Chronic kidney disease and risk of incident myocardial

Clinical research
European Heart Journal (2006) 27, 1245–1250
Prevention and epidemiology
Chronic kidney disease and risk of incident myocardial
infarction and all-cause and cardiovascular disease
mortality in middle-aged men and women from the
general population
Christa Meisinger1,2*, Angela Döring2, and Hannelore Löwel2 for the KORA Study Group
Central Hospital of Augsburg, MONICA/KORA Myocardial Infarction Registry, Stenglinstr. 2, D-86156 Augsburg, Germany;
and 2 GSF National Research Center for Environment and Health, Institute of Epidemiology, Neuherberg, Germany
Received 24 November 2005; revised 24 February 2006; accepted 23 March 2006; online publish-ahead-of-print 12 April 2006
Cohort study;
Kidney function;
Myocardial infarction;
Aims Chronic kidney disease (CKD) was found to be an independent risk factor for all-cause mortality as
well as adverse cardiovascular disease (CVD) events in high-risk populations. Findings from populationbased studies are scarce and inconsistent. We investigated the gender-specific association of CKD with
all-cause mortality, cardiovascular mortality, and incident myocardial infarction (MI) in a populationbased cohort.
Methods and results The study was based on 3860 men and 3674 women (aged 45–74 years) who
participated in one of the three MONICA Augsburg surveys between 1984 and 1995. CKD was defined
by an estimated glomerular filtration rate between 15 and 59 mL/min/1.73 m2. Hazard ratios (HRs)
were estimated from Cox proportional hazard models. In this study, 890 total deaths, 400 CVD
deaths, and 321 incident MIs occurred in men up to 31 December 2002; the corresponding numbers in
women were 442, 187, and 102. In multivariable analyses, the HR for women with CKD compared to
women with preserved renal function was significant for incident MI [HR 1.67; 95% confidence interval
(CI) 1.07–2.61] and CVD mortality (HR 1.60; 95% CI 1.17–2.18). In men, CKD was also significantly associated with incident MI (HR 1.51; 95% CI 1.09–2.10) and CVD mortality (HR 1.48; 95% CI 1.15–1.92) after
adjustment for common CVD risk factors. In contrast, men and women with CKD had no significant
increased risk of all-cause mortality.
Conclusion CKD was strongly associated with an increased risk of incident MI and CVD mortality independent from common cardiovascular risk factors in men and women from the general population.
Chronic kidney disease (CKD) is a worldwide public health
problem with an increasing incidence and prevalence.1
The increase in the number of persons with CKD is
reflected in the rising number of people with end stage
renal disease (ESRD) treated by dialysis or kidney transplantation.2 In the past, the incidence of ESRD reached
about 135 new patients per million in Europe and 336
new patients per million in the USA.3 Furthermore, in
several studies it was shown that a decreased level of
kidney function is an independent risk factor for all-cause
mortality as well as adverse cardiovascular disease (CVD)
events, such as myocardial infarction (MI) and stroke.4–7
These findings were, in particular, based on studies conducted in high-risk populations, for example in patients
with CVD or CVD risk factors.4–7 However, data from the
general population on this issue are scarce and the findings
are less consistent.8–12 In addition, very few population-
* Corresponding author. Tel:
þ 49 821 400 4373; fax: þ 49 821 400 2838.
E-mail address: [email protected]
based data are available in Europe.13 In the present study,
we investigated the association between CKD and incident
MI, CVD mortality, and all-cause mortality in persons aged
45–74 years from the general population. To answer the
question whether CKD is likewise a risk factor for the different outcomes in both sexes, all analyses were performed
separately for men and women.
The presented data were derived from the population based
MONICA (monitoring trends and determinants on cardiovascular diseases) Augsburg (southern Germany) studies conducted between
1984 and 1995. The MONICA Augsburg project was part of the multinational WHO MONICA project and the design of the project has
been described in detail elsewhere.14,15 Three independent crosssectional surveys were carried out in the city of Augsburg and the
counties Augsburg and Aichach–Friedberg in 1984/85 (S1), 1989/90
(S2) and 1994/95 (S3) to estimate the prevalence and distribution
of cardiovascular risk factors among men and women. Altogether
13 427 persons (6725 men, 6702 women, response 77%) aged
& The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: [email protected]
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Data collection
Baseline information on socio-demographic variables, smoking
habits, physical activity level, medication use, and alcohol consumption were gathered by trained medical staff during a standardized interview. In addition, all the participants underwent an
extensive standardized medical examination including the collection of a blood sample. All measurement procedures have been
described elsewhere in detail.14 Body mass index (BMI) was calculated as weight in kilograms divided by height in square metres.
Participants were classified as active during leisure time if they regularly participated in sports in summer and winter and if they were
active for at least 1 h per week in either season. Actual hypertension was defined as blood pressure values 140/90 mmHg and/or
use of anti-hypertensive medication given that the subjects were
aware of being hypertensive. Dyslipidaemia was defined as the
ratio of total cholesterol to high density cholesterol 5.0. History
of CVD was defined as prevalent MI or prevalent stroke at baseline.
Clinical chemical measurements
A non-fasting venous blood sample was obtained from all study
participants while sitting. Total serum cholesterol analyses were
carried out using an enzymatic method (CHOD-PAP, Boehringer
Mannheim, Germany). HDL cholesterol was also measured enzymatically after precipitation of the apoprotein B-containing lipoproteins
with phosphotungstate/Mg2þ (Boehringer Mannheim, Germany).
Serum creatinine was determined using an automated Jaffe
method in S1 and S2 (Technicon, SMAC autoanalyzer; Tarrytown,
NY) and using an enzymatic method in S3 (creatinine PAP,
Boehringer Mannheim, Germany). The enzymatic method was calibrated according to the Jaffe method. Serum uric acid was
measured by the uricase method in S1 and S2. In S3, serum uric
acid was determined with an enzymatic colorimetric reaction
(Uric Acid PAP, Boehringer Mannheim). Internal and external
quality control was performed according to the WHO MONICA
Assessment of renal function
The abbreviated Modification of Diet in Renal Disease Study Group
equation1 was used to calculate eGFR:
eGFR (mL/min/1.73 m2) ¼ 186.3 (serum creatinine21.154) (age20.203) 0.742 (if female) 1.212 (if black), where serum
creatinine is measured in mg/dL, and age in years.
The study population was stratified into two groups by the level of
kidney function, namely, eGFR of 15–59 mL/min/1.73 m2, and eGFR
of 60 mL/min/1.73 m2. This cut-point was chosen as an eGFR of
15–59 mL/min/1.73 m2 represents a moderate to severe decrease
of GFR defined by the NKF K/DOQI guidelines.16 Thus, the term
CKD was used for an eGFR between 15 and 59 mL/min/1.73 m2 in
the present study.
The endpoints used in this study were incidence of fatal or non-fatal
MI including sudden cardiac death, mortality from any CVD, and allcause mortality. Mortality was ascertained by regularly checking the
vital status of all sampled persons of the MONICA surveys through
the population registries inside and outside the study area; this procedure guaranteed that the vital status of cohort members who had
moved out of the study area could also be assessed. Death certificates were obtained from local health departments and coded for
the underlying cause of death by a single trained person using the
9th revision of the International Classification of Diseases (ICD-9).
MIs were identified through the population-based MONICA/KORA
Augsburg coronary event registry for the 25 to 74-year-old study
population and censored at the 75th year of age.17 This registry
monitors the occurrence of all in- and out-of-hospital fatal and nonfatal MIs among the 25 to 74-year-old inhabitants of the study
region.17 An MI was considered as incident if it was the first during
follow-up in a person without a history of heart attack in the baseline survey. Up to 31 December 2000, the diagnosis of a major nonfatal MI was based on the MONICA algorithm taking into account
symptoms, cardiac enzymes, and ECG changes.17 Since 1 January
2001 all patients with MI diagnosed according to ESC and ACC criteria were included.18,19 Coronary deaths were validated by death
certificates, autopsy report, chart review, and information from
the coroner or the last treating physician.
Statistical analyses
For analyses of MI, event times were computed as the time from
baseline examination to the occurrence of the first event and for
analyses of total and cardiovascular mortality, event times were calculated as times to death. For all-cause and CVD mortality (ICD-9:
390–459), subjects without events were censored at their last
date of follow-up. For incidence estimates, that is non-fatal MIs
and fatal coronary events, the follow-up times were censored for
men and women at death or when they reached the age of 75
years after which the register-based monitoring of coronary
events ceases. Means or proportions for baseline demographic and
clinical characteristics were computed for men and women with
and without CKD. The x 2 test was used to test the differences in prevalences. The t-test was used to compare means. The interquartile
range (IQR) was defined as the interval from the 25%-quantile to the
75%-quantile. Hazard ratios (HRs) were computed for persons with a
moderate to severe decrease of eGFR (15–59 mL/min/1.73 m2) as
compared with persons with an eGFR of 60 mL/min/1.73 m2 in
Cox proportional hazards models. The first model included eGFR
and in addition age (continuous) and survey. The second model
included all previous factors plus actual hypertension (yes/no), dyslipidaemia (yes/no), level of physical activity (active/inactive),
smoking status (regular smoking, that is a subject who smoked at
least one cigarette per day at baseline, yes/no), alcohol intake
(men: 0, .0, and ,40 or 40 g/day; women: 0, .0, and ,20 or
20 g/day), BMI (continuous), and history of diabetes (yes/no and
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25–74 years participated in at least one of the three cross-sectional
studies. All persons who took part in more than one survey were
included once only with data collected at the first visit. All subjects
were prospectively followed within the framework of the
Cooperative Health Research in the Region of Augsburg (KORA).
The present study was restricted to 45–74 year old study participants (n ¼ 7823; 3993 men, 3830 women). Up to 31 December
2002, 890 men and 442 women in this age-range had died. None
of the study participants were excluded from analysis due to insufficient follow-up.
For the present analyses using mortality as outcome, we excluded
all subjects with incomplete data on any of the included variable
(n ¼ 285). Furthermore, we excluded four study participants with
an estimated glomerular filtration rate (eGFR) ,15 mL/min/
1.73 m2, because such a GFR is defined as kidney failure in the
National Kidney Foundation (NKF) Kidney Disease Outcomes
Quality Initiative (K/DOQI) guidelines.16 Finally, the prospective
analyses comprised 3860 men and 3674 women aged 45–74 years
at baseline for the outcomes of all-cause and CVD mortality.
For the analyses using incident MI as outcome, we excluded 277
study participants with incomplete data on any of the included variables, four persons with an eGFR ,15 mL/min/1.73 m2, and 249
persons with a prevalent MI at baseline. Furthermore, for these analyses, 142 men and 120 women who moved outside the study area
during follow-up were censored at the date of the move. Thus,
these analyses comprised 3662 men and 3631 women aged 45–74
years at baseline.
Written informed consent was obtained from each study participant and the study was approved by the local Ethics Committee.
C. Meisinger et al.
CKD and cardiovascular events
unknown). For the mortality outcomes fully adjusted models 2 were
also adjusted for history of CVD.
The above analyses were repeated by including eGFR as a continuous variable. HRs were computed for an increase of 10 mL/min/
1.73 m2 of eGFR.
The assumption of proportionality of hazards was assessed by
fitting models stratified by risk factor categories, then plotting
the log (-log(survival)) curves to check parallelism. No severe deviations from parallelism were evident. The assumption of linearity
was assessed graphically by studying the smoothed martingal
residuals from the null model plotted against the covariate variables. Kaplan–Meier survival plots of eGFR groups in relation to
the different outcomes were examined. Comparisons between survival curves were performed using Log Rank test. Results are presented as HRs and 95% confidence interval (CI). Significance tests
were two tailed and P-values ,0.05 are stated as statistically significant. All analyses were performed using the Statistical Analysis
System (Version 8.2, SAS Institute Inc., Cary, NC, USA).
In Table 1, gender specific differences in the baseline
characteristics between persons with and without CKD are
given. Men and women with CKD were more likely to be
older, to have dyslipidaemia, and a history of diabetes and
CVD. They were more likely to be hypertensive, to be nonsmokers, and less likely to have a high daily alcohol
intake. These men and women were also more likely to
have a higher BMI, higher uric acid, and serum creatinine
levels. During follow-up (median follow-up period 12.5
years; IQR: 7.8–13.1), 890 total deaths, 400 CVD deaths,
and 321 incident MIs occurred in men; the corresponding
numbers in women were 442, 187, and 102 (Table 2).
Table 2 also describes the observed crude incidence rates
for the different outcomes by categories of kidney function.
Men and women with CKD had higher crude rates for allcause mortality, CVD mortality, and first ever MI compared
with men and women without CKD. In all categories and
The present large population-based study confirmed associations of reduced eGFR and increased risk of CVD mortality.
The risk associated with CKD was apparent in men and
women from the general population. In addition, this
study showed a strong association between CKD and first
ever coronary heart disease event in men and women
without a history of MI independent of traditional
Table 1 Baseline characteristics by gender and level of kidney function
eGFR Group (mL/min/1.73 m2)
Age (years)
Education (,12 years, %)
BMI (kg/m2)
History of diabetes (%)
History of CVD (%)
Actual hypertension (%)
Use of anti-hypertensive agents (%)
Alcohol intake (%)
0 g/day
0.1–19.9 g/day (women),
0.1–39.9 g/day (men)
20 g/day (women), 40 g/day (men)
Regular smoking (%)
Physically active (%)
Dyslipidaemia (%)
Serum creatininea
Serum uric acid
Geometric mean.
Men (n ¼ 3860)
Women (n ¼ 3674)
15–59 (n ¼ 480)
60 (n ¼ 3380)
15–59 (n ¼ 753)
60 (n ¼ 2921)
62.4 (8.2)
28.2 (3.5)
57.2 (7.9)
27.8 (3.5)
61.5 (7.2)
28.4 (4.6)
56.6 (7.8)
27.6 (4.8)
1.5 (1.2)
6.4 (1.4)
52.4 (7.2)
1.0 (1.1)
5.7 (1.3)
80.9 (13.7)
1.1 (1.2)
5.0 (1.3)
51.9 (7.5)
0.8 (1.1)
4.1 (1.1)
77.6 (12.8)
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for all outcomes, the crude incidence rates were higher in
men than in women. Kaplan–Meier survival analysis
showed a greater probability of an incident MI, CVD mortality, and all-cause mortality in men and women with CKD
(Figures 1–3).
In Cox proportional hazards analyses the age- and
survey-adjusted HRs were significantly increased for incident MI and CVD mortality in women with CKD compared
with women with preserved renal function. In men, CKD
was also significantly associated with incident MI and CVD
mortality in age- and survey-adjusted analysis. After multivariable adjustment, the independent associations
remained significant in both sexes (Table 3). In contrast,
men and women with CKD had no significantly increased
risk of all-cause mortality.
When eGFR was included as a continuous variable in the
Cox proportional hazard models, in men an increment of
10 mL/min/1.73 m2 of eGFR was associated with a significant decrease in the risk of an incident MI (HR 0.91; 95%
CI 0.84–0.99), but not with a significant decrease in CVD
mortality (HR 0.96; 95% CI 0.89–1.03) and all-cause mortality (HR 1.04; 95% CI 0.99–1.08) after multivariable adjustment. In women, an increase of 10 mL/min/1.73 m2 of eGFR
was significantly associated with incident MI (HR 0.88; 95% CI
0.77–1.00) and CVD mortality (HR 0.85; 95% CI 0.78–0.94),
but not with all-cause mortality (HR 0.97; 95% CI
0.91–1.04) in multivariable adjusted analyses.
C. Meisinger et al.
Table 2 Outcomes by level of kidney function
eGFR (mL/min/1.73 m2)
Incident MI
Number of participants
3 221
2 894
Person-years (PY)
3 141
32 703
6 438
30 975
Events/10 000 PY
All-cause mortality
Number of participants
3 380
2 921
Person-years (PY)
4 373
38 321
8 270
34 886
Events/10 000 PY
CVD mortality
Number of participants
3 380
2 921
Person-years (PY)
4 373
38 321
8 270
34 886
Events/10 000 PY
Figure 1 (A) Survival curves for incident MI by eGFR category. MONICA/
KORA Cohort Study, men aged 45–74 years at baseline. (B) Survival curves
for incident MI by eGFR category. MONICA/KORA Cohort Study, women aged
45–74 years at baseline.
cardiovascular risk factors. However, the present findings
did not provide support for a significant relationship
between CKD and all-cause mortality in both sexes.
Prior studies including subjects at high risk for CVD
consistently demonstrated an independent association
between reduced level of kidney function and CVD
events, as well as CVD mortality.7,20–22 However, previous community-based studies have shown discordant
results.8–12 Because of the different methods of estimating
GFR used in the hitherto existing studies direct comparisons
between the investigations are difficult. Some studies used
serum creatinine levels as a marker of renal function,8,9,23
other examinations were based on the Cockcroft–Gault
equation.13 In accordance with some recent studies,10–12
in the present study the modification of Diet in Renal
Disease (MDRD)Study equation for GFR was used, because
it has been thoroughly validated in adults.1
The Framingham Heart Study9 showed that serum creatinine levels between 136 and 265 mmol/L for men and
between 120 and 265 mmol/L for women were associated
with all-cause mortality in men, but not in women.
Furthermore, in multivariable analyses baseline kidney
disease was not associated with incident CVD events or
CVD mortality.9 Also, the National Health and Nutrition
Examination Survey (NHANES) I follow-up study8 observed
a significant association between moderate renal insufficiency, defined as a creatinine of 122 to 177 mmol/L in
men and 104 to 146 mmol/L in women, and all-cause as
well as CVD mortality in unadjusted analyses. However,
after adjustment for traditional cardiovascular risk factors
both associations lost significance. Therefore, the authors
concluded that the relationship between moderate renal
insufficiency and CVD, demonstrated in other epidemiologic
studies, appears to be due to co-occurrence of renal insufficiency with traditional cardiovascular risk factors. In contrast to these studies, the British Regional Heart Study
observed an association between serum creatinine and
CVD mortality in middle-aged men with a baseline serum
creatinine level of 130 mmol/L (HR 1.4, 95% CI 1.0–2.1)
when compared with men with baseline serum creatinine
values ,116 mmol/L.23 Muntner et al.11 investigated the
association between MDRD-calculated GFR, and CHD and
CVD mortality among NHANES II participants. Compared
with subjects with a GFR 90 mL/min subjects with a baseline GFR ,70 mL/min had a significantly increased risk of
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Figure 2 (A) Survival curves for CVD mortality by eGFR category. MONICA/
KORA Cohort Study, men aged 45–74 years at baseline. (B) Survival curves
for CVD mortality by eGFR category. MONICA/KORA Cohort Study, women
aged 45–74 years at baseline.
CKD and cardiovascular events
Table 3 HRs (95% CI) for outcomes in men and women with CKD
Incident MI (fatal
and non-fatal)
All-cause mortality
CVD mortality
Age- and
1.50 (1.09–2.08)
1.75 (1.13–2.71)
1.51 (1.09–2.10)
1.67 (1.07–2.61)
1.17 (0.97–1.41)
1.16 (0.94–1.44)
1.17 (0.97–1.41)
1.12 (0.90–1.39)
1.55 (1.20–2.00)
1.74 (1.28–2.35)
1.48 (1.15–1.92)
1.60 (1.17–2.18)
Adjusted for age, survey, history of diabetes, regular smoking, BMI,
alcohol intake, actual hypertension, physical activity, and dyslipidaemia;
outcomes all-cause and CVD mortality: additional adjustment for history
of CVD.
both CHD mortality (HR 1.68, 95% CI 1.23–2.30) and CVD
mortality (HR 1.68, 95% CI 1.33–2.13) in multivariable analysis. Moreover, the level of GFR was an independent risk
factor for atherosclerotic cardiovascular disease (ASCVD)
and de novo ASCVD in the Atherosclerosis Risk in
Communities (ARIC) Study.12 The Hoorn Study showed that
mild-to-moderate loss of renal function is strongly associated with an increased risk of cardiovascular mortality
even after adjustment for traditional cardiovascular risk
factors, markers of inflammation, and markers of endothelial dysfunction.13 Finally, recently a pooled analysis of
four community-based longitudinal studies (ARIC,
Cardiovascular Health Study, Framingham Heart Study, and
Framingham Offspring Study) found that in adjusted analyses CKD was a risk factor for the composite outcome of
all-cause mortality and CVD in the general population (HR
1.19; 95% CI 1.07–1.32). In contrast to the present study,
that study was very large, and therefore it had sufficient
power to investigate the effect of CKD on all outcomes in
subjects without CVD at baseline.10
The present results are in line with the hypothesis that
renal function itself is implicated in the association with
cardiovascular disease. Because we did not observe a significant relationship between CKD and all-cause mortality
it can be assumed that CKD is a specific independent predictor of cardiovascular events and not an unspecific
marker of health status or unhealthy lifestyle. The
reasons for the high cardiovascular risk in persons with
CKD remain unknown.24 A possible explanation could be
that a decrease in renal function may be associated with
other non-traditional risk factors that were not taken into
consideration in this study. Such factors include for
example, changes in coagulation, lipids, endothelial
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Figure 3 (A) Survival curves for all-cause mortality by eGFR category.
MONICA/KORA Cohort Study, men aged 45–74 years at baseline. (B) Survival
curves for all-cause mortality by eGFR category. MONICA/KORA Cohort
Study, women aged 45–74 years at baseline.
dysfunction, homocysteine and/or the presence of
anemia, oxidative stress, and inflammation.24,25 On the
other hand, CKD may be the result of both duration and
severity of other causes of cardiovascular disease, such as
hypertension. Thus, reduced kidney function may reflect
residual confounding from CVD risk factors. Furthermore,
it is thinkable that CKD may exacerbate the effect of
CVD risk factors and may, therefore, promote the atherosclerotic process.
The MONICA/KORA Augsburg Study has several limitations
that need to be considered. Although we adjusted for a
variety of confounders, confounding by unmeasured variables cannot be excluded. Particularly, no data on recently
identified CVD risk factors, such as CRP and homocysteine,
could be taken into consideration. Prior studies have
shown that estimates of GFR depend critically upon the
accuracy and precision of the creatinine measurement
used in their calculation.26 In the present study, the definition of CKD was based on a single measurement of
serum creatinine at baseline examination; thus, misclassification bias cannot entirely be ruled out. Because the study
was limited to men and women of German nationality
between 45 and 74 years of age, caution should be used in
generalizing these results to other populations and other
age-groups, respectively. The strengths of the MONICA/
KORA Augsburg Cohort Study are primarily its prospective
design, the representativeness of the cohort, based on a
random sample of the general population and the availability of data on lifestyle and multiple cardiovascular risk
In conclusion, the present study showed that CKD is
strongly associated with an increased risk of incident MI
and CVD mortality in men and women from the general
population. The underlying mechanism behind this relationship is unclear but seems to be independent from common
risk factors such as hypertension, diabetes, smoking, BMI,
alcohol intake, physical activity, and dyslipidaemia. Thus,
estimation of GFR in addition to the consideration of
present conventional risk factors may be a valuable tool
for individual cardiovascular risk assessment. Further
studies are needed to investigate the pathophysiological
mechanisms underlying this association.
C. Meisinger et al.
The KORA research platform and the MONICA Augsburg studies were
initiated and financed by the GSF—National Research Center for
Environment and Health, which is funded by the German Federal
Ministry of Education, Science, Research and Technology and by
the State of Bavaria. Morbidity and Mortality follow-ups in 1997/
98 and 2002/03 were in addition supported by grants from the
Federal Ministry of Education, Science, Research and Technology
(01 ER 9701/4) and the German Research Foundation (DFG) (TH
784/2-1), respectively. We thank all members of the GSF Institute
of Epidemiology and the field staff in Augsburg who were involved
in the planning and conduct of the study. Finally, we express our
appreciation to all the study participants.
Conflict of interest: none declared.
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