@article {697, title = {Cardiovascular disease risk status in elderly persons with renal insufficiency.}, journal = {Kidney Int}, volume = {62}, year = {2002}, month = {2002 Sep}, pages = {997-1004}, abstract = {

BACKGROUND: Renal insufficiency has been independently associated with incident cardiovascular disease events in some, but not all, prospective studies. We determined the prevalence of elevated cardiovascular disease risk status among elderly persons with renal insufficiency.

METHODS: This study is a cross-sectional analysis using data collected at the baseline visit of the Cardiovascular Health Study, which enrolled 5888 community dwelling adults aged 65 years or older from four clinical centers in the United States. Renal insufficiency was defined as a serum creatinine level > or =1.3 mg/dL in women and > or =1.5 mg/dL in men. The outcomes of this study included prevalent cardiovascular disease [prior coronary heart disease (CHD) or stroke], subclinical cardiovascular disease (abnormal values of ankle-arm index, carotid ultrasound, and echocardiography) and elevated cardiovascular risk based upon a diagnosis of diabetes and the Framingham equations. The association between renal insufficiency and cardiovascular risk status was estimated with and without adjustment for other cardiovascular predictors.

RESULTS: Among the 5808 participants with creatinine levels measured at entry, 15.9\% of men (N = 394), and 7.6\% of women (N = 254) had renal insufficiency. The prevalence of either clinical or subclinical cardiovascular disease was 64\% in persons with renal insufficiency compared with 43\% in those without it [odds ratio (OR) 2.34; 95\% confidence interval (95\% CI), 1.96, 2.80]. After adjustment for other cardiovascular risk factors, renal insufficiency remained significantly associated with clinical and subclinical cardiovascular disease (adjusted OR 1.43; 95\% CI, 1.18, 1.75), but the magnitude of association was substantially reduced. After combining clinical and subclinical cardiovascular disease, diabetes, and an estimated risk>20\% by the Framingham equations, 78\% of men and 61\% of women with renal insufficiency had elevated cardiovascular risk status.

CONCLUSIONS: Renal insufficiency is a marker for elevated cardiovascular disease risk in community dwelling elderly adults.

}, keywords = {Age Distribution, Aged, Cholesterol, HDL, Cholesterol, LDL, Coronary Disease, Creatinine, Cross-Sectional Studies, Female, Humans, Kidney Failure, Chronic, Male, Prevalence, Prospective Studies, Risk Factors}, issn = {0085-2538}, doi = {10.1046/j.1523-1755.2002.00522.x}, author = {Shlipak, Michael G and Fried, Linda F and Crump, Casey and Bleyer, Anthony J and Manolio, Teri A and Tracy, Russell P and Furberg, Curt D and Psaty, Bruce M} } @article {719, title = {Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency.}, journal = {Circulation}, volume = {107}, year = {2003}, month = {2003 Jan 07}, pages = {87-92}, abstract = {

BACKGROUND: Renal insufficiency has been associated with cardiovascular disease events and mortality in several prospective studies, but the mechanisms for the elevated risk are not clear. Little is known about the association of renal insufficiency with inflammatory and procoagulant markers, which are potential mediators for the cardiovascular risk of kidney disease.

METHODS AND RESULTS: The cross-sectional association of renal insufficiency with 8 inflammatory and procoagulant factors was evaluated using baseline data from the Cardiovascular Health Study, a population-based cohort study of 5888 subjects aged > or =65 years. C-reactive protein, fibrinogen, factor VIIc, and factor VIIIc levels were measured in nearly all participants; interleukin-6, intercellular adhesion molecule-1, plasmin-antiplasmin complex, and D-dimer levels were measured in nearly half of participants. Renal insufficiency was defined as a serum creatinine level > or =1.3 mg/dL in women and > or =1.5 mg/dL in men. Multivariate linear regression was used to compare adjusted mean levels of each biomarker in persons with and without renal insufficiency after adjustment for other baseline characteristics. Renal insufficiency was present in 647 (11\%) of Cardiovascular Health Study participants. After adjustment for baseline differences, levels of C-reactive protein, fibrinogen, interleukin-6, factor VIIc, factor VIIIc, plasmin-antiplasmin complex, and D-dimer were significantly greater among persons with renal insufficiency (P<0.001). In participants with clinical, subclinical, and no cardiovascular disease at baseline, the positive associations of renal insufficiency with these inflammatory and procoagulant markers were similar.

CONCLUSION: Renal insufficiency was independently associated with elevations in inflammatory and procoagulant biomarkers. These pathways may be important mediators leading to the increased cardiovascular risk of persons with kidney disease.

}, keywords = {Aged, alpha-2-Antiplasmin, Biomarkers, Blood Coagulation Factors, C-Reactive Protein, Cardiovascular Diseases, Cohort Studies, Creatinine, Cross-Sectional Studies, Female, Fibrin Fibrinogen Degradation Products, Fibrinogen, Fibrinolysin, Humans, Inflammation, Interleukin-6, Male, Prospective Studies, Renal Insufficiency, Risk Factors}, issn = {1524-4539}, doi = {10.1161/01.cir.0000042700.48769.59}, author = {Shlipak, Michael G and Fried, Linda F and Crump, Casey and Bleyer, Anthony J and Manolio, Teri A and Tracy, Russell P and Furberg, Curt D and Psaty, Bruce M} } @article {735, title = {Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals.}, journal = {J Am Coll Cardiol}, volume = {41}, year = {2003}, month = {2003 Apr 16}, pages = {1364-72}, abstract = {

OBJECTIVES: This study was designed to evaluate the relationship between elevated creatinine levels and cardiovascular events.

BACKGROUND: End-stage renal disease is associated with high cardiovascular morbidity and mortality. The association of mild to moderate renal insufficiency with cardiovascular outcomes remains unclear.

METHODS: We analyzed data from the Cardiovascular Health Study, a prospective population-based study of subjects, aged >65 years, who had a serum creatinine measured at baseline (n = 5,808) and were followed for a median of 7.3 years. Proportional hazards models were used to examine the association of creatinine to all-cause mortality and incident cardiovascular mortality and morbidity. Renal insufficiency was defined as a creatinine level > or =1.5 mg/dl in men or > or =1.3 mg/dl in women.

RESULTS: An elevated creatinine level was present in 648 (11.2\%) participants. Subjects with elevated creatinine had higher overall (76.7 vs. 29.5/1,000 years, p < 0.001) and cardiovascular (35.8 vs. 13.0/1,000 years, p < 0.001) mortality than those with normal creatinine levels. They were more likely to develop cardiovascular disease (54.0 vs. 31.8/1,000 years, p < 0.001), stroke (21.1 vs. 11.9/1,000 years, p < 0.001), congestive heart failure (38.7 vs. 17/1,000 years, p < 0.001), and symptomatic peripheral vascular disease (10.6 vs. 3.5/1,000 years, p < 0.001). After adjusting for cardiovascular risk factors and subclinical disease measures, elevated creatinine remained a significant predictor of all-cause and cardiovascular mortality, total cardiovascular disease (CVD), claudication, and congestive heart failure (CHF). A linear increase in risk was observed with increasing creatinine.

CONCLUSIONS: Elevated creatinine levels are common in older adults and are associated with increased risk of mortality, CVD, and CHF. The increased risk is apparent early in renal disease.

}, keywords = {Aged, Cardiovascular Diseases, Confidence Intervals, Creatinine, Female, Heart Failure, Humans, Intermittent Claudication, Kidney Failure, Chronic, Male, Odds Ratio, Predictive Value of Tests, Survival Analysis}, issn = {0735-1097}, doi = {10.1016/s0735-1097(03)00163-3}, author = {Fried, Linda F and Shlipak, Michael G and Crump, Casey and Bleyer, Anthony J and Gottdiener, John S and Kronmal, Richard A and Kuller, Lewis H and Newman, Anne B} } @article {773, title = {Chronic renal insufficiency and cardiovascular events in the elderly: findings from the Cardiovascular Health Study.}, journal = {Am J Geriatr Cardiol}, volume = {13}, year = {2004}, month = {2004 Mar-Apr}, pages = {81-90}, abstract = {

In the Cardiovascular Health Study, the authors sought to evaluate the impact of chronic renal insufficiency (CRI) on cardiovascular risk status and outcomes in a representative sample of community-dwelling elderly adults. Defined as a serum creatinine level > or =1.3 mg/dL in women and > or =1.5 mg/dL in men, CRI was present in 647 (11\%) of 5808 participants. At baseline, the prevalence of clinical or subclinical cardiovascular disease was 64\% in participants with CRI and 43\% in those without CRI (odds ratio, 2.34; 95\% confidence interval, 1.96-2.80). The incidence of cardiovascular disease events during follow-up was 3\% per year in participants with creatinine levels <1.10 mg/dL and increased steadily to reach 7\% per year in those with creatinine > or =1.70 mg/dL. Among the possible mediators for the association between CRI and cardiovascular morbidity are inflammatory (C-reactive protein, fibrinogen, and interleukin-6) and hemostatic (factor VII, factor VIII, plasmin-antiplasmin product, and D-dimer) biomarkers, all of which were significantly elevated in Cardiovascular Health Study participants with CRI. Future studies should evaluate the contribution of novel and traditional cardiovascular risk factors to the cardiovascular risk of elderly persons with CRI. The identification of CRI in the elderly and the use of cardiovascular prevention therapies represent a major opportunity to reduce their burden of cardiovascular morbidity.

}, keywords = {Aged, Blood Coagulation Factors, Cardiovascular Diseases, Chronic Disease, Creatinine, Cystatin C, Cystatins, Female, Fibrinogen, Geriatric Assessment, Humans, Incidence, Male, Prevalence, Renal Insufficiency, Risk Factors}, issn = {1076-7460}, doi = {10.1111/j.1076-7460.2004.02125.x}, author = {Shlipak, Michael G and Fried, Linda F and Stehman-Breen, Catherine and Siscovick, David and Newman, Anne B} } @article {775, title = {The presence of frailty in elderly persons with chronic renal insufficiency.}, journal = {Am J Kidney Dis}, volume = {43}, year = {2004}, month = {2004 May}, pages = {861-7}, abstract = {

BACKGROUND: Frailty has been defined as a tool to define individuals who lack functional reserve and are at risk for functional decline. We hypothesized that chronic renal insufficiency (CRI) would be associated with a greater prevalence of frailty and disability in the elderly.

METHODS: This cross-sectional analysis used baseline data collected from the Cardiovascular Health Study, which enrolled 5,888 community-dwelling adults aged 65 years or older from 4 clinical centers in the United States. Renal insufficiency is defined as a serum creatinine level of 1.3 mg/dL or greater (> or =115 micromol/L) in women and 1.5 mg/dL or greater (> or =133 micromol/L) in men. Frailty is defined by the presence of 3 of the following abnormalities: unintentional weight loss, self-reported exhaustion, measured weakness, slow walking speed, and low physical activity. Disability is defined as any self-reported difficulty with activities of daily living.

RESULTS: Among 5,808 participants with creatinine levels measured at entry, 15.9\% of men (n = 394) and 7.6\% of women (n = 254) had CRI. Prevalences of frailty (15\% versus 6\%; P < 0.001) and disability (12\% versus 7\%; P = 0.001) were greater in participants with CRI compared with those with normal renal function. After multivariate adjustment for comorbidity, CRI remained significantly associated with frailty (odds ratio, 1.76; 95\% confidence interval, 1.28 to 2.41), but not disability (odds ratio, 1.26; 95\% confidence interval, 0.94 to 1.69).

CONCLUSION: Elderly persons with CRI have a high prevalence of frailty, which may signal their risk for progression to adverse health outcomes. If confirmed in other studies, identification of frailty in patients with CRI may warrant special interventions to preserve their independence, quality of life, and survival.

}, keywords = {Activities of Daily Living, Aged, Cross-Sectional Studies, Female, Frail Elderly, Humans, Kidney Failure, Chronic, Male, United States}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2003.12.049}, author = {Shlipak, Michael G and Stehman-Breen, Catherine and Fried, Linda F and Song, Xiao and Siscovick, David and Fried, Linda P and Psaty, Bruce M and Newman, Anne B} } @article {854, title = {Associations between retinal microvascular abnormalities and declining renal function in the elderly population: the Cardiovascular Health Study.}, journal = {Am J Kidney Dis}, volume = {46}, year = {2005}, month = {2005 Aug}, pages = {214-24}, abstract = {

BACKGROUND: Microvascular abnormalities in the kidney are common histopathologic findings in individuals with chronic kidney disease or renal failure. These abnormalities may represent one manifestation of ongoing systemic microvascular damage. We hypothesized that retinal microvascular abnormalities, when present, would be associated with progressive renal dysfunction in elderly individuals.

METHODS: The Cardiovascular Health Study (CHS) is a prospective, multicenter, cohort study initiated in 1989 designed to examine cardiovascular risk factors, morbidity, and mortality in elderly Americans. As part of an ancillary study, CHS participants underwent retinal photography in 1997 and 1998. Retinal microvascular abnormalities were assessed and graded by using standardized measures. Retinal microvascular abnormalities were defined as retinopathy (hard and soft exudates, hemorrhages, or microaneurysms) and/or retinal arteriolar abnormalities (arteriovenous nicking, focal arteriolar narrowing, or lowest quartile arteriole-venule ratio). Associations between these abnormalities and observed 4-year changes in serum creatinine levels and estimated glomerular filtration rates (eGFRs) from study years 5 to 9 (encompassing years 1994 to 2001) were examined by using regression modeling.

RESULTS: A total of 1,394 CHS participants had retinal and serum creatinine data. After adjustments for age, race, sex, weight, diabetes, hypertension, angiotensin-converting enzyme inhibitor use, and proteinuria, participants with retinopathy showed a significant increase in serum creatinine level and decline in eGFR compared with those without retinopathy during the 4-year study period (+0.24 mg/dL [+21 micromol/L] versus -0.21 mg/dL [-19 micromol/L] and -0.48 mL/min/1.73 m2 [-0.01 mL/s/1.73 m2] versus +1.74 mL/min/1.73 m2 [+0.03 mL/s/1.73 m2], respectively). Participants with retinopathy also were significantly more likely to have an observed significant deterioration in renal function, defined as a 0.3-mg/dL (27-micromol/L) increase in serum creatinine level or 20\% or greater decline in eGFR (odds ratio, 3.20; 95\% confidence interval, 1.58 to 6.50; and odds ratio, 2.84; 95\% confidence interval, 1.56 to 5.16, respectively). These associations remained in separate stratified analyses of patients with and without diabetes. The presence of retinal arteriolar abnormalities was not associated with deteriorating renal function.

CONCLUSION: Retinal microvascular abnormalities defined as retinopathy were significantly associated with renal function deterioration. The observed findings were independent of effects of any associated diabetes or hypertension. These findings suggest that systemic microvascular disease may be associated with progressive renal dysfunction in the elderly population.

}, keywords = {African Americans, Aged, Aged, 80 and over, Aging, Antihypertensive Agents, Capillaries, Cohort Studies, Comorbidity, Creatinine, Diabetes Mellitus, Disease Progression, European Continental Ancestry Group, Female, Glomerular Filtration Rate, Humans, Hypertension, Kidney, Male, Photography, Prospective Studies, Proteinuria, Retina, Retinal Diseases, Retinal Vessels}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2005.05.005}, author = {Edwards, Matthew S and Wilson, David B and Craven, Timothy E and Stafford, Jeanette and Fried, Linda F and Wong, Tien Y and Klein, Ronald and Burke, Gregory L and Hansen, Kimberley J} } @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 {873, title = {Cystatin C and incident peripheral arterial disease events in the elderly: results from the Cardiovascular Health Study.}, journal = {Arch Intern Med}, volume = {165}, year = {2005}, month = {2005 Dec 12-26}, pages = {2666-70}, abstract = {

BACKGROUND: The association of cystatin C, a novel marker of renal function, with risk for developing complications related to peripheral arterial disease (PAD) has not been examined.

METHODS: We evaluated the hypothesis that a high cystatin C concentration is independently associated with future PAD events among 4025 participants in the Cardiovascular Health Study who underwent serum cystatin C measurement at the 1992-1993 visit and who did not have PAD at baseline. The association of cystatin C quintiles with time to first lower-extremity PAD procedure (bypass surgery, angioplasty, or amputation) was evaluated using multivariable proportional hazards models. Secondary analyses were conducted using quintiles of serum creatinine level and estimated glomerular filtration rate (eGFR).

RESULTS: The annualized risk of undergoing a procedure for PAD was 0.43\% per year among participants in the highest cystatin C quintile (>1.27 mg/L) compared with 0.21\% per year or less in all other quintiles. After multivariable adjustment for known risk factors for PAD, elevated cystatin C levels remained associated with the outcome (hazard ratio, 2.5 for highest vs lowest quintile of cystatin C, 95\% confidence interval, 1.2-5.1). The highest quintiles of serum creatinine level and eGFR were not associated with future PAD events in either unadjusted or adjusted analyses.

CONCLUSION: Elevated concentrations of cystatin C were independently predictive of incident PAD events among community-dwelling elderly patients.

}, keywords = {Aged, Cohort Studies, Cystatin C, Cystatins, Female, Health Surveys, Humans, Longitudinal Studies, Male, Peripheral Vascular Diseases, Predictive Value of Tests, Risk Factors, ROC Curve, United States}, issn = {0003-9926}, doi = {10.1001/archinte.165.22.2666}, author = {O{\textquoteright}Hare, Ann M and Newman, Anne B and Katz, Ronit and Fried, Linda F and Stehman-Breen, Catherine O and Seliger, Stephen L and Siscovick, David S and Shlipak, Michael G} } @article {862, title = {Cystatin C and subclinical brain infarction.}, journal = {J Am Soc Nephrol}, volume = {16}, year = {2005}, month = {2005 Dec}, pages = {3721-7}, abstract = {

Subclinical brain infarcts (SBI) are common in the elderly and are associated with covert neurologic and cognitive impairment. Although renal impairment is associated with accelerated cerebrovascular disease and an increased risk for clinically apparent brain infarct, few studies have examined the relationship between renal function and SBI, and these may have been limited by the inaccuracy of creatinine as a renal function marker. A cross-sectional study was performed among older adults in the Cardiovascular Health Study to examine associations between SBI and two serum markers of renal function: Serum creatinine (SCr) and cystatin C (CysC). Patients had cranial magnetic resonance imaging and renal markers measured in 1992 to 1993. Logistic regression was used to estimate the associations between renal function (estimated by 1/SCr and 1/CysC) and SBI, controlling for potential confounding factors. SBI were present in 789 (28.7\%) of 2784 participants. A linear association with SBI was observed for 1/CysC (per 1-SD decrement; odds ratio [OR] 1.20; 95\% confidence interval [CI] 1.09 to 1.32; P < 0.001) but not for 1/SCr (OR 1.08; 95\% CI 0.98 to 1.19; P = 0.14), for which a quadratic U-shaped association was suggested (P = 0.004). In a model with both markers, 1/CysC was linearly associated with SBI (OR 1.26; P < 0.001), whereas 1/SCr was not (OR 1.06; P = 0.3). The prevalence of SBI was directly associated with quintile of CysC, whereas the association between SCr and SBI was U-shaped, with greater prevalence at high and low levels. Compared with creatinine, CysC, a novel marker of renal function, has a stronger and more direct association with SBI in the elderly.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Biomarkers, Brain Infarction, Confidence Intervals, Creatinine, Cross-Sectional Studies, Cystatin C, Cystatins, Disease Progression, Female, Geriatric Assessment, Humans, Incidence, Ischemic Attack, Transient, Magnetic Resonance Imaging, Male, Odds Ratio, Predictive Value of Tests, Prognosis, Risk Assessment, Sensitivity and Specificity, Severity of Illness Index, Sex Factors, Survival Analysis}, issn = {1046-6673}, doi = {10.1681/ASN.2005010006}, author = {Seliger, Stephen L and Longstreth, W T and Katz, Ronit and Manolio, Teri and Fried, Linda F and Shlipak, Michael and Stehman-Breen, Catherine O and Newman, Anne and Sarnak, Mark and Gillen, Daniel L and Bleyer, Anthony and Siscovick, David S} } @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 {827, title = {Cystatin C concentration as a risk factor for heart failure in older adults.}, journal = {Ann Intern Med}, volume = {142}, year = {2005}, month = {2005 Apr 05}, pages = {497-505}, abstract = {

BACKGROUND: Previous studies that evaluated the association of kidney function with incident heart failure may be limited by the insensitivity of serum creatinine concentration for detecting abnormal kidney function.

OBJECTIVE: To compare serum concentrations of cystatin C (a novel marker of kidney function) and creatinine as predictors of incident heart failure.

DESIGN: Observational study based on measurement of serum cystatin C from frozen sera obtained at the 1992-1993 visit of the Cardiovascular Health Study. Follow-up occurred every 6 months.

SETTING: Adults 65 years of age or older from 4 communities in the United States.

PARTICIPANTS: 4384 persons without previous heart failure who had measurements of serum cystatin C and serum creatinine.

MEASUREMENTS: Incident heart failure.

RESULTS: The mean (+/-SD) serum concentrations of cystatin C and creatinine were 82 +/- 25 nmol/L (1.10 +/- 0.33 mg/L) and 89 +/- 34 micromol/L (1.01 +/- 0.39 mg/dL), respectively. During a median follow-up of 8.3 years (maximum, 9.1 years), 763 (17\%) participants developed heart failure. After adjustment for demographic factors, traditional and novel cardiovascular risk factors, cardiovascular disease status, and medication use, sequential quintiles of cystatin C concentration were associated with a stepwise increased risk for heart failure in Cox proportional hazards models (hazard ratios, 1.0 [reference], 1.30 [95\% CI, 0.96 to 1.75], 1.44 [CI, 1.07 to 1.94], 1.58 [CI, 1.18 to 2.12], and 2.16 [CI, 1.61 to 2.91]). In contrast, quintiles of serum creatinine concentration were not associated with risk for heart failure in adjusted analysis (hazard ratios, 1.0 [reference], 0.77 [CI, 0.59 to 1.01], 0.85 [CI, 0.64 to 1.13], 0.97 [CI, 0.72 to 1.29], and 1.14 [CI, 0.87 to 1.49]).

LIMITATIONS: The mechanism by which cystatin C concentration predicts risk for heart failure remains unclear.

CONCLUSIONS: The cystatin C concentration is an independent risk factor for heart failure in older adults and appears to provide a better measure of risk assessment than the serum creatinine concentration. *For a full list of participating Cardiovascular Health Study investigators and institutions, see http://www.chs-nhlbi.org.

}, keywords = {Aged, Biomarkers, Creatinine, Cystatin C, Cystatins, Female, Follow-Up Studies, Glomerular Filtration Rate, Heart Failure, Humans, Incidence, Kidney, Kidney Function Tests, Male, Risk Factors, United States}, issn = {1539-3704}, doi = {10.7326/0003-4819-142-7-200504050-00008}, author = {Sarnak, Mark J and Katz, Ronit and Stehman-Breen, Catherine O and Fried, Linda F and Jenny, Nancy Swords and Psaty, Bruce M and Newman, Anne B and Siscovick, David and Shlipak, Michael G} } @article {816, title = {Cystatin-C and mortality in elderly persons with heart failure.}, journal = {J Am Coll Cardiol}, volume = {45}, year = {2005}, month = {2005 Jan 18}, pages = {268-71}, abstract = {

OBJECTIVES: We sought to evaluate cystatin-C, a novel measure of renal function, as a predictor of mortality in elderly persons with heart failure (HF) and to compare it with creatinine.

BACKGROUND: Renal function is an important prognostic factor in patients with HF, but creatinine levels, which partly reflect muscle mass, may be insensitive for detecting renal insufficiency.

METHODS: A total of 279 Cardiovascular Health Study participants with prevalent HF and measures of serum cystatin-C and creatinine were followed for mortality outcomes over a median of 6.5 years.

RESULTS: Median creatinine and cystatin-C levels were 1.05 mg/dl and 1.26 mg/l. Each standard deviation increase in cystatin-C (0.35 mg/l) was associated with a 31\% greater adjusted mortality risk (95\% confidence interval [CI] 20\% to 43\%, p < 0.001), whereas each standard deviation increase in creatinine (0.39 mg/dl) was associated with a 17\% greater adjusted mortality risk (95\% CI 1\% to 36\%, p = 0.04). When both measures were combined in a single adjusted model, cystatin-C remained associated with elevated mortality risk (hazard ratio 1.60, 95\% CI 1.32 to 1.94), whereas creatinine levels appeared associated with lower risk (hazard ratio 0.73, 95\% CI 0.57 to 0.95).

CONCLUSIONS: Cystatin-C is a stronger predictor of mortality than creatinine in elderly persons with HF. If confirmed in future studies, this new marker of renal function could improve risk stratification in patients with HF.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Creatinine, Cystatin C, Cystatins, Female, Follow-Up Studies, Glomerular Filtration Rate, Heart Failure, Humans, Male, Pilot Projects, Predictive Value of Tests, Risk Assessment, Survival Analysis}, issn = {0735-1097}, doi = {10.1016/j.jacc.2004.09.061}, author = {Shlipak, Michael G and Katz, Ronit and Fried, Linda F and Jenny, Nancy Swords and Stehman-Breen, Catherine O and Newman, Anne B and Siscovick, David and Psaty, Bruce M and Sarnak, Mark J} } @article {865, title = {Kidney function as a predictor of noncardiovascular mortality.}, journal = {J Am Soc Nephrol}, volume = {16}, year = {2005}, month = {2005 Dec}, pages = {3728-35}, abstract = {

Chronic kidney disease is associated with a higher risk for cardiovascular mortality, as well as all-cause mortality. Whether chronic kidney disease is a predictor of noncardiovascular mortality is less clear. To further explore the latter, the association of kidney function with total noncardiovascular mortality and cause-specific mortality was assessed in the Cardiovascular Health Study, a community-based cohort of older individuals. Kidney disease was assessed using cystatin C and estimated GFR in 4637 participants in 1992 to 1993. Participants were followed until June 30, 2001. Deaths were adjudicated as cardiovascular or noncardiovascular disease by committee, and an underlying cause of death was assigned. The associations of kidney function with total noncardiovascular mortality and cause-specific mortality were analyzed by proportional hazards regression. Noncardiovascular mortality rates increased with higher cystatin C quartiles (16.8, 17.1, 21.6, and 50.0 per 1000 person-years). The association of cystatin C with noncardiovascular mortality persisted after adjustment for demographic factors; the presence of diabetes, C-reactive protein, hemoglobin, and prevalent cardiovascular disease; and measures of atherosclerosis (hazard ratio 1.69; 95\% confidence interval 1.33 to 2.15, for the fourth quartile versus the first quartile). Results for estimated GFR were similar. The risk for noncardiac deaths attributed to pulmonary disease, infection, cancer, and other causes was similarly associated with cystatin C levels. Kidney function predicts noncardiovascular mortality from multiple causes in the elderly. Further research is needed to understand the mechanisms and evaluate interventions to reduce the high mortality rate in chronic kidney disease.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Cardiovascular Diseases, Cause of Death, Cohort Studies, Confidence Intervals, Creatinine, Cystatin C, Cystatins, Female, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Kidney Function Tests, Longitudinal Studies, Male, Probability, Proportional Hazards Models, Risk Assessment, Severity of Illness Index, Survival Analysis, United States}, issn = {1046-6673}, doi = {10.1681/ASN.2005040384}, author = {Fried, Linda F and Katz, Ronit and Sarnak, Mark J and Shlipak, Michael G and Chaves, Paulo H M and Jenny, Nancy Swords and Stehman-Breen, Catherine and Gillen, Dan and Bleyer, Anthony J and Hirsch, Calvin and Siscovick, David and Newman, Anne B} } @article {912, title = {Cystatin C and prognosis for cardiovascular and kidney outcomes in elderly persons without chronic kidney disease.}, journal = {Ann Intern Med}, volume = {145}, year = {2006}, month = {2006 Aug 15}, pages = {237-46}, abstract = {

BACKGROUND: Cystatin C is an alternative measure of kidney function that may have prognostic importance among elderly persons who do not meet standard criteria for chronic kidney disease (estimated glomerular filtration rate [GFR] > or =60 mL/min per 1.73 m2).

OBJECTIVE: To evaluate cystatin C as a prognostic biomarker for death, cardiovascular disease, and incident chronic kidney disease among elderly persons without chronic kidney disease.

DESIGN: Cohort study.

SETTING: The Cardiovascular Health Study, a population-based cohort recruited from 4 communities in the United States.

PARTICIPANTS: 4663 elderly persons.

MEASUREMENTS: Measures of kidney function were creatinine-based estimated GFR by using the Modification of Diet in Renal Disease equation and cystatin C concentration. Outcomes were death, cardiovascular death, noncardiovascular death, heart failure, stroke, myocardial infarction, and incident chronic kidney disease during follow-up (median, 9.3 years).

RESULTS: At baseline, 78\% of participants did not have chronic kidney disease (estimated GFR > or =60 mL/min per 1.73 m2) and mean cystatin C concentration, creatinine concentration, and estimated GFR were 1.0 mg/L, 79.6 micromol/L (0.9 mg/dL), and 83 mL/min per 1.73 m2, respectively. Cystatin C concentrations (per SD, 0.18 mg/L) had strong associations with death (hazard ratio, 1.33 [95\% CI, 1.25 to 1.40]), cardiovascular death (hazard ratio, 1.42 [CI, 1.30 to 1.54]), noncardiovascular death (hazard ratio, 1.26 [CI, 1.17 to 1.36]), incident heart failure (hazard ratio, 1.28 [CI, 1.17 to 1.40]), stroke (hazard ratio, 1.22 [CI, 1.08 to 1.38]), and myocardial infarction (hazard ratio, 1.20 [CI, 1.06 to 1.36]) among these participants. Serum creatinine concentrations had much weaker associations with each outcome and only predicted cardiovascular death. Participants without chronic kidney disease who had elevated cystatin C concentrations (> or =1.0 mg/L) had a 4-fold risk for progressing to chronic kidney disease after 4 years of follow-up compared with those with cystatin C concentrations less than 1.0 mg/L.

LIMITATIONS: Because this study did not directly measure GFR or albuminuria, the extent to which cystatin C may be influenced by nonrenal factors was not determined and participants with albuminuria might have been misclassified as having no kidney disease.

CONCLUSIONS: Among elderly persons without chronic kidney disease, cystatin C is a prognostic biomarker of risk for death, cardiovascular disease, and chronic kidney disease. In this setting, cystatin C seems to identify a "preclinical" state of kidney dysfunction that is not detected with serum creatinine or estimated GFR.

}, keywords = {Aged, Biomarkers, Cardiovascular Diseases, Creatinine, Cystatin C, Cystatins, Glomerular Filtration Rate, Humans, Kidney, Longitudinal Studies, Prognosis, Proportional Hazards Models, Renal Insufficiency, Chronic, Risk Factors}, issn = {1539-3704}, doi = {10.7326/0003-4819-145-4-200608150-00003}, author = {Shlipak, Michael G and Katz, Ronit and Sarnak, Mark J and Fried, Linda F and Newman, Anne B and Stehman-Breen, Catherine and Seliger, Stephen L and Kestenbaum, Brian and Psaty, Bruce and Tracy, Russell P and Siscovick, David S} } @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 {933, title = {Association of kidney function with incident hip fracture in older adults.}, journal = {J Am Soc Nephrol}, volume = {18}, year = {2007}, month = {2007 Jan}, pages = {282-6}, abstract = {

Kidney dysfunction is associated with bone loss, and patients with ESRD have an increased risk for hip fracture. However, the association of mild to moderate kidney disease with hip fracture has not been studied previously. The association of kidney function with incident hip fracture was examined among participants in the Cardiovascular Health Study, a community-based cohort of older individuals. The primary measure of kidney function was serum cystatin C, a measure that does not depend on lean mass. Hip fractures were identified using International Classification of Diseases, Ninth Revision codes for hospitalizations. A total of 4699 individuals had cystatin C measured in 1992 to 1993 and did not have a hip fracture before cystatin C measurement. The association of kidney function with hip fracture was analyzed with Cox proportional hazards models. Analyses were conducted separately for men and women. After a mean follow-up of 7.1 yr, 195 incident hip fractures occurred in women and 79 occurred in men. Higher cystatin C levels were associated with a higher risk for fracture in women (hazard ratio [HR] 1.26; 95\% confidence interval [CI] 1.14 to 1.38 per SD) and in men (HR 1.27; 95\% CI 1.11 to 1.46). After multivariable adjustment, higher cystatin C levels were significantly associated with hip fracture in women (HR 1.16; 95\% CI 1.01, 1.33) but not in men (HR 1.14; 95\% CI 0.86 to 1.52), although the magnitude of the association was similar. Kidney dysfunction, as assessed by cystatin C, is associated with an increased risk for hip fracture. Further studies are needed to evaluate potential mediators of this relationship and to assess whether interventions can decrease this risk.

}, keywords = {Aged, Aged, 80 and over, Cystatin C, Cystatins, Female, Hip Fractures, Humans, Kidney, Kidney Failure, Chronic, Longitudinal Studies, Male, Osteoporosis, Prospective Studies, Risk Factors, Sex Factors}, issn = {1046-6673}, doi = {10.1681/ASN.2006050546}, author = {Fried, Linda F and Biggs, Mary Louise and Shlipak, Michael G and Seliger, Stephen and Kestenbaum, Bryan and Stehman-Breen, Catherine and Sarnak, Mark and Siscovick, David and Harris, Tamara and Cauley, Jane and Newman, Anne B and Robbins, John} } @article {964, title = {Individual and neighborhood socioeconomic status and progressive chronic kidney disease in an elderly population: The Cardiovascular Health Study.}, journal = {Soc Sci Med}, volume = {65}, year = {2007}, month = {2007 Aug}, pages = {809-21}, abstract = {

Few studies have focused on the association between socioeconomic status (SES) and progressive chronic kidney disease (pCKD) in an elderly population. We conducted a cohort study of 4735 Cardiovascular Health Study participants, ages 65 and older and living in 4 US communities, to examine the independent risk of pCKD associated with income, education and living in a low SES area. pCKD was defined as creatinine elevation 0.4 mg/dL (35 micromol/L) over a 4-7 year follow-up or CKD hospitalization. Area SES was characterized using measures of income, wealth, education and occupation for 1990 (corresponding to time of enrollment) US Census block groups of residence. Age and study site-adjusted incidence rates (per 1000 person years) of pCKD by quartiles of area-level SES score, income and education showed decreasing rates with increasing SES. Cox proportional hazards models showed that living in the lowest SES area quartile, as opposed to the highest, was associated with 50\% greater risk of pCKD, after adjusting for age, gender, study site, baseline creatinine, and individual-level SES. This increased risk and trend persisted after adjusting for lifestyle risk factors, diabetes and hypertension. We found no significant independent associations between pCKD and individual-level income or education (after adjusting for all other SES factors). As such, living in a low SES area is associated with greater risk of pCKD in an elderly US population.

}, keywords = {Age Factors, Aged, Cohort Studies, Female, Humans, Incidence, Kidney Failure, Chronic, Male, Proportional Hazards Models, Residence Characteristics, Risk Factors, Sex Factors, Social Class, United States}, issn = {0277-9536}, doi = {10.1016/j.socscimed.2007.04.011}, author = {Merkin, Sharon Stein and Diez Roux, Ana V and Coresh, Josef and Fried, Linda F and Jackson, Sharon A and Powe, Neil R} } @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} } @article {972, title = {Relationship of uric acid with progression of kidney disease.}, journal = {Am J Kidney Dis}, volume = {50}, year = {2007}, month = {2007 Aug}, pages = {239-47}, abstract = {

BACKGROUND: Uric acid levels are increased in patients with kidney dysfunction. We tested the hypothesis that uric acid may be associated with kidney disease progression.

STUDY DESIGN: Cohort study.

SETTING \& PARTICIPANTS: 5,808 participants of the Cardiovascular Health Study.

PREDICTOR: Uric acid levels.

OUTCOMES \& MEASUREMENTS: Kidney disease progression was defined as a decrease in estimated glomerular filtration rate (GFR) of 3 mL/min/1.73 m(2) per year or greater (>or=0.05 mL/s) and as incident chronic kidney disease (CKD). Measures of kidney function were estimated GFR using the Modification of Diet in Renal Disease Study equation.

RESULTS: Higher quintiles of uric acid levels were associated with greater prevalences of estimated GFR less than 60 mL/min/1.73 m(2) (<1.00 mL/s) of 7\%, 14\%, 12\%, 25\%, and 42\% for quintiles 1 (6.90 mg/dL [>410 micromol/L]), respectively. In comparison, there was only a modest, but significant, association between quintiles of uric acid levels and progression of kidney function decrease, with adjusted odds ratios of 1.0, 0.88 (95\% confidence interval [CI], 0.64 to 1.21), 1.23 (95\% CI, 0.87 to 1.75), 1.47 (95\% CI, 1.04 to 2.07), and 1.49 (95\% CI, 1.00 to 2.22) for quintiles 1 through 5, respectively. No significant association was found between uric acid level and incident CKD (adjusted odds ratio, 1.00; 95\% CI, 0.89 to 1.14).

LIMITATIONS: Measurements of albuminuria were not available.

CONCLUSIONS: Uric acid levels are associated strongly with prevalent CKD. In comparison, greater uric acid levels had a significant, but much weaker, association with progression of kidney disease.

}, keywords = {Aged, Aged, 80 and over, Cohort Studies, Cross-Sectional Studies, Disease Progression, Female, Glomerular Filtration Rate, Humans, Kidney Diseases, Male, Prospective Studies, Uric Acid}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2007.05.013}, author = {Chonchol, Michel and Shlipak, Michael G and Katz, Ronit and Sarnak, Mark J and Newman, Anne B and Siscovick, David S and Kestenbaum, Bryan and Carney, Jan Kirk and Fried, Linda F} } @article {1015, title = {Cardiovascular risk factors and incident acute renal failure in older adults: the cardiovascular health study.}, journal = {Clin J Am Soc Nephrol}, volume = {3}, year = {2008}, month = {2008 Mar}, pages = {450-6}, abstract = {

BACKGROUND AND OBJECTIVES: Although the elderly are at increased risk for acute renal failure, few prospective studies have identified risk factors for acute renal failure in the elderly.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: The associations of cardiovascular disease risk factors, subclinical cardiovascular disease, and clinical coronary heart disease with the risk for development of acute renal failure were examined in older adults in the Cardiovascular Health Study, a prospective cohort study of community-dwelling older adults. Incident hospitalized cases of acute renal failure were identified through hospital discharge International Classification of Diseases, Ninth Revision codes and confirmed through physician diagnoses of acute renal failure in discharge summaries.

RESULTS: Acute renal failure developed in 225 (3.9\%) of the 5731 patients during a median follow-up period of 10.2 yr. In multivariate analyses, diabetes, current smoking, hypertension, C-reactive protein, and fibrinogen were associated with acute renal failure. Prevalent coronary heart disease was associated with incident acute renal failure, and among patients without prevalent coronary heart disease, subclinical vascular disease measures were also associated with acute renal failure: Low ankle-arm index (< or =0.9), common carotid intima-media thickness, and internal carotid intima-media thickness.

CONCLUSIONS: In this large, population-based, prospective cohort study, cardiovascular risk factors and both subclinical and clinical vascular disease were associated with incident acute renal failure in the elderly.

}, keywords = {Acute Kidney Injury, Aged, Cardiovascular Diseases, Female, Follow-Up Studies, Humans, Male, Prospective Studies, Risk Factors}, issn = {1555-905X}, doi = {10.2215/CJN.02610607}, author = {Mittalhenkle, Anuja and Stehman-Breen, Catherine O and Shlipak, Michael G and Fried, Linda F and Katz, Ronit and Young, Bessie A and Seliger, Stephen and Gillen, Daniel and Newman, Anne B and Psaty, Bruce M and Siscovick, David} } @article {1013, title = {Cystatin C and aging success.}, journal = {Arch Intern Med}, volume = {168}, year = {2008}, month = {2008 Jan 28}, pages = {147-53}, abstract = {

BACKGROUND: To our knowledge, the effect of kidney function on successful aging has not been examined.

METHODS: We evaluated the relationship between cystatin C and aging success during a 6-year follow-up in the Cardiovascular Health Study, a community-based cohort of older adults (aged >or= 65 years). Successful aging was defined as remaining free of cardiovascular disease, cancer, and chronic obstructive pulmonary disease and having intact physical and cognitive functioning. In adjusted analysis, an accelerated failure time model was used to evaluate the percentage reduction in successful years by level of cystatin C. A separate Cox proportional hazards model evaluated whether cystatin C was related to incident physical and cognitive disability.

RESULTS: A total of 2140 participants had cystatin C measured and were free of the previously mentioned conditions at baseline. Their mean age was 74 years. The mean cystatin C level, creatinine level, and estimated glomerular filtration rate were 1.06 mg/L, 0.93 mg/dL, and 78 mL/min/1.73 m(2), respectively (to convert cystatin C to nanomoles per liter, multiply by 75; and to convert creatinine to micromoles per liter, multiply by 88.4). A total of 873 participants reached a first event in follow-up, 138 because of cognitive disability, 238 because of physical disability, 34 because of chronic obstructive pulmonary disease, 146 because of cancer, and 317 because of cardiovascular disease. The adjusted percentage reduction in successful life years in the highest vs the lowest quartile of cystatin C was 27\% (95\% confidence interval, 11\%-39\%). The highest vs lowest quartile of cystatin C also was independently associated with incident cognitive or physical disability (hazard ratio, 1.39; 95\% confidence interval, 1.00-1.98).

CONCLUSION: A higher cystatin C level, even within a range of relatively normal kidney function, was associated with unsuccessful aging.

}, keywords = {Aged, Aging, Biomarkers, Creatinine, Cystatin C, Cystatins, Female, Follow-Up Studies, Glomerular Filtration Rate, Humans, Kidney, Male}, issn = {0003-9926}, doi = {10.1001/archinternmed.2007.40}, author = {Sarnak, Mark J and Katz, Ronit and Fried, Linda F and Siscovick, David and Kestenbaum, Brian and Seliger, Stephen and Rifkin, Dena and Tracy, Russell and Newman, Anne B and Shlipak, Michael G} } @article {1012, title = {Cystatin C concentration as a predictor of systolic and diastolic heart failure.}, journal = {J Card Fail}, volume = {14}, year = {2008}, month = {2008 Feb}, pages = {19-26}, abstract = {

BACKGROUND: Risk factors for heart failure (HF) may differ according to ejection fraction (EF). Higher cystatin C, a marker of kidney dysfunction, is associated with incident HF, but previous studies did not determine EF at diagnosis. We hypothesized that kidney dysfunction would predict diastolic HF (DHF) better than systolic HF (SHF) in the Cardiovascular Health Study.

METHODS AND RESULTS: Cystatin C was measured in 4453 participants without HF at baseline. Incident HF was categorized as DHF (EF > or = 50\%) or SHF (EF < 50\%). We compared the association of cystatin C with the risk for DHF and SHF, after adjustment for age, sex, race, medications, and HF risk factors. During 8 years of follow-up, 167 participants developed DHF and 206 participants developed SHF. After adjustment, sequentially higher quartiles of cystatin C were associated with risk for SHF (competing risks hazard ratios 1.0 [reference], 1.99 [95\% confidence interval 1.14-3.48], 2.32 [1.32-4.07], 3.17 [1.82-5.50], P for trend < .001). The risk for DHF was apparent only at the highest cystatin C quartile (hazard ratios 1.0 [reference], 1.09 [0.62-1.89], 1.08 [0.61-1.93], and 1.83 [1.07-3.11]).

CONCLUSIONS: Cystatin C levels are linearly associated with the incidence of systolic HF, whereas only the highest concentrations of cystatin C predict diastolic HF.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Cohort Studies, Confidence Intervals, Cystatin C, Cystatins, Echocardiography, Female, Heart Failure, Diastolic, Heart Failure, Systolic, Humans, Longitudinal Studies, Male, Predictive Value of Tests, Probability, Proportional Hazards Models, Risk Assessment, Sensitivity and Specificity, Stroke Volume, Survival Analysis}, issn = {1532-8414}, doi = {10.1016/j.cardfail.2007.09.002}, author = {Moran, Andrew and Katz, Ronit and Smith, Nicolas L and Fried, Linda F and Sarnak, Mark J and Seliger, Stephen L and Psaty, Bruce and Siscovick, David S and Gottdiener, John S and Shlipak, Michael G} } @article {1037, title = {A physiologic index of comorbidity: relationship to mortality and disability.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {63}, year = {2008}, month = {2008 Jun}, pages = {603-9}, abstract = {

BACKGROUND: In older adults, there is often substantial undiagnosed chronic disease detectable on noninvasive testing, not accounted for by most comorbidity indices. We developed a simple physiologic index of comorbidity by scoring five noninvasive tests across the full range of values. We examined the predictive validity of this index for mortality and disability.

METHODS: There were 2928 (mean age 74.5 years, 60\% women, 85\% white, and 15\% black) participants in the Cardiovascular Health Study (1992-1993) who had carotid ultrasound, pulmonary function testing, brain magnetic resonance scan, serum cystatin-C, and fasting glucose. These were combined into a single physiologic index of comorbid chronic disease on a scale of 0-10. Cox proportional hazard models were used to predict mortality, mobility limitation, and activities of daily living (ADL) difficulty after a maximum of 9 years.

RESULTS: The range of the physiologic index was quite broad, with very few individuals having total scores of either 0 or 10. Those with an index of 7-10 had a hazard ratio of 3.80 (95\% confidence interval, 2.82-5.13) for mortality compared to those with scores of 0-2, after adjustment for demographics, behavioral risk factors, and clinically diagnosed conditions. Associations with mobility limitation and ADL difficulty were also significant. The index explained about 40\% of the age effect on mortality risk.

CONCLUSION: Older adults with low levels of markers of chronic disease are rather rare but have remarkably good health outcomes. The ability of such an index to distinguish usual from low risk might provide an opportunity to better understand optimal health in old age.

}, keywords = {Activities of Daily Living, Aged, Comorbidity, Disabled Persons, Female, Health Status, Humans, Male, Mobility Limitation, Mortality, Predictive Value of Tests, Proportional Hazards Models}, issn = {1079-5006}, doi = {10.1093/gerona/63.6.603}, author = {Newman, Anne B and Boudreau, Robert M and Naydeck, Barbara L and Fried, Linda F and Harris, Tamara B} } @article {1062, title = {Rapid kidney function decline and mortality risk in older adults.}, journal = {Arch Intern Med}, volume = {168}, year = {2008}, month = {2008 Nov 10}, pages = {2212-8}, abstract = {

BACKGROUND: Impaired kidney function is associated with increased mortality risk in older adults. It remains unknown, however, whether longitudinal declines in kidney function are independently associated with increased cardiovascular and all-cause mortality in older adults.

METHODS: The Cardiovascular Health Study evaluated a cohort of community-dwelling older adults enrolled from 1989 to 1993 in 4 US communities with follow-up through 2005. Among 4380 participants, the slope of annual decline in estimated glomerular filtration rate (eGFR) was estimated using both serum creatinine (eGFR(creat)) and cystatin C (eGFR(cys)) rates, which were measured at baseline, year 3, and year 7 of follow-up. Rapid decline in eGFR was defined as a loss greater than 3 mL/min/1.73 m(2) per year, and cardiovascular and all-cause mortality were assessed over a mean of 9.9 years of follow-up.

RESULTS: Mean (SD) levels of creatinine and cystatin C were 0.93 (0.30) mg/dL and 1.03 (0.25) mg/L, respectively; mean (SD) eGFR(creat) and eGFR(cys) were 79 (23) mL/min/1.73 m(2) and 79 (19) mL/min/1.73 m(2), respectively. Individuals with rapid decline measured by eGFR(creat) (n = 714; 16\%) had increased risk of cardiovascular (adjusted hazard ratio [AHR], 1.70; 95\% confidence interval [CI], 1.40-2.06) and all-cause (AHR, 1.73; 95\% CI, 1.54-1.94) mortality. Individuals with rapid decline measured by eGFR(cys) (n = 1083; 25\%) also had increased risk of cardiovascular (AHR, 1.53; 95\% CI, 1.29-1.80) and all-cause (AHR, 1.53; 95\% CI, 1.38-1.69) mortality. The association of rapid decline in eGFR with elevated mortality risk did not differ across subgroups based on baseline kidney function, age, sex, race, or prevalent coronary heart disease.

CONCLUSION: Rapid decline in eGFR is associated with an increased risk of cardiovascular and all-cause mortality in older adults, independent of baseline eGFR and other demographic variables.

}, keywords = {Aged, Cardiovascular Diseases, Creatinine, Cystatins, Female, Glomerular Filtration Rate, Humans, Kidney, Male, Mortality}, issn = {1538-3679}, doi = {10.1001/archinte.168.20.2212}, author = {Rifkin, Dena E and Shlipak, Michael G and Katz, Ronit and Fried, Linda F and Siscovick, David and Chonchol, Michel and Newman, Anne B and Sarnak, Mark J} } @article {1056, title = {Association of renal function with cardiac calcifications in older adults: the cardiovascular health study.}, journal = {Nephrol Dial Transplant}, volume = {24}, year = {2009}, month = {2009 Mar}, pages = {834-40}, abstract = {

BACKGROUND: Aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) are highly prevalent in patients with end-stage renal disease. It is less well established whether milder kidney disease is associated with cardiac calcifications. We evaluated the relationships between renal function and MAC, aortic annular calcification (AAC) and AVS in the elderly.

METHODS: From the Cardiovascular Health Study, a community-based cohort of ambulatory adults >or= age 65, a total of 3929 individuals (mean +/- SD age 74 +/- 5 years, 60\% women) were evaluated with two-dimensional echocardiography. Renal function was assessed by means of creatinine-based estimated glomerular filtration rate (eGFR) and cystatin C.

RESULTS: The prevalences of MAC and AAC were significantly higher in individuals with an eGFR < 45 mL/ min/1.73 m(2) (P < 0.01 for each), and cystatin C levels were significantly higher in individuals with MAC or AAC compared to individuals without these cardiac calcifications (P < 0.001 for each). After multivariate-adjustment, an eGFR <45 mL/min/1.73 m(2) was significantly associated with MAC [odds ratio 1.54 (95\% CI 1.16-2.06), P = 0.003] and not associated with AAC [1.30 (0.97-1.74), P = 0.085] and AVS [1.15 (0.86-1.53), P = 0.355]. In addition, cystatin C levels were independently associated with MAC [odds ratio per SD 1.12 (1.05-1.21), P = 0.001] and not associated with AAC [1.07 (1.00-1.15), P = 0.054] and AVS [0.99 (0.93-1.06), P = 0.82]. Furthermore, the prevalence of multiple cardiac calcifications was higher in subjects with an eGFR < 45 mL/ min/1.73 m(2) and increased per quartile of cystatin C (P-values < 0.001). In addition, a significant trend was observed between an eGFR < 45 mL/min/1.73 m(2), increasing levels of cystatin C and the number of cardiac calcifications (P < 0.05).

CONCLUSIONS: In a community-based cohort of the elderly, moderate kidney disease as defined by an eGFR <45 mL/min/1.73m(2) and elevated levels of cystatin C was associated with prevalent MAC. In addition, a significant trend was observed between an eGFR <45 mL/min/1.73m(2), increasing levels of cystatin C and the number of cardiac calcifications. No associations were found between renal function and AAC or AVS.

}, keywords = {Aged, Aortic Valve, Calcinosis, Case-Control Studies, Cohort Studies, Creatinine, Cystatin C, Female, Glomerular Filtration Rate, Heart Valve Diseases, Humans, Kidney Diseases, Male, Mitral Valve, Risk Factors}, issn = {1460-2385}, doi = {10.1093/ndt/gfn544}, author = {Asselbergs, Folkert W and Mozaffarian, Dariush and Katz, Ronit and Kestenbaum, Bryan and Fried, Linda F and Gottdiener, John S and Shlipak, Michael G and Siscovick, David S} } @article {1061, title = {Change in cardiovascular risk factors with progression of kidney disease.}, journal = {Am J Nephrol}, volume = {29}, year = {2009}, month = {2009}, pages = {334-41}, abstract = {

BACKGROUND: Prior studies evaluating the relationship of kidney disease with cardiovascular risk factors have been limited by their cross-sectional design. We evaluated the change in lipids, inflammatory and procoagulant biomarkers with decline in kidney function in a nested case-cohort study in the Cardiovascular Health Study, a community-based study of adults aged >65 years.

METHODS: Individuals with an increase in serum creatinine >or=0.3 mg/dl (baseline to 3 years later, n = 207) were matched to controls of similar age, race, gender, diabetes and baseline serum creatinine, but whose change in creatinine was <0.3 mg/dl. Baseline and change in risk factors were analyzed with conditional logistic regression.

RESULTS: Changes in C-reactive protein were similar. In contrast, cases had larger increases in fibrinogen (OR 1.38 per standard deviation, 95\% confidence interval 1.08-1.76) and factor VIII [1.38 (1.10-1.72)] and larger decreases in HDL [OR 0.80 (0.64, 1.00)]. Change in interleukin-6 was greater in cases than controls, but this did not persist after multivariate adjustment. However, in linear regression, change in interleukin-6 was correlated with change in creatinine.

CONCLUSION: Cardiovascular risk factors and kidney function may change concurrently. This could lead to an increased risk of cardiovascular disease as kidney function worsens.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, C-Reactive Protein, Cholesterol, HDL, Creatinine, Diabetes Mellitus, Factor VIII, Female, Follow-Up Studies, Humans, Hypertension, Renal, Interleukin-6, Logistic Models, Male, Prevalence, Renal Insufficiency, Chronic, Risk Factors, Vasculitis}, issn = {1421-9670}, doi = {10.1159/000166598}, author = {Fried, Linda F and Katz, Ronit and Cushman, Mary and Sarnak, Mark and Shlipak, Michael G and Kuller, Lewis and Newman, Anne B} } @article {1057, title = {Clinical and subclinical cardiovascular disease and kidney function decline in the elderly.}, journal = {Atherosclerosis}, volume = {204}, year = {2009}, month = {2009 May}, pages = {298-303}, abstract = {

OBJECTIVE: Kidney function decline in elderly persons may be the result of microvascular atherosclerosis. As a proxy for the renovascular system, we evaluated the association of clinical and subclinical cardiovascular disease (CVD) with kidney function decline.

METHODS: This study included 4380 subjects from the Cardiovascular Health Study, a longitudinal, community-based cohort of persons aged >or=65 from 4 U.S. communities. Creatinine and cystatin C were measured at baseline, year 3, and year 7; eligible subjects had at least two measures. Creatinine-based estimated glomerular filtration rate (eGFR(creat)) was calculated using the MDRD equation. Rapid kidney function decline was defined as an annual eGFR loss >3 mL/min/1.73 m(2). Predictors of rapid kidney decline included prevalent and subclinical measures of CVD.

RESULTS: Mean decline in eGFR(creat) was 0.4+/-2.6/year; 714 (16\%) had rapid progression. In multivariate models adjusted for demographics, cardiovascular risk factors, and inflammation, prevalent stroke (OR, 95\% CI: 1.55, 1.16-2.08) and heart failure (OR, 95\% CI: 1.80, 1.40-2.31) were independent predictors of rapid kidney decline. Among persons without clinical CV, the subclinical disease measures ankle-arm index <0.9 (OR, 95\% CI: 1.67, 1.25-2.24), common carotid intima-media thickness (>or=1.14 mm) (OR, 95\% CI: 1.52, 1.12-2.06) and internal carotid intima-media thickness (>1.82 mm) (OR, 95\% CI: 1.50, 1.12-2.02) had independent associations with rapid kidney function decline. Results were similar using cystatin C.

CONCLUSION: Clinical atherosclerosis and heart failure and subclinical measures of CVD have independent associations with kidney function decline progression in the elderly, suggesting an underlying role of renal atherosclerosis.

}, keywords = {Age Factors, Aged, Atherosclerosis, Cardiovascular Diseases, Creatinine, Cystatin C, Female, Glomerular Filtration Rate, Heart Failure, Humans, Kidney, Kidney Diseases, Linear Models, Longitudinal Studies, Male, Odds Ratio, Risk Assessment, Risk Factors, Time Factors, United States}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2008.08.016}, author = {Shlipak, Michael G and Katz, Ronit and Kestenbaum, Bryan and Fried, Linda F and Siscovick, David and Sarnak, Mark J} } @article {1110, title = {Cystatin C, albuminuria, and mortality among older adults with diabetes.}, journal = {Diabetes Care}, volume = {32}, year = {2009}, month = {2009 Oct}, pages = {1833-8}, abstract = {

OBJECTIVE: Albuminuria and impaired glomerular filtration rate (GFR) are each associated with poor health outcomes among individuals with diabetes. Joint associations of albuminuria and impaired GFR with mortality have not been comprehensively evaluated in this population.

RESEARCH DESIGN AND METHODS: This is a cohort study among Cardiovascular Health Study participants with diabetes, mean age 78 years. GFR was estimated using serum cystatin C and serum creatinine. Albumin-to-creatinine ratio (ACR) was measured in single-voided urine samples.

RESULTS: Of 691 participants, 378 died over 10 years of follow-up. Cystatin C-estimated GFR <60 ml/min per 1.73 m(2), creatinine-based estimated GFR <60 ml/min per 1.73 m(2), and urine ACR > or =30 mg/g were each associated with increased mortality risk with hazard ratios of 1.73 (95\% CI 1.37-2.18), 1.54 (1.21-1.97), and 1.73 (1.39-2.17), respectively, adjusting for age, sex, race, diabetes duration, hypoglycemic medications, hypertension, BMI, smoking, cholesterol, lipid-lowering medications, prevalent cardiovascular disease (CVD), and prevalent heart failure. Cystatin C-estimated GFR and urine ACR were additive in terms of mortality risk. Cystatin C-estimated GFR predicted mortality more strongly than creatinine-based estimated GFR.

CONCLUSIONS: Albuminuria and impaired GFR were independent, additive risk factors for mortality among older adults with diabetes. These findings support current recommendations to regularly assess both albuminuria and GFR in the clinical care of patients with diabetes; a focus on interventions to prevent or treat CVD in the presence of albuminuria, impaired GFR, or both; and further consideration of cystatin C use in clinical care.

}, keywords = {Aged, Aged, 80 and over, Albuminuria, Creatinine, Cystatin C, Diabetes Mellitus, Female, Glomerular Filtration Rate, Humans, Kidney Function Tests, Male, Risk Factors}, issn = {1935-5548}, doi = {10.2337/dc09-0191}, author = {de Boer, Ian H and Katz, Ronit and Cao, Jie J and Fried, Linda F and Kestenbaum, Bryan and Mukamal, Ken and Rifkin, Dena E and Sarnak, Mark J and Shlipak, Michael G and Siscovick, David S} } @article {1131, title = {Obesity and change in estimated GFR among older adults.}, journal = {Am J Kidney Dis}, volume = {54}, year = {2009}, month = {2009 Dec}, pages = {1043-51}, abstract = {

BACKGROUND: The prevalence of chronic kidney disease is growing most rapidly among older adults; however, determinants of impaired kidney function in this population are not well understood. Obesity assessed in midlife has been associated with chronic kidney disease.

STUDY DESIGN: Cohort study.

SETTING \& PARTICIPANTS: 4,295 participants in the community-based Cardiovascular Health Study, aged >or= 65 years.

PREDICTORS: Body mass index, waist circumference, and fat mass measured using bioelectrical impedance.

OUTCOME: Change in glomerular filtration rate (GFR) during 7 years of follow-up.

MEASUREMENTS: Longitudinal estimates of GFR calculated using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation.

RESULTS: Estimated GFR decreased by an average of 0.4 +/- 3.6 mL/min/1.73 m(2)/y, and rapid GFR loss (>3 mL/min/1.73 m(2)/y) occurred in 693 participants (16\%). Baseline body mass index, waist circumference, and fat mass were each associated with increased risk of rapid GFR loss: ORs, 1.19 (95\% CI, 1.09-1.30) per 5 kg/m(2), 1.25 (95\% CI, 1.16-1.36) per 12 cm, and 1.14 (95\% CI, 1.05-1.24) per 10 kg after adjustment for age, sex, race, and smoking. The magnitude of increased risk was larger for participants with estimated GFR < 60 mL/min/1.73 m(2) at baseline (P for interaction < 0.05). Associations were substantially attenuated by further adjustment for diabetes, hypertension, and C-reactive protein level. Obesity measurements were not associated with change in GFR estimated using serum cystatin C level.

LIMITATIONS: Few participants with advanced chronic kidney disease at baseline, no direct GFR measurements.

CONCLUSION: Obesity may be a modifiable risk factor for the development and progression of kidney disease in older adults.

}, keywords = {Aged, Aging, Body Composition, Body Mass Index, Chronic Disease, Cohort Studies, Creatinine, Cystatin C, Female, Glomerular Filtration Rate, Humans, Kidney, Kidney Diseases, Longitudinal Studies, Male, Obesity, Risk Factors}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2009.07.018}, author = {de Boer, Ian H and Katz, Ronit and Fried, Linda F and Ix, Joachim H and Luchsinger, Jose and Sarnak, Mark J and Shlipak, Michael G and Siscovick, David S and Kestenbaum, Bryan} } @article {1089, title = {Rate of kidney function decline in older adults: a comparison using creatinine and cystatin C.}, journal = {Am J Nephrol}, volume = {30}, year = {2009}, month = {2009}, pages = {171-8}, abstract = {

BACKGROUND/AIMS: The aim of this study was to determine the decline in the estimated glomerular filtration rate (eGFR) in elderly persons and to compare estimates based on creatinine and cystatin C.

METHODS: In the Cardiovascular Health Study, GFR changes in an elderly cohort were estimated from serum creatinine and cystatin C measured at baseline, year 3 and year 7 in 4,380 participants (age 72 +/- 5 years at entry). Outcomes were mean eGFR decline, incident chronic kidney disease (CKD) and rapid decline in eGFR (annual loss >3 ml/min/1.73 m(2)).

RESULTS: Mean annual eGFR loss as estimated from creatinine was 0.4 +/- 3.6 ml/min/1.73 m(2), with 16\% of the participants experiencing a rapid decline. Mean eGFR loss as estimated from cystatin C was 1.8 +/- 2.6, with 25\% of the participants experiencing a rapid decline (p < 0.001 for both). Among participants without baseline CKD, incident CKD was detected at year 7 in 10\% (n = 263) using creatinine and 19\% (n = 544) using cystatin C (p < 0.001). Increasing age was the strongest predictor of rapid decline; adjusted odds ratios were 1.38 (1.16-1.65), 1.62 (1.31-1.99) and 2.96 (2.28-3.84) for participants aged 70-74, 75-79 and 80+ at baseline, compared with those aged 65-69.

CONCLUSION: In elderly persons, cystatin C estimated substantially larger declines in kidney function than creatinine did. Defining the optimal measurement of kidney function in elderly persons should be a high priority for future research.

}, keywords = {Age Factors, Aged, Creatinine, Cystatin C, Disease Progression, Female, Glomerular Filtration Rate, Humans, Kidney, Kidney Diseases, Male, Risk Factors}, issn = {1421-9670}, doi = {10.1159/000212381}, author = {Shlipak, Michael G and Katz, Ronit and Kestenbaum, Bryan and Fried, Linda F and Newman, Anne B and Siscovick, David S and Stevens, Lesley and Sarnak, Mark J} } @article {1128, title = {Age and cystatin C in healthy adults: a collaborative study.}, journal = {Nephrol Dial Transplant}, volume = {25}, year = {2010}, month = {2010 Feb}, pages = {463-9}, abstract = {

BACKGROUND: Kidney function declines with age, but a substantial portion of this decline has been attributed to the higher prevalence of risk factors for kidney disease at older ages. The effect of age on kidney function has not been well described in a healthy population across a wide age spectrum.

METHODS: The authors pooled individual-level cross-sectional data from 18 253 persons aged 28-100 years in four studies: the Cardiovascular Health Study; the Health, Aging and Body Composition Study; the Multi-Ethnic Study of Atherosclerosis and the Prevention of Renal and Vascular End-Stage Disease cohort. Kidney function was measured by cystatin C. Clinical risk factors for kidney disease included diabetes, hypertension, obesity, smoking, coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure.

RESULTS: Across the age range, there was a strong, non-linear association of age with cystatin C concentration. This association was substantial, even among participants free of clinical risk factors for kidney disease; mean cystatin C levels were 46\% higher in participants 80 and older compared with those <40 years (1.06 versus 0.72 mg/L, P < 0.001). Participants with one or more risk factors had higher cystatin C concentrations for a given age, and the age association was slightly stronger (P < 0.001 for age and risk factor interaction).

CONCLUSIONS: There is a strong, non-linear association of age with kidney function, even in healthy individuals. An important area for research will be to investigate the mechanisms that lead to deterioration of kidney function in apparently healthy persons.

}, keywords = {Adult, Aged, Aged, 80 and over, Cross-Sectional Studies, Cystatin C, Humans, Kidney, Middle Aged, Reference Values}, issn = {1460-2385}, doi = {10.1093/ndt/gfp474}, author = {Odden, Michelle C and Tager, Ira B and Gansevoort, Ron T and Bakker, Stephan J L and Katz, Ronit and Fried, Linda F and Newman, Anne B and Canada, Robert B and Harris, Tamara and Sarnak, Mark J and Siscovick, David and Shlipak, Michael G} } @article {1149, title = {Albuminuria, impaired kidney function and cardiovascular outcomes or mortality in the elderly.}, journal = {Nephrol Dial Transplant}, volume = {25}, year = {2010}, month = {2010 May}, pages = {1560-7}, abstract = {

BACKGROUND: Kidney disease is a risk factor for mortality and cardiovascular disease in older adults, but the separate and combined effects of albuminuria and cystatin C, a novel marker of glomerular filtration, are not known.

METHODS: We examined associations of these markers with mortality and cardiovascular outcomes during a median follow-up of 8.3 years in 3291 older adults in the Cardiovascular Health Study. Kidney disease was assessed using urinary albumin/creatinine ratio (ACR), cystatin C and Modification of Diet in Renal Disease estimated glomerular filtration rate (eGFR). We defined subgroups based on presence of microalbuminuria (MA, ACR > 30 mg/g) and categories of normal kidney function (cystatin C < 1.0 mg/L and eGFR > 60 mL/min/1.73 m(2)); preclinical kidney disease (cystatin C level > 1.0 mg/l but eGFR > 60 mL/min/1.73 m(2)); and chronic kidney disease (CKD) (eGFR < 60 mL/min/1.73 m(2)). Cox proportional hazards models were used to examine associations between these six subgroups and all-cause or cardiovascular mortality, myocardial infarction and heart failure.

RESULTS: One thousand one hundred fifty (34.9\%) had normal kidney function (12.2\% with MA), 1518 (46.1\%) had preclinical kidney disease (17.9\% with MA) and 622 (18.9\%) had CKD (47\% with MA). After adjustment, the presence of either preclinical kidney disease or MA was associated with an over 50\% increase in mortality risk; the presence of both was associated with a 2.4-fold mortality risk. Those with CKD and MA were at highest risk, with a nearly 4-fold mortality risk.

CONCLUSION: Elevated cystatin C and albuminuria are common, identify different subsets of the older population, and are independent, graded risk factors for cardiovascular disease and mortality.

}, keywords = {Aged, Albuminuria, Cardiovascular Diseases, Creatinine, Cystatin C, Female, Glomerular Filtration Rate, Heart Failure, Humans, Male, Myocardial Infarction, Risk Factors}, issn = {1460-2385}, doi = {10.1093/ndt/gfp646}, author = {Rifkin, Dena E and Katz, Ronit and Chonchol, Michel and Fried, Linda F and Cao, Jie and de Boer, Ian H and Siscovick, David S and Shlipak, Michael G and Sarnak, Mark J} } @article {1190, title = {Association between baseline kidney function and change in CRP: an analysis of the cardiovascular health study.}, journal = {Nephron Clin Pract}, volume = {115}, year = {2010}, month = {2010}, pages = {c114-21}, abstract = {

BACKGROUND: In cross-sectional analyses, C-reactive protein (CRP) levels are inversely related to levels of kidney function. The relationship between kidney function and subsequent changes in CRP is unknown.

METHODS: We studied 4,364 individuals from the Cardiovascular Health Study, a longitudinal cohort of community-dwelling older adults. Baseline eGFRcys was estimated using cystatin C. CRP was measured at baseline and after 3 and 7 years of follow-up; slopes of change in CRP were calculated.

RESULTS: The mean (SD) age of the cohort was 72 (5.2) years; mean (SD) eGFRcys was 78.9 (18.4) ml/min/1.73 m(2). The median (interquartile range IQR) baseline CRP was 2.39 (1.22, 4.33) mg/l; the median (IQR) yearly change in CRP was -0.0051 (-0.020 to 0.27) mg/l/year. After adjustment for demographic characteristics and the initial level of CRP, each standard deviation lower baseline eGFR was associated with a small and non-significant yearly increase in CRP (0.032 mg/l/year; 95\% CI: -0.005 to 0.070, p = 0.094).

CONCLUSIONS: We did not find a relationship between eGFR and subsequent changes in CRP. The association between kidney function and CRP in cross-sectional analyses may reflect unmeasured confounding by atherosclerosis; alternatively, the burden of comorbidity and interval mortality in this population may have masked a stronger longitudinal association between kidney function and change in CRP. Further study in younger populations may clarify whether impaired kidney function leads to change in inflammation over time.

}, keywords = {Aged, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Cohort Studies, Cross-Sectional Studies, Female, Follow-Up Studies, Glomerular Filtration Rate, Humans, Kidney Function Tests, Longitudinal Studies, Male, Residence Characteristics}, issn = {1660-2110}, doi = {10.1159/000312874}, author = {Rifkin, Dena E and Katz, Ronit and Fried, Linda F and Kestenbaum, Bryan and Jenny, Nancy Swords and Newman, Anne B and Siscovick, David S and Shlipak, Michael G and Sarnak, Mark J} } @article {1177, title = {Cystatin C and sudden cardiac death risk in the elderly.}, journal = {Circ Cardiovasc Qual Outcomes}, volume = {3}, year = {2010}, month = {2010 Mar}, pages = {159-64}, abstract = {

BACKGROUND: Recent studies have demonstrated an association between moderate kidney dysfunction and sudden cardiac death in people with cardiovascular disease.

METHODS AND RESULTS: The study was a longitudinal analysis among 4465 participants from the Cardiovascular Health Study without prevalent cardiovascular disease at baseline. Cystatin C and creatinine were measured from baseline sera. Sudden cardiac death (SCD) was defined as a sudden pulseless condition from a cardiac origin in a previously stable individual that occurred out of the hospital or in the emergency room. The association between cystatin C tertiles and SCD was determined with multivariate Cox proportional hazards. A similar analysis compared SCD incidence across creatinine-based estimated glomerular filtration rate (eGFR) tertiles. Over a median follow-up of 11.2 years, 91 adjudicated SCD events occurred. The annual incidence of SCD events increased across cystatin C tertiles: 10 events per 10 000 person years in tertile 1, 25 events per 10 000 person years in tertile 2, and 32 events per 10 000 person-years in the highest cystatin C tertile. These associations persisted after multivariate adjustment: hazards ratio=2.72; 95\% confidence interval, 1.44 to 5.16 in tertile 2 and hazards ratio=2.67; 95\% confidence interval, 1.33 to 5.35 in tertile 3. After multivariate adjustment, the rate of SCD also increased in a linear distribution across creatinine-based eGFR tertiles: 15 events per 10 000 person-years in tertile 1, 22 events per 10 000 person-years in tertile 2, and 27 events per 10 000 person-years in tertile 3. No significant associations, however, remained between creatinine-based eGFR and SCD after multivariable adjustment.

CONCLUSIONS: Impaired kidney function, as measured by cystatin C, has an independent association with SCD risk among elderly persons without clinical cardiovascular disease.

}, keywords = {Age Factors, Aged, Biomarkers, Chi-Square Distribution, Creatinine, Cystatin C, Death, Sudden, Cardiac, Female, Glomerular Filtration Rate, Humans, Incidence, Kidney Diseases, Longitudinal Studies, Male, Proportional Hazards Models, Risk Assessment, Risk Factors, Time Factors, United States, Up-Regulation}, issn = {1941-7705}, doi = {10.1161/CIRCOUTCOMES.109.875369}, author = {Deo, Rajat and Sotoodehnia, Nona and Katz, Ronit and Sarnak, Mark J and Fried, Linda F and Chonchol, Michel and Kestenbaum, Bryan and Psaty, Bruce M and Siscovick, David S and Shlipak, Michael G} } @article {1127, title = {Inflammatory biomarkers and decline in kidney function in the elderly: the Cardiovascular Health Study.}, journal = {Nephrol Dial Transplant}, volume = {25}, year = {2010}, month = {2010 Jan}, pages = {119-24}, abstract = {

BACKGROUND: Cross-sectional studies have demonstrated a consistent and linear association between circulating inflammatory markers and kidney function. The objective of this study was to determine whether elevated markers of inflammation are independently associated with longitudinal kidney function decline.

METHODS: This study included 4128 subjects from the Cardiovascular Health Study. Cystatin C was measured at baseline, 3 years later and 7 years later; eligible subjects had at least two measures. Cystatin C-based estimated glomerular filtration rate (eGFR(cysC)) was estimated, and rapid kidney function decline was defined as an annual loss of eGFR(cysC) >3 mL/min/1.73 m(2). Predictors included ten inflammatory and procoagulant biomarkers: C-reactive protein, interleukin-6, intercellular adhesion molecule-1, white blood cell count, fibrinogen, factor VII, factor VIII, D-dimer, plasmin-antiplasmin complex and serum albumin.

RESULTS: During the study, 1059 subjects (26\%) had a rapid decline in kidney function. In contrast to the other nine inflammatory or procoagulant biomarkers, serum albumin had a consistent and inverse association with rapid kidney function decline [final adjusted logistic regression model: 1.14-fold increased odds (95\% CI 1.06-1.23) of rapid decline per standard deviation lower albumin]. The lowest quartile of albumin had an odds ratio of 1.55 (95\% CI 1.23-1.96) for rapid decline compared with the highest quartile. These associations persisted after adjusting the albumin models for CRP, IL-6 and fibrinogen.

CONCLUSIONS: In contrast to nine other inflammatory and procoagulant markers, only lower baseline levels of serum albumin were consistently associated with a rapid decline in kidney function, as measured by cystatin C-based eGFR.

}, keywords = {Aged, Biomarkers, C-Reactive Protein, Cohort Studies, Cystatin C, Female, Glomerular Filtration Rate, Humans, Inflammation, Intercellular Adhesion Molecule-1, Interleukin-6, Kidney, Logistic Models, Longitudinal Studies, Male, Prospective Studies, Serum Albumin}, issn = {1460-2385}, doi = {10.1093/ndt/gfp429}, author = {Keller, Christopher and Katz, Ronit and Sarnak, Mark J and Fried, Linda F and Kestenbaum, Bryan and Cushman, Mary and Shlipak, Michael G} } @article {1286, title = {Chronic kidney disease in octogenarians.}, journal = {Clin J Am Soc Nephrol}, volume = {6}, year = {2011}, month = {2011 Jun}, pages = {1410-7}, abstract = {

BACKGROUND AND OBJECTIVES: There are limited data on the prevalence of chronic kidney disease (CKD) and its clinical importance in the very old. We examined the prevalence of CKD in octogenarians and its association with cardiovascular disease (CVD).

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: In a cross-sectional analysis of 1028 participants from the Cardiovascular Health Study All Stars, we evaluated association of prevalent CKD with CVD using multivariable logistic regression. CKD was defined as eGFR of <60 ml/min per 1.73 m(2). GFR was estimated using CKD-Epi creatinine and cystatin C equations that incorporate coefficients for age, gender, and race (eGFR(EPI), eGFR(CYS3var)) and the one-variable cystatin C equation (eGFR(CYS1var)). Prevalent CVD was defined as a composite of coronary heart disease, heart failure, and stroke.

RESULTS: Mean age was 86 years, 64\% were women, 86\% were Caucasians, 14\% had diabetes, and 39\% had prevalent CVD. Mean eGFR(EPI), eGFR(CYS3var), and eGFR(CYS1var) were 59, 62, and 70 ml/min per 1.73 m(2), and 51\%, 46\%, and 33\% had CKD, respectively. Associations of CKD with CVD varied by equation in adjusted analyses: CKD(EPI) (OR, 1.53; 95\% CI, 1.15 to 2.03), CKD(CYS3var) (OR, 1.67; 95\% CI, 1.25, 2.23), and CKD(CYS1var) (OR, 2.09; 95\% CI, 1.55, 2.83).

CONCLUSIONS: Reduced eGFR is highly prevalent in octogenarians, and the eGFR(CYS1var) equation yielded the lowest prevalence of CKD but the strongest association with prevalent CVD. Because there are no validated estimating equations in the elderly, estimation of kidney function on the basis of on any one equation should be interpreted with caution.

}, keywords = {Age Factors, Aged, 80 and over, Analysis of Variance, Biomarkers, Cardiovascular Diseases, Chi-Square Distribution, Chronic Disease, Creatinine, Cross-Sectional Studies, Cystatin C, Diabetes Mellitus, Female, Glomerular Filtration Rate, Humans, Kidney, Kidney Diseases, Logistic Models, Male, Models, Biological, Prevalence, Risk Assessment, Risk Factors, United States}, issn = {1555-905X}, doi = {10.2215/CJN.08801010}, author = {Shastri, Shani and Tighiouart, Hocine and Katz, Ronit and Rifkin, Dena E and Fried, Linda F and Shlipak, Michael G and Newman, Anne B and Sarnak, Mark J} } @article {1256, title = {Cystatin C identifies chronic kidney disease patients at higher risk for complications.}, journal = {J Am Soc Nephrol}, volume = {22}, year = {2011}, month = {2011 Jan}, pages = {147-55}, abstract = {

Although cystatin C is a stronger predictor of clinical outcomes associated with CKD than creatinine, the clinical role for cystatin C is unclear. We included 11,909 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS) and assessed risks for death, cardiovascular events, heart failure, and ESRD among persons categorized into mutually exclusive groups on the basis of the biomarkers that supported a diagnosis of CKD (eGFR <60 ml/min per 1.73 m(2)): creatinine only, cystatin C only, both, or neither. We used CKD-EPI equations to estimate GFR from these biomarkers. In MESA, 9\% had CKD by the creatinine-based equation only, 2\% had CKD by the cystatin C-based equation only, and 4\% had CKD by both equations; in CHS, these percentages were 12, 4, and 13\%, respectively. Compared with those without CKD, the adjusted hazard ratios (HR) for mortality in MESA were: 0.80 (95\% CI 0.50 to 1.26) for CKD by creatinine only; 3.23 (95\% CI 1.84 to 5.67) for CKD by cystatin C only; and 1.93 (95\% CI 1.27 to 2.92) for CKD by both; in CHS, the adjusted HR were 1.09 (95\% CI 0.98 to 1.21), 1.78 (95\% CI 1.53 to 2.08), and 1.74 (95\% CI 1.58 to 1.93), respectively. The pattern was similar for cardiovascular disease (CVD), heart failure, and kidney failure outcomes. In conclusion, among adults diagnosed with CKD using the creatinine-based CKD-EPI equation, the adverse prognosis is limited to the subset who also have CKD according to the cystatin C-based equation. Cystatin C may have a role in identifying persons with CKD who have the highest risk for complications.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Cardiovascular Diseases, Chronic Disease, Creatinine, Cystatin C, Disease Progression, Female, Glomerular Filtration Rate, Heart Failure, Humans, Kidney Diseases, Kidney Failure, Chronic, Male, Middle Aged, Predictive Value of Tests, Retrospective Studies, Risk Factors}, issn = {1533-3450}, doi = {10.1681/ASN.2010050483}, author = {Peralta, Carmen A and Katz, Ronit and Sarnak, Mark J and Ix, Joachim and Fried, Linda F and de Boer, Ian and Palmas, Walter and Siscovick, David and Levey, Andrew S and Shlipak, Michael G} } @article {1277, title = {Longitudinal association of depressive symptoms with rapid kidney function decline and adverse clinical renal disease outcomes.}, journal = {Clin J Am Soc Nephrol}, volume = {6}, year = {2011}, month = {2011 Apr}, pages = {834-44}, abstract = {

BACKGROUND AND OBJECTIVES: Depression is a risk indicator for adverse outcomes in dialysis patients, but its prognostic impact in individuals who are not yet on dialysis is unknown. This study examines whether depressive symptoms are longitudinally associated with renal function decline, new-onset chronic kidney disease (CKD), ESRD, or hospitalization with acute kidney injury (AKI).

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: Depressive symptoms were measured in a longitudinal cohort study with the 10-item Centers for Epidemiologic Studies Depression scale using a previously validated cut-off value (>=8). CKD at study entry and during follow-up was defined as an estimated GFR (eGFR) < 60 ml/min per m(2). Outcomes were rapid decline in eGFR (>3 ml/min per m(2) per year), new-onset CKD, ESRD (U.S. Renal Data System-based), and AKI (based on adjudicated medical record review). The median follow-up duration was 10.5 years.

RESULTS: Depressed participants (21.2\%) showed a higher prevalence of CKD at baseline compared with nondepressed participants in multivariable analysis. Depression was associated with a subsequent risk of rapid decline in eGFR, incident ESRD, and AKI, but not incident CKD in unadjusted models. In multivariable analyses, only associations of depressive symptoms with AKI remained significant.

CONCLUSIONS: Elevated depressive symptoms are associated with subsequent adverse renal disease outcomes. The depression-related elevated risk of AKI was independent of traditional renal disease risk factors and may in part be explained by the predictive value of depression for acute coronary syndromes and heart failure hospitalizations that can be complicated by AKI.

}, keywords = {Acute Kidney Injury, Aged, Chronic Disease, Cohort Studies, Comorbidity, Depression, Female, Follow-Up Studies, Glomerular Filtration Rate, Humans, Kidney Diseases, Longitudinal Studies, Male}, issn = {1555-905X}, doi = {10.2215/CJN.03840510}, author = {Kop, Willem J and Seliger, Stephen L and Fink, Jeffrey C and Katz, Ronit and Odden, Michelle C and Fried, Linda F and Rifkin, Dena E and Sarnak, Mark J and Gottdiener, John S} } @article {1314, title = {Potential explanatory factors for higher incident hip fracture risk in older diabetic adults.}, journal = {Curr Gerontol Geriatr Res}, volume = {2011}, year = {2011}, month = {2011}, pages = {979270}, abstract = {

Type 2 diabetes is associated with higher fracture risk. Diabetes-related conditions may account for this risk. Cardiovascular Health Study participants (N = 5641; 42.0\% men; 15.5\% black; 72.8{\textpm}5.6 years) were followed 10.9 {\textpm} 4.6 years. Diabetes was defined as hypoglycemic medication use or fasting glucose (FG) >=126 mg/dL. Peripheral artery disease (PAD) was defined as ankle-arm index <0.9. Incident hip fractures were from medical records. Crude hip fracture rates (/1000 person-years) were higher for diabetic vs. non-diabetic participants with BMI <25 (13.6, 95\% CI: 8.9-20.2 versus 11.4, 95\% CI: 10.1-12.9) and BMI >=25 to <30 (8.3, 95\% CI: 5.7-11.9 versus 6.6, 95\% CI: 5.6-7.7), but similar for BMI >=30. Adjusting for BMI, sex, race, and age, diabetes was related to fractures (HR = 1.34; 95\% CI: 1.01-1.78). PAD (HR = 1.25 (95\% CI: 0.92-1.57)) and longer walk time (HR = 1.07 (95\% CI: 1.04-1.10)) modified the fracture risk in diabetes (HR = 1.17 (95\% CI: 0.87-1.57)). Diabetes was associated with higher hip fracture risk after adjusting for BMI though this association was modified by diabetes-related conditions.

}, issn = {1687-7071}, doi = {10.1155/2011/979270}, author = {Strotmeyer, Elsa S and Kamineni, Aruna and Cauley, Jane A and Robbins, John A and Fried, Linda F and Siscovick, David S and Harris, Tamara B and Newman, Anne B} } @article {1350, title = {Vitamin D, parathyroid hormone, and sudden cardiac death: results from the Cardiovascular Health Study.}, journal = {Hypertension}, volume = {58}, year = {2011}, month = {2011 Dec}, pages = {1021-8}, abstract = {

Recent studies have demonstrated greater risks of cardiovascular events and mortality among persons who have lower 25-hydroxyvitamin D (25-OHD) and higher parathyroid hormone (PTH) levels. We sought to evaluate the association between markers of mineral metabolism and sudden cardiac death (SCD) among the 2312 participants from the Cardiovascular Health Study who were free of clinical cardiovascular disease at baseline. We estimated associations of baseline 25-OHD and PTH concentrations individually and in combination with SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, and kidney function. During a median follow-up of 14 years, there were 73 adjudicated SCD events. The annual incidence of SCD was greater among subjects who had lower 25-OHD concentrations, 2 events per 1000 for 25-OHD >=20 ng/mL and 4 events per 1000 for 25-OHD <20 ng/mL. Similarly, SCD incidence was greater among subjects who had higher PTH concentrations, 2 events per 1000 for PTH <65 pg/mL and 4 events per 1000 for PTH >=65 pg/mL. Multivariate adjustment attenuated associations of 25-OHD and PTH with SCD. Finally, 267 participants (11.7\% of the cohort) had high PTH and low 25-OHD concentrations. This combination was associated with a >2-fold risk of SCD after adjustment (hazard ratio: 2.19 [95\% CI: 1.17-4.10]; P=0.017) compared with participants with normal levels of PTH and 25-OHD. The combination of lower 25-OHD and higher PTH concentrations appears to be associated independently with SCD risk among older adults without cardiovascular disease.

}, keywords = {Aged, Cardiovascular Diseases, Comorbidity, Death, Sudden, Cardiac, Diabetes Mellitus, Female, Follow-Up Studies, Humans, Hypertension, Incidence, Kidney, Male, Middle Aged, Minerals, Parathyroid Hormone, Proportional Hazards Models, Risk Factors, Socioeconomic Factors, United States, Vitamin D}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.111.179135}, author = {Deo, Rajat and Katz, Ronit and Shlipak, Michael G and Sotoodehnia, Nona and Psaty, Bruce M and Sarnak, Mark J and Fried, Linda F and Chonchol, Michel and de Boer, Ian H and Enquobahrie, Daniel and Siscovick, David and Kestenbaum, Bryan} } @article {1368, title = {Chronic kidney disease, insulin resistance, and incident diabetes in older adults.}, journal = {Clin J Am Soc Nephrol}, volume = {7}, year = {2012}, month = {2012 Apr}, pages = {588-94}, abstract = {

BACKGROUND AND OBJECTIVES: Insulin resistance is a complication of advanced CKD. Insulin resistance is less well characterized in earlier stages of CKD. The response of the pancreatic β cell, effects on glucose tolerance, and risk of diabetes are not clear.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: The Cardiovascular Health Study included 4680 adults without baseline diabetes. The Chronic Kidney Disease Epidemiology Collaboration creatinine equation was used to obtain the estimated GFR (eGFR). Insulin resistance was evaluated as fasting insulin concentration. The insulin sensitivity index, β cell function, and glucose tolerance were assessed by oral glucose tolerance testing. Incident diabetes was defined as fasting glucose >=126 mg/dl, nonfasting glucose >=200 mg/dl, or use of glucose-lowering medications.

RESULTS: Mean age was 72.5 years (range, 65-98 years). Mean eGFR was 72.2 (SD 17.1) ml/min per 1.73 m(2). After adjustment, each 10 ml/min per 1.73 m(2) lower eGFR was associated with a 2.2\% higher fasting insulin concentration (95\% confidence interval [CI], 1.4\%, 2.9\%; P<0.001) and a 1.1\% lower insulin sensitivity index (95\% CI, 0.03\%, 2.2\%; P=0.04). Surprisingly, eGFR was associated with an augmented β cell function index (P<0.001), lower 2-hour glucose concentration (P=0.002), and decreased risk of glucose intolerance (P=0.006). Over a median 12 years{\textquoteright} follow-up, 437 participants (9.3\%) developed diabetes. eGFR was not associated with the risk of incident diabetes.

CONCLUSIONS: Among older adults, lower eGFR was associated with insulin resistance. However, with lower eGFR, β cell function was appropriately augmented and risks of impaired glucose tolerance and incident diabetes were not increased.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Biomarkers, Chronic Disease, Creatinine, Diabetes Mellitus, Female, Glomerular Filtration Rate, Glucose Tolerance Test, Health Surveys, Humans, Hypoglycemic Agents, Incidence, Insulin, Insulin Resistance, Insulin-Secreting Cells, Kidney, Kidney Diseases, Linear Models, Male, Proportional Hazards Models, Risk Assessment, Risk Factors, United States}, issn = {1555-905X}, doi = {10.2215/CJN.11861111}, author = {Pham, Hien and Robinson-Cohen, Cassianne and Biggs, Mary L and Ix, Joachim H and Mukamal, Kenneth J and Fried, Linda F and Kestenbaum, Bryan and Siscovick, David S and de Boer, Ian H} } @article {1372, title = {Insulin resistance, cystatin C, and mortality among older adults.}, journal = {Diabetes Care}, volume = {35}, year = {2012}, month = {2012 Jun}, pages = {1355-60}, abstract = {

OBJECTIVE: Insulin resistance is a risk factor for cardiovascular and noncardiovascular diseases. Impaired kidney function is linked with insulin resistance and may affect relationships of insulin resistance with health outcomes.

RESEARCH DESIGN AND METHODS: We performed a cohort study of 3,138 Cardiovascular Health Study participants (age >= 65 years) without diabetes. Insulin sensitivity index (ISI) was calculated from fasting and 2-h postload insulin and glucose concentrations. Associations of ISI and fasting insulin concentration with all-cause mortality were tested using Cox proportional hazards models, adjusting for demographic variables, prevalent cardiovascular disease, lifestyle variables, waist circumference, and LDL cholesterol. Subsequent models were additionally adjusted for or stratified by glomerular filtration rate estimated using serum cystatin C (eGFR).

RESULTS: A total of 1,810 participants died during the 14.7-year median follow-up. Compared with the highest quartile of ISI, the lowest quartile (most insulin resistant) was associated with 21\% (95\% CI 6-41) and 11\% (-3 to 29) higher risks of death without and with adjustment for eGFR, respectively. Compared with the lowest quartile of fasting insulin concentration, the highest quartile was associated with 22\% (4-43) and 4\% (-12 to 22) higher risks of death without and with adjustment for eGFR, respectively. Similar attenuation by eGFR was observed when blood pressure, triglycerides, HDL cholesterol, and C-reactive protein were included in models.

CONCLUSIONS: Insulin resistance measured as ISI or fasting insulin concentration is associated with increased risk of death among older adults, adjusting for conventional confounding characteristics. Impaired kidney function may mediate or confound this relationship.

}, keywords = {Aged, Aged, 80 and over, Blood Glucose, Blood Pressure, C-Reactive Protein, Cardiovascular Diseases, Cholesterol, HDL, Cholesterol, LDL, Cohort Studies, Cystatin C, Fasting, Female, Glomerular Filtration Rate, Humans, Insulin Resistance, Life Style, Male, Mortality, Predictive Value of Tests, Proportional Hazards Models, Renal Insufficiency, Risk Factors, Triglycerides, Waist Circumference}, issn = {1935-5548}, doi = {10.2337/dc11-1657}, author = {de Boer, Ian H and Katz, Ronit and Chonchol, Michel B and Fried, Linda F and Ix, Joachim H and Kestenbaum, Bryan and Mukamal, Kenneth J and Peralta, Carmen A and Siscovick, David S} } @article {1395, title = {Kidney function and mortality in octogenarians: Cardiovascular Health Study All Stars.}, journal = {J Am Geriatr Soc}, volume = {60}, year = {2012}, month = {2012 Jul}, pages = {1201-7}, abstract = {

OBJECTIVES: To examine the association between kidney function and all-cause mortality in octogenarians.

DESIGN: Retrospective analysis of prospectively collected data.

SETTING: Community.

PARTICIPANTS: Serum creatinine and cystatin C were measured in 1,053 Cardiovascular Health Study (CHS) All Stars participants.

MEASUREMENTS: Estimated glomerular filtration rate (eGFR) was determined using the Chronic Kidney Disease Epidemiology Collaboration creatinine (eGFR(CR) ) and cystatin C one-variable (eGFR(CYS) ) equations. The association between quintiles of kidney function and all-cause mortality was analyzed using unadjusted and adjusted Cox proportional hazards models.

RESULTS: Mean age of the participants was 85, 64\% were female, 66\% had hypertension, 14\% had diabetes mellitus, and 39\% had prevalent cardiovascular disease. There were 154 deaths over a median follow-up of 2.6 years. The association between eGFR(CR) and all-cause mortality was U-shaped. In comparison with the reference quintile (64-75 mL/min per 1.73 m(2) ), the highest (>= 75 mL/min per 1.73 m(2) ) and lowest (<= 43 mL/min per 1.73 m(2) ) quintiles of eGFR(CR) were independently associated with mortality (hazard ratio (HR) = 2.49, 95\% confidence interval (CI) = 1.36-4.55; HR = 2.28, 95\% CI = 1.26-4.10, respectively). The association between eGFR(CYS) and all-cause mortality was linear in those with eGFR(CYS) of less than 60 mL/min per 1.73 m(2) , and in the multivariate analyses, the lowest quintile of eGFR(CYS) (<52 mL/min per 1.73 m(2) ) was significantly associated with mortality (HR = 2.04, 95\% CI = 1.12-3.71) compared with the highest quintile (>0.88 mL/min per 1.73 m(2) ).

CONCLUSION: Moderate reduction in kidney function is a risk factor for all-cause mortality in octogenarians. The association between eGFR(CR) and all-cause mortality differed from that observed with eGFR(CYS) ; the relationship was U-shaped for eGFR(CR) , whereas the risk was primarily present in the lowest quintile for eGFR(CYS) .

}, keywords = {Aged, 80 and over, Analysis of Variance, Cardiovascular Diseases, Chi-Square Distribution, Creatinine, Cystatin C, Diabetes Mellitus, Female, Glomerular Filtration Rate, Humans, Hypertension, Kidney Diseases, Male, Prevalence, Proportional Hazards Models, Retrospective Studies, Risk Factors, United States}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2012.04046.x}, author = {Shastri, Shani and Katz, Ronit and Rifkin, Dena E and Fried, Linda F and Odden, Michelle C and Peralta, Carmen A and Chonchol, Michel and Siscovick, David and Shlipak, Michael G and Newman, Anne B and Sarnak, Mark J} } @article {1328, title = {Leukocyte telomere length is associated with noninvasively measured age-related disease: The Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {67}, year = {2012}, month = {2012 Apr}, pages = {409-16}, abstract = {

BACKGROUND: Most studies of leukocyte telomere length (LTL) focus on diagnosed disease in one system. A more encompassing depiction of health is disease burden, defined here as the sum of noninvasively measured markers of structure or function in different organ systems. We determined if (a) shorter LTL is associated with greater age-related disease burden and (b) shorter LTL is less strongly associated with disease in individual systems or diagnosed chronic conditions (cardiovascular disease, stroke, pulmonary disease, diabetes, kidney disease, arthritis, or depression).

METHODS: LTL was measured by Southern blots of terminal restriction fragment length. Age-related disease was measured noninvasively and included carotid intima-media thickness, lung vital capacity, white matter grade, cystatin-C, and fasting glucose; each graded 0 (best tertile), 1 (middle tertile), or 2 (worst tertile) and summed (0 to 10) to estimate disease burden. Of 419 participants randomly selected for LTL measurement, 236 had disease burden assessed (mean [SD] age 74.2 [4.9] years, 42.4\% male, 86.8\% white, and 13.2\% black).

RESULTS: Mean (SD) LTL was 6,312 (615) bp, and disease score was 4.7 (2.1) points. An SD higher disease score (β [SE] = -132 [47] bp, p < .01), age (β [SE] = -107 [46], p = .02) or carotid thickness (β [SE] = -95 [40] bp, p = .02) was associated with shorter LTL, but diagnosed conditions or number of conditions were not associated with LTL. Disease score attenuated the effect of age on LTL by 35\%.

CONCLUSION: LTL was associated with a characterization of age-related disease burden across multiple physiologic systems, which was comparable to, but independent of, its association with age.

}, keywords = {African Americans, Aged, Aged, 80 and over, Cardiovascular Diseases, Carotid Intima-Media Thickness, Chronic Disease, Cystatin C, European Continental Ancestry Group, Female, Humans, Leukocytes, Lung, Male, Middle Aged, Telomere Homeostasis}, issn = {1758-535X}, doi = {10.1093/gerona/glr173}, author = {Sanders, Jason L and Fitzpatrick, Annette L and Boudreau, Robert M and Arnold, Alice M and Aviv, Abraham and Kimura, Masayuki and Fried, Linda F and Harris, Tamara B and Newman, Anne B} } @article {5999, title = {Blood pressure components and decline in kidney function in community-living older adults: the Cardiovascular Health Study.}, journal = {Am J Hypertens}, volume = {26}, year = {2013}, month = {2013 Aug}, pages = {1037-44}, abstract = {

BACKGROUND: Although hypertension contributes to kidney dysfunction in the general population, the contributions of elevated systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) to kidney function decline in community-dwelling older adults are unknown.

METHODS: We used linear and logistic regression to examine the separate and combined associations of SBP, DBP, and PP at baseline with kidney function decline among 4,365 older adults in the Cardiovascular Health Study. We used cystatin C to estimate glomerular filtration rate on 3 occasions over 7 years of follow-up. We defined rapid decline >= 3ml/min/year.

RESULTS: Average age was 72.2 and mean (standard deviation) SBP, DBP, and PP were 135 (21), 71 (11), and 65 (18) mm Hg, respectively. SBP and PP, rather than DBP, were most significantly associated with kidney function decline. In adjusted linear models, each 10-mm Hg increment in SBP and PP was associated with 0.13ml/min/year (-0.19, -0.08, P < 0.001) and 0.15-ml/min/year faster decline (-0.21, -0.09, P < 0.001), respectively. Each 10-mm Hg increment in DBP was associated with a nonsignificant 0.10-ml/min/year faster decline (95\% confidence interval, -0.20, 0.01). In adjusted logistic models, SBP had the strongest associations with rapid decline, with 14\% increased hazard of rapid decline (95\% confidence interval, 10\% to 17\%, P < 0.01) per 10mm Hg. In models combining BP components, only SBP consistently had independent associations with rapid decline.

CONCLUSIONS: Our findings suggest that elevated BP, particularly SBP, contributes to declining kidney function in older adults.

}, keywords = {Aged, Blood Pressure, Cohort Studies, Cystatin C, Diastole, Disease Progression, Female, Glomerular Filtration Rate, Humans, Hypertension, Logistic Models, Longitudinal Studies, Male, Pulse, Renal Insufficiency, Chronic, Systole}, issn = {1941-7225}, doi = {10.1093/ajh/hpt067}, author = {Rifkin, Dena E and Katz, Ronit and Chonchol, Michel and Shlipak, Michael G and Sarnak, Mark J and Fried, Linda F and Newman, Anne B and Siscovick, David S and Peralta, Carmen A} } @article {5996, title = {Fibroblast growth factor 23, bone mineral density, and risk of hip fracture among older adults: the cardiovascular health study.}, journal = {J Clin Endocrinol Metab}, volume = {98}, year = {2013}, month = {2013 Aug}, pages = {3323-31}, abstract = {

CONTEXT: Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that also inhibits calcitriol synthesis.

OBJECTIVE: Our objective was to evaluate the relationships of plasma FGF23 concentrations with bone mineral density (BMD) and hip fracture in community-dwelling older adults.

DESIGN AND SETTING: Linear regression and Cox proportional hazard models were used to examine the associations of plasma FGF23 concentrations with BMD and incident hip fracture, respectively. Analyses were also stratified by chronic kidney disease.

PARTICIPANTS: Participants included 2008 women and 1329 men >=65 years from the 1996 to 1997 Cardiovascular Health Study visit.

MAIN OUTCOME MEASURES: Dual x-ray absorptiometry measured total hip (TH) and lumbar spine (LS) BMD in 1291 participants. Hip fracture incidence was assessed prospectively through June 30, 2008 by hospitalization records in all participants.

RESULTS: Women had higher plasma FGF23 concentrations than men (75 [56-107] vs 66 [interquartile range = 52-92] relative units/mL; P < .001). After adjustment, higher FGF23 concentrations were associated with greater total hip and lumbar spine BMD in men only (β per doubling of FGF23 = 0.02, with 95\% confidence interval [CI] = 0.001-0.04 g/cm(2), and 0.03 with 95\% CI = 0.01-0.06 g/cm(2)). During 9.6 {\textpm} 5.1-11.0 years of follow-up, 328 hip fractures occurred. Higher FGF23 concentrations were not associated with hip fracture risk in women or men (adjusted hazard ratio = 0.95, with 95\% CI = 0.78-1.15, and 1.09 with 95\% CI = 0.82-1.46 per doubling of FGF23). Results did not differ by chronic kidney disease status (P > .4 for interactions).

CONCLUSIONS: In this large prospective cohort of community-dwelling older adults, higher FGF23 concentrations were weakly associated with greater lumbar spine and total hip BMD but not with hip fracture risk.

}, keywords = {Aged, Aged, 80 and over, Bone Density, Female, Fibroblast Growth Factors, Hip Fractures, Humans, Longitudinal Studies, Male, Middle Aged, Prospective Studies, Risk, Spinal Fractures}, issn = {1945-7197}, doi = {10.1210/jc.2013-1152}, author = {Jovanovich, Anna and B{\r u}zkov{\'a}, Petra and Chonchol, Michel and Robbins, John and Fink, Howard A and de Boer, Ian H and Kestenbaum, Bryan and Katz, Ronit and Carbone, Laura and Lee, Jennifer and Laughlin, Gail A and Mukamal, Kenneth J and Fried, Linda F and Shlipak, Michael G and Ix, Joachim H} } @article {1409, title = {Hemoglobin decline, function, and mortality in the elderly: the cardiovascular health study.}, journal = {Am J Hematol}, volume = {88}, year = {2013}, month = {2013 Jan}, pages = {5-9}, abstract = {

While anemia is associated with poor functional and mortality outcomes in the elderly, the impact of hemoglobin decline is less studied. We evaluated the determinants and consequences of hemoglobin decline in 3,758 non-anemic participants from the Cardiovascular Health Study, a prospective cohort of community-dwelling elderly >=65 years old at baseline and followed for up to 16 years. Hemoglobin was measured at baseline and 3 years later and anemia defined by World Health Organization (WHO) criteria. We modeled hemoglobin decline in two ways: (1) per each 1 g/dL decrease in hemoglobin and (2) development of anemia by the WHO criteria. Among participants without baseline anemia, hemoglobin decreased by 0.4 g/dL and 9\% developed anemia over 3 years. Baseline increasing age, female sex, diabetes, and kidney disease predicted hemoglobin decline over 3 years. Baseline increasing age, being African-American, and kidney disease predicted anemia development over 3 years. Hemoglobin decline was associated with subsequent worse cognitive function in men and anemia development with subsequent worse cognitive function in women. Both anemia development (HR 1.39, 95\% CI 1.15, 1.69) and hemoglobin decline (HR 1.11, 95\% CI 1.04, 1.18 per 1 g/dL decrease) predicted subsequent mortality in men and women. Hemoglobin decreases identified a large group of elderly individuals at risk for subsequent adverse outcomes who would not be identified using the WHO anemia criteria. These data may allow clinicians to identify at-risk elderly individuals for early intervention to improve the quality and quantity of life.

}, keywords = {African Americans, Age Factors, Aged, Aged, 80 and over, Anemia, Diabetes Complications, Female, Follow-Up Studies, Hemoglobins, Humans, Kidney Diseases, Male, Prospective Studies, Quality of Life, Risk Factors, Sex Factors, Survival Rate, Time Factors, World Health Organization}, issn = {1096-8652}, doi = {10.1002/ajh.23336}, author = {Zakai, Neil A and French, Benjamin and Arnold, Alice M and Newman, Anne B and Fried, Linda F and Robbins, John and Chaves, Paulo and Cushman, Mary} } @article {5854, title = {Hypertension and low HDL cholesterol were associated with reduced kidney function across the age spectrum: a collaborative study.}, journal = {Ann Epidemiol}, volume = {23}, year = {2013}, month = {2013 Mar}, pages = {106-11}, abstract = {

PURPOSE: To determine if the associations among established risk factors and reduced kidney function vary by age.

METHODS: We pooled cross-sectional data from 14,788 nondiabetics aged 40 to 100 years in 4 studies: Cardiovascular Health Study, Health, Aging, and Body Composition Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-Stage Disease cohort.

RESULTS: Hypertension and low high-density lipoprotein (HDL) cholesterol were associated with reduced cystatin C-based estimated glomerular filtration rate (eGFR) across the age spectrum. In adjusted analyses, hypertension was associated with a 2.3 (95\% confidence interval [CI], 0.1, 4.4), 5.1 (95\% CI, 4.1, 6.1), and 6.9 (95\%~CI, 3.0, 10.4) mL/min/1.73 m(2) lower eGFR in participants 40 to 59, 60 to 79, and at least 80~years, respectively (P for interaction < .001). The association of low HDL cholesterol with reduced kidney function was also greater in the older age groups: 4.9 (95\% CI, 3.5, 6.3), 7.1 (95\% CI, 6.0, 8.3), 8.9 (95\% CI, 5.4, 11.9) mL/min/1.73 m(2) (P for interaction < .001). Smoking and obesity were associated with reduced kidney function in participants under 80 years. All estimates of the potential population impact of the risk factors were modest.

CONCLUSIONS: Hypertension, obesity, smoking, and low HDL cholesterol are modestly associated with reduced kidney function in nondiabetics. The associations of hypertension and HDL cholesterol with reduced kidney function seem to be stronger in older adults.

}, keywords = {Adult, Age Factors, Aged, Aged, 80 and over, Aging, Causality, Cholesterol, LDL, Cohort Studies, Comorbidity, Cross-Sectional Studies, Cystatin C, Female, Humans, Hypertension, Kidney Function Tests, Male, Netherlands, Obesity, Prevalence, Renal Insufficiency, Chronic, Risk Factors, Smoking, United States}, issn = {1873-2585}, doi = {10.1016/j.annepidem.2012.12.004}, author = {Odden, Michelle C and Tager, Ira B and Gansevoort, Ron T and Bakker, Stephan J L and Fried, Linda F and Newman, Anne B and Katz, Ronit and Satterfield, Suzanne and Harris, Tamara B and Sarnak, Mark J and Siscovick, David and Shlipak, Michael G} } @article {6136, title = {Kidney function and prevalent and incident frailty.}, journal = {Clin J Am Soc Nephrol}, volume = {8}, year = {2013}, month = {2013 Dec}, pages = {2091-9}, abstract = {

BACKGROUND AND OBJECTIVES: Kidney disease is associated with physiologic changes that may predispose to frailty. This study sought to investigate whether lower levels of kidney function were associated with prevalent or incident frailty in Cardiovascular Health Study (CHS) participants.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: CHS enrolled community-dwelling adults age >=65 years between 1989-1990 and 1992-1993. To examine prevalent frailty, included were 4150 participants without stroke, Parkinson disease, prescribed medications for Alzheimer disease or depression, or severely impaired cognition. To examine incident frailty, included were a subset of 3459 participants without baseline frailty or development of exclusion criteria during follow-up. The primary predictor was estimated GFR (eGFR) calculated using serum cystatin C (eGFR(cys)). Secondary analyses examined eGFR using serum creatinine (eGFR(SCr)). Outcomes were prevalent frailty and incident frailty at 4 years of follow-up. Frailty was ascertained on the basis of weight loss, exhaustion, weakness, slowness, and low physical activity.

RESULTS: The mean age was 75 years and the median eGFR(cys) was 73 ml/min per 1.73 m(2). Among participants with an eGFR(cys) <45 ml/min per 1.73 m(2), 24\% had prevalent frailty. In multivariable analysis and compared with eGFR(cys) >=90 ml/min per 1.73 m(2), eGFR(cys) categories of 45-59 (odds ratio [OR], 1.80; 95\% confidence interval [CI], 1.17 to 2.75) and 15-44 (OR, 2.87; 95\% CI, 1.72 to 4.77) were associated with higher odds of frailty, whereas 60-75 (OR, 1.14; 95\% CI, 0.76 to 1.70) was not. In multivariable analysis, eGFR(cys) categories of 60-75 (incidence rate ratio [IRR], 1.72; 95\% CI, 1.07 to 2.75) and 15-44 (IRR, 2.28; 95\% CI, 1.23 to 4.22) were associated with higher incidence of frailty whereas 45-59 (IRR, 1.53; 95\% CI, 0.90 to 2.60) was not. Lower levels of eGFR(SCr) were not associated with higher risk of prevalent or incident frailty.

CONCLUSIONS: In community-dwelling elders, lower eGFR(cys) was associated with a higher risk of prevalent and incident frailty whereas lower eGFR(SCr) was not. These findings highlight the importance of considering non-GFR determinants of kidney function.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aging, Biomarkers, Creatinine, Cross-Sectional Studies, Cystatin C, Fatigue, Female, Frail Elderly, Geriatric Assessment, Glomerular Filtration Rate, Humans, Incidence, Independent Living, Kidney, Kidney Diseases, Logistic Models, Male, Motor Activity, Multivariate Analysis, Muscle Weakness, Odds Ratio, Phenotype, Prevalence, Prospective Studies, Risk Factors, Time Factors, United States, Weight Loss}, issn = {1555-905X}, doi = {10.2215/CJN.02870313}, author = {Dalrymple, Lorien S and Katz, Ronit and Rifkin, Dena E and Siscovick, David and Newman, Anne B and Fried, Linda F and Sarnak, Mark J and Odden, Michelle C and Shlipak, Michael G} } @article {6659, title = {Development and validation of a model to predict 5-year risk of death without ESRD among older adults with CKD.}, journal = {Clin J Am Soc Nephrol}, volume = {10}, year = {2015}, month = {2015 Mar 6}, pages = {363-71}, abstract = {

BACKGROUND AND OBJECTIVES: CKD is associated with mortality. Accurate prediction tools for mortality may guide clinical decision-making, particularly among elderly persons with CKD.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: A prediction equation was developed for 5-year risk of mortality among participants with CKD in the Cardiovascular Health Study. Sixteen candidate predictor variables were explored, which included demographics, physical examination measures, comorbidity, medication use, and kidney function measures (eGFR calculated from serum creatinine and the CKD Epidemiology Collaboration equation and the urine albumin-to-creatinine ratio). Models were developed using Cox regression and evaluated using c statistics. A final parsimonious model was externally validated in an independent cohort of community-living elders with CKD in the Health, Aging, and Body Composition Study.

RESULTS: The development cohort included 828 participants who had a mean age of 80 ({\textpm}5.6) years and an eGFR of 47 ({\textpm}11) ml/min per 1.73 m(2), and median albumin-to-creatinine ratio of 13 (interquartile range 6-51) mg/g. The validation cohort included 789 participants who had a mean age of 74 ({\textpm}2.8) years and an eGFR of 50 ({\textpm}9) ml/min per 1.73 m(2), and median albumin-to-creatinine ratio of 13 (interquartile range 6-42) mg/g. The final model for 5-year mortality risk included age, sex, race, eGFR, urine albumin-to-creatinine ratio, smoking, diabetes mellitus, and history of heart failure and stroke (c statistic=0.72; 95\% confidence interval, 0.68 to 0.74). When a point-based system was assigned for each of nine variables in the equation, the estimated risk of death within 5 years ranged from 3.8\% among participants with the lowest scores to 83.6\% among participants with nine points. The model performed fair in external validation (c statistic=0.69; 95\% confidence interval, 0.64 to 0.74).

CONCLUSIONS: A simple prediction tool using nine readily available clinical variables can assist in predicting 5-year mortality risk in elderly patients with CKD, which may be useful in counseling patients and guiding clinical decision making.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Albuminuria, Continental Population Groups, Creatinine, Diabetes Mellitus, Female, Glomerular Filtration Rate, Heart Failure, Humans, Male, Proportional Hazards Models, Regression Analysis, Renal Insufficiency, Chronic, Risk Factors, Sex Factors, Smoking, Stroke}, issn = {1555-905X}, doi = {10.2215/CJN.04650514}, author = {Bansal, Nisha and Katz, Ronit and de Boer, Ian H and Peralta, Carmen A and Fried, Linda F and Siscovick, David S and Rifkin, Dena E and Hirsch, Calvin and Cummings, Steven R and Harris, Tamara B and Kritchevsky, Stephen B and Sarnak, Mark J and Shlipak, Michael G and Ix, Joachim H} } @article {6990, title = {Fibroblast Growth Factor-23 and Frailty in Elderly Community-Dwelling Individuals: The Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {64}, year = {2016}, month = {2016 Feb}, pages = {270-6}, abstract = {

OBJECTIVES: To evaluate whether fibroblast growth factor 23 (FGF-23) is related to frailty and to characterize the nature of their joint association with mortality.

DESIGN: Cross-sectional analysis for frailty and longitudinal cohort analysis for mortality.

SETTING: Cardiovascular Health Study.

PARTICIPANTS: Community-dwelling individuals (N = 2,977; mean age 77.9 {\textpm} 4.7, 40\% male, 83\% white).

MEASUREMENTS: The predictor was serum FGF-23 concentration (C-terminal enzyme-linked immunosorbent assay), and the outcomes were frailty status (determined according to frailty phenotype criteria of weight loss, weakness, exhaustion, slowness, and low physical activity) and mortality. Multinomial logistic regression was used to assess the cross-sectional association between FGF-23 and frailty and prefrailty, adjusting for demographic characteristics, cardiovascular disease and risk factors, and kidney markers. Proportional hazards Cox proportional hazards regression was used to assess the association between FGF-23, frailty, and all-cause mortality.

RESULTS: Mean estimated glomerular filtration rate (eGFR) was 64 {\textpm} 17 mL/min per 1.73 m(2) . Median FGF-23 was 70.3 RU/mL (interquartile range 53.4-99.2); 52\% were prefrail, and 13\% were frail. After multivariate adjustment, each doubling in FGF-23 concentration was associated with 38\% (95\% confidence interval (CI) = 17-62\%) higher odds of frailty than of nonfrailty and 16\% (95\% CI = 3-30\%) higher odds of prefrailty. FGF-23 (hazard ratio (HR) = 1.16, 95\% CI = 1.10-1.23) and frailty (HR = 1.82, 95\% CI = 1.57-2.12) were independently associated with mortality, but neither association was meaningfully attenuated when adjusted for the other.

CONCLUSION: In a large cohort of older adults, higher FGF-23 was independently associated with prevalent frailty and prefrailty. FGF-23 and frailty were independent and additive risk factors for mortality. FGF-23 may be a marker for functional outcomes.

}, keywords = {Aged, Anthropometry, Biomarkers, Cardiovascular Diseases, Cross-Sectional Studies, Enzyme-Linked Immunosorbent Assay, Female, Fibroblast Growth Factors, Frail Elderly, Glomerular Filtration Rate, Humans, Independent Living, Longitudinal Studies, Male, Phenotype, Risk Factors, Surveys and Questionnaires}, issn = {1532-5415}, doi = {10.1111/jgs.13951}, author = {Beben, Tomasz and Ix, Joachim H and Shlipak, Michael G and Sarnak, Mark J and Fried, Linda F and Hoofnagle, Andrew N and Chonchol, Michel and Kestenbaum, Bryan R and de Boer, Ian H and Rifkin, Dena E} }