Very Low Levels of Microalbuminuria Are Associated With

Increased Risk of Coronary Heart Disease and Death

Independently of Renal Function, Hypertension, and Diabetes
Klaus Klausen, MD; Knut Borch-Johnsen, MD, DMSc; Bo Feldt-Rasmussen, MD, DMSc;
Gorm Jensen, MD, DMSc; Peter Clausen, MD, PhD; Henrik Scharling, MSc;
Merete Appleyard, RLT; Jan Skov Jensen, MD, PhD, DMSc
BackgroundThe aim of this study was to assess the level of urinary albumin excretion (microalbuminuria), which is
associated with increased risk of coronary heart disease and death, in the population. Microalbuminuria has been
suggested as an atherosclerotic risk factor. However, the lower cutoff level of urinary albumin excretion is unknown.
It is also unknown whether impaired renal function confounds the association.
Methods and ResultsIn the Third Copenhagen City Heart Study in 1992 to 1994, 2762 men and women 30 to 70 years
of age underwent a detailed cardiovascular investigation program, including a timed overnight urine sample. The
participants were then followed up prospectively by registers until 1999 with respect to coronary heart disease and until
2001 with respect to death. During follow-up, 109 incident cases of coronary heart disease and 276 deaths were traced.
A urinary albumin excretion above the upper quartile, ie, 4.8 g/min, was associated with increased risk of coronary
heart disease (RR, 2.0; 95% CI, 1.4 to 3.0; P0.001) and death (RR, 1.9; 95% CI, 1.5 to 2.4; P0.001) independently
of age, sex, renal creatinine clearance, diabetes mellitus, hypertension, and plasma lipids. Lower levels of urinary
albumin excretion were not associated with increased risk.
ConclusionsMicroalbuminuria, defined as urinary albumin excretion 4.8 g/min (corresponding to 6.4 g/min
during daytime), is a strong and independent determinant of coronary heart disease and death. Our suggestion is to
redefine microalbuminuria accordingly and perform intervention studies. (Circulation. 2004;110:32-35.)
Key Words: albumins coronary disease mortality renal function

icroalbuminuria was originally defined among patients

with diabetes mellitus as 20 to 200 g albumin excreted
in the urine per minute (15 to 150 g/min in urine samples
collected at night)1 and was associated with increased risk of
chronic renal failure.2,3 Later, it was shown that microalbuminuria among patients with diabetes reflects systemic vascular
damage4 7 and increased risk of coronary heart disease (CHD)
independently of renal function.8 10 Microalbuminuria is present
in 30% of middle-aged patients with either type 1 or type 2
diabetes mellitus.11 However, in persons without diabetes, urinary albumin excretion is generally far from the level seen in
diabetes.12,13 Nevertheless, population studies of nondiabetic
individuals have demonstrated that even small amounts of
albumin excreted in the urine are associated with increased risk
of CHD.12,14 24
In the present study, we aimed to assess the lower cutoff
level for urinary albumin excretion associated with increased
risk of CHD and death. Furthermore, we measured renal
function because it could affect the association between
microalbuminuria and the risk of CHD and death.25

Methods
Study Population
The study was performed as a substudy of the Third Copenhagen City
Heart Study, 1992 to 1994, a longitudinal epidemiological survey of
cardiovascular disease and its known and potential risk factors.26 About
16 000 subjects were randomly drawn by the Copenhagen Population
Register, and 10 200 (64%) participated. All participants between 30
and 70 years of age were asked to collect a timed overnight urine
sample. A total of 3645 urine samples were received. Included in the
analysis were 2762 participants (1268 men, 1494 women) who had no
history of CHD for whom a total set of data were obtained. All subjects
included gave their informed consent to participate. The study, performed in accordance with the Second Helsinki Declaration, was
approved by the regional ethics committee.

Baseline Variables
Data about medication and smoking were recorded. Diabetes was
defined as self-reported disease, use of antidiabetic medicine or
insulin, and/or nonfasting plasma glucose 11.1 mmol/L (colorimetric enzymatic method). Blood pressure was measured in subjects
in the sitting position on the left upper arm after a 5-minute rest. A
London School of Hygiene sphygmomanometer was used. Hypertension was defined as systolic blood pressure 140 mm Hg,

Received September 4, 2003; de novo received November 17, 2003; revision received March 9, 2004; accepted March 11, 2004.
From the Copenhagen City Heart Study, Epidemiological Research Unit, Bispebjerg University Hospital, Copenhagen, Denmark.
Correspondence to Dr Jan Skov Jensen, Department of Cardiology P., Post 163, Gentofte University Hospital, Niels Andersensvej 65, DK-2900
Hellerup, Denmark. E-mail jsje@c.dk
2004 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org

DOI: 10.1161/01.CIR.0000133312.96477.48

32
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Klausen et al

Microalbuminuria and Coronary Heart Disease

33

TABLE 1. Baseline Characteristics of the Third Copenhagen City Heart Study Population in 19921994 Divided Into
Individuals Who Developed CHD and/or Died During Follow-Up and Control Subjects
Control Subjects for CHD
(n2653)
Men, %

45 (4347)

CHD
(n109)
57 (4866)

Control Subjects for Death

(n2486)
44 (4246)

Death
(n276)
59 (5365)

Age, y

55.0 (54.655.4)

61.5 (60.362.7)*

54.6 (54.255.0)

61.2 (60.462.0)*

Systolic blood pressure, mm Hg

136 (135137)

145 (141150)*

135 (134136)

145 (142148)*

Diastolic blood pressure, mm Hg

86 (8587)

89 (8691)

86 (8587)

89 (8790)*

8 (79)

27 (1935)*

8 (79)

18 (1323)

Antihypertensive medicine, %
Smokers, %

49 (4751)

Body mass index, kg/m2

58 (4967)

48 (4650)

66 (6072)

25.7 (25.525.9)

26.8 (26.027.6)

25.7 (25.525.9)

26.3 (25.826.8)

Diabetics, %

2.8 (2.23.4)

10.1 (4.415.8)

2.5 (1.93.1)

9.1 (5.714.5)

Plasma total cholesterol, mmol/L

6.2 (6.16.3)

6.6 (6.46.9)

6.2 (6.16.3)

6.3 (6.16.5)

Plasma HDL cholesterol, mmol/L

1.58 (1.561.60)

1.43 (1.331.52)

1.57 (1.561.59)

1.54 (1.471.61)

Renal creatinine clearance, mL/(minm2)

43 (4244)

41 (3844)

43 (4244)

40 (3942)

Urine albumin excretion, g/min

3.4 (3.33.5)

5.2 (4.16.7)*

3.3 (3.23.4)

5.4 (4.76.3)*

Values in parentheses indicate 95% CIs. Continuous variables are given as means, except for urine albumin excretion, which is given as geometric
mean.
*P0.0001; P0.0005; P0.001; P0.005; P0.01; P0.05 vs control subjects.

diastolic blood pressure 85 mm Hg, and/or use of antihypertensive

drugs. Body mass index was calculated as weight divided by height
squared. Plasma total and HDL cholesterol and serum creatinine
were measured by enzymatic colorimetric methods.
The urinary albumin concentration was measured by an ELISA
technique,27 and urinary albumin excretion was calculated as
urinary albumin concentration multiplied by the diureses. Urinary
creatinine concentration was measured by a colorimetric method,
and renal clearance of creatinine was calculated as the ratio of
urine to serum concentration multiplied by the diuresis and was
adjusted for body surface area as calculated by this formula:
0.007184weight(0.425)height(0.725) [mL/(minm 2)] and
was taken as an index of glomerular filtration rate.

[geometric mean, 5.4 g/min (95% CI, 4.7 to 6.3) versus 3.3
g/min (95% CI, 3.2 to 3.4; P0.0001; Table 1)].
The Figure shows the age- and sex-adjusted RRs of CHD and
death according to interquartile intervals of urinary albumin
excretion. The risk of both CHD and death was significantly
increased if urinary albumin excretion was above the upper
quartile (ie, 4.8 g/min). In subsequent analyses, we therefore

Follow-Up
All participants were followed until December 31, 1998, with respect
to development of CHD (ICD-10 codes I20.0 through I25.9) and
until August 31, 2001, with respect to death or emigration by means
of the National Patient Register, National Register of Causes of
Death, and Civil Registration System. The completeness of case
finding from the sample was 95%.28

Statistical Analysis
Differences in baseline characteristics between groups were compared by Students t test and the 2 test. RRs were calculated as
hazard ratios by Cox proportional-hazards regression analysis with
age as the underlying time scale, thereby adjusting for age in all
analyses. We also included renal function, diabetes, and hypertension in the analysis because these factors are known to be correlated
to urinary albumin excretion, as well as CHD and death. Furthermore, we included plasma concentrations of total cholesterol and
HDL cholesterol. Probability values 5% were taken as significant.

Results
During follow-up, 109 incident cases of CHD and 276 deaths were
identified. They were at baseline characterized by higher levels of
the conventional atherosclerotic risk factors (Table 1). Furthermore,
subjects who developed CHD during follow-up had higher urinary
albumin excretion than control subjects [geometric mean, 5.2
g/min (95% CI, 4.1 to 6.7) versus 3.4 g/min (3.3 to 3.5);
P0.0001]. This was also the case among subjects who died

RRs of CHD (top) and death (bottom) according to interquartile

intervals of urine albumin excretion among 2762 participants in
Third Copenhagen City Heart Study. Bars indicate 95% CIs;
25%-ile, 2.1 g/min; 50%-ile, 3.0 g/min; and 75%-ile, 4.8
g/min.

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34

Circulation

July 6, 2004

TABLE 2. RRs of CHD and Death During 7 to 9 Years of Follow-Up Associated With Elevated Urinary
Albumin Excretion at Baseline in 1268 Men and 1494 Women From the Third Copenhagen City Heart Study
CHD

Death

All
(n109)

Men
(n62)

Women
(n47)

All
(n276)

Men
(n163)

Women
(n113)

UAE 4.8 g/min

2.2 (1.53.3)*

2.1 (1.33.5)

2.5 (1.44.4)

2.0 (1.62.5)*

1.9 (1.42.6)*

2.2 (1.53.2)*

UAE 4.8 g/min

2.3 (1.53.3)*

2.2 (1.33.6)

2.4 (1.34.4)

2.0 (1.62.6)*

2.0 (1.52.7)*

2.1 (1.43.1)*

UAE 4.8 g/min#

2.0 (1.32.9)

1.7 (1.03.0)

2.3 (1.44.1)

1.9 (1.52.4)*

1.8 (1.32.5)*

2.1 (1.43.1)*

UAE 15 g/min

2.8 (1.64.9)*

3.3 (1.76.2)*

1.8 (0.55.8)

2.9 (2.14.0)*

2.9 (1.94.3)*

3.0 (1.65.4)

UAE 15 g/min

2.8 (1.65.0)*

3.4 (1.86.5)*

1.7 (0.55.5)

2.9 (2.14.0)*

2.8 (1.94.2)*

3.0 (1.65.4)*

UAE 15 g/min#

2.2 (1.34.0)

2.4 (1.24.8)

1.5 (0.44.9)

2.5 (1.83.6)*

2.4 (1.63.7)*

2.8 (1.55.1)

Urinary albumin excretion (UAE) 4.8 g/min is reference. Values in parentheses indicate 95% CIs.
*P0.001; P0.005; P0.01; P0.05
Adjusted for age; adjusted for age and renal creatinine clearance; #adjusted for age, renal creatinine clearance, presence of
hypertension, presence of diabetes mellitus, plasma total cholesterol, and plasma HDL cholesterol.

defined microalbuminuria as a urinary albumin excretion 4.8

g/min. For comparison, we also analyzed the risk associated
with urinary albumin excretion 15 g/min (ie, the cutoff level
used among diabetes patients).
Urinary albumin excretion 4.8 g/min was associated with a
significantly increased risk of CHD and death of 2 in both men
and women, and it was mainly unaffected by adjustment for age,
creatinine clearance, hypertension, diabetes, and total and HDL
cholesterol (Table 2). Urinary albumin excretion 15 g/min was
also associated with a significantly increased risk of death of 3 in
both men and women regardless of age, creatinine clearance,
hypertension, diabetes, and total and HDL cholesterol. This was
also the case regarding CHD in men, whereas the risk of CHD
in women was not increased significantly when urinary albumin
excretion was 15 g/min (Table 2).

Discussion
This prospective population study of 2762 men and women
30 to 70 years of age with a 7- to 9-year follow-up has
confirmed the results from previous reports of increased risk
of CHD and death associated with small amounts of albumin
excreted in the urine, ie, microalbuminuria.12,14 24,29 To
specify the risk level of urinary albumin excretion in a simple
manner with sufficient statistical power and without any
presumptions, we stratified the population according to quartiles of urinary albumin excretion. Thus, the major novel
observation in the present study was that a urinary albumin
excretion rate exceeding only 4.8 g/min (corresponding to
6.4 g/min during daytime)30 strongly predicts CHD and
death, and the predictive effect is independent of age, sex,
renal function, diabetes, hypertension, and lipids. Furthermore, because of the pronounced intraindividual variability of
urinary albumin excretion and thus regression dilution,31 the
estimated risks of CHD and death associated with microalbuminuria may be underestimated.
Data from the recent HOPE study suggested that any level
of microalbuminuria predicts CHD in individuals with or
without diabetes.32 The risk increased with the ratio of urinary
albumin to creatinine concentration, starting well below the
usually defined level of microalbuminuria, as in our study.
Thus, the HOPE study suggested that a 0.4-mg/mmol in-

crease in the ratio of urinary albumin to creatinine concentration led to a 5.9% higher age- and sex-adjusted risk of
CHD.32 In contrast, we observed in our study that the risk of
CHD and death remarkably increased when a 4.8-g/min
threshold of urinary albumin excretion was exceeded.
Among diabetes patients, microalbuminuria is usually defined
as an albumin excretion of 15 to 150 g/min in a urine sample
collected during night,1 although the risk of CHD and death may
be increased at even lower levels.8,32,33 This definition is of
limited clinical relevance as a cardiovascular risk factor in the
general population. First, 3% of the healthy population has
urinary albumin excretion in this range.34 Second, the risk of
CHD among women with urinary albumin excretion 15
g/min was not significantly increased in the present study,
perhaps because of insufficient power. The traditional definition
of microalbuminuria1 is based on the level of urinary albumin
excretion in patients with diabetes that predicts the development
of clinical diabetic nephropathy. We suggest the definition be
revised according to the level that increases the risk of CHD and
death in the general population. In the present study, this level
was found to be 5 g/min, corresponding to an albumin
concentration of 6 mg/L and an albumin-to-creatinine ratio of
0.7 mg/mmol in a morning urine sample (data not shown).
This cutoff level has also been suggested from previous population studies using the albumin-to-creatinine ratio in a spot urine
sample,14,23 which may be a more practical approach in clinical
practice. We recognize that many additional factors potentially
may influence the urinary albumin excretion in a population
study, eg, response rate, population size, age range, frequency of
urinary tract infection, and urine collection and examination
methods. Despite these factors, the presence of microalbuminuria in a single urine sample seems to increase the risk.14
A prior study has shown that reduced renal creatinine
clearance is an independent predictor of CHD in middle-aged
subjects.25 We therefore adjusted the association between
microalbuminuria and risk of CHD and death for renal
creatinine clearance. We found no confounding influence of
renal creatinine clearance on the association.
We have previously proposed that microalbuminuria may
reflect a systemic transvascular leakiness of macromolecules,
including albumin and lipoproteins.4 7,35,36 In a recent study,

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Klausen et al
however, we were unable to support this hypothesis in both
diabetic and nondiabetic individuals (J.S. Jensen et al, unpublished data, 2004). It is likely that microalbuminuria emerges
later in the atherosclerotic process.3739 Intervention trials
against, for example, modifiable risk factors in persons with
microalbuminuria would be of relevance to obtain further
evidence for screening for microalbuminuria in the population.
In conclusion, microalbuminuria is a strong determinant of
CHD and death independently of age, sex, hypertension,
diabetes mellitus, renal function, and lipids. From these
observations, we suggest changing the usual definition of
microalbuminuria, ie, urinary albumin excretion 15 g/min
(in nocturnal collections), to 5 g/min (or albumin-to-creatinine ratio 0.7 mg/mmol) and including it in the individual risk assessment of atherosclerotic cardiovascular disease.

Acknowledgments
The study was funded by the Danish Heart Foundation, Novo
Foundation, Nordisk Insulin Foundation, and Boehringer-Mannheim
GmbH.

Microalbuminuria and Coronary Heart Disease

18.

19.

20.

21.

22.

23.

24.

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Very Low Levels of Microalbuminuria Are Associated With Increased Risk of Coronary
Heart Disease and Death Independently of Renal Function, Hypertension, and Diabetes
Klaus Klausen, Knut Borch-Johnsen, Bo Feldt-Rasmussen, Gorm Jensen, Peter Clausen, Henrik
Scharling, Merete Appleyard and Jan Skov Jensen
Circulation. 2004;110:32-35; originally published online June 21, 2004;
doi: 10.1161/01.CIR.0000133312.96477.48
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2004 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

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