@article {831, title = {Cardiovascular mortality risk in chronic kidney disease: comparison of traditional and novel risk factors.}, journal = {JAMA}, volume = {293}, year = {2005}, month = {2005 Apr 13}, pages = {1737-45}, abstract = {

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 mortality.

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 cardiovascular risk.

}, keywords = {Aged, Cardiovascular Diseases, Chronic Disease, Humans, Kidney Diseases, Longitudinal Studies, Risk Factors}, issn = {1538-3598}, doi = {10.1001/jama.293.14.1737}, author = {Shlipak, Michael G and Fried, Linda F and Cushman, Mary and Manolio, Teri A and Peterson, Do and Stehman-Breen, Catherine and Bleyer, Anthony and Newman, Anne and Siscovick, David and Psaty, Bruce} } @article {840, title = {Cystatin C and the risk of death and cardiovascular events among elderly persons.}, journal = {N Engl J Med}, volume = {352}, year = {2005}, month = {2005 May 19}, pages = {2049-60}, abstract = {

BACKGROUND: Cystatin C is a serum measure of renal function that appears to be independent of age, sex, and lean muscle mass. We compared creatinine and cystatin C levels as predictors of mortality from cardiovascular causes and from all causes in the Cardiovascular Health Study, a cohort study of elderly persons living in the community.

METHODS: Creatinine and cystatin C were measured in serum samples collected from 4637 participants at the study visit in 1992 or 1993; follow-up continued until June 30, 2001. For each measure, the study population was divided into quintiles, with the fifth quintile subdivided into thirds (designated 5a, 5b, and 5c).

RESULTS: Higher cystatin C levels were directly associated, in a dose-response manner, with a higher risk of death from all causes. As compared with the first quintile, the hazard ratios (and 95 percent confidence intervals) for death were as follows: second quintile, 1.08 (0.86 to 1.35); third quintile, 1.23 (1.00 to 1.53); fourth quintile, 1.34 (1.09 to 1.66); quintile 5a, 1.77 (1.34 to 2.26); 5b, 2.18 (1.72 to 2.78); and 5c, 2.58 (2.03 to 3.27). In contrast, the association of creatinine categories with mortality from all causes appeared to be J-shaped. As compared with the two lowest quintiles combined (cystatin C level, < or =0.99 mg per liter), the highest quintile of cystatin C (> or =1.29 mg per liter) was associated with a significantly elevated risk of death from cardiovascular causes (hazard ratio, 2.27 [1.73 to 2.97]), myocardial infarction (hazard ratio, 1.48 [1.08 to 2.02]), and stroke (hazard ratio, 1.47 [ 1.09 to 1.96]) after multivariate adjustment. The fifth quintile of creatinine, as compared with the first quintile, was not independently associated with any of these three outcomes.

CONCLUSIONS: Cystatin C, a serum measure of renal function, is a stronger predictor of the risk of death and cardiovascular events in elderly persons than is creatinine.

}, keywords = {Aged, Biomarkers, Cardiovascular Diseases, Cerebrospinal Fluid Proteins, Creatinine, Cystatin C, Cystatins, Female, Follow-Up Studies, Glomerular Filtration Rate, Humans, Kidney, Kidney Diseases, Male, Mortality, Multivariate Analysis, Prognosis, Risk}, issn = {1533-4406}, doi = {10.1056/NEJMoa043161}, author = {Shlipak, Michael G and Sarnak, Mark J and Katz, Ronit and Fried, Linda F and Seliger, Stephen L and Newman, Anne B and Siscovick, David S and Stehman-Breen, Catherine} } @article {876, title = {Cystatin-C and inflammatory markers in the ambulatory elderly.}, journal = {Am J Med}, volume = {118}, year = {2005}, month = {2005 Dec}, pages = {1416}, abstract = {

PURPOSE: Inflammatory factors are elevated in persons with severe renal dysfunction, but their association across all levels of renal function is unclear. We compared cystatin-C, a novel marker of renal function, with creatinine and estimated glomerular filtration rate (eGFR) as predictors of C-reactive protein and fibrinogen levels.

METHODS: This study is a cross-sectional analysis to evaluate cystatin-C, creatinine, and eGFR as predictors of the inflammatory markers C-reactive protein and fibrinogen. Participants included 4637 ambulatory elderly patients from the Cardiovascular Health Study. Multivariate linear regression was used to determine the independent associations of each renal function measurement with the inflammatory marker outcomes.

RESULTS: After adjustment for confounding factors, cystatin-C was correlated with both C-reactive protein (coefficient = 0.13; 95\% confidence interval: 0.10-1.16, P <.0001) and fibrinogen levels (0.15; 0.13-0.18, P <.0001). Associations were larger than those for creatinine and C-reactive protein (0.05; 0.02-0.07, P = .003) or fibrinogen (0.07; 0.04-0.10, P <.0001). Adjusted levels of C-reactive protein increased incrementally across quintiles of cystatin-C, from a median of 2.2 mg/L in quintile 1 to 3.7 mg/L in quintile 5. In contrast, both C-reactive protein and fibrinogen had U-shaped associations with quintiles of creatinine and eGFR, because the inflammatory markers were equivalently elevated in quintiles 1 and 5.

CONCLUSIONS: The finding of a significant linear association of cystatin-C and inflammation markers suggests that even small reductions in renal function may be associated with adverse pathophysiologic consequences.

}, keywords = {Age Factors, Aged, Biomarkers, C-Reactive Protein, Cross-Sectional Studies, Cystatin C, Cystatins, Female, Fibrinogen, Glomerular Filtration Rate, Humans, Kidney Diseases, Male, Predictive Value of Tests, Sensitivity and Specificity}, issn = {1555-7162}, doi = {10.1016/j.amjmed.2005.07.060}, author = {Shlipak, Michael G and Katz, Ronit and Cushman, Mary and Sarnak, Mark J and Stehman-Breen, Catherine and Psaty, Bruce M and Siscovick, David and Tracy, Russell P and Newman, Anne and Fried, Linda} } @article {908, title = {Kidney function predicts the rate of bone loss in older individuals: the Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {61}, year = {2006}, month = {2006 Jul}, pages = {743-8}, abstract = {

BACKGROUND: Results of cross-sectional analyses of the association of kidney function with bone mineral density (BMD) have been conflicting. We examined the association of cystatin-C, a new marker of kidney function that is unrelated to lean mass, with initial and follow-up BMD, in an ancillary study of the Cardiovascular Health Study, a population-based cohort of individuals > or = 65 years old.

METHODS: Two years after measurement of cystatin-C and other covariates, the first BMD was measured in Pittsburgh, Pennsylvania and Davis, California, by using dual energy x-ray absorptiometry. Follow-up BMD was measured in Pittsburgh 4 years later. Associations of cystatin-C with initial BMD and the change in BMD (\%/y) at the hip were examined with linear regression. Analyses were conducted separately for men and women.

RESULTS: In 1519 participants who had cystatin-C and initial BMD assessed, 614 had follow-up BMD. The percent annual change in BMD at the total hip by cystatin-C quartiles was -0.24, -0.13, -0.40, and -0.66\%/y (first to fourth quartile) in women and -0.02, -0.30, -0.18, and -0.94\%/y in men. After adjusting for potential confounders, cystatin-C was marginally associated with initial BMD in men but not women. Cystatin-C was associated with bone loss in men; after adjustment for weight loss, cystatin-C was not associated with bone loss in women.

CONCLUSION: Kidney dysfunction, as assessed by cystatin-C, is associated with a more rapid loss of BMD at the hip, especially in men. Further studies are needed to confirm these findings and to determine whether this loss leads to an elevated risk of fracture.

}, keywords = {Absorptiometry, Photon, Aged, Bone Density, Creatinine, Cystatin C, Cystatins, Female, Hip, Humans, Kidney Diseases, Kidney Function Tests, Linear Models, Longitudinal Studies, Male, Osteoporosis, Predictive Value of Tests}, issn = {1079-5006}, doi = {10.1093/gerona/61.7.743}, author = {Fried, Linda F and Shlipak, Michael G and Stehman-Breen, Catherine and Mittalhenkle, Anuja and Seliger, Stephen and Sarnak, Mark and Robbins, John and Siscovick, David and Harris, Tamara B and Newman, Anne B and Cauley, Jane A} } @article {975, title = {Kidney function, electrocardiographic findings, and cardiovascular events among older adults.}, journal = {Clin J Am Soc Nephrol}, volume = {2}, year = {2007}, month = {2007 May}, pages = {501-8}, abstract = {

Chronic kidney disease (CKD) is associated with cardiovascular (CV) disease and mortality. It is not known whether cardiac rhythm disturbances are more prevalent among individuals with CKD or whether resting electrocardiogram findings predict future CV events in the CKD setting. Data were obtained from the Cardiovascular Health Study, a community-based study of adults aged >/=65 yr. After exclusions for prevalent heart disease, atrial fibrillation, implantable pacemaker, or antiarrhythmic medication use, 3238 participants were analyzed. CKD was defined by an estimated GFR <60 ml/min per 1.73 m(2). Outcomes were adjudicated incident heart failure (HF), incident coronary heart disease (CHD), and mortality. Participants with CKD had longer PR and corrected QT intervals compared with those without CKD; however, differences in electrocardiographic markers were explained by traditional CV risk factors and CV medication use. After adjustment for known risk factors, each 10-ms increase in the QRS interval was associated with a 15\% greater risk for incident HF (95\% confidence interval [CI] 1.04 to 1.27), a 13\% greater risk for CHD (95\% CI 1.04 to 1.24), and a 17\% greater risk for mortality (95\% CI 1.09, 1.25) among CKD participants. Each 5\% increase in QTI was associated with a 42\% (95\% CI 1.23 to 1.65), 22\% (95\% CI 1.07 to 1.40), and 10\% (95\% CI 0.98 to 1.22) greater risk for HF, CHD, and mortality, respectively. Associations seemed stronger for participants with CKD; however, no significant interactions were detected. Resting electrocardiographic abnormalities are common in CKD and independently predict future clinical CV events in this setting.

}, keywords = {Aged, Aged, 80 and over, Cardiac Output, Low, Cardiovascular Diseases, Chronic Disease, Coronary Disease, Electrocardiography, Female, Humans, Kidney, Kidney Diseases, Male, Risk Assessment}, issn = {1555-905X}, doi = {10.2215/CJN.04231206}, author = {Kestenbaum, Bryan and Rudser, Kyle D and Shlipak, Michael G and Fried, Linda F and Newman, Anne B and Katz, Ronit and Sarnak, Mark J and Seliger, Stephen and Stehman-Breen, Catherine and Prineas, Ronald and Siscovick, David S} }