Atherosclerosis and Lipoproteins |
From the Centre of Preventive Medicine, Glostrup University Hospital, Glostrup (K.B.-J., M.S., J.S.J.); the Department of Nephrology, Rigshospitalet, University Hospital (B.F.-R.); and the Department of Nephrology, Herlev University Hospital, Herlev (S.S.), Denmark.
Correspondence to Chief Physician Knut Borch-Johnsen, MD, MSc, Steno Diabetes Centre, Niels Steensensvej 2, DK-2820 Gentofte, Denmark. E-mail kbjo{at}novo.dk
| Abstract |
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Key Words: urinary albumin excretion microalbuminuria ischemic heart disease atherosclerosis
| Introduction |
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Several studies have demonstrated an association between slightly increased urinary albumin excretion and cardiovascular risk factors, even in the general population.13 14 15 16 17 18 19 In the Copenhagen City Heart Study, we found that otherwise-healthy individuals with a urinary albumin excretion level >90th percentile (>7 µg/min) were characterized by higher blood pressures and lower plasma concentrations of apolipoprotein A-1 and HDL cholesterol.20 Furthermore, they had a generalized transvascular leakiness for albumin.21 These observations suggest that individuals with slightly increased urinary albumin excretion may be at increased risk for the subsequent development of ischemic heart disease (IHD). The pathogenic mechanisms leading to increased risk are still unknown, but microalbuminuria has been suggested as a marker of endothelial dysfunction and hyperpermeability to macromolecules,22 23 which occurs early in atherogenesis24
In 1995 Kuusisto et al25 showed that in elderly (mean age, 69 years), nondiabetic individuals who were followed up for 3.5 years, microalbuminuria was a marker for subsequent development of coronary heart disease. This was particularly evident in patients with hyperinsulinemia. These authors defined microalbuminuria as a urinary A/C ratio exceeding that for the upper quintile of the entire population under study (A/C ratio >3.22 mg/mmol, corresponding to a urinary albumin excretion well above 20 µg/min). This excretion rate is high for nondiabetic individuals compared with our data26 27 and data from other, predominantly population-based studies.13 14 15 16 17 18 19 28
In the present study, we followed our previous definition of microalbuminuria for the nondiabetic population,20 21 26 27 ie, urinary albumin excretion >90th percentile. With this definition, the aim of our study was to 1) analyze whether microalbuminuria predicts subsequent development of IHD (IHD) in young and middle-aged individuals (30 to 60 years) and ii) study the interaction between microalbuminuria and established atherosclerotic risk factors in the prediction of IHD.
| Methods |
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Atherosclerotic Risk Factors
Fasting blood samples were drawn for measurement of plasma total
cholesterol, HDL cholesterol, and plasma
triglycerides (enzymatic colorimetric
methods: CHOL CHOD-PAP, HDL cholesterol precipitant, and
GPO-PAP, respectively; Peridichrom, Boehringer Mannheim GmbH).
Blood glucose was not measured. Blood pressure was measured 3 times to
the nearest 2 mm Hg in sitting position with use of a London
School of Hygiene sphygmomanometer and an appropriately sized cuff.
Height and weight were measured. As part of a different subproject,
all individuals underwent ultrasound examination of both kidneys and
the urinary tract.
Microalbuminuria
Urine samples were collected as first morning spot urine
samples. After a dip-stick test, aliquots were stored at -20°C for
the following 11 to 12 years. Urine analyses for
albumin and creatinine concentrations were
performed in 1995. Urinary albumin was measured using an
ELISA-technique (dilution 1:100; lower detection limit, 0.1 mg/l;
interassay CV, 8.3%; intra-assay CV, 2.1%).32 Urinary
creatinine was measured by a reaction rate kinetic
principle, thus eliminating pseudocreatinines (intra-assay
CV, 1%; interassay CV, 2%).33 We defined the lower 90%
range of the albumin-to-creatinine ratio as normal
and the upper 10% (corresponding to an A/C ratio >0.65 mg/mmol) as
abnormal. This definition is in accordance with a recent
recommendation.34 Individuals were excluded if they had
IHD, diabetes, glucosuria. hematuria (by urinary dip-stick-test),
history of renal disease, history of urinary tract infection within 3
months of entry to the study, or an abnormal ultrasonic examination of
the kidneys or urinary tract at baseline. Diabetes was classified as
yes/no based on the questionnaire item, "Has a doctor ever told you
that you suffer from diabetes?"
Ischemic Heart Disease
Based on the Danish personal identification code (so-called
CPR-number), all individuals were followed up until death, emigration,
or December 31, 1993. Information on vital status, cause of death,
hospital admissions, and diagnoses were traced in national registers.
We identified all cases with fatal or nonfatal myocardial infarction,
angina pectoris, or IHD (ICD-8 code No. 410 to 414).35
Studies of the validity of the Danish Hospital Discharge Register have
shown that between 89% and 99% of clinically manifest myocardial
infarctions are registered.36 37 38
Statistical Analysis
Baseline characteristics in the patients developing IHD and
those not developing IHD were compared using Student's t
test or the
2 test. The effect of the baseline
parameters on the risk of developing IHD was
analyzed by Cox proportional-hazards regression
analysis with the conditional forward selection procedure. The
free from IHD survival during follow-up for individuals in the lower
90% range and upper 10% of urinary A/C-ratio was compared with a
Kaplan-Meier-plot and log-rank test statistics. All variables
independently predicting the development of IHD (P<0.05)
were tested for interaction with microalbuminuria on the
risk of IHD. The graphical presentations given in Figures 2a
through 2e are all based on combinations of the combined
effect of microalbuminuria and the second risk factor,
adjusted for the effect of all remaining risk factors (ie, age, sex,
body mass index, systolic blood pressure, smoking,
cholesterol [total and HDL], and
triglycerides). In the categorical analyses,
systolic blood pressure was categorized as normal (<140
mm Hg), borderline (140 to 160 mm Hg), or hypertensive
(>160 mm Hg) according to the recommendations from WHO.
Cholesterol was categorized as normal (<5.2 mmol/L),
slightly elevated (5.2 to 7.0 mmol/L), or high (>7.0
mmol/L). These cutoff levels were chosen on the basis existing
intervention studies, where 5.2 corresponded to the treatment target in
the 4S Study39 and 7.0 corresponded to the high level
in the West of Scotland trial.40 HDL was categorized as
low (<0.9 mmol/L), intermediate (0.9 to 1.5 mmol/L), or high
(>1.5 mmol/L). The analyses were performed by the
statistical software package SPSS for Windows, version
6.0.
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| Results |
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Table 2
shows the results of the
Cox-regression analyses. Microalbuminuria was
associated with a 2.3-fold increased risk of IHD compared with
normoalbuminuric individuals. This effect is of the same
magnitude as that for male sex, high age (10-year increase), and
current smoking. When the RR of IHD was compared in dec, corrected for
the effect of other risk factors and after Bonferroni correction for
multiple testing; the risk of IHD did not increase further with higher
levels of the A/C ratio.
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As shown in Figure 1
, the crude
survival free from IHD during follow-up among normoalbuminuric
individuals was 97% compared with 91% in the group with
microalbuminuria (P<0.0001). After adjusting
for the effects of age, sex, smoking, blood pressure, total
cholesterol, HDL cholesterol,
triglycerides, and body mass index, the 10-year
disease-free survival was 99% and 97% in the 2 groups, respectively
(P=0.005). This decrease in risk difference was mainly due
to older age and higher blood pressures in the subjects developing
IHD.
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Figure 2a
through 2e shows the
combined effect of microalbuminuria and each of the other
significant risk factors. Each panel has been adjusted for the effect
of all other significant risk factors. A/C ratio and sex both
contributed to the risk of IHD (Figure 2a
), but no significant
interaction between the 2 variables was found. Thus, males with
microalbuminuria had a risk of IHD 5.1 times higher than
normoalbuminuric females.
The combined effect of smoking and microalbuminuria is
shown in Figure 2b
. In nonsmokers, microalbuminuria
alone did not have a significant effect, but there was a significant
interaction between smoking and microalbuminuria
(P<0.01). Thus, smoking alone was associated with a RR of
IHD of 2.5 in normoalbuminuric individuals but 5.6 in smokers
with microalbuminuria.
Elevated systolic blood pressure (Figure 2c
) and
microalbuminuria both conferred an increased risk of IHD.
This was the case for mild hypertension (systolic blood
pressure 141 to 160 mm Hg) as well as for more severe
hypertension (>160 mm Hg), where the combined effect of
hypertension and microalbuminuria was increased 3.3 times
and 5.3 times, respectively.
For total and HDL cholesterol, an effect of lipid
levels as well as microalbuminuria was observed (Figure 2d
and 2e
). The combined effect of cholesterol
>7.0 mmol/L and microalbuminuria was an RR for IHD of
10.5 compared with normoalbuminuric individuals with a
total-cholesterol level <5.2 mmol/L. HDL
cholesterol <0.9 mmol/L with
microalbuminuria was associated with an RR of 6.1 compared
with normoalbuminuric individuals with HDL
cholesterol >1.5 mmol/L.
| Discussion |
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On the basis of findings in patients with insulin-dependent or noninsulin-dependent diabetes mellitus, we had previously advanced the hypothesis that microalbuminuria is a marker of a generalized vascular dysfunction (the "Steno Hypothesis"22 ). In recent years, elevated urinary albumin excretion has been also demonstrated in nondiabetic individuals,7 13 14 15 16 17 18 19 20 21 25 26 27 28 42 and it has been found to be associated with elevated blood pressure, dyslipidemia, and high plasma insulin levels.13 14 15 16 17 18 19 20 27 45 Hypertension and dyslipidemia are both well-established risk factors for the development of cardiovascular disease. Furthermore, in a cross-sectional, population-based study of >2600 individuals from the Copenhagen City Heart Study, we have demonstrated that microalbuminuria is associated with the prevalence of cardiovascular disease.27
In the present study, we found that microalbuminuria is a predictor of the development of IHD, independent of other established atherosclerotic risk factors such as male sex, arterial hypertension, dyslipidemia, smoking, old age, and obesity. The general effect of microalbuminuria in this study was that the risk associated with conventional risk factors was more than doubled when the individual had microalbuminuria as well. The specific pathogenic mechanisms behind this association are still poorly understood. We have previously shown that healthy individuals with microalbuminuria have a generalized increase in transvascular escape of albumin.21 In animals, increased transvascular albumin transport is associated with an increased transport of lipoproteins into the arterial wall,46 47 and therefore we speculated that microalbuminuria might be a marker of increased susceptibility to the atherogenic effect of other established risk factors rather than a classic risk factor per se (ie, directly involved in the pathogenic mechanism). However, no significant interaction was observed between microalbuminuria and dyslipidemia for the development of IHD in this study.
In the present study, we used the urinary A/C ratio as a
marker of albumin excretion rate. The classic definition of
microalbuminuria was established in diabetology on the
basis of the cut-off level that predicted the development of diabetic
nephropathy (ie, >30 mg/24 h).4 48 For
screening purposes in population-based studies, collection of 24-hour
urine samples would be difficult or almost impossible. In a previous
study, we used overnight urine sampling, but even with this protocol we
had an
50% dropout rate in a population-based
survey.27 In the present study, we used a spot urine
collection to increase compliance. Because albumin
concentration in the urine is affected by the level of
diuresis, we adjusted for this by dividing albumin
concentrations by urinary creatinine
concentration.49 Investigating
microalbuminuria with the A/C ratio is less precise than
using the albumin excretion rate per se in urine, thereby
detracting from the possibility of demonstrating a positive
association. Also, we used only 1 urine sample to classify our
individuals. With an intra-individual day-to day-variability in
albumin excretion of 25% to 40%50 51 52 this gives
a high for random misclassification, further reducing the chance of
detecting a positive association. In the present study, we
collected the urine samples in 1983 to 1984. The samples were stored at
-20°C for >10 years before analysis. Long-term storage of
urine samples will cause some degradation of
albumin.53 Previously, we had shown that over a
period of 15 months, the relative degree of degradation is independent
of the initial albumin concentration.54 In the
present study, we analyzed the effect of urinary A/C ratio
based on the relative ranking in deciles; thus, degradation of
albumin should not affect our results. It should, however, be
noted that the urinary A/C ratios at entry into the study were likely
than the values given in the present investigation.
In this study as well as in our previous work, we defined microalbuminuria as a urinary albumin excretion exceeding the upper 90th percentile of the distribution in the general population. This definition differs from the conventional definition in diabetology, ie, a urinary albumin excretion exceeding 30 mg/24 h, or 20 µg/min. Even in diabetic patients, the risk of developing cardiovascular disease probably increases at lower levels of urinary albumin excretion.6 In the nondiabetic population, microalbuminuria would primarily be of interest as a potential predictor of macrovascular disease, not renal disease. Our aim was to study whether slightly elevated urinary albumin excretion might be a clinically relevant risk marker for development of IHD. Because we found that the increased risk of IHD was confined to the upper decile of urinary albumin excretion, we have shown that this cut-off level represents the clinically relevant definition of microalbuminuria in the general population. Owing to the long storage of the urine samples we are not, however, able to identify the exact "at-risk level" of the A/C ratio.
This population-based study demonstrated that a slightly increased urinary A/C ratio is a potent and clinically relevant risk marker for the development of IHD. Because microalbuminuria predicts IHD independently of other classic atherosclerotic risk factors and moreover, interacts with the effect of smoking, this suggests that an increased atherogenic susceptibility is conferred. Thus, individuals with other atherosclerotic risk factors such as smoking, dyslipidemia, and hypertension should have their urinary albumin excretion measured, because this piece of information contributes to the classification of the individual as a high-risk or high-susceptibility individual. It is unknown whether individuals with microalbuminuria also will benefit more from intervention, but we would recommend that future controlled clinical trials should focus on answering this question, as it could lead to a more targeted and focused strategy for the prevention of IHD.
| Acknowledgments |
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Received August 20, 1998; accepted November 24, 1998.
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