Author + information
- Received March 5, 2012
- Revision received June 6, 2012
- Accepted June 7, 2012
- Published online September 18, 2012.
- Dena E. Rifkin, MD, MS⁎,†,⁎ (, )
- Joachim H. Ix, MD, MAS⁎,†,
- Christina L. Wassel, PhD⁎,
- Michael H. Criqui, MD, MPH⁎ and
- Matthew A. Allison, MD, MPH⁎
- ↵⁎Reprint requests and correspondence:
Dr. Dena E. Rifkin, University of California-San Diego, Mail code 9111H, Division of Nephrology, 3350 La Jolla Village Drive, San Diego, California 92161
Objectives The goal of this study was to assess the associations between renal artery calcification (RAC) and mortality in a healthy outpatient cohort with no known cardiovascular disease (CVD).
Background Studies in individuals with known diabetes and kidney disease have suggested that RAC confers additional mortality risk independent of coronary artery calcification, but this hypothesis has not been explored in healthier populations.
Methods RAC was assessed by using computed tomography scan in healthy outpatients with no known CVD. Cox proportional hazards models were used to examine the association of RAC with mortality.
Results The mean age of participants was 57 years; 42.6% were women. RAC was present in 622 (14%) of 4,450 participants. Over a median follow-up of 8.2 years, there were 178 deaths. After adjustment for age, sex, diabetes, smoking, cholesterol, and family history of CVD, the presence of RAC conferred a >60% increased hazard for all-cause mortality (hazard ratio [HR]: 1.63 [95% confidence interval (CI): 1.17 to 2.29]). Adjustment for calcification in other vascular beds attenuated this association (HR: 1.40 [95% CI: 0.99 to 1.97]). Adjustment for hypertension, a potential mediator of the association, did not substantially change the results (HR: 1.44 [95% CI: 1.02 to 2.03]). Adding RAC to a model including Framingham risk and coronary artery calcification improved the predictive ability of the model, from 0.73 to 0.77 (p = 0.0002); the net reclassification index was 14.4% for the addition of RAC. Results for cardiovascular mortality were not significant and were limited by the small number of cardiovascular deaths.
Conclusions RAC was associated with an increased risk of subsequent all-cause mortality in healthy outpatient individuals, independent of traditional cardiac risk factors. The risk was modestly attenuated by adjustment for vascular calcification in other vascular beds, suggesting partial confounding by systemic calcified atherosclerosis. The effect did not seem to be mediated by hypertension.
Among those without clinically apparent cardiovascular disease (CVD), coronary artery calcification (CAC), a marker of subclinical CVD, has been established as a risk factor for incident cardiovascular events and mortality (1,2). An increased prevalence of renal arterial disease, including stenosis and calcification, has been noted in persons with coronary artery disease and systemic vascular disease (3,4). Calcification of the renal arteries has also been reported in studies of individuals with overt renovascular disease (5). Despite these known relationships, the association of calcification in the renal vasculature with mortality has not been described. Thus, it is unclear if renal artery calcification (RAC) is simply a marker of systemic vascular calcium burden or whether it provides independent risk information.
There are reasons to believe that RAC may be an independent risk factor for mortality. RAC is linked with calcification in other vascular beds (6) but is less common than coronary calcification in population-based studies. Its presence may thus suggest a different and possibly more severe vascular calcification phenotype. The presence of RAC may also be a marker of atherosclerosis-mediated hypertension with activation of the renin-angiotensin system (7). In support of this link, RAC has been associated, in asymptomatic individuals, with prevalent hypertension independent of the presence or severity of calcification in other vascular beds (8). In addition, RAC may be related to kidney dysfunction, which has well-documented associations with cardiovascular disease and mortality (9). In select populations with diabetes and proteinuric kidney disease, the presence of RAC has been associated with more rapid progression of kidney disease and with mortality (10). To our knowledge, however, no previous study has evaluated the link between RAC and mortality in the general population.
Using data from a large cohort of adults without CVD who underwent whole-body computed tomography (CT) scans primarily for cardiac risk assessment, the relation between RAC and all-cause mortality was investigated. We hypothesized that RAC would be associated with mortality, independent of traditional cardiovascular risk factors, and that this association would be independent of systemic calcification. Given the association between RAC and hypertension, we hypothesized that hypertension would at least partially mediate this association.
This study comprised a cohort of community-dwelling individuals (N = 4,950) who were seen for preventive medicine services, including whole-body CT scanning, at a university-affiliated center in La Jolla, California, between 1999 and 2003. This cohort has been described in detail previously (8,11). In brief, this was a population in which subjects either self-referred or were referred on the recommendation of their personal physician as an adjunct to their standard preventive health care. The majority of these individuals (99%) had no known coronary disease at the time of the visit. The visit included an assessment of standard cardiac risk factors and whole-body CT scans extending from the carotid arteries to the symphysis pubis. Coronary calcium was scored at the time of the preventive visit and reported to the subject. Calcification in other vascular beds was scored for research purposes after the visit had taken place.
All subjects completed a detailed health history, including self-reported medication use for hypertension, diabetes, or high cholesterol, and had serum lipid and glucose measurements obtained by finger stick using the Cholestech LDX system (Alere, Inc., Waltham, Massachusetts). Participants were included regardless of whether they were fasting at the time of the laboratory tests. Excluded were individuals with a history of CVD (myocardial infarction, stroke, transient ischemic attack, angina, or coronary revascularization; n = 45); subjects whose scans did not allow scoring of renal artery calcium data (n = 452); and subjects for whom vital status could not be determined (n = 3). A total of 4,450 individuals were included in the final analysis.
Because the study involved de-identified, existing data, a waiver of informed consent was granted by the University of California, San Diego, institutional review board, which approved the study.
Clinical, laboratory, and history measures
Blood pressure was measured in the right upper extremity after the subject had rested in the seated position for 5 min. Hypertension was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, and/or reported use of antihypertensive medication. Diabetes mellitus was defined by current use of antiglycemic medications or a casual glucose level >200 mg/dl. Individuals with a total:high-density lipoprotein cholesterol ratio >5 and/or those who reported the use of a medication to treat high cholesterol levels were classified as dyslipidemic. Family history of congenital heart disease (CHD) was defined as a CHD event before age 55 years in a first-degree relative. Smoking status was classified as current, former, or never.
An Imatron C-150 scanner (GE Medical Systems, Milwaukee, Wisconsin) was used to obtain CT scans from the base of the skull to the pubic symphysis. All images were obtained during a single session using 100-ms scan time and proceeded caudally from the base of the skull to the symphysis pubis. Each bed was obtained by a distinct scan of the segment in question using the following slice thicknesses: 3 mm for the coronary bed; 6 mm through the neck, abdomen, and pelvis; and 5 mm for the thorax. Measurements of calcified atherosclerosis were obtained in the following vascular beds: coronary, carotid, thoracic aorta, abdominal aorta, renal, and iliac arteries. The coronary and carotid images were analyzed at the time of the CT scan; other vascular beds were analyzed retrospectively. Calcium scoring in the different vascular beds was performed by using the method described by Agatston et al. (12). Calcium in the renal arteries was categorized as arising from the ostium or within the renal arterial segment on each side. The sum of the right and left ostial and arterial segments of the renal arteries were used to calculate an RAC score. Similar sums were used to calculate calcium burden in the other vascular beds. The number of vascular beds other than the renal arteries with calcium present was then tabulated. The reader for renal artery calcium only viewed images that contained the renal arteries; this individual was blinded to the scores for the other beds.
All-cause mortality was determined through August 31, 2009, by using Social Security Death Index searches to determine mortality status for all individuals in the cohort. Date and cause of death were obtained from death certificate information.
To examine demographic associations with the presence of RAC, this variable was dichotomized based on presence (score >0) or absence (score of zero) of any RAC. Differences in the distributions of baseline characteristics between those with and without RAC were described using t or chi-square tests, as appropriate.
To examine the effects of the burden of RAC, we further divided those with non-zero RAC scores into quintiles. For graphical modeling, we compared each of these quintiles of RAC versus the group with no RAC. In addition, multivariate models were examined by using the continuous RAC score among those with RAC; because the distribution of RAC scores was highly skewed, this score was log-transformed for mortality analyses, setting the log-score of those without calcium to zero.
Kaplan-Meier curves were examined to visually inspect the mortality rates of those with and without RAC. Subsequently, Cox proportional hazards models were constructed to examine the adjusted association between RAC and all-cause and cardiovascular mortality. Initial models were adjusted for age and sex. A second model was adjusted for most traditional risk factors (former or current smoking, dyslipidemia, diabetes, and family history of CVD). A third model adjusted for the CAC score (modeled as log[CAC + 1]). We then adjusted for atherosclerosis in other vascular beds (carotid, thoracic and abdominal aorta, and iliac arteries), using the number of other beds affected divided by the number of other beds with scorable calcium (e.g., percentage of other beds affected) as an adjustment variable. We tested for heterogeneity in the association of RAC on mortality according to age and sex.
We postulated that the association between RAC and mortality might be mediated by hypertension, because hypertension can be caused by atherosclerotic renovascular disease and because hypertension itself is then a risk factor for mortality. Thus, we examined whether hypertension mediated the association between RAC and mortality. Nested models were developed, first without and then with adjustment for hypertension; we then examined the change in the hazard ratios (HRs) of RAC.
HRs and 95% confidence intervals (CIs) were calculated for each estimate. We also tested for proportionality of hazards by visual examination of log(−log) survival curves. All of the p values were 2 tailed, with a p value <0.05 considered to indicate statistical significance.
Last, receiver-operating characteristic curves were developed for prediction of all-cause mortality and cardiovascular mortality. Because the study outcome of interest was mortality rather than cardiovascular events, the base model included the calculated Framingham hard CHD score because this best approximates mortality rather than event-based risk (13,14); risk cutoffs of <5%, 5% to 15%, and >15% were chosen for the low, intermediate, and high groups, respectively, because standard predefined thresholds have not been established for all-cause mortality. Additional models added CAC, RAC, or both (modeled as log[CAC+1] and log[RAC+1]) to the base model. We additionally calculated the integrated discrimination index and net reclassification index (NRI) (15) for adding CAC, RAC, and both to these models and tested whether these improvements were statistically significant.
All of the statistical analyses were conducted by using SAS version 4.3 (SAS Institute, Inc., Cary, North Carolina).
Of the 4,450 study subjects, 622 (14%) had RAC. These individuals were older (mean age 68.8 vs. 54.8 years) and more likely to have diabetes, hyperlipidemia, and a history of smoking than those without RAC (Table 1). Individuals with RAC were also more likely to have systolic hypertension and to have calcification in other vascular beds; those with RAC had on average 4.3 other vascular beds with calcification present, whereas those without RAC had 1.9 other vascular beds with calcification present (6,8).
In total, 178 deaths (41 were cardiovascular related) occurred over a median 8.2 years of follow-up; univariate associations between variables of interest and mortality are shown in Table 2. Those with greater burden of RAC had lower survival rates (log-rank p value for trend <0.01) (Fig. 1). Among those without RAC, the age-adjusted mortality rate was 2.3 per 1,000 person-years (95% CI: 1.88 to 3.02), and among those with RAC, the age-adjusted mortality rate was 4.24 per 1,000 person-years (95% CI: 2.97 to 6.07). There was a significant trend toward increasing age-adjusted mortality rates with increasing quintiles of RAC (p < 0.001) (Fig. 2).
In models adjusted for age and sex, the presence of RAC was associated with a 76% higher risk of death (Table 3). After further adjustment for demographic and cardiac risk factors, the presence of RAC still conferred a >60% increase in mortality risk and remained associated with a nearly 40% increase in risk (HR: 1.40 [95% CI: 0.99 to 1.97]) after adjustment for vascular calcification in other locations.
In age- and sex-adjusted proportional hazards models, each log-increase in RAC score among the 622 participants with any RAC present conferred a modest increase in the hazard of mortality (HR: 1.18 [95% CI: 0.98 to 1.4]). Additional adjustment for cardiovascular risk factors and number of other calcified beds further attenuated this association (HR: 1.14 [95% CI: 0.94 to 1.38]).
When the possible mediating effect of hypertension was evaluated, we found little attenuation of mortality risk by hypertension, regardless of whether hypertension was added before or after addition of other adjustment variables. For example, adjusting for hypertension after adjustment for other traditional risk factors (after model 2) (Table 3) changed the HR associated with the presence of RAC minimally from 1.63 (95% CI: 1.17 to 2.29) to 1.66 (95% CI: 1.18 to 2.34); adding hypertension at the end of the modeling process had a similar minimal effect on the hazard associated with the presence of RAC. The receiver-operating characteristic models (Fig. 3) adding CAC and RAC to a predictive model, including the hard FRS, demonstrated improvement in the C-statistic, integrated discrimination index, and NRI with sequential addition of CAC and RAC (Table 4). Adding RAC to a model including hard Framingham risk score and CAC generated an improvement in the C-statistic from 0.73 to 0.77 (p = 0.0002). The NRI for the model including RAC compared with that including Framingham risk score and CAC was 14.4% (p for comparison = 0.002).
A set of parallel models were conducted for cardiovascular mortality. There were 41 confirmed cardiovascular deaths available for analysis. Table 3 shows Cox proportional hazards regression models, which demonstrate attenuation of the risk for cardiovascular mortality with relatively wide confidence limits after addition of successive adjustment variables. Similarly, Table 4 displays the C-statistic values, integrated discrimination index, and NRI analyses for cardiovascular mortality; although the addition of RAC to these models improved these values, the improvements did not reach statistical significance.
RAC was a relatively common occurrence in this cohort of asymptomatic adults, affecting 14%, and was associated with a substantial increase in mortality risk even after adjustment for demographic and traditional cardiovascular risk factors. RAC was more prevalent in those with vascular calcification in other beds, and adjustment for the presence of other vascular calcification and hypertension attenuated but did not eliminate the association between RAC and mortality. Despite this adjustment, individuals with RAC remained at approximately 50% greater mortality risk.
We considered whether hypertension was a potential mediator of the remaining association between RAC and mortality. In these analyses, hypertension had a trivial effect on the association regardless of when it was added to the models, suggesting that the association between RAC and mortality was independent of hypertension. Previous angiographic studies have demonstrated that RAC is not strongly associated with overt, flow-limiting renal arterial disease (15). Our data support the hypothesis that the independent effect of RAC on mortality is not entirely explained by decreased blood flow to the kidney and corresponding increases in blood pressure as mediated by the renin-angiotensin system, but is instead part of a systemic vascular calcification phenotype in which vascular calcification and hypertension may be parallel processes.
In previous studies, RAC was strongly associated with calcification in other vascular beds in those with diabetes (16), in those with overt renovascular disease (17), and in those without clinical CVD (6). These findings suggest that RAC is likely part of a systemic process and contributes to mortality risk perhaps by marking the severity of the atherosclerotic disease burden.
We are aware of 1 small study examining RAC and mortality, which evaluated a cohort of 172 individuals with diabetes and kidney disease (10). In that study, RAC had significant associations with a combined outcome of end-stage renal disease and mortality even after adjustment for CAC. The study participants did not have measures of calcification in vascular beds other than the coronary and renal beds, and the prevalence of both RAC and CAC were substantially higher than in our study (31% and 74%, respectively). That study reported only a combined end point, with most events being progression to end-stage renal disease, and separate analyses of mortality outcomes were not presented. Our study extends the finding of an independent association of RAC with mortality to a healthy, outpatient population with a relatively low prevalence of RAC and to nondiabetic individuals.
Our findings should be interpreted in the context of existing data regarding noncoronary vascular calcification. Although previous studies have shown that CAC is associated with both cardiovascular and all-cause mortality (19,20), findings for noncoronary calcium have not been entirely consistent and seem to depend on the vascular bed and outcome studied. Thoracic calcification, for example, has been associated with total mortality and CVD events (21,22); abdominal aortic calcification has been linked to CVD and CVD-related mortality (23). Although our findings were suggestive of a stronger association between renal artery calcification and all-cause mortality rather than cardiovascular mortality, the number of cardiovascular deaths was relatively small, and the lack of significant association seen in this study therefore does not eliminate the possibility of an association with CVD mortality. It is also possible that the presence of RAC makes individuals more hemodynamically fragile and less likely to survive noncardiac illnesses, thus explaining the substantially higher all-cause mortality rates in those with RAC.
The clinical utility of whole-body CT screening, with analysis of RAC as part of a multibed analysis, is still uncertain and these screenings cannot yet be recommended as part of routine risk stratification. Whole-body CT scans expose the individual to substantial radiation (24) and incur the added risk of incidental findings requiring further evaluation and invasive management. Our data suggest, however, that determination of RAC may add to the prognostic information contained in such scans above that gleaned from analysis of standard Framingham risk factors and of calcification in other vascular beds.
Study strengths and limitations
The strengths of our study include a large sample size, the availability of calcification in multiple vascular beds, and the long follow-up time for mortality. We were able to adjust for standard CVD risk factors as well as detailed measures of vascular calcification in the coronary arteries as well as in other beds.
Limitations include the use of a self-referred cohort of subjects rather than a community sample. These participants did not have estimated glomerular filtration rate or proteinuria measured at the time of the whole-body scan, and we therefore do not have renal function measures to correlate with RAC. If estimated glomerular filtration rate or proteinuria is a true confounder of the association between RAC and mortality, however, one would have to postulate that decreased kidney function leads to both RAC and mortality. We do not know of supportive data for this hypothesis. RAC might itself cause a decreased estimated glomerular filtration rate, which is then a risk factor for mortality (mediation); we cannot assess this by using the available data. History of CVD and of CVD risk factors was by self-report and was not confirmed via review of medical charts. We did not have information about the ethnic background of the participants, nor do we have information about peripheral vascular disease, other comorbid diseases, or details of exercise habits. We cannot exclude the possibility of residual confounding because of these limits on the covariates available to us.
RAC was associated with all-cause mortality independent of traditional cardiac risk factors. The association was attenuated but was still present after adjustment for vascular calcification in other locations and was minimally attenuated by adjustment for hypertension. Adding RAC to a predictive model of all-cause mortality using the Framingham hard CHD score and the CAC score improved the predictive value of the model. For cardiovascular mortality, the findings were limited by the number of cardiovascular deaths, and Cox proportional hazards models did not demonstrate significance after multivariate adjustment.
Further work should examine whether similar associations are seen in groups with a higher prevalence of diabetes and vascular disease, because the findings may differ across populations, and should investigate the associations of RAC with CVD events and CVD mortality in these higher-risk populations.(18)
Dr. Rifkin was supported by K23 DK091521. Dr Allison was supported by AHA0475029N.
All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Andrew Einstein, MD, served as Guest Editor of the paper.
- Abbreviations and Acronyms
- coronary artery calcification
- congenital heart disease
- computed tomography
- cardiovascular disease
- net reclassification index
- renal artery calcification
- Received March 5, 2012.
- Revision received June 6, 2012.
- Accepted June 7, 2012.
- American College of Cardiology Foundation
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