-105.[Medline] [Order article via Infotrieve]
- Bigazzi R, Bianchi S, Campese VM, Baldari G. Prevalence of microalbuminuria in a large population of patients with mild to moderate essential hypertension. Nephron. 1992;61:94-97.[Medline] [Order article via Infotrieve]
- Agewall S, Persson B, Samuelsson O, Ljungman S, Herlitz H, Fagerberg B. Microalbuminuria in treated hypertensive men at high risk of coronary disease: the Risk Factor Intervention Study Group. J Hypertens. 1993;11:461-469.[Medline] [Order article via Infotrieve]
- Mimram A, Ribstein J, DuCailar G, Halimi J-M. Albuminuria in normal and essential hypertension. J Diabetes Complications. 1994;8:150-156.[Medline] [Order article via Infotrieve]
-
Hoegholm A, Bang LE, Kristensen KS, Nielsen JW, Holm
J. Microalbuminuria in 411 untreated individuals
with established hypertension, white coat hypertension, and
normotension. Hypertension. 1994;24:101-105.
[Abstract/Free Full Text] - James AM, Fotherby MD, Potter JF. Microalbuminuria in elderly hypertensives: reproducibility and relation to clinic and ambulatory blood pressure. J Hypertens. 1994;12:309-314.[Medline] [Order article via Infotrieve]
- James AM, Fotherby MD, Potter JF. Screening test for microalbuminuria in non diabetic elderly subjects and their relation to blood pressure. Clin Sci. 1995;88:185-190.[Medline] [Order article via Infotrieve]
- Summerson JH, Bell RA, Konen JC. Racial differences in the prevalence of microalbuminuria in hypertension. Am J Kidney Dis. 1995;26:577-579.[Medline] [Order article via Infotrieve]
- Palatini P, Graniero GR, Mormino P, Mattarei M, Sanzuol F, Cignacco GB, Gregori S, Garavelli G, Pegoraro F, Maraglino G, Bortolazzi A, Accurso V, Dorigatti F, Graniero F, Gelisio R, Businaro R, Vriz O, Dal Follo M, Camarotto A, Pessina AC. Prevalence and clinical correlates of microalbuminuria in stage I hypertension. Am J Hypertens. 1996;89:334-341.
-
Erley CM, Risler T. Microalbuminuria
in primary hypertension: is it a marker of glomerular
damage? Nephrol Dial Transplant. 1994;9:1713-1715.
[Free Full Text] -
Pedrinelli R, Di Bello V, Catapano G, Talarico L,
Materazzi F, Santoro G, Giusti C, Mosca F, Melillo E, Ferrari M.
Microalbuminuria is a marker of left
ventricular hypertrophy but not
hyperinsulinemia in nondiabetic atherosclerotic
patients. Arterioscler Thromb. 1993;13:900-906.
[Abstract/Free Full Text] - Bianchi S, Bigazzi R, Campese VM. Increased cardiovascular events in patients with hypertension and microalbuminuria. J Am Soc Nephrol. 1996;7:1546. Abstract.
- Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499-502.[Abstract]
- Mangili R, Deferrari G, Di Mario U, Giampietro O, Navalesi R, Nosadini R, Rigamonti G, Spezia R, Crepaldi G, for the Italian Microalbuminuria Study Group. Prevalence of hypertension and microalbuminuria in adult type 1 (insulin dependent) diabetic patients without renal failure in Italy: validation of screening techniques to detect albuminuria. Acta Diabetol. 1992;29:156-166.
- Rose GA, Blackburn H. Cardiovascular Survey Methods. Geneva, Switzerland: World Health Organization Monograph Series, No 56; 1968:1-188.
- Pooling Project Research Group. Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: final reports of the Pooling Project. J Chronic Dis. 1978;31:201-306.[Medline] [Order article via Infotrieve]
- Keith NM, Wagener HP, Barker MW. Some different types of essential hypertension: their course and prognosis. Am J Med Sci. 1939;197:332-343.
- Snedecor GW, Cochran WG. Statistical Methods. 6th ed. Ames, Iowa: Ames Iowa State University Press; 1967.
- Weisberg S. Applied Linear Regression. New York, NY: John Wiley & Sons Inc; 1980:1-283.
- Tryon RC, Bailey DE. Cluster Analysis. New York, NY: McGraw-Hill Book Co; 1970:1-347.
- Zavaroni I, Bonini L, Gasparini P, Zuccarelli A, Dall'Aglio E, Barilli L, Cioni F, Strata A, Reaven GM. Dissociation between urinary albumin excretion and variables associated with insulin resistance in a healthy population. J Intern Med. 1996;240:151-156.[Medline] [Order article via Infotrieve]
- Ritz E, Nowicki M, Fliser D, Horner D, Klimm HP. Proteinuria and hypertension. Kidney Int. 1994;46(suppl 47):S76-S80.
- Woo J, Cockram CS, Swaminathan R, Lau E, Chan A, Cheung R. Microalbuminuria and other cardiovascular risk factors in non diabetic subjects. Int J Cardiol. 1992;37:345-350.[Medline] [Order article via Infotrieve]
- Gould M, Mohamed-Ali V, Goubet SA, Yudkin JS, Haines AP. Microalbuminuria: association with height and sex in non diabetic subjects. Br Med J. 1993;306:240-242.
- Winocour PH, Harland JOE, Millar JP, Laker MF, Alberti KGMM. Microalbuminuria and associated cardiovascular risk factors in the community. Atherosclerosis. 1992;93:71-81.[Medline] [Order article via Infotrieve]
- Redon J, Liao Y, Lozano JV, Miralles A, Pascual JM, Cooper RS. Ambulatory blood pressure and microalbuminuria in essential hypertension: role of circadian variability. J Hypertens. 1994;12:947-953.[Medline] [Order article via Infotrieve]
- Swislocki ALM, Hoffman BB, Reaven GM. Insulin resistance, glucose intolerance and hyperinsulinemia in patients with hypertension. Am J Hypertens. 1989;2:419-423.[Medline] [Order article via Infotrieve]
- Facchini F, Chen I, Hollenbeck CB, Reaven GM. Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance and plasma uric acid concentration. JAMA. 1991;266:3008-3011.[Abstract]
-
Bianchi S, Bigazzi R, Quinones Galvan A, Muscelli E,
Baldari G, Pecori N, Ciociaro D, Ferrannini E, Natali A. Insulin
resistance in microalbuminuric hypertension: sites and
mechanisms. Hypertension. 1995;26:789-795.
[Abstract/Free Full Text] - Pedrinelli R, Gianpietro O, Carmassi F, Melillo E, Dell'Omo G, Catapano G, Matteucci E, Talarico L, Morale M, De Negri F, Di Bello V. Microalbuminuria and endothelial dysfunction in essential hypertension. Lancet. 1994;344:14-18.[Medline] [Order article via Infotrieve]
- Redon J, Youlian L, Lozano JV, Miralles A, Baldo E, Cooper RS. Factors related to the presence of microalbuminuria in essential hypertension. Am J Hypertens. 1994;7:801-807.[Medline] [Order article via Infotrieve]
- Samuelsson O, Wilhelmsen L, Elmfeldt D, Pennert K, Wedel H, Wikstrand J, Berglund G. Predictors of cardiovascular morbidity in treated hypertension: results from the primary preventive trial in Goteborg, Sweden. J Hypertens. 1985;3:167-176.[Medline] [Order article via Infotrieve]
- Kannel WB, Gordon T, Castelli WP, Margolis JR. Electrocardiographic left ventricular hypertrophy and risk of coronary heart disease: the Framingham Study. Ann Intern Med. 1970;72:813-822.
- Sullivan JM, Vander Zwaag R, el-Zeky F, Ramanathan KB, Mirvis DM. Left ventricular hypertrophy: effect on survival. J Am Coll Cardiol. 1993;22:508-513.[Abstract]
-
Schouten EG, Vandenbroucke JP, Van Der Heide-Wessel C,
Van Der Heide RM. Retinopathy as an independent
indicator of all-causes mortality. Int J Epidemiol. 1986;15:234-236.
[Abstract/Free Full Text] - Schmieder R, Grube E, Ruddel H, Schlebush H, Schulte W. Microproteinuria as a marker for target organ damage in essential hypertension. Klin Wochenschr. 1990;68:256-262.[Medline] [Order article via Infotrieve]
- Cerasola G, Cottone S, D'Ignoto G, Grasso L, Mangano MT, Carapelle E, Nardi E, Andronico G, Fulantelli MA, Marcellino T, Seddio G. Microalbuminuria as a predictor of cardiovascular damage in essential hypertension. J Hypertens. 1989;7(suppl 6):S332-S333.
- Biesenbach G, Zazgornik J. High prevalence of hypertensive retinopathy and coronary heart disease in hypertensive patients with persistent microalbuminuria under short intensive antihypertensive therapy. Clin Nephrol. 1994;41:211-218.[Medline] [Order article via Infotrieve]
- Bigazzi R, Bianchi S, Nenci R, Baldari D, Baldari G, Campese VM. Increased thickness of the carotid artery in patients with essential hypertension and microalbuminuria. J Hum Hypertens. 1995;9:827-833.[Medline] [Order article via Infotrieve]
- Del Sette M, Zagami P, Angeli S, Finocchi C, Gandolfo C, Pontremoli R. Carotid diameter, wall thickness, and parietal stress in essential hypertension. Stroke. 1995;26:2373-2374.
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