From the Department of Nephrology and Endocrinology, State University
Hospital, Copenhagen (P.C., B.F.-R.), and the Copenhagen City Heart Study,
Epidemiological Research Unit, Bispebjerg Municipal Hospital, University of
Copenhagen (J.S.J., K.B.-J., G.J.), Denmark.
Correspondence to Peter Clausen, MD, Department 2131 of Nephrology and Endocrinology, State University Hospital, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark.
In cross-sectional studies of nondiabetic subjects with elevated UAER,
office BP elevation has been demonstrated to be part of a clustering of
known atherosclerotic risk factors.19 20 However,
both the BP elevation and the changes in plasma lipoproteins of
nondiabetic subjects with elevated UAER have been slight in these
studies and do not alone explain the impact of elevated UAER on
cardiovascular risk. Therefore, more extensive studies
of BP and UAER are warranted; in particular, studies of 24-hour BP and
UAER would be of interest for a number of reasons.
In normal subjects, the circadian variation of BP shows highest values
during the morning, a gradual decrease during the course of the day,
and a nocturnal drop during sleep.21 Ambulatory
BP has been shown in cross-sectional studies to correlate better with
indices of hypertensive cardiovascular complications
than office BP,22 and in prospective studies
ambulatory BP is superior to office BP in predicting target organ
damage.23 Absence of the normal nocturnal BP fall
has been shown to be of particular significance in some
studies.24 25
UAER has been demonstrated to correlate more strongly to ambulatory BP
than to office BP among hypertensive and diabetic
subjects26 27 ; UAER has been shown to correlate
in short-term urinary collections to concomitant BP measurements in a
study of 13 healthy subjects.28 Furthermore, a
blunted nocturnal BP fall has been demonstrated in diabetic patients
with microalbuminuria (UAER, 15 to 150 µg/min) or
diabetic nephropathy.29 30
We hypothesized that elevated ambulatory BP and a disturbed circadian
variation of BP were present in clinically healthy subjects with
elevated UAER. This would partly account for the independent predictive
value of elevated UAER for later atherosclerotic
cardiovascular disease. The present study aimed to
test this hypothesis by correlating UAER to 24-hour mean BP values, BP
loads, and nocturnal BP reduction.
Of a total of 7089 participants, 3645 (51%) collected a timed
overnight urine sample, and 2946 had a negative urinalysis (Figure 1
The remaining 71 subjects were invited to participate in the
present study, and 51 (72%) answered positively. Before entrance
into the study, the elevation of UAER in each of these potential
participants was confirmed because of the known large intraindividual
variation of UAER.33 Because the mean urine flow
in the reference population was 1 mL/min, we chose an albumin
concentration in the range of 6.6 to 150 mg/L in at least 1 of 2 mailed
first morning–voided spot urine samples, with a negative urinalysis as
entrance criterion to the study; thus, 29 eligible subjects were left,
comprising the group with elevated UAER. At the examination day, 1
additional subject was excluded because of a fasting blood glucose
concentration of 10 mmol/L, and 1 subject was excluded because of
repeated hematuria in 2 separated timed urine collections and a blood
hemoglobin concentration of 5.3 mmol/L. A flow diagram (Figure 1
A normoalbuminuric control group (n=46) was established
by random and consecutive invitation of 1 to 3 age- and gender-matched
subjects with an UAER of
All subjects included gave their informed consent to participation. The
study was performed in accordance with the Second Helsinki Declaration
and was approved by the regional ethics committee.
Protocol
Height and weight were recorded, BMI was calculated
(weight/height2), and concentrations of
albumin, creatinine, potassium, and sodium in
plasma as well as hemoglobin in blood were measured using standard
laboratory methods.
Diastolic (Korotkoff phase V) and systolic office
BPs were measured in duplicate with a standard mercury sphygmomanometer
(Trimline, PyMaH Corp) and an appropriately sized cuff after 10 minutes
of supine rest. The mean of the two readings was taken as office
BP.
Ambulatory BP was measured concomitantly with the urine collection with
a portable automatic BP monitor (TM 2421, A&D), which has been
validated according to the protocols of the Association for the
Advancement of Medical Instrumentation and of the British Hypertension
Society.35 The device automatically rejects
readings with a heart rate <35 or >200 bpm, systolic BP <60
or >280 mm Hg, diastolic BP <40 or >160
mm Hg, or pulse BP (systolic-diastolic) <10 or
>150 mm Hg. No additional editing was performed. The device was
programmed to measure BP every 15th minute during
daytime7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 and every 30th minute at night as
previously recommended.36 Two 24-hour BP
recordings were unsuccessful because of technical errors (1 in
a subject with elevated UAER and 1 in a subject with
normoalbuminuria), and the oscillometric measurements in
the remaining subjects [98% (79 to 100%) successful readings] are
presented. The participants recorded actual time points for
going to bed and rising in the morning for accurate appraisal of awake
and sleep BPs. Values were averaged for each hour before the awake,
sleep, and 24-hour BPs and pulse pressures were calculated. BP load was
calculated as the proportion of the recorded pressures exceeding
140/90 awake or 120/80 at sleep. This parameter has been
shown to be superior to mean 24-hour BP values in correlation with
different hemodynamic
parameters.37
Information was recorded regarding present and prior smoking
and drinking habits. Study subjects were divided into smokers and
nonsmokers, and in each subject, present cigarette consumption and
lifetime cigarette consumption was estimated. As lifetime cigarette
consumption, the number of "pack-years" (20 cigarettes per day in 1
year) was estimated. Only a few subjects consumed no alcohol, and an
estimate of present alcohol consumption and lifetime consumption (1
drink-year=one drink per day in 1 year) was made.
Statistical Analysis
All tests were performed using Statistica version 5.0 (StatSoft
Inc).
These differences were confirmed by ambulatory BP monitoring that
demonstrated significantly higher systolic,
diastolic, and pulse BPs in subjects with elevated UAER.
Even though a greater difference in BP was demonstrated between the
groups while asleep than awake, no significant difference in the
nocturnal reduction of either systolic or diastolic
BP between subjects with elevated UAER and subjects with
normoalbuminuria was found. Both systolic and
diastolic BP loads were significantly higher in subjects
with elevated UAER than in subjects with normoalbuminuria.
All BP values are given in Table 2
A negative correlation between UAER and nocturnal BP reduction could
not be demonstrated in either normoalbuminuric subjects or
subjects with elevated UAER.
Ten of the subjects originally classified as having an elevated
UAER excreted albumin in the normoalbuminuric range
when reexamined [3.9 (2.8 to 6.3) µg/min]. Five of the subjects
originally classified as being normoalbuminuric had a current
UAER exceeding 6.6 µg/min [12.0 (7.8 to 20.3) µg/min]. If these
subjects were excluded from the analysis, the difference
between the 2 groups in 24-hour mean systolic BP was 137±13
versus 125±9 mm Hg, P<0.0005, and 24-hour mean
diastolic BP 80±8 mm Hg versus 74±7,
P<0.02.
No significant differences in BMI, smoking habits, or alcohol
consumption were present between the 2 groups (Table 1
Current UAER confirmed that the selection procedure successfully
had identified 2 groups with differing UAER: 3.5 (0 to 20.3) µg/min
versus 22.5 (2.3 to 147.8) µg/min,
P<10-6.
Elevated UAER is an independent risk factor for later atherosclerotic
cardiovascular disease in nondiabetic
subjects,5 6 7 8 and the purpose of this study was
to investigate whether differences in BP loads and circadian variation
of BP could explain this association independently of any preexisting
morbidity. As a consequence, we decided to examine a selected group of
clinically healthy subjects with an elevated UAER, which was confirmed
in spot urine samples. Hence, the conclusions of this study may not be
valid for the total nondiabetic population with elevated UAER. However,
we hypothesize that elevated UAER reflects a generalized vascular
dysfunction and precedes later atherosclerotic
cardiovascular disease.38 To
investigate whether the independent predictive value of UAER for later
cardiovascular disease is explained instead by BP
disturbances, the exclusion criteria were a necessity.
Five of the subjects originally classified as being
normoalbuminuric and 10 of the subjects originally classified
as having an elevated UAER excreted albumin, deviating from the
original group criteria. For several reasons, we feel that this
difference in a single measurement does not change the subject's
status as having normoalbuminuria or elevated UAER in
intergroup comparisons or correlation estimates. The status was
previously defined on the basis of 3 urine collections. UAER has a high
intraindividual variation.33 The current UAER was
not included as part of the grouping procedure but rather to have UAER
measured simultaneously with ambulatory BP monitoring. The
difference in mean current UAER was highly significant between the
groups despite the overlap. However, if the subjects with a current
UAER differing from the original grouping criteria were excluded from
the analyses, the differences in ambulatory BP estimates were
magnified.
None of the standard laboratory measurements revealed any abnormalities
or any differences between the groups (Table 1
The 2 groups were well matched for age, gender, BMI, smoking, and
alcohol consumption. A significant positive correlation between BMI and
UAER was seen within the normoalbuminuric group. However, this
correlation was not found within the group of subjects with elevated
UAER, and the differences in UAER and BP measurements between the two
groups are not likely to be explained by the slight insignificant
difference in mean BMI between the groups.
In studies of patients with diabetes, a negative association between
UAER and nocturnal BP reduction has been
demonstrated,29 30 which was not the case in our
study of healthy subjects. This might be explained by a coexistence in
diabetic patients of elevation of UAER and other diabetic
complications, such as autonomic neuropathy or impaired
renal function caused by nephropathy. Both of these
conditions are known to cause blunted nocturnal BP
reduction.39 40
A significantly higher pulse pressure
(systolic-diastolic BP) was demonstrated in
subjects with elevated UAER by office BP measurement as well as
ambulatory BP monitoring. Elevated systolic BP without parallel
elevations in diastolic BP may be ascribed to reduced
aortic compliance,41 owing to the stiffening of
the vessel wall that is often seen in association with aortic
atherosclerosis.42 This in turn
reflects general atherosclerosis and predicts clinical
cardiovascular disease.43 44 45 The
finding is in accordance with the hypothesis that elevated UAER is an
indicator of preclinical atherosclerosis.
In normoalbuminuric subjects, we found a significant
correlation between UAER and office systolic BP but not between
UAER and office diastolic BP. This is in accordance with
earlier reports of weak correlations between UAER and office BP in the
general population,15 16 even though these
correlations are not confirmed in all studies.46
However, more precise correlations between UAER and 24-hour BP levels
were demonstrated in normoalbuminuric subjects with regard to
both systolic and diastolic BP, confirming earlier
reports of superiority of 24-hour BP monitoring to office BP
measurements in illustrating the renal effect of the BP
level.27 28 When the correlations were calculated
within the normoalbuminuric group excluding subjects with a
current UAER exceeding the original grouping criterion, the
correlations between UAER and BP were weakened because of the reduction
in numbers, and the correlations to office BP values as well as 24-hour
systolic BP lost significance. However, all other ambulatory BP
estimates still correlated significantly to UAER.
UAER has a high intraindividual variation with higher values in daytime
and is influenced by upright posture and physical
activity.33 47 As a consequence, we collected
overnight urine samples to measure UAER in this study, and as expected,
the highest correlation coefficient between BP and UAER was found
between nighttime systolic BP and UAER. However, similar
correlations were demonstrated between 24-hour or daytime
systolic BP values and UAER, confirming the association between
UAER and the overall BP level in normal subjects. Calculation of BP
loads revealed similar correlation coefficients to UAER, but these
values were not greater than other estimates of ambulatory BP.
These positive correlations between current UAER and BP may very well
indicate a direct causal relationship between systemic (and thus
possibly intrarenal) BP and transglomerular transport of
albumin in healthy subjects with normal UAER.
In contrast, among subjects with elevated UAER, much higher UAER was
seen at identical BP levels, and no significant correlations between BP
and UAER were found. This was also the case when the correlations were
calculated excluding the subjects with a current UAER in the
normoalbuminuric range. In these subjects, the increased
urinary loss of albumin therefore might be caused by changes in
the properties of the glomerular filter rather than
hemodynamic changes. This would be in accordance with a
number of previous observations. First, the glomerular
filtration of albumin is partly dependent on properties of the
glomerular filter,48 and in diabetes
mellitus the combination of microalbuminuria, loss of
glomerular charge and size selectivity, and increased
transcapillary escape rate of albumin has been
proposed to indicate a generalized vascular
dysfunction.38 Second, in reports from our group,
generalized transvascular albumin leakiness, as well as reduced
glomerular size and charge selectivity, has been
demonstrated in clinically healthy subjects with elevated
UAER.49 50
The participants in the study will be followed up to investigate the
possible influence of the elevated UAER on the later risk for
hypertension, atherosclerotic cardiovascular disease,
or nephropathy.
In conclusion, this study demonstrated that apparently healthy subjects
with elevated UAER had slightly but significantly higher 24-hour
systolic and diastolic BP levels in addition to
increased BP loads compared with normoalbuminuric control
subjects. The nocturnal reduction of BP was, however, normal.
Furthermore, higher pulse pressure was demonstrated in subjects with
elevated UAER, which may be an indicator of reduced aortic compliance
as a consequence of subclinical atherosclerosis. The
demonstrated differences in BP may offer a partial explanation for the
association between elevated urinary albumin excretion and
atherosclerotic cardiovascular disease.
Received November 14, 1997;
first decision December 16, 1997;
accepted March 2, 1998.
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© 1998 American Heart Association, Inc.
Scientific Contributions
Ambulatory Blood Pressure and Urinary Albumin Excretion in Clinically Healthy Subjects
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Abstract—A slightly elevated urinary
albumin excretion rate (UAER) is a predictor of atherosclerotic
cardiovascular disease. The mechanism is unknown, but
moderate office blood pressure elevation has been demonstrated as part
of a clustering of known atherosclerotic risk factors in subjects with
elevated UAER. Because 24-hour ambulatory blood pressure is a superior
predictor of hypertensive target organ involvement, we aimed to
investigate blood pressure profile in clinically healthy subjects with
elevated UAER. Ambulatory blood pressure monitoring was performed with
a portable recorder in 27 subjects with an elevated UAER (>6.6
µg/min, overnight urine collection) and 46 normoalbuminuric
control subjects. Mean±SD systolic and diastolic
ambulatory blood pressures (24-hour) were significantly higher in
subjects with elevated UAER than in normoalbuminuric controls
(134±12 versus 128±11 mm Hg and 78±7 versus 75±6 mm Hg,
P<0.05), as were systolic and
diastolic blood pressure loads [median (range): 42% (6 to
94%) versus 23% (1 to 89%) and 20% (0 to 68%) versus 6% (0 to
62%), P<0.05]. The circadian variation of blood
pressure was normal in subjects with elevated UAER. However, the
increased urinary loss of albumin could not be solely related
to the higher blood pressure. In conclusion, apparently healthy
subjects with elevated UAER had slightly but significantly higher
24-hour systolic and diastolic blood pressure
levels in addition to increased blood pressure loads but normal
circadian variation. The demonstrated differences in blood pressure may
offer a partial explanation for the association between elevated
urinary albumin excretion and atherosclerotic
cardiovascular risk.
Key Words: blood pressure, ambulatory • atherosclerosis • cardiovascular disease • risk factors • albuminuria
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Aslightly elevated
UAER is an independent predictor of cardiovascular
disease in major population-based studies.1 2 3 4 5 6 7 8
The reason for this association is unknown but may in part be related
to BP. Thus, among hypertensive subjects, the prevalence of elevated
UAER is increased and associated with a poor
prognosis.9 10 11 UAER also has been shown to
correlate with office BP in hypertensive and diabetic
subjects9 12 13 14 as well as the general
population,15 16 and pharmacological treatment
often reduces the UAER concomitantly with the reduction in
BP.17 18
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Study Population
All subjects were recruited from the CCHS, 1992–1994, a
longitudinal epidemiological survey of cardiovascular
disease and its known and potential risk
factors.31 In total, 11 290 inhabitants aged 30
to 70 years who lived in a well-defined area surrounding the State
University Hospital were invited to a health examination that included
collection of a timed overnight urine sample for measurement of UAER.
Within the first 10 months of the study, 1011 participants from 30 to
70 years of age had delivered an overnight urine sample with a negative
urinalysis (Nephur Test + Leuco, Boehringer Mannheim). On this
basis, a reference group was established in which the median (10th to
90th interpercentile range) UAER was 2.3 (0 to 6.6) µg/min. UAER
above the 90th percentile (6.6 µg/min) was considered elevated in
this population.32 
). Among these, all participants from 40
to 65 years old with an UAER >6.6 µg/min (90th percentile in the
reference group) and <150 µg/min (to avoid patients with subclinical
nephrological disease) were identified. Any subject with a history of
atherosclerotic disease (myocardial infarction, angina pectoris,
stroke, or intermittent claudication), hypertension (systolic
BP 
160 mm Hg or diastolic BP 95 mm Hg or
use of antihypertensive medication), renal disease, diabetes,
inflammatory rheumatic disease, coagulation disorder, or regular
consumption of medicine was excluded to avoid preexisting disease as a
confounder; this exclusion procedure left 85 of 248 subjects identified
as eligible for study. However, at subsequent reinterview, 14 had
developed medical conditions that excluded them on the basis of the
original exclusion criteria established since their participation in
the CCHS.
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[in a new window]
Figure 1. Flow diagram showing the selection of
candidates with elevated UAER for the present study from the CCHS
and the reasons for the reduction in numbers. *Number of participants
in the CCHS. 
Exclusion criteria: atherosclerotic disease,
hypertension, renal disease, diabetes, inflammatory rheumatic disease,
coagulation disorder, or regular consumption of medicine based on
information from the CCHS. 
Excluded based on criteria met at
reinterview. §Excluded on the examination date because of fasting
blood glucose concentration of 10 mmol/L (1 participant)
or repeated hematuria combined with blood hemoglobin concentration of
5.3 mmol/L (1 participant), respectively.
)
illustrates the reduction in numbers and the reasons for these
reductions in the selection of the candidates with elevated UAER for
the study. 
6.6 µg/min for each subject with elevated
UAER. In the 2 first morning–voided spot urine samples, the
requirement for entrance in this control group was an albumin
concentration of 6.6 mg/L and negative urinalysis in both. All
subjects studied were white. Basic characteristics of
normoalbuminuric controls and subjects with elevated UAER are
given in Table 1.
View this table:
[in a new window]
Table 1. Basal Characteristics, Cigarette and Alcohol
Consumption, UAER, and Standard Laboratory Measurements in Clinically
Healthy Subjects With Normoalbuminuria or Elevated
UAER
Between the first and second day of examination, the
participants collected a repeated overnight urine sample, and the
urinary albumin concentration was measured with an
enzyme-linked immunosorbent assay technique as previously
described.34 The intraassay and interassay
coefficients of variation were both 5.5%. UAER was calculated from
urinary albumin concentration, urine volume, and urine
collection time and designated "current UAER."
Normally distributed continuous variables are given as
mean±SD and nonnormally distributed continuous variables as median
(range). Comparison of variables between groups was made with
unpaired Student's t test or Mann-Whitney U test
for normally and nonnormally distributed variables, respectively.
2 tests were used to compare distribution of
categorical variables. Correlations were determined by Spearman's
nonparametric test. Differences with a probability value of
<0.05 were considered significant.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Office systolic BP was significantly higher in subjects
with elevated UAER, whereas no difference in office
diastolic BP could be demonstrated. The resulting "pulse
pressure" (systolic-diastolic BP) was
significantly higher in subjects with elevated UAER. . As
shown in a graphic presentation, the circadian variation of
BP in subjects with elevated UAER is identical to the variation in
normoalbuminuric subjects but is displayed at a higher level
(Figure 2). In normoalbuminuric
subjects, UAER was significantly correlated to most BP estimates (Table 3, Figure 3). In contrast, no significant
correlations were found between UAER and any of the BP estimates in
subjects with elevated UAER (Table 3, Figure 4).
View this table:
[in a new window]
Table 2. Systolic and Diastolic Office and Ambulatory BP
Measurements in Clinically Healthy Subjects With Normoalbuminuria or
Elevated UAER
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[in a new window]
Figure 2. Twenty-four-hour profile of hourly mean
systolic and diastolic BPs in clinically healthy
subjects with elevated UAER (n=26, 
) and normoalbuminuric
controls (n=45, 
). Vertical bars are standard deviations.
View this table:
[in a new window]
Table 3. Correlations Between Current UAER and Office and
Ambulatory BP in Clinically Healthy Subjects With Normoalbuminuria or
Elevated UAER
View larger version (8K):
[in a new window]
Figure 3. Correlation between 24-hour mean systolic
ambulatory BP and current UAER in normoalbuminuric clinically
healthy subjects (n=45; r=0.44, P<0.005
by Spearman).
View larger version (8K):
[in a new window]
Figure 4. Correlation between 24-hour mean systolic
ambulatory BP and current UAER in clinically healthy subjects with
elevated UAER (n=26; r=0.14, NS by Spearman). ). A
significant positive correlation between BMI and UAER was found within
the normoalbuminuric group (r=0.48,
P<0.001) but not within the group with elevated UAER
(r=0.34, NS).
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
This study has confirmed a previously reported slight elevation of
office BP in clinically healthy normotensive subjects with elevated
UAER by demonstrating higher BP levels in subjects both during the
daytime and while asleep, and higher BP loads using ambulatory BP
monitoring. However, no disturbances in the circadian BP
variation was found. The demonstrated higher BP is likely to contribute
to the increased cardiovascular risk in subjects with
elevated UAER. ).
Selected Abbreviations and Acronyms
BMI
=
body mass index
BP
=
blood pressure
CCHS
=
Copenhagen City Heart Study
UAER
=
urinary albumin excretion rate
Acknowledgments
This study was supported by grants from the Foersom Foundation,
the Danish Medical Association Research Foundation, the Danish
Foundation of A.P. Møller for the Advancement of Medical Science, the
Foundation of P.A. Messerschmidt and wife, and the Danish Medical
Research Council.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
Jarrett RJ, Viberti GC, Argyropoulus A, Hill RD,
Mahmud U, Murrels TJ. Microalbuminuria predicts mortality
in non-insulin-dependent diabetes. Diabet Med. 1984;1:17–19.[Medline]
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