Although chronic kidney disease has been well established as a risk factor for cardiovascular disease, the converse association of cardiovascular disease with kidney disease progression has received less attention. In this study, we found both clinical and subclinical cardiovascular disease to have independent associations with faster declines in kidney function. Clinical heart failure had the strongest association - nearly 1ml/min/1.73m2 faster decline in kidney function and a near doubling in the odds of rapid decline. Among participants without clinical cardiovascular disease, measures of subclinical atherosclerosis, decreased AAI and increased carotid IMT, were significantly associated with faster kidney function decline. These findings demonstrate that prevalent and subclinical cardiovascular disease are risk factors for kidney function decline in older adults, and suggest that atherosclerosis and heart failure may play important roles in kidney dysfunction among this population.
Prior studies had suggested that atherosclerosis is a potentially important mechanism of kidney disease in older persons. This link was observed nearly two decades ago by Kasiske and colleagues who found that subjects with mild atherosclerosis had fewer atherosclerotic glomeruli than age and sex matched individuals with moderate to severe atherosclerosis. Age and intrarenal vascular disease were correlated with the extent of glomerulosclerosis in that study.6
In addition, an early analysis from CHS found that higher carotid intima medial thickness was among the predictors of worsening renal function (creatinine increase ≥ 0.3mg/dl) after the first 3 years of follow up.2
Furthermore, in CHS, Mittalhenkle et al. recently found that cardiovascular risk factors, subclinical cardiovascular disease and clinical cardiovascular disease were all independent predictors of acute renal failure.28
Along with our findings, these results suggest that atherosclerosis and heart failure may result in declining “renal reserve”, which increases the susceptibility for acute renal failure, chronic kidney disease, and kidney disease and progression.
Our results extend the prior findings of Elsayed and colleagues who examined the association of a combined clinical CV disease predictor variable with change in creatinine using a pooled public access dataset that included CHS and the Atherosclerosis Risk in Communities cohort. The authors found that the combined clinical cardiovascular disease variable predicted rising creatinine levels, but the authors did not differentiate the type of clinical cardiovascular disease, nor did they evaluate subclinical cardiovascular disease measures. In our study, clinical heart failure appeared to have a much stronger impact on kidney function than atherosclerotic cardiovascular events. This effect could be a result of chronically impaired renal blood flow from diminished cardiac output and diuretic use, and from excessive activation of the renin-angiotensin aldosterone system. The apparent effect of clinical heart failure on predicting declining kidney function is further evidence of the challenging management of patients with combined heart failure and kidney disease, which has been dubbed the “cardiorenal syndrome.”29
The associations of clinical and subclinical CV disease with progressive decline in kidney function may be a marker of underlying microvascular renovascular disease in the kidney. Renovascular disease has been shown to be an under-detected cause of progressive kidney disease11
, and has strong associations with older age and with cardiovascular disease at other locations10, 30
. Based on clinical definitions for significant stenosis of the renal artery, approximately 7% of screened elderly persons have renovascular disease7
. Yet, a much larger population of elderly persons likely have atherosclerotic plaques in smaller renal arteries and arteries, which may compromise renal perfusion to the kidney and diminish GFR over time.
This study has several important limitations to consider. Most importantly, both creatinine and cystatin C are indirect approximations for GFR, and direct measures of GFR were unavailable. The equations used to estimate GFR were derived primarily in non-elderly populations, so their applicability to this elderly cohort is uncertain. Our multivariate analyses may have over-adjusted for potential mediators of an effect of atherosclerosis on kidney function decline, as we adjusted for inflammatory markers which may result from atherosclerosis. The null results for LVH and systolic dysfunction may be attributable to the mild spectrum of disease in this cohort; we cannot exclude an important effect of advanced systolic dysfunction on kidney disease progression. Kidney function decline in the elderly may be disproportionately related to atherosclerosis compared to kidney decline in younger populations, so our findings may not be generalizable. Finally, both clinical and subclinical CVD are imprecise surrogates for atherosclerosis within the vasculature of the kidney.
In summary, clinical cardiovascular disease, particularly heart failure, was independently associated with declining kidney function in the elderly. Subclinical cardiovascular disease measures had moderate, but significant associations with declining kidney function. These results suggest that atherosclerosis and heart failure have important effects on the progression of kidney disease in older adults. Future study should evaluate whether interventions aimed at cardiovascular prevention can successfully delay the progression of kidney disease in the elderly.