Adjusted absolute risk increases for each subgroup (with vs without
chronic kidney disease) were determined by multiplying the annual cardiovascular
mortality risk among participants in that subgroup without the candidate risk
factor (persons with chronic kidney disease who did not have left ventricular
hypertrophy or anemia, for example) by the increased relative risk for the
predictor variable (adjusted hazard ratio−1). Error bars indicate 95%
confidence intervals. Risk factors are defined in the “Definitions”
paragraph in the “Methods” section of the text.
Receiver operating characteristic (ROC) curves demonstrate the relative
ability of traditional risk factors and traditional plus novel risk factors
to predict cardiovascular death. Among participants with chronic kidney disease,
the area under the curve (AUC) for traditional risk factors was 0.73 (95%
confidence interval, 0.70-0.77). Adding novel risk factors increased the AUC
to 0.74 (95% CI, 0.71-0.78; P for difference = .15).
Among participants without chronic kidney disease, ROC curves also did not
differ significantly when comprising traditional risk factors (AUC, 0.73;
95% CI, 0.69-0.76) or traditional plus novel risk factors (AUC, 0.72; 95%
CI, 0.68-0.75; P for difference = .16).
Because alcohol use had a hazard ratio <1.0, this calculation was made
with the reciprocal of the hazard ratio.
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Shlipak MG, Fried LF, Cushman M, et al. Cardiovascular Mortality Risk in Chronic Kidney DiseaseComparison of Traditional and Novel Risk Factors. JAMA. 2005;293(14):1737–1745. doi:10.1001/jama.293.14.1737
Context Elderly persons with chronic kidney disease have substantial risk for
cardiovascular mortality, but the relative importance of traditional and novel
risk factors is unknown.
Objective To compare traditional and novel risk factors as predictors of cardiovascular
Design, Setting, and Patients A total of 5808 community-dwelling persons aged 65 years or older living
in 4 communities in the United States participated in the Cardiovascular Health
Study cohort. Participants were initially recruited from 1989 to June 1990;
an additional 687 black participants were recruited in 1992-1993. The average
length of follow-up in this longitudinal study was 8.6 years.
Main Outcome Measures Cardiovascular mortality among those with and without chronic kidney
disease. Chronic kidney disease was defined as an estimated glomerular filtration
rate of less than 60 mL/min per 1.73 m2.
Results Among the participants, 1249 (22%) had chronic kidney disease at baseline.
The cardiovascular mortality risk rate was 32 deaths/1000 person-years among
those with chronic kidney disease vs 16/1000 person-years among those without
it. In multivariate analyses, diabetes, systolic hypertension, smoking, low
physical activity, nonuse of alcohol, and left ventricular hypertrophy were
predictors of cardiovascular mortality in persons with chronic kidney disease
(all P values <.05). Among the novel risk factors,
only log C-reactive protein (P = .05) and
log interleukin 6 (P<.001) were associated with
the outcome as linear predictors. Traditional risk factors were associated
with the largest absolute increases in risks for cardiovascular deaths among
persons with chronic kidney disease: for left ventricular hypertrophy, there
were 25 deaths per 1000 person-years; current smoking, 20 per 1000 person-years;
physical inactivity, 15 per 1000 person-years; systolic hypertension, 14 per
1000 person-years; diabetes, 14 per 1000 person-years; and nonuse of alcohol,
11 per 1000 person-years vs 5 deaths per 1000 person-years for those with
increased C-reactive protein and 5 per 1000 person-years for those with increased
interleukin 6 levels. A receiver operating characteristic analysis found that
traditional risk factors had an area under the curve of 0.73 (95% confidence
interval, 0.70-0.77) among those with chronic kidney disease. Adding novel
risk factors only increased the area under the curve to 0.74 (95% confidence
interval, 0.71-0.78; P for difference = .15).
Conclusions Traditional cardiovascular risk factors had larger associations with
cardiovascular mortality than novel risk factors in elderly persons with chronic
kidney disease. Future research should investigate whether aggressive lifestyle
intervention in patients with chronic kidney disease can reduce their substantial
The National Kidney Foundation, American Heart Association, and the
Seventh Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure have classified the presence of chronic kidney
disease as a cardiovascular risk factor.1-3 Chronic
kidney disease is associated with substantially increased risk for cardiovascular
disease morbidity and mortality, independent of traditional cardiovascular
risk factors such as diabetes, hypertension, lipoprotein levels, and tobacco
addition, certain novel cardiovascular risk factors are more prevalent in
persons with chronic kidney disease, including elevated inflammatory and prothrombotic
factors (C-reactive protein [CRP], fibrinogen, interleukin 6 [IL-6], and factor
VIII), and lipoprotein(a) (Lp[a]), and decreased hemoglobin levels. These
novel risk factors have been discussed as potential mechanisms for the elevated
cardiovascular risk of chronickidney disease,7-9 but
few studies have evaluated their association with cardiovascular events in
persons with chronic kidney disease or compared the strength of association
of traditional and novel cardiovascular risk factors. Though the National
Institutes of Health and the National Kidney Foundation have prioritized the
reduction of cardiovascular disease burden in persons with chronic kidney
disease, prevention efforts will first require an in-depth understanding of
the determinants of cardiovascular risk in persons with chronic kidney disease.10
In the Cardiovascular Health Study (CHS), a well-characterized cohort
of elderly persons with a high prevalence of chronic kidney disease, we compared
the association of traditional and novel risk factors with cardiovascular
mortality among subgroups of participants with and without chronic kidney
disease at baseline. In addition, we estimated the absolute risk associated
with each candidate risk factor and constructed receiver operating characteristic
(ROC) curves to estimate the aggregate predictive utility of traditional and
novel risk factors.11
The CHS is a prospective cohort study of risk factors for cardiovascular
disease in elderly men and women. The study recruited eligible persons who
resided in the households of individuals identified from an age-stratified
random sample from Medicare eligibility lists in Forsyth County, North Carolina;
Sacramento County, California; Washington County, Maryland; and Pittsburgh,
Pa. Household members and spouses of the person being recruited were also
invited to participate in the CHS if they met the following inclusion criteria:
(1) at least 65 years, (2) not institutionalized, (3) expected to remain in
the current community for 3 years or longer, (4) not under active treatment
for cancer, and (5) gave written informed consent without requiring a proxy
respondent at entry. Among those who met the eligibility requirements and
were invited to participate, 57% were enrolled. The initial 5201 participants
(original cohort) were enrolled from 1989 to June 1990; an additional 687
black participants (African-American cohort) were recruited and enrolled in
1992-1993. Race was self-reported in 5 categories: white, black, American
Indian/American Native, Asian/Pacific Islander, other. A separate question
addressed Hispanic heritage. Race was subsequently collapsed into white, black,
and other because the nonwhite or nonblack proportion was very small. The
baseline examination for each cohort included a medical history, physical
examination, laboratory testing, and assessments of cardiovascular disease
status. The study design, quality-control procedures, laboratory methods,
and blood pressure measurement procedures have been published previously.12
This study was approved by the internal review boards of the University
of California, San Francisco, University of Washington, and University of
This analysis included all participants with creatinine measures at
baseline (5808). Serum creatinine was measured using the Kodak Ektachem 700
Analyzer (Eastman Kodak, Rochester, NY), a colorimetric method. We estimated
glomerular filtration rate (GFR) using the modified formula of Levey et al,10 and categorized chronic kidney disease as a GFR less
than 60 mL/min per 1.73 m2, based on recommendations of the National
Kidney Foundation.3 Serum creatinine in the
Modification of Diet in Renal Disease (MDRD) study and subsequently in a subset
of individuals included in the Third National Health and Nutrition Examination
Survey (NHANES III) were both analyzed at the Cleveland Clinic laboratory.
Because creatinine values vary across clinical laboratories, we calibrated
the creatinine concentration in our current study to the Cleveland Clinic
laboratory indirectly using a method previously reported by Manjunath and
colleagues,13 and others.14-16 This
calibration technique is based on the population-based recruitment of CHS
and assumes that the mean serum creatinine comparable for a given age, race,
and sex strata in CHS should be comparable with NHANES III. A linear regression
of data combining each study individually with NHANES III showed that serum
creatinine values were 0.11 mg/dL (9.72 μmol/L) higher in the original
cohort of CHS and 0.04 mg/dL (3.53 μmol/L) higher in the CHS African American
cohort. These values were then subtracted from measured creatinine levels
before use in the current study.
Traditional risk factors were measured and categorized on all CHS participants.
Each was dichotomized to facilitate comparisons of their association with
the outcome with other risk factors. These variables were defined as follows:
systolic hypertension (systolic blood pressure ≥140 mm Hg); diabetes (history
of diabetes, use of hypoglycemic agent or insulin, or fasting glucose ≥126
mg/dL [>7.0 mmol/L]); current smoking; high-density lipoprotein ([HDL] ≤40
mg/dL [<1.04 mmol/L]); low-density lipoprotein ([LDL] ≥130 mg/dL (>3.37
mmol/L)]; triglycerides ≥200 mg/dL (2.26 mmol/L); regular alcohol use (≥2
drinks/wk); obesity (body mass index [BMI] ≥30 [calculated as weight in
kilograms divided by the square of height in meters]); physical inactivity
(lowest quartile of CHS reported energy expenditure)17;
and left ventricular hypertrophy (LVH) by electrocardiogram.18 Subsequent
analyses evaluated systolic blood pressure, HDL, LDL, and triglyceride levels,
alcohol use (drinks/wk), BMI, and physical activity as continuous variables.
All serum measures were conducted from baseline specimens.
Novel risk factors were measured on stored serum or plasma among either
theentire cohort of CHS participants (CRP, fibrinogen, IL-6, and hemoglobin)
or among the original cohort only (Lp[a] and factor VIII coagulant activity)
from the baseline visit. The specific assays used for each measure were as
follows: fibrinogen, BBL Fibrometer (Becton-Dickson, Cockeysville, Md)19,20; factor VIIIc, Coag-A-Mate (Organon
Teknika, Dublin, Ireland)19-21;
and IL-6, ultrasensitive enzyme-linked immunosorbent assay (R&D Systems,
Minneapolis, Minn). C-reactive protein was measured using an enzyme-linked
immunosorbent assay developed by the CHS central blood laboratory (CHS Blood
Laboratory, Colchester, Vt). Lipoprotein(a) was measured with a monoclonal
antibody–based enzyme-linked immunosorbent assay.22 The
reagents for Lp(a) were obtained from Genentech (South San Francisco, Calif).
Results are expressed in terms of the Lp(a) lipoprotein protein concentration
(excluding lipid), with reference to a purified standard calibrated by quantitative
amino acid analysis. The overall coefficient of variation for Lp(a) lipoprotein
measurements in this study was 7.5%. Anemia was defined as hemoglobin of 12
mg/dL or less for both men and women. Abnormal levels for each of the other
novel risk factors were defined by the highest quartile. Additional models
analyzed hemoglobin, CRP, fibrinogen, IL-6, Lp(a), and factor VIIIc as continuous
variables per standard deviation.
All fatal events were reviewed and classified by a mortality review
committee using information from death certificates, autopsy and coroners'
forms, hospital records, and interviews with attending physicians, next of
kin, and witnesses. Deaths were classified as cardiovascular or noncardiovascular;
cardiovascular death was defined as mortality caused by coronary heart disease,
heart failure, peripheral vascular disease, and cerebrovascular disease.13 The outcome of this analysis was time to cardiovascular
death. Participants were censored when they left the study or died from a
The prevalence or the level of each traditional and novel risk factor
was initially compared among persons with and without chronic kidney disease,
using χ2 tests or t tests as appropriate.
To compare the association of each dichotomized risk factor with cardiovascular
mortality among persons with and without chronic kidney disease, proportional
hazards models were constructed, stratified by chronic kidney disease presence.
In model 1, these models were adjusted for age, sex, race, education, medication
use (candidates were β-blockers, calcium channel blockers, angiotensin-converting
enzyme inhibitors, and diuretics) and prevalent cardiovascular disease (defined
by prior myocardial infarction, coronary revascularization, or cerebrovascular
disease), and the individual risk factor of interest. In model 2, the stratified
models were also adjusted for all the other traditional risk factors defined
above. Candidate novel risk factors were not combined in multivariate analyses.
To evaluate for the presence of multiplicative interactions, we created
a product term for each risk factor with chronic kidney disease and evaluated
its significance in the multivariate model. These same methods were repeated
for the risk factors when analyzed as continuous variables. C-reactive protein
and IL-6 levels were log-transformed for these analyses because of their skewed
distribution. Interactions of race and sex were tested with each risk factor
for predicting the outcome of cardiovascular mortality.
We next estimated the absolute risk for each dichotomized traditional
and novel risk factor, stratified by the presence of chronic kidney disease.
The absolute risks were estimated by multiplying the incidence rate of the
unexposed group by the adjusted relative risk increase (adjusted hazard ratio
− 1) of the predictor. For example, the absolute risk associated with
diabetes in the no–chronic kidney disease stratum was calculated by
multiplying the incidence rate for cardiovascular death in participants with
neither diabetes nor chronic kidney disease by the adjusted relative risk
increase for diabetes within the no–chronic kidney disease strata. Similarly,
the absolute risk associated with diabetes within the chronic kidney disease
stratum was determined by the product of the cardiovascular mortality incidence
in nondiabetics with chronic kidney disease and the adjusted relative risk
increase for diabetes within the chronic kidney disease subgroup.
To compare traditional and novel risk factors in aggregate, we constructed
ROC curves and determined their area under the curve (AUC). This method evaluated
the overall ability of the risk factor collection to discriminate participants
who would or would not subsequently die from a cardiovascular cause. Stratified
by the presence of chronic kidney disease, we first determined the AUC for
traditional risk factors alone; then, we calculated the AUC for the combined
traditional plus novel risk factors. We compared the AUC of the 2 ROC curves
within each chronic kidney disease strata using the method described by DeLong
Intercooled Stata 8 (StataCorp LP, College Station, Tex) and SPSS 12
(SSPS, Chicago, Ill) were used for the statistical analyses. P values <.05 were considered statistically significant.
At study entry, 1249 (22%) participants had chronic kidney disease,
defined by an estimated GFR of less than 60 mL/min per 1.73 m2.
Participants with chronic kidney disease were on average 3 years older; were
more likely to be men and white; were less likely to have more than a high
school education; and had a greater prevalence of cardiovascular disease than
those without chronic kidney disease (Table 1). Those with chronic kidney disease also had higher levels of triglycerides
and lower HDL cholesterol levels. Participants with chronic kidney disease
used less alcohol, were less physically active, and had a greater prevalence
of LVH. Among the novel risk factors,mean levels of CRP, fibrinogen, IL-6,
factor VIIIc, and Lp(a) were higher and hemoglobin was lower among those with
than among those without chronic kidney disease.
During an average follow-up time of 8.6 years, the annual risk of cardiovascular
mortality was 32 per 1000 person-years among participants with baseline chronic
kidney disease (342 events) and 16 per 1000 person-years among participants
without chronic kidney disease (750 events). Diabetes, systolic hypertension,
current smoking, low physical activity, and LVH were strongly associated with
elevated risk among participants with and without chronic kidney disease,
and alcohol use was associated with decreased risk even after adjustment for
all other traditional risk factors (Table 2).
Low HDL, elevated LDL, and triglyceride levels and obesity were not associated
with the outcome in persons with or without chronic kidney disease. Although
the point estimates for diabetes and LVH were modestly smaller and for low
physical activity modestly larger among participants with chronic kidney disease,
we observed no significant interactions among the 10 traditional risk factors
with chronic kidney disease for predicting cardiovascular death.
In contrast to our findings for traditional risk factors, certain novel
risk factors appeared to have weaker associations with cardiovascular mortality
among participants with chronic kidney disease compared with the associations
among those without chronic kidney disease (Table
2). Among the inflammatory and procoagulant factors evaluated, elevated
levels of CRP, fibrinogen, and factor VIIIc had strong associations with cardiovascular
mortality in participants without chronic kidney disease, but none was a significant
predictor of the outcome in the chronic kidney disease group after multivariate
analysis. We observed a significant interaction (P<.05)
between presence of chronic kidney disease and both CRP and factor VIIIc for
predicting cardiovascular mortality, whereas the interaction of chronic kidney
disease with fibrinogen was of borderline significance (P = .09). Elevated levels of IL-6 had a somewhat stronger
association with the outcome in the non–chronic kidney disease subgroup,
though the test for interaction was not significant (P = .23).
The association of elevated levels of Lp(a) with cardiovascular mortality
was similar in both groups, but only significant in persons without chronic
kidney disease. Anemia was not significantly associated with the outcome in
The comparisons of traditional and novel risk factors were repeated
with most risk factors analyzed as continuous variables per standard deviation
(Table 3). Systolic blood pressure had
similar and significant associations with increased risk and physical activity
with decreased risk of cardiovascular mortality in the subgroups with and
without chronic kidney disease. As with the dichotomized predictors, LDL and
HDL levels, triglycerides, and BMI were not associated with the outcome in
either subgroup, and no significant interactions were observed.
Among the novel risk factors, log CRP, fibrinogen, and factor VIIIc
levels again appeared to have larger associations with cardiovascular mortality
in the subgroup without chronic kidney disease although the tests for interaction
were only significant for fibrinogen and factor VIIIc (Table 3). The association of log IL-6 with the outcome was strong
and equivalent in the participants with or without chronic kidney disease.
Lipoprotein(a) and hemoglobin levels were not significantly associated with
the outcome in either subgroup when modeled as a continuous variable.
We tested for interactions of sex and race with each risk factor as
predictors of the outcome. None of these was significant at a level of P<.20.
For the 6 traditional risk factors that were significantly associated
with cardiovascular mortality and the 6 novel risk factors, we estimated the
absolute risk of each for cardiovascular mortality. This metric can be interpreted
as the average annual increase in cardiovascular mortality risk on an absolute
scale that is attributable to the risk factor within each subgroup of participants
(with and without chronic kidney disease). Among those with chronic kidney
disease (average risk of 32 cardiovascular deaths/1000 person-years), traditional
risk factors were associated with the largest absolute elevations in cardiovascular
mortality risk: LVH, an increased risk of 25 per 1000 person-years, and current
smoking, an increased risk of 20 per 1000 person-years, were associated with
the greatest increments of risk, followed by physical inactivity, an increased
risk of 15 per 1000 person-years; diabetes an increased risk of 14 per 1000
person-years; and systolic hypertension, an increased risk of 14 cardiovascular
deaths per 1000 person-years. Alcohol use was associated with a decreased
risk of 11 deaths per 1000 person-years (Figure
1). The novel risk factors were associated with smaller increases
in risk that were not statistically significant: lower hemoglobin had an increased
risk of 9 deaths per 1000 person-years; elevated Lp(a), an increased risk
of 6 deaths per 1000 person-years; IL-6, an increased risk of 5 deaths per
1000 person-years; and CRP, an increased risk of 5 deaths per 1000 person-years
Among participants without chronic kidney disease (average risk of 16
cardiovascular deaths/1000 person-years), LVH (increased risk of 17/1000 person-years),
diabetes (increased risk of 15/1000 person-years), and current smoking (increased
risk of 13/1000 person-years) had the largest associations with mortality
risk (Figure 1). Although increased
CRP, fibrinogen, IL-6, factor VIIIc, and Lp(a) were all significantly associated
with cardiovascular death, the absolute increase in risk ranged only from
4 deaths per 1000 for those with elevated Lp(a) to 8 deaths per 1000 person-years
for those with elevated CRP levels (Figure 1).
Among participants with chronic kidney disease, the strong associations
of traditional risk factors with cardiovascular mortality were reflected by
the AUC of 0.73 (95% confidence interval [CI], 0.70-0.77; Figure 2). Adding novel risk factors had only a slight effect, increasing
the AUC to 0.74 (95% CI, 0.71-0.78; P for difference = .15).
Similarly, ROC curves among participants without chronic kidney disease (Figure 2) did not differ significantly when developed
from traditional risk factors (AUC, 0.73; 95% CI, 0.69-0.76) or traditional
novel risk factors (AUC, 0.72; 95% CI, 0.68-0.75; P for
difference = .16).
In a community-based sample of elderly persons with chronic kidney disease,
traditional risk factors were better predictors of cardiovascular mortality
than novel risk factors. In descending order by their absolute risk, LVH,
current smoking, physical inactivity, diabetes, elevated systolic blood pressure,
and nonuse of alcohol were associated with substantial elevations in cardiovascular
mortality risk among participants with chronic kidney disease. Among the novel
risk factors evaluated, none was associated with elevated cardiovascular risk
in this subgroup as a dichotomized predictor, although log IL-6 and log CRP
predicted risk as linear variables. In ROC analysis, the 10 traditional risk
factors accrued an AUC of 0.73, similar to that observed in the Framingham
Heart Study; whereas the 6 novel risk factors had no significant additional
utility for predicting the outcome.24 These
findings may suggest that the most promising future interventions to reduce
cardiovascular mortality risk in elderly persons with chronic kidney disease
would be intense modification of established risk factors rather than the
pursuit of interventions to reduce levels of novel risk factors.
Prior literature evaluating the cardiovascular risk of persons with
chronic kidney disease has largely been composed of longitudinal studies demonstrating
elevated cardiovascular risk in persons with chronic kidney disease compared
with persons with normal renal function and cross-sectional studies demonstrating
that a variety of traditional and novel cardiovascular risk factors are elevated
in the setting of chronic kidney disease. The relative importance of elevations
in novel risk factors for determining cardiovascular risk in persons with
chronic kidney disease has been relatively unexplored until recently.8 Muntner and colleagues25 published
a report from the Atherosclerosis Risk in Communities (ARIC) cohort of middle-aged
adults that evaluated predictors of chronic heart disease events (myocardial
infarction, cardiovascular death, or coronary revascularization) in participants
with chronic kidney disease. These investigators also found strong associations
of systolic blood pressure, diabetes, and current smoking with chronic heart
disease events in persons with chronic kidney disease although their findings
differed from ours because anemia, increased fibrinogen, and lower albumin
levels did predict chronic heart disease events in analyses adjusted for age,
race, sex, current smoking, diabetes, hypertension, total cholesterol, and
clinical site. Muntner et al, however, did not present results with more extensive
multivariate adjustment. Our cohort differs from ARIC in exclusively recruiting
elderly persons, having a higher prevalence of chronic kidney disease (22%
vs 5%), and having a different array of traditional and novel predictors.
A recent case-control analysis by Knight et al26 from
the Nurses’ Health Study found an opposite interaction from ours because
inflammatory factors (CRP, IL-6, and soluble tumor necrosis factor receptors
I and II) were associated with greater coronary artery disease risk among
participants with estimated GFR lower than 75 than in those with a GFR higher
than 75. Other than the inclusion of men, the primary differences between
our study and that of Knight et al are that the CHS had a higher prevalence
of participants with chronic kidney disease, included exclusively elderly
persons, and had a different cardiovascular outcome.
The potential implication of our article is that traditional risk factors
may be the optimal targets for cardiovascular risk reduction in elderly patients
with chronic kidney disease. Not only were these risk factors the strongest
predictors of cardiovascular mortality, but several of them have proved and
established interventions to modify their risk. In combination, the additive
associations of these traditional risk factors with cardiovascular mortality
in elderly persons with chronic kidney disease suggest great potential for
beneficial interventions. On the other hand, we cannot assume that treating
each of these traditional risk factors would lower cardiovascular mortality
risk by the amount suggested in these analyses. Among these 6 traditional
risk factors that predicted the outcome, only systolic blood pressure control
has been shown in clinical trials to be a modifiable risk factor for cardiovascular
events in the elderly. Although many health benefits are known to result from
tobacco cessation, exercise, and glycemic control, we cannot assume that such
interventions would necessarily reduce cardiovascular mortality in elderly
persons with chronic kidney disease. Nevertheless, our findings raise the
hypothesis that cardiovascular prevention efforts would be most productive
if focused on aggressive lifestyle interventions and blood pressure control
in this population.
Our finding that levels of CRP, fibrinogen, and factor VIIIc had larger
associations with cardiovascular mortality in persons without chronic kidney
disease is intriguing. In contrast, increased levels of IL-6 had a nearly
equivalent association with the outcome in participants with or without chronic
kidney disease. One possibility is that the levels of CRP, fibrinogen, and
factor VIIIc are increased in the setting of chronic kidney disease, not because
of increased production but rather due to their decreased renal clearance
or degradation. Thus, the statistical association of their plasma levels with
cardiovascular risk might be diminished in the setting of chronic kidney disease.
An alternative explanation for these findings of interaction between the 3
biomarkers and chronic kidney disease for predicting cardiovascular mortality
is that they could be chance findings.
The absence of an association between hemoglobin and cardiovascular
mortality in our study differs from the associations of anemia with cardiovascular
events observed in previous studies.15,27,28 One
possibility is that the prevalence of anemia (defined as hemoglobin <12
g/dL in men and women) was too low at 4.2% to allow a precise estimate; however,
we also found no association with hemoglobin evaluated as a linear variable.
In addition, an association of anemia with the outcome could have been obscured
by our adjustment for prevalent cardiovascular disease.
This study has several important limitations to consider. In our primary
analyses, we dichotomized all of the risk factors to define absolute risks
and to compare them across traditional and novel risk factors. Although this
method may have reduced statistical power for detecting an association, the
findings were similar when risk factors were evaluated as continuous variables.
Another important issue is that the population consisted of community-dwelling
elderly persons with chronic kidney disease; these findings may not generalize
to younger populations with primary renal diseases. The observation that chronic
kidney disease was more common in white than black participants raises the
concern that our white and black participants may not be equally representative
of the general community. We also defined chronic kidney disease based on
estimated GFR rather than on actual measures of renal function; however, direct
measures of GFR are expensive and cumbersome and are rarely used in large
epidemiologic studies.29 Finally, this study
involved multiple comparisons and subgroup analyses with a single outcome,
and thus had the potential for chance positive and negative findings.
In conclusion, we report that traditional cardiovascular risk factors
had larger associations with cardiovascular mortality than novel risk factors
in a community-based cohort of elderly persons with chronic kidney disease.
Our findings suggest that interventions that aggressively target control of
systolic blood pressure and glucose levels, tobacco cessation, and increased
physical activity may have the greatest potential to reduce cardiovascular
risk in this high-risk population. Although certain inflammatory and procoagulant
factors were less strongly associated with cardiovascular risk in participants
with chronic kidney disease, this finding requires confirmation in future
studies. Future research should investigate whether aggressive lifestyle intervention
in patients with chronic kidney disease can reduce their substantial cardiovascular
Corresponding Author: Michael G. Shlipak,
MD, MPH, General Internal Medicine Section, VA Medical Center (111A1), 4150
Clement St, San Francisco, CA 94121 (firstname.lastname@example.org).
AuthorContributions: Mr Peterson and Dr Siscovick had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Shlipak, Fried, Cushman,
Acquisition of data: Cushman, Peterson, Siscovick,
Analysis and interpretation of data: Shlipak,
Cushman, Manolio, Peterson, Stehman-Breen, Newman, Bleyer, Newman, Siscovick,
Drafting of the manuscript: Shlipak, Cushman,
Peterson, Stehman-Breen, Bleyer.
Critical revision of the manuscript for important
intellectual content: Shlipak, Fried, Cushman, Manolio, Peterson, Newman,
Bleyer, Newman, Siscovick, Psaty.
Statistical analysis: Shlipak, Peterson, Bleyer,
Obtained funding: Shlipak, Newman, Siscovick,
Administrative, technical, or material support:
Study supervision: Stehman-Breen, Newman, Siscovick.
Financial Disclosures: Dr Fried has received
honoraria from Pfizer and research support from Boehringer Ingelheim. Dr Stehman-Breen
is an employee of Amgen Inc. No other authors reported financial disclosures.
Funding Support: Drs Shlipak and Fried are
funded by grant R01 HL073208-01 from the National Heart, Lung, and Blood Institute.
Dr Shlipak is also supported by the American Federation for Aging Research
and National Institute on Aging (Paul Beeson Scholars Program) and the Robert
Wood Johnson Foundation (Generalist Faculty Scholars Program). Dr Fried is
supported by an Advanced Research Career Development Award from the Medical
Service of Veterans Affairs. The CHS Study is supported by contracts N01-HC-85079
through N01-HC-85086, N01-HC-35129, and N01 HC-15103 from the National Heart,
Lung, and Blood Institute.
Role of the Sponsor: This study was funded
through contracts with the National Heart, Lung, and Blood Institute (NHLBI)
and included substantial NHLBI involvement in data collection, analysis, and
interpretation and manuscript preparation.
Acknowledgment: A full list of participating
CHS investigators and institutions can be found at http://www.chs-nhlbi.org