In individuals without clinical cardiovascular disease, mild kidney impairment measured using cystatin C level was strongly associated with common and internal carotid IMT in unadjusted analyses. However, this relationship was accounted for predominately by age. We found no independent association between either cystatin C level or CKD with common or internal carotid IMT. This observation suggests that accelerated atherosclerosis is unlikely to be the primary mechanism explaining the independent association of cystatin C level with cardiovascular risk.
Few prior studies have evaluated the association of mild kidney dysfunction with carotid IMT. Earlier work found that participants on hemodialysis therapy have greater atherosclerotic burden, manifested by higher carotid IMT,15-19
and IMT is an independent predictor of death and cardiovascular events in this population.20-22
Predialysis patients have an atherosclerotic burden similar to persons on dialysis therapy, suggesting that increased carotid IMT is a function of kidney disease, rather than dialysis itself.23
but not all,28
studies have shown higher carotid IMT in participants with moderate to severe kidney disease. However, such an association was not observed in persons with milder kidney damage. Zhang et al29
examined 1,046 persons of Chinese descent and found that carotid IMT values in participants with eGFR of 30 to 60 mL/min/1.73 m2
and 60 to 90 mL/min/1.73 m2
were not significantly different from those with eGFR of 90 mL/min/1.73 m2
or greater after adjustment for cardiovascular risk factors. In 95 participants with kidney disease (mean chromium-51 EDTA-measured GFR, 36 ± 16 mL/min/1.73 m2
), Briet et al30
found no difference in mean carotid IMT compared with healthy controls.
Although cystatin C has elucidated associations between kidney function and cardiovascular events that were not detected by using eGFR,7
initial studies have been inconclusive for its association with carotid IMT. Watanabe et al38
noted a correlation between serum cystatin C level and carotid IMT (r
= 0.54; P
< 0.001) in a study of 60 hypertensive patients, although there was no adjustment for potential confounders because it was not the primary end point. Rodondi et al39
recently found that cystatin C level was not independently associated with carotid atherosclerosis in a study population including 523 younger adults aged 35 to 64 years, primarily of African descent. Our study expands upon the findings of these prior studies to a larger and more diverse cohort with a broader range of cystatin C levels. The absence of an association in this group with more preserved kidney function suggests that impaired kidney function may have an association with accelerated atherosclerosis only in persons with severe kidney disease. Albuminuria, a manifestation of atherosclerotic microvascular disease, also had no association with carotid IMT in a study by Kramer et al40
in the MESA cohort. Conversely, a smaller study by Rodoni et al39
found a direct association in their participants.
These findings should be interpreted in the context of other studies that evaluated the association of mild to moderately impaired kidney function with subclinical cardiovascular disease measures. In MESA, Ix et al41,42
similarly found that cystatin C levels had a linear association with measures of vascular calcification (valvular and coronary artery calcium) in unadjusted analyses, yet had no association after multivariable adjustment for demographic characteristics and traditional risk factors. The absence of an association between cystatin C level with vascular calcification supports our findings that early kidney disease does not appear to be associated with increased levels of atherosclerosis. Conversely, cystatin C levels greater than 1.0 mg/L, the high quintile within MESA, were independently associated with greater left ventricular mass index and prevalent left ventricular hypertrophy.43
In addition, cystatin C levels had linear and independent associations with inflammatory marker44-47
and systolic blood pressure levels.48
The importance of this work is to elucidate the mechanisms underlying the remarkably strong association of cystatin C level with cardiovascular disease, which is independent of traditional risk factors,6,49
and prevalent cardiovascular disease.6,7
Our null finding implies that accelerated atherosclerosis is unlikely to be the primary mechanism. However, there are other candidate mediators for which roles are yet to be clarified, such as vascular stiffness, left ventricular remodeling, and volume overload. Other cardiovascular lesions also have been described in people with CKD, including arteriolosclerosis, medial vascular calcification, and cardiac fibrosis.8,50
However, progressive atherosclerosis may have greater importance in persons with more advanced CKD.
There are several limitations to this study. First, this study is limited by its cross-sectional design. Therefore, we cannot determine whether kidney function predicts the progression of atherosclerosis over time. In addition, serum cystatin C level and carotid IMT may be manifestations of parallel processes of atherosclerosis. Another limitation is the potential for misclassification error in both the predictor and outcome variables. We do not have a direct measure of GFR and therefore cannot determine how accurately cystatin C or creatinine levels reflect actual kidney function in this study. Also, the range of cystatin C levels is lower than in the ambulatory cohorts in which cystatin C level has predicted increased cardiovascular risk.6,7,49
The absence of a statistically significant association therefore may reflect the healthier spectrum of kidney function in this population. Additionally, there may not be an independent association between cystatin C level and atherosclerosis burden in this particular population because limited atherosclerosis is present. However, our carotid IMT range is similar to studies that found associations between carotid IMT and cardiovascular events,11,12,14
and analyses were similar in persons older than 65 years, a subgroup with a higher IMT. Furthermore, our multivariate analysis of internal carotid IMT may have been overfit because some covariates, such as blood pressure, may be a result of kidney dysfunction. Finally, although carotid IMT has been independently associated with increased risk of cardiovascular events, carotid artery IMT is only one measure of atherosclerosis and may not represent all vascular disease in the body.
In conclusion, the evaluation of subclinical cardiovascular measures is important for elucidating the mechanisms for the strong association between impaired kidney function and increased cardiovascular risk. Based on our findings, processes other than accelerated atherosclerosis should be evaluated as candidate mechanisms.