Beyond (or Back to) Traditional Risk Factors: Preventing Cardiovascular Disease in Patients with Chronic Kidney Disease

Patients with chronic kidney disease carry an extraordinarily high risk for cardiovascular disease (CVD). In fact, most patients with chronic kidney disease will die of CVD before reaching end-stage kidney disease (1). A logical starting point for CVD prevention efforts in this population is determining the extent to which traditional CVD risk factors (that is, smoking, blood pressure, diabetes, and hypercholesterolemia) are responsible for the excess risk for CVD. In this issue, Muntner and colleagues (2) highlight the possibility that other risk factors, commonly termed nontraditional risk factors, also contribute to the burden of CVD in this population. The setting is the Third National Health and Nutrition Examination Survey. In this large, representative survey of more than 15 000 noninstitutionalized U.S. adults, participants were stratified by level of estimated glomerular filtration rate. The highest category ( 90 mL/min per 1.73 m2) included healthy persons and those with stage 1 chronic kidney disease, the intermediate category (60 to 89 mL/min per 1.73 m2) corresponded to stage 2, and the lowest category (15 to 59 mL/min per 1.73 m2) corresponded to stages 3 and 4 (3). The principal finding of this well-done study is a high prevalence of nontraditional CVD risk factors among persons with chronic kidney disease. In brief, the lowest level of kidney function was associated with a higher prevalence of detectable C-reactive protein; elevated C-reactive protein levels; high levels of plasma fibrinogen, homocysteine, and lipoprotein(a); and low levels of apolipoprotein A1. While there was a trend toward high apolipoprotein B levels with reduced kidney function, this relationship was nonsignificant. In general, the relationships between risk factors and kidney function appeared to be progressive, yet the authors did not explicitly test whether the data were most consistent with a linear versus a nonlinear model. In fact, the relationships appeared nonlinearthat is, the prevalence of most risk factors rose sharply at the lowest level of kidney function. Both in the general population and in patients with chronic kidney disease, the biological and clinical relevance of these nontraditional risk factors is uncertain. Whether they are etiologically related to the occurrence of CVD or are merely noncausal markers of CVD risk is unclear from the available evidence. In the setting of kidney disease, there is also a marked potential for reverse causality (4). At the heart of this conundrum is the high correlation of nontraditional and traditional risk factors. For example, apolipoprotein A1 is highly correlated with high-density lipoprotein cholesterol, and apolipoprotein B with low-density lipoprotein cholesterol. The relationship between homocysteine and traditional risk factors is particularly striking. In the Hordaland Homocysteine Study (5), elevated plasma homocysteine levels were associated with virtually all major CVD risk factors, including male sex, older age, cigarette smoking, systolic and diastolic blood pressure, total cholesterol and triglyceride levels, and physical inactivity. With the exception of age and sex, each of these traditional risk factors is measured with considerable imprecision. Hence, one can reasonably question whether homocysteine is truly an independent risk factor, as suggested by many observational studies, or whether homocysteine is the ultimate confounder because traditional risk factors are measured imprecisely or not at all. Ascertaining the biological and prognostic relevance of nontraditional risk factors in prospective observational studies and in clinical trials will be challenging (6, 7). In observational studies, separating the effects of highly correlated variables is fraught with difficulty and can lead to unstable or even biased associations when these variables are simultaneously included in the same model. Clinical trials provide the strongest evidence in support of therapeutic interventions. However, therapies that target a risk factor may be unavailable or, if available, affect several risk factors simultaneously. Of the nontraditional risk factors studied by Muntner and colleagues, only 1 has a specific therapy: Folate supplementation lowers homocysteine levels but has no well-accepted effects on other risk factors. In contrast, weight loss lowers C-reactive protein level but also affects lipid levels, insulin resistance, and blood pressure. Statin therapy for dyslipidemia leads to parallel changes in lipoprotein cholesterol concentrations and corresponding apolipoproteins. For example, in 1 trial, atorvastatin reduced low-density lipoprotein cholesterol and apolipoprotein B concentrations by 34% and 32%, respectively, and increased high-density lipoprotein cholesterol and apolipoprotein A1 concentrations by 7% and 5%, respectively (8). Other trials have documented that statin therapy reduces lipoprotein(a) (9) and C-reactive protein levels (10). Hence, reliance on clinical trials to tease apart the biological relevance of nontraditional risk factors may be a misplaced hope. The evolution of research on nontraditional risk factors in the general population might presage what will happen as researchers explore the role of nontraditional risk factors in chronic kidney disease. Initial enthusiasm for nontraditional risk factors (11) has often been replaced by great caution (12). In a recent series of papers (13-15), upwards of 90% of patients with coronary heart disease had at least 1 traditional risk factor (smoking, dyslipidemia, high blood pressure, or diabetes); furthermore, several nontraditional risk factors, including C-reactive protein, lipoprotein(a), fibrinogen, and homocysteine levels, appeared to contribute little beyond traditional risk factors, at least in terms of prognostic information. While these findings will certainly be debated, I wonder whether we will reach the same conclusions about these risk factors in the setting of chronic kidney disease. Early evidence suggests otherwise. In an analysis that applied the Framingham risk equation to a population with advanced chronic kidney disease, predicted coronary heart disease risk was similar to, not substantially higher than, that of the general population (16). The authors concluded that nontraditional risk factors contribute to coronary heart disease risk in patients with chronic kidney disease. My own hunch is that nontraditional risk factors have a modest causal role in the pathogenesis of CVD in the general population and a much greater role in patients with chronic kidney disease. I also suspect that we have substantially underestimated the effects of traditional risk factors. In particular, the strength of the relationship between blood pressure and CVD has probably been underestimated, in part because of enormous measurement error and in part because office blood pressure does not capture a potentially important dimension of blood pressure, namely, diurnal patterns. Sustained nocturnal blood pressurea dimension rarely measured in observational studieshas emerged as a risk factor for CVD (17, 18). Of interest, patients with chronic kidney disease have an extremely high prevalence of elevated nocturnal blood pressure (19). While high nocturnal blood pressure may represent an adaptive response to maintain glomerular filtration rate, it is likely that such blood pressure elevations also accelerate vascular damage. In short, the verdict is uncertain. We don't know which, if any, nontraditional risk factors account for the enormous risk for CVD in patients with chronic kidney disease. How to proceed will certainly stimulate erudite debate and perhaps a few clinical trials. In the meantime, aggressive management of traditional risk factors is a sensible, albeit largely unproven, strategy to prevent CVD in patients with chronic kidney disease.