TY - JOUR T1 - Cardiovascular disease risk status in elderly persons with renal insufficiency. JF - Kidney Int Y1 - 2002 A1 - Shlipak, Michael G A1 - Fried, Linda F A1 - Crump, Casey A1 - Bleyer, Anthony J A1 - Manolio, Teri A A1 - Tracy, Russell P A1 - Furberg, Curt D A1 - Psaty, Bruce M KW - Age Distribution KW - Aged KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Coronary Disease KW - Creatinine KW - Cross-Sectional Studies KW - Female KW - Humans KW - Kidney Failure, Chronic KW - Male KW - Prevalence KW - Prospective Studies KW - Risk Factors AB -

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.

VL - 62 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12164883?dopt=Abstract ER - TY - JOUR T1 - Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency. JF - Circulation Y1 - 2003 A1 - Shlipak, Michael G A1 - Fried, Linda F A1 - Crump, Casey A1 - Bleyer, Anthony J A1 - Manolio, Teri A A1 - Tracy, Russell P A1 - Furberg, Curt D A1 - Psaty, Bruce M KW - Aged KW - alpha-2-Antiplasmin KW - Biomarkers KW - Blood Coagulation Factors KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cohort Studies KW - Creatinine KW - Cross-Sectional Studies KW - Female KW - Fibrin Fibrinogen Degradation Products KW - Fibrinogen KW - Fibrinolysin KW - Humans KW - Inflammation KW - Interleukin-6 KW - Male KW - Prospective Studies KW - Renal Insufficiency KW - Risk Factors AB -

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.

VL - 107 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12515748?dopt=Abstract ER - TY - JOUR T1 - Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals. JF - J Am Coll Cardiol Y1 - 2003 A1 - Fried, Linda F A1 - Shlipak, Michael G A1 - Crump, Casey A1 - Bleyer, Anthony J A1 - Gottdiener, John S A1 - Kronmal, Richard A A1 - Kuller, Lewis H A1 - Newman, Anne B KW - Aged KW - Cardiovascular Diseases KW - Confidence Intervals KW - Creatinine KW - Female KW - Heart Failure KW - Humans KW - Intermittent Claudication KW - Kidney Failure, Chronic KW - Male KW - Odds Ratio KW - Predictive Value of Tests KW - Survival Analysis AB -

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.

VL - 41 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12706933?dopt=Abstract ER - TY - JOUR T1 - Chronic renal insufficiency and cardiovascular events in the elderly: findings from the Cardiovascular Health Study. JF - Am J Geriatr Cardiol Y1 - 2004 A1 - Shlipak, Michael G A1 - Fried, Linda F A1 - Stehman-Breen, Catherine A1 - Siscovick, David A1 - Newman, Anne B KW - Aged KW - Blood Coagulation Factors KW - Cardiovascular Diseases KW - Chronic Disease KW - Creatinine KW - Cystatin C KW - Cystatins KW - Female KW - Fibrinogen KW - Geriatric Assessment KW - Humans KW - Incidence KW - Male KW - Prevalence KW - Renal Insufficiency KW - Risk Factors AB -

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.

VL - 13 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15010654?dopt=Abstract ER - TY - JOUR T1 - The presence of frailty in elderly persons with chronic renal insufficiency. JF - Am J Kidney Dis Y1 - 2004 A1 - Shlipak, Michael G A1 - Stehman-Breen, Catherine A1 - Fried, Linda F A1 - Song, Xiao A1 - Siscovick, David A1 - Fried, Linda P A1 - Psaty, Bruce M A1 - Newman, Anne B KW - Activities of Daily Living KW - Aged KW - Cross-Sectional Studies KW - Female KW - Frail Elderly KW - Humans KW - Kidney Failure, Chronic KW - Male KW - United States AB -

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.

VL - 43 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15112177?dopt=Abstract ER - TY - JOUR T1 - Cardiovascular mortality risk in chronic kidney disease: comparison of traditional and novel risk factors. JF - JAMA Y1 - 2005 A1 - Shlipak, Michael G A1 - Fried, Linda F A1 - Cushman, Mary A1 - Manolio, Teri A A1 - Peterson, Do A1 - Stehman-Breen, Catherine A1 - Bleyer, Anthony A1 - Newman, Anne A1 - Siscovick, David A1 - Psaty, Bruce KW - Aged KW - Cardiovascular Diseases KW - Chronic Disease KW - Humans KW - Kidney Diseases KW - Longitudinal Studies KW - Risk Factors AB -

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.

VL - 293 IS - 14 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15827312?dopt=Abstract ER - TY - JOUR T1 - Cystatin C and incident peripheral arterial disease events in the elderly: results from the Cardiovascular Health Study. JF - Arch Intern Med Y1 - 2005 A1 - O'Hare, Ann M A1 - Newman, Anne B A1 - Katz, Ronit A1 - Fried, Linda F A1 - Stehman-Breen, Catherine O A1 - Seliger, Stephen L A1 - Siscovick, David S A1 - Shlipak, Michael G KW - Aged KW - Cohort Studies KW - Cystatin C KW - Cystatins KW - Female KW - Health Surveys KW - Humans KW - Longitudinal Studies KW - Male KW - Peripheral Vascular Diseases KW - Predictive Value of Tests KW - Risk Factors KW - ROC Curve KW - United States AB -

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.

VL - 165 IS - 22 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16344426?dopt=Abstract ER - TY - JOUR T1 - Cystatin C and the risk of death and cardiovascular events among elderly persons. JF - N Engl J Med Y1 - 2005 A1 - Shlipak, Michael G A1 - Sarnak, Mark J A1 - Katz, Ronit A1 - Fried, Linda F A1 - Seliger, Stephen L A1 - Newman, Anne B A1 - Siscovick, David S A1 - Stehman-Breen, Catherine KW - Aged KW - Biomarkers KW - Cardiovascular Diseases KW - Cerebrospinal Fluid Proteins KW - Creatinine KW - Cystatin C KW - Cystatins KW - Female KW - Follow-Up Studies KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Diseases KW - Male KW - Mortality KW - Multivariate Analysis KW - Prognosis KW - Risk AB -

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.

VL - 352 IS - 20 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15901858?dopt=Abstract ER - TY - JOUR T1 - Cystatin C concentration as a risk factor for heart failure in older adults. JF - Ann Intern Med Y1 - 2005 A1 - Sarnak, Mark J A1 - Katz, Ronit A1 - Stehman-Breen, Catherine O A1 - Fried, Linda F A1 - Jenny, Nancy Swords A1 - Psaty, Bruce M A1 - Newman, Anne B A1 - Siscovick, David A1 - Shlipak, Michael G KW - Aged KW - Biomarkers KW - Creatinine KW - Cystatin C KW - Cystatins KW - Female KW - Follow-Up Studies KW - Glomerular Filtration Rate KW - Heart Failure KW - Humans KW - Incidence KW - Kidney KW - Kidney Function Tests KW - Male KW - Risk Factors KW - United States AB -

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.

VL - 142 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15809461?dopt=Abstract ER - TY - JOUR T1 - Cystatin-C and inflammatory markers in the ambulatory elderly. JF - Am J Med Y1 - 2005 A1 - Shlipak, Michael G A1 - Katz, Ronit A1 - Cushman, Mary A1 - Sarnak, Mark J A1 - Stehman-Breen, Catherine A1 - Psaty, Bruce M A1 - Siscovick, David A1 - Tracy, Russell P A1 - Newman, Anne A1 - Fried, Linda KW - Age Factors KW - Aged KW - Biomarkers KW - C-Reactive Protein KW - Cross-Sectional Studies KW - Cystatin C KW - Cystatins KW - Female KW - Fibrinogen KW - Glomerular Filtration Rate KW - Humans KW - Kidney Diseases KW - Male KW - Predictive Value of Tests KW - Sensitivity and Specificity AB -

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

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

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

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

VL - 118 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16378798?dopt=Abstract ER - TY - JOUR T1 - Cystatin-C and mortality in elderly persons with heart failure. JF - J Am Coll Cardiol Y1 - 2005 A1 - Shlipak, Michael G A1 - Katz, Ronit A1 - Fried, Linda F A1 - Jenny, Nancy Swords A1 - Stehman-Breen, Catherine O A1 - Newman, Anne B A1 - Siscovick, David A1 - Psaty, Bruce M A1 - Sarnak, Mark J KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Creatinine KW - Cystatin C KW - Cystatins KW - Female KW - Follow-Up Studies KW - Glomerular Filtration Rate KW - Heart Failure KW - Humans KW - Male KW - Pilot Projects KW - Predictive Value of Tests KW - Risk Assessment KW - Survival Analysis AB -

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.

VL - 45 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15653026?dopt=Abstract ER - TY - JOUR T1 - Kidney function as a predictor of noncardiovascular mortality. JF - J Am Soc Nephrol Y1 - 2005 A1 - Fried, Linda F A1 - Katz, Ronit A1 - Sarnak, Mark J A1 - Shlipak, Michael G A1 - Chaves, Paulo H M A1 - Jenny, Nancy Swords A1 - Stehman-Breen, Catherine A1 - Gillen, Dan A1 - Bleyer, Anthony J A1 - Hirsch, Calvin A1 - Siscovick, David A1 - Newman, Anne B KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cause of Death KW - Cohort Studies KW - Confidence Intervals KW - Creatinine KW - Cystatin C KW - Cystatins KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney Failure, Chronic KW - Kidney Function Tests KW - Longitudinal Studies KW - Male KW - Probability KW - Proportional Hazards Models KW - Risk Assessment KW - Severity of Illness Index KW - Survival Analysis KW - United States AB -

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.

VL - 16 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16251239?dopt=Abstract ER - TY - JOUR T1 - A prospective study of anemia status, hemoglobin concentration, and mortality in an elderly cohort: the Cardiovascular Health Study. JF - Arch Intern Med Y1 - 2005 A1 - Zakai, Neil A A1 - Katz, Ronit A1 - Hirsch, Calvin A1 - Shlipak, Michael G A1 - Chaves, Paulo H M A1 - Newman, Anne B A1 - Cushman, Mary KW - Age Factors KW - Aged KW - Anemia KW - California KW - Female KW - Follow-Up Studies KW - Health Status KW - Hemoglobins KW - Humans KW - Male KW - Maryland KW - Multivariate Analysis KW - North Carolina KW - Observation KW - Pennsylvania KW - Prospective Studies KW - Risk Factors KW - Severity of Illness Index KW - Survival Rate AB -

BACKGROUND: Anemia is viewed as a negative prognostic factor in the elderly population; its independent impact on survival is unclear.

METHODS: Baseline hemoglobin quintiles and anemia, as defined by the World Health Organization criteria, were assessed in relation to mortality in the Cardiovascular Health Study, a prospective cohort study with 11.2 years of follow-up of 5888 community-dwelling men and women 65 years or older, enrolled in 1989-1990 or 1992-1993 in 4 US communities.

RESULTS: A total of 1205 participants were in the lowest hemoglobin quintile (<13.7 g/dL for men; <12.6 g/dL for women), and 498 (8.5%) were anemic (<13 g/dL for men; <12 g/dL for women). A reverse J-shaped relationship with mortality was observed; age-, sex-, and race-adjusted hazard ratios (95% confidence interval [CI]) in the first and fifth quintiles, compared with the fourth quintile, were 1.42 (95% CI, 1.25-1.62) and 1.24 (95% CI, 1.09-1.42). After multivariate adjustment, these hazard ratios were 1.33 (95% CI, 1.15-1.54) and 1.17 (95% CI, 1.01-1.36). The demographic- and fully-adjusted hazard ratios of anemia for mortality were 1.57 (95% CI, 1.38-1.78) and 1.38 (95% CI, 1.19-1.54). Adjustment for causes and consequences of anemia (renal function, inflammation, or frailty) did not reduce associations.

CONCLUSIONS: Lower and higher hemoglobin concentrations and anemia by World Health Organization criteria were independently associated with increased mortality. The World Health Organization criteria did not identify risk as well as a lower hemoglobin value. Additional study is needed on the clinically valid definition for and causes of anemia in the elderly and on the increased mortality at the extremes of hemoglobin concentrations.

VL - 165 IS - 19 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16246985?dopt=Abstract ER - TY - JOUR T1 - Cystatin C and prognosis for cardiovascular and kidney outcomes in elderly persons without chronic kidney disease. JF - Ann Intern Med Y1 - 2006 A1 - Shlipak, Michael G A1 - Katz, Ronit A1 - Sarnak, Mark J A1 - Fried, Linda F A1 - Newman, Anne B A1 - Stehman-Breen, Catherine A1 - Seliger, Stephen L A1 - Kestenbaum, Brian A1 - Psaty, Bruce A1 - Tracy, Russell P A1 - Siscovick, David S KW - Aged KW - Biomarkers KW - Cardiovascular Diseases KW - Creatinine KW - Cystatin C KW - Cystatins KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Longitudinal Studies KW - Prognosis KW - Proportional Hazards Models KW - Renal Insufficiency, Chronic KW - Risk Factors AB -

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.

VL - 145 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16908914?dopt=Abstract ER - TY - JOUR T1 - Kidney function predicts the rate of bone loss in older individuals: the Cardiovascular Health Study. JF - J Gerontol A Biol Sci Med Sci Y1 - 2006 A1 - Fried, Linda F A1 - Shlipak, Michael G A1 - Stehman-Breen, Catherine A1 - Mittalhenkle, Anuja A1 - Seliger, Stephen A1 - Sarnak, Mark A1 - Robbins, John A1 - Siscovick, David A1 - Harris, Tamara B A1 - Newman, Anne B A1 - Cauley, Jane A KW - Absorptiometry, Photon KW - Aged KW - Bone Density KW - Creatinine KW - Cystatin C KW - Cystatins KW - Female KW - Hip KW - Humans KW - Kidney Diseases KW - Kidney Function Tests KW - Linear Models KW - Longitudinal Studies KW - Male KW - Osteoporosis KW - Predictive Value of Tests AB -

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.

VL - 61 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16870638?dopt=Abstract ER - TY - JOUR T1 - Mortality and cardiovascular risk across the ankle-arm index spectrum: results from the Cardiovascular Health Study. JF - Circulation Y1 - 2006 A1 - O'Hare, Ann M A1 - Katz, Ronit A1 - Shlipak, Michael G A1 - Cushman, Mary A1 - Newman, Anne B KW - Aged KW - Ankle KW - Arm KW - Blood Pressure KW - Body Mass Index KW - Cholesterol, LDL KW - Female KW - Follow-Up Studies KW - Humans KW - Longitudinal Studies KW - Male KW - Peripheral Vascular Diseases KW - Risk Factors KW - Smoking AB -

BACKGROUND: A low ankle-arm index (AAI) is a strong predictor of mortality and cardiovascular events. A high AAI also appears to be associated with higher mortality risk in select populations. However, mortality and cardiovascular risk across the AAI spectrum have not been described in a more broadly defined population.

METHODS AND RESULTS: We examined total and cardiovascular mortality and cardiovascular events across the AAI spectrum among 5748 participants in the Cardiovascular Health Study (CHS). The mean age of the sample population was 73+/-6 years, and the sample included 3289 women (57%) and 883 blacks (15%). The median duration of follow-up was 11.1 (0.1 to 12) years for mortality and 9.6 (0.1 to 12.1) years for cardiovascular events. There were 2311 deaths (953 of which were cardiovascular) and 1491 cardiovascular events during follow-up. After adjustment for potential confounders, AAI measurements < or =0.60 (hazard ratio [HR] 1.82, 95% CI 1.42 to 2.32), 0.61 to 0.7 (HR 2.08, 95% CI 1.61 to 2.69), 0.71 to 0.8 (HR 1.80, 95% CI 1.44 to 2.26), 0.81 to 0.9 (HR 1.73 95% CI 1.43 to 2.11), 0.91 to 1.0 (HR 1.40, 95% CI 1.20 to 1.63), and >1.40 (HR 1.57, 95% CI 1.07 to 2.31) were associated with higher mortality risk from all causes compared with the referent group (AAI 1.11 to 1.20). The pattern was similar for cardiovascular mortality. For cardiovascular events, risk was higher at all AAI levels <1 but not for AAI levels >1.4 (HR 1.00, 95% CI 0.57 to 1.74). The association of a high AAI with mortality was stronger in men than in women and in younger than in older cohort members.

CONCLUSIONS: In a cohort of community-dwelling elders, mortality risk was higher than the referent category of 1.11 to 1.2 among participants with AAI values above the traditional cutpoint of 0.9 (ie, 0.91 to 1.0 and >1.4), and the specific association of AAI with mortality varied by age and gender.

VL - 113 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16432070?dopt=Abstract ER - TY - JOUR T1 - Association of kidney function with incident hip fracture in older adults. JF - J Am Soc Nephrol Y1 - 2007 A1 - Fried, Linda F A1 - Biggs, Mary Louise A1 - Shlipak, Michael G A1 - Seliger, Stephen A1 - Kestenbaum, Bryan A1 - Stehman-Breen, Catherine A1 - Sarnak, Mark A1 - Siscovick, David A1 - Harris, Tamara A1 - Cauley, Jane A1 - Newman, Anne B A1 - Robbins, John KW - Aged KW - Aged, 80 and over KW - Cystatin C KW - Cystatins KW - Female KW - Hip Fractures KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Longitudinal Studies KW - Male KW - Osteoporosis KW - Prospective Studies KW - Risk Factors KW - Sex Factors AB -

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.

VL - 18 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17167115?dopt=Abstract ER - TY - JOUR T1 - Kidney function, electrocardiographic findings, and cardiovascular events among older adults. JF - Clin J Am Soc Nephrol Y1 - 2007 A1 - Kestenbaum, Bryan A1 - Rudser, Kyle D A1 - Shlipak, Michael G A1 - Fried, Linda F A1 - Newman, Anne B A1 - Katz, Ronit A1 - Sarnak, Mark J A1 - Seliger, Stephen A1 - Stehman-Breen, Catherine A1 - Prineas, Ronald A1 - Siscovick, David S KW - Aged KW - Aged, 80 and over KW - Cardiac Output, Low KW - Cardiovascular Diseases KW - Chronic Disease KW - Coronary Disease KW - Electrocardiography KW - Female KW - Humans KW - Kidney KW - Kidney Diseases KW - Male KW - Risk Assessment AB -

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.

VL - 2 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17699457?dopt=Abstract ER - TY - JOUR T1 - Relationship of uric acid with progression of kidney disease. JF - Am J Kidney Dis Y1 - 2007 A1 - Chonchol, Michel A1 - Shlipak, Michael G A1 - Katz, Ronit A1 - Sarnak, Mark J A1 - Newman, Anne B A1 - Siscovick, David S A1 - Kestenbaum, Bryan A1 - Carney, Jan Kirk A1 - Fried, Linda F KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Cross-Sectional Studies KW - Disease Progression KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney Diseases KW - Male KW - Prospective Studies KW - Uric Acid AB -

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.

VL - 50 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17660025?dopt=Abstract ER - TY - JOUR T1 - Cardiovascular risk factors and incident acute renal failure in older adults: the cardiovascular health study. JF - Clin J Am Soc Nephrol Y1 - 2008 A1 - Mittalhenkle, Anuja A1 - Stehman-Breen, Catherine O A1 - Shlipak, Michael G A1 - Fried, Linda F A1 - Katz, Ronit A1 - Young, Bessie A A1 - Seliger, Stephen A1 - Gillen, Daniel A1 - Newman, Anne B A1 - Psaty, Bruce M A1 - Siscovick, David KW - Acute Kidney Injury KW - Aged KW - Cardiovascular Diseases KW - Female KW - Follow-Up Studies KW - Humans KW - Male KW - Prospective Studies KW - Risk Factors AB -

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.

VL - 3 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18256380?dopt=Abstract ER - TY - JOUR T1 - Cystatin C and aging success. JF - Arch Intern Med Y1 - 2008 A1 - Sarnak, Mark J A1 - Katz, Ronit A1 - Fried, Linda F A1 - Siscovick, David A1 - Kestenbaum, Brian A1 - Seliger, Stephen A1 - Rifkin, Dena A1 - Tracy, Russell A1 - Newman, Anne B A1 - Shlipak, Michael G KW - Aged KW - Aging KW - Biomarkers KW - Creatinine KW - Cystatin C KW - Cystatins KW - Female KW - Follow-Up Studies KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Male AB -

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.

VL - 168 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18227360?dopt=Abstract ER - TY - JOUR T1 - Cystatin C concentration as a predictor of systolic and diastolic heart failure. JF - J Card Fail Y1 - 2008 A1 - Moran, Andrew A1 - Katz, Ronit A1 - Smith, Nicolas L A1 - Fried, Linda F A1 - Sarnak, Mark J A1 - Seliger, Stephen L A1 - Psaty, Bruce A1 - Siscovick, David S A1 - Gottdiener, John S A1 - Shlipak, Michael G KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Cohort Studies KW - Confidence Intervals KW - Cystatin C KW - Cystatins KW - Echocardiography KW - Female KW - Heart Failure, Diastolic KW - Heart Failure, Systolic KW - Humans KW - Longitudinal Studies KW - Male KW - Predictive Value of Tests KW - Probability KW - Proportional Hazards Models KW - Risk Assessment KW - Sensitivity and Specificity KW - Stroke Volume KW - Survival Analysis AB -

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.

VL - 14 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18226769?dopt=Abstract ER - TY - JOUR T1 - Rapid kidney function decline and mortality risk in older adults. JF - Arch Intern Med Y1 - 2008 A1 - Rifkin, Dena E A1 - Shlipak, Michael G A1 - Katz, Ronit A1 - Fried, Linda F A1 - Siscovick, David A1 - Chonchol, Michel A1 - Newman, Anne B A1 - Sarnak, Mark J KW - Aged KW - Cardiovascular Diseases KW - Creatinine KW - Cystatins KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Male KW - Mortality AB -

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.

VL - 168 IS - 20 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19001197?dopt=Abstract ER - TY - JOUR T1 - Association of chronic kidney disease with the spectrum of ankle brachial index the CHS (Cardiovascular Health Study). JF - J Am Coll Cardiol Y1 - 2009 A1 - Ix, Joachim H A1 - Katz, Ronit A1 - de Boer, Ian H A1 - Kestenbaum, Brian R A1 - Allison, Matthew A A1 - Siscovick, David S A1 - Newman, Anne B A1 - Sarnak, Mark J A1 - Shlipak, Michael G A1 - Criqui, Michael H KW - Aged KW - Aged, 80 and over KW - Ankle Brachial Index KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Chronic Disease KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney Diseases KW - Lipids KW - Male KW - Risk Factors AB -

OBJECTIVES: This study sought to determine the association of chronic kidney disease (CKD) with high ankle brachial index (ABI) measurement and to compare its strength with that of CKD with a low ABI.

BACKGROUND: CKD is an important risk factor for cardiovascular disease (CVD) events. A high ABI, a marker of lower extremity arterial stiffness, is associated with CVD events and mortality. The association between CKD and high ABI is unknown.

METHODS: The CHS (Cardiovascular Health Study) enrolled community-living people >65 years of age and measured kidney function and ABI. Glomerular filtration rate (GFR) was estimated using equations that incorporated either cystatin C or creatinine, and CKD was defined by estimated GFR <60 ml/min/1.73 m(2). The ABI was categorized as low (<0.90), low-normal (0.90 to 1.09), normal (1.10 to 1.40), and high (>1.40 or incompressible). Multinomial logistic regression was used to evaluate the associations of CKD with ABI categories.

RESULTS: Among 4,513 participants, 23% had CKD, 13% had a low ABI, and 3% had a high ABI. In models adjusted for age, sex, race, hypertension, diabetes, smoking, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and C-reactive protein, cystatin C-based CKD was associated with both low ABI (relative risk [RR]: 2.0; 95% confidence interval [CI]: 1.6 to 2.5; p <0.001) and high ABI (RR: 1.6; 95% CI: 1.0 to 2.3; p = 0.03). Results were similar when CKD was defined by creatinine.

CONCLUSIONS: CKD is associated with both the high and the low extremes of ABI in community-living older people. Future studies should evaluate whether arterial stiffness is an important mechanism leading to CVD in people with CKD.

VL - 54 IS - 13 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19761940?dopt=Abstract ER - TY - JOUR T1 - Association of renal function with cardiac calcifications in older adults: the cardiovascular health study. JF - Nephrol Dial Transplant Y1 - 2009 A1 - Asselbergs, Folkert W A1 - Mozaffarian, Dariush A1 - Katz, Ronit A1 - Kestenbaum, Bryan A1 - Fried, Linda F A1 - Gottdiener, John S A1 - Shlipak, Michael G A1 - Siscovick, David S KW - Aged KW - Aortic Valve KW - Calcinosis KW - Case-Control Studies KW - Cohort Studies KW - Creatinine KW - Cystatin C KW - Female KW - Glomerular Filtration Rate KW - Heart Valve Diseases KW - Humans KW - Kidney Diseases KW - Male KW - Mitral Valve KW - Risk Factors AB -

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.

VL - 24 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18840892?dopt=Abstract ER - TY - JOUR T1 - Change in cardiovascular risk factors with progression of kidney disease. JF - Am J Nephrol Y1 - 2009 A1 - Fried, Linda F A1 - Katz, Ronit A1 - Cushman, Mary A1 - Sarnak, Mark A1 - Shlipak, Michael G A1 - Kuller, Lewis A1 - Newman, Anne B KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - C-Reactive Protein KW - Cholesterol, HDL KW - Creatinine KW - Diabetes Mellitus KW - Factor VIII KW - Female KW - Follow-Up Studies KW - Humans KW - Hypertension, Renal KW - Interleukin-6 KW - Logistic Models KW - Male KW - Prevalence KW - Renal Insufficiency, Chronic KW - Risk Factors KW - Vasculitis AB -

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.

VL - 29 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18948687?dopt=Abstract ER - TY - JOUR T1 - Clinical and subclinical cardiovascular disease and kidney function decline in the elderly. JF - Atherosclerosis Y1 - 2009 A1 - Shlipak, Michael G A1 - Katz, Ronit A1 - Kestenbaum, Bryan A1 - Fried, Linda F A1 - Siscovick, David A1 - Sarnak, Mark J KW - Age Factors KW - Aged KW - Atherosclerosis KW - Cardiovascular Diseases KW - Creatinine KW - Cystatin C KW - Female KW - Glomerular Filtration Rate KW - Heart Failure KW - Humans KW - Kidney KW - Kidney Diseases KW - Linear Models KW - Longitudinal Studies KW - Male KW - Odds Ratio KW - Risk Assessment KW - Risk Factors KW - Time Factors KW - United States AB -

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.

VL - 204 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18848325?dopt=Abstract ER - TY - JOUR T1 - Cystatin C, albuminuria, and mortality among older adults with diabetes. JF - Diabetes Care Y1 - 2009 A1 - de Boer, Ian H A1 - Katz, Ronit A1 - Cao, Jie J A1 - Fried, Linda F A1 - Kestenbaum, Bryan A1 - Mukamal, Ken A1 - Rifkin, Dena E A1 - Sarnak, Mark J A1 - Shlipak, Michael G A1 - Siscovick, David S KW - Aged KW - Aged, 80 and over KW - Albuminuria KW - Creatinine KW - Cystatin C KW - Diabetes Mellitus KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney Function Tests KW - Male KW - Risk Factors AB -

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.

VL - 32 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19587367?dopt=Abstract ER - TY - JOUR T1 - Multiple loci associated with indices of renal function and chronic kidney disease. JF - Nat Genet Y1 - 2009 A1 - Köttgen, Anna A1 - Glazer, Nicole L A1 - Dehghan, Abbas A1 - Hwang, Shih-Jen A1 - Katz, Ronit A1 - Li, Man A1 - Yang, Qiong A1 - Gudnason, Vilmundur A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Smith, Albert V A1 - Arking, Dan E A1 - Astor, Brad C A1 - Boerwinkle, Eric A1 - Ehret, Georg B A1 - Ruczinski, Ingo A1 - Scharpf, Robert B A1 - Chen, Yii-Der Ida A1 - de Boer, Ian H A1 - Haritunians, Talin A1 - Lumley, Thomas A1 - Sarnak, Mark A1 - Siscovick, David A1 - Benjamin, Emelia J A1 - Levy, Daniel A1 - Upadhyay, Ashish A1 - Aulchenko, Yurii S A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Chasman, Daniel I A1 - Paré, Guillaume A1 - Ridker, Paul M A1 - Kao, W H Linda A1 - Witteman, Jacqueline C A1 - Coresh, Josef A1 - Shlipak, Michael G A1 - Fox, Caroline S KW - Chromosome Mapping KW - Cohort Studies KW - Genetic Variation KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Meta-Analysis as Topic KW - Mucoproteins KW - Netherlands KW - Polymorphism, Single Nucleotide KW - Prevalence KW - Uromodulin AB -

Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m(2)) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 × 10(-8)) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein, and rare mutations in UMOD cause mendelian forms of kidney disease. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.

VL - 41 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19430482?dopt=Abstract ER - TY - JOUR T1 - Obesity and change in estimated GFR among older adults. JF - Am J Kidney Dis Y1 - 2009 A1 - de Boer, Ian H A1 - Katz, Ronit A1 - Fried, Linda F A1 - Ix, Joachim H A1 - Luchsinger, Jose A1 - Sarnak, Mark J A1 - Shlipak, Michael G A1 - Siscovick, David S A1 - Kestenbaum, Bryan KW - Aged KW - Aging KW - Body Composition KW - Body Mass Index KW - Chronic Disease KW - Cohort Studies KW - Creatinine KW - Cystatin C KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Diseases KW - Longitudinal Studies KW - Male KW - Obesity KW - Risk Factors AB -

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.

VL - 54 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19782454?dopt=Abstract ER - TY - JOUR T1 - Rapid decline of kidney function increases cardiovascular risk in the elderly. JF - J Am Soc Nephrol Y1 - 2009 A1 - Shlipak, Michael G A1 - Katz, Ronit A1 - Kestenbaum, Bryan A1 - Siscovick, David A1 - Fried, Linda A1 - Newman, Anne A1 - Rifkin, Dena A1 - Sarnak, Mark J KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Creatinine KW - Cystatin C KW - Female KW - Glomerular Filtration Rate KW - Heart Failure KW - Humans KW - Longitudinal Studies KW - Male KW - Myocardial Infarction KW - Peripheral Vascular Diseases KW - Renal Insufficiency, Chronic KW - Risk Factors KW - Stroke KW - Time Factors KW - United States AB -

Chronic kidney disease (CKD), defined at a specific time point, is an important risk factor for cardiovascular disease. Whether the rate of kidney function decline contributes additional cardiovascular risk is unknown. In the Cardiovascular Health Study, we compared the associations of changes in kidney function during the first 7 yr with the incidence of heart failure (HF), myocardial infarction (MI), stroke, and peripheral arterial disease (PAD) during the subsequent 8 yr. We defined a rapid decline in cystatin C-based estimated GFR as >3 ml/min per 1.73 m(2)/yr, on the basis of determination at baseline, year 3, and year 7. Among eligible participants, 1083 (24%) had rapid kidney decline. The incidence of each type of cardiovascular event was significantly higher among patients with rapid decline (all P < 0.001). After multivariate adjustment for demographics, cardiovascular disease risk factors, and baseline kidney function, rapid kidney function decline was significantly associated with HF (adjusted hazard ratio [HR] 1.32; 95% confidence interval [CI] 1.13 to 1.53), MI (HR 1.48; 95% CI 1.21 to 1.83), and PAD (HR 1.67; 95% CI 1.02 to 2.75) but not with stroke (HR 1.19; 95% CI 0.97 to 1.45). The association of rapid decline with each outcome did not differ by the presence or absence of CKD. In conclusion, declining kidney function associates with higher risk for HF, MI, and PAD among patients with or without CKD.

VL - 20 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19892934?dopt=Abstract ER - TY - JOUR T1 - Rate of kidney function decline in older adults: a comparison using creatinine and cystatin C. JF - Am J Nephrol Y1 - 2009 A1 - Shlipak, Michael G A1 - Katz, Ronit A1 - Kestenbaum, Bryan A1 - Fried, Linda F A1 - Newman, Anne B A1 - Siscovick, David S A1 - Stevens, Lesley A1 - Sarnak, Mark J KW - Age Factors KW - Aged KW - Creatinine KW - Cystatin C KW - Disease Progression KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Diseases KW - Male KW - Risk Factors AB -

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.

VL - 30 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19349699?dopt=Abstract ER - TY - JOUR T1 - Age and cystatin C in healthy adults: a collaborative study. JF - Nephrol Dial Transplant Y1 - 2010 A1 - Odden, Michelle C A1 - Tager, Ira B A1 - Gansevoort, Ron T A1 - Bakker, Stephan J L A1 - Katz, Ronit A1 - Fried, Linda F A1 - Newman, Anne B A1 - Canada, Robert B A1 - Harris, Tamara A1 - Sarnak, Mark J A1 - Siscovick, David A1 - Shlipak, Michael G KW - Adult KW - Aged KW - Aged, 80 and over KW - Cross-Sectional Studies KW - Cystatin C KW - Humans KW - Kidney KW - Middle Aged KW - Reference Values AB -

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.

VL - 25 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19749145?dopt=Abstract ER - TY - JOUR T1 - Albuminuria, impaired kidney function and cardiovascular outcomes or mortality in the elderly. JF - Nephrol Dial Transplant Y1 - 2010 A1 - Rifkin, Dena E A1 - Katz, Ronit A1 - Chonchol, Michel A1 - Fried, Linda F A1 - Cao, Jie A1 - de Boer, Ian H A1 - Siscovick, David S A1 - Shlipak, Michael G A1 - Sarnak, Mark J KW - Aged KW - Albuminuria KW - Cardiovascular Diseases KW - Creatinine KW - Cystatin C KW - Female KW - Glomerular Filtration Rate KW - Heart Failure KW - Humans KW - Male KW - Myocardial Infarction KW - Risk Factors AB -

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.

VL - 25 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20008829?dopt=Abstract ER - TY - JOUR T1 - Alcohol consumption and kidney function decline in the elderly: alcohol and kidney disease. JF - Nephrol Dial Transplant Y1 - 2010 A1 - Menon, Vandana A1 - Katz, Ronit A1 - Mukamal, Kenneth A1 - Kestenbaum, Bryan A1 - de Boer, Ian H A1 - Siscovick, David S A1 - Sarnak, Mark J A1 - Shlipak, Michael G KW - Aged KW - Aging KW - Alcohol Drinking KW - Cohort Studies KW - Cystatin C KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Diseases KW - Male KW - Prospective Studies AB -

BACKGROUND: Alcohol consumption appears to be protective for cardiovascular disease; however, its relationship with kidney disease is unclear.

METHODS: This prospective cohort study included 4343 subjects from the Cardiovascular Health Study, a longitudinal, community-based cohort of persons aged ≥65 from four US communities. We used previously defined categories based on weekly alcohol consumption: none, former, <1 drink, 1-6 drinks, 7-13 drinks and ≥14 drinks. Cystatin C was measured at baseline, year 3 and year 7; eligible subjects had at least two measures. Estimated GFR(cys) was calculated from cystatin C. The primary outcome was rapid kidney function as an annual estimated GFR (eGFR(cys)) loss >3 mL/min/1.73 m(2)/year.

RESULTS: Eight percent of the cohort reported former alcohol use and 52% reported current alcohol consumption. During a mean follow-up of 5.6 years, 1075 (25%) participants had rapid kidney function decline. In adjusted logistic regression models, there was no association between alcohol use and kidney function decline (odds ratio, 95% confidence interval: none = reference; former = 1.18, 0.89-1.56; <1 drink = 1.20, 0.99-1.47; 1-6 = 1.18, 0.95-1.45; 7-13 = 1.10, 0.80-1.53; >14 = 0.89, 0.61-1.13). Results were similar with kidney function decline as a continuous outcome.

CONCLUSIONS: Our results suggest that moderate alcohol consumption has neither adverse nor beneficial effects on kidney function. Although clinicians will need to consider the potential deleterious effects associated with alcohol consumption, there does not appear to be a basis for recommending that older adults discontinue or initiate light to moderate alcohol consumption to protect against kidney disease.

VL - 25 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20400446?dopt=Abstract ER - TY - JOUR T1 - Association between baseline kidney function and change in CRP: an analysis of the cardiovascular health study. JF - Nephron Clin Pract Y1 - 2010 A1 - Rifkin, Dena E A1 - Katz, Ronit A1 - Fried, Linda F A1 - Kestenbaum, Bryan A1 - Jenny, Nancy Swords A1 - Newman, Anne B A1 - Siscovick, David S A1 - Shlipak, Michael G A1 - Sarnak, Mark J KW - Aged KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Follow-Up Studies KW - Glomerular Filtration Rate KW - Humans KW - Kidney Function Tests KW - Longitudinal Studies KW - Male KW - Residence Characteristics AB -

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.

VL - 115 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20413990?dopt=Abstract ER - TY - JOUR T1 - Common genetic variants associate with serum phosphorus concentration. JF - J Am Soc Nephrol Y1 - 2010 A1 - Kestenbaum, Bryan A1 - Glazer, Nicole L A1 - Köttgen, Anna A1 - Felix, Janine F A1 - Hwang, Shih-Jen A1 - Liu, Yongmei A1 - Lohman, Kurt A1 - Kritchevsky, Stephen B A1 - Hausman, Dorothy B A1 - Petersen, Ann-Kristin A1 - Gieger, Christian A1 - Ried, Janina S A1 - Meitinger, Thomas A1 - Strom, Tim M A1 - Wichmann, H Erich A1 - Campbell, Harry A1 - Hayward, Caroline A1 - Rudan, Igor A1 - de Boer, Ian H A1 - Psaty, Bruce M A1 - Rice, Kenneth M A1 - Chen, Yii-Der Ida A1 - Li, Man A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Coresh, Josef A1 - Yang, Qiong A1 - Levy, Daniel A1 - van Rooij, Frank J A A1 - Dehghan, Abbas A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - van Duijn, Cornelia M A1 - Shlipak, Michael G A1 - Kao, W H Linda A1 - Witteman, Jacqueline C M A1 - Siscovick, David S A1 - Fox, Caroline S KW - Adult KW - Aged KW - European Continental Ancestry Group KW - Female KW - Fibroblast Growth Factors KW - Gene Frequency KW - Genetic Loci KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Kidney KW - Male KW - Middle Aged KW - Phosphorus KW - Polymorphism, Single Nucleotide KW - Receptors, Calcium-Sensing KW - Sex Factors KW - Sodium-Phosphate Cotransporter Proteins, Type IIa AB -

Phosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR <45 ml/min per 1.73 m(2) to focus on phosphorus metabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the HapMap and combined study-specific findings using meta-analysis. We tested top polymorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies 0.08 to 0.49 associate with serum phosphorus concentration (P = 3.5 x 10(-16) to 3.6 x 10(-7)). Three loci were near genes encoding the kidney-specific type IIa sodium phosphate co-transporter (SLC34A1), the calcium-sensing receptor (CASR), and fibroblast growth factor 23 (FGF23), proteins that contribute to phosphorus metabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yet-undetermined roles in phosphorus homeostasis. In the replication sample, five of seven top polymorphisms associate with serum phosphorous concentrations (P < 0.05 for each). In conclusion, common genetic variants associate with serum phosphorus in the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorus regulation.

VL - 21 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20558539?dopt=Abstract ER - TY - JOUR T1 - Cystatin C and sudden cardiac death risk in the elderly. JF - Circ Cardiovasc Qual Outcomes Y1 - 2010 A1 - Deo, Rajat A1 - Sotoodehnia, Nona A1 - Katz, Ronit A1 - Sarnak, Mark J A1 - Fried, Linda F A1 - Chonchol, Michel A1 - Kestenbaum, Bryan A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - Shlipak, Michael G KW - Age Factors KW - Aged KW - Biomarkers KW - Chi-Square Distribution KW - Creatinine KW - Cystatin C KW - Death, Sudden, Cardiac KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Incidence KW - Kidney Diseases KW - Longitudinal Studies KW - Male KW - Proportional Hazards Models KW - Risk Assessment KW - Risk Factors KW - Time Factors KW - United States KW - Up-Regulation AB -

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.

VL - 3 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20233980?dopt=Abstract ER - TY - JOUR T1 - Impaired kidney function and atrial fibrillation in elderly subjects. JF - J Card Fail Y1 - 2010 A1 - Deo, Rajat A1 - Katz, Ronit A1 - Kestenbaum, Bryan A1 - Fried, Linda A1 - Sarnak, Mark J A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - Shlipak, Michael G KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Follow-Up Studies KW - Glomerular Filtration Rate KW - Humans KW - Kidney Diseases KW - Kidney Function Tests KW - Male AB -

BACKGROUND: Impaired kidney function is associated with increased risk for cardiovascular events. We evaluated whether kidney function is associated with atrial fibrillation (AF) risk in elderly persons.

METHODS AND RESULTS: Subjects were participants in the Cardiovascular Health Study (CHS), a population-based cohort of ambulatory elderly. Measures of kidney function were cystatin C and creatinine-based estimated glomerular filtration rate (eGFR). Among the 4663 participants, 342 (7%) had AF at baseline and 579 (13%) developed incident AF during follow-up (mean 7.4 years). In unadjusted analyses, cystatin C quartiles were strongly associated with prevalent AF with a nearly 3-fold odds in the highest quartile compared with the lowest (HR=1.19, 95% CI [0.80-1.76] in quartile 2; HR=2.00, 95% CI [1.38-2.88] in quartile 3; and HR=2.87, 95% CI [2.03-4.07] in quartile 4). This increased risk for prevalent AF remained significant after multivariate adjustment. The risk for incident AF increased across cystatin C quartiles in the unadjusted analysis (HR=1.37, 95% CI [1.07-1.75] in quartile 2; HR=1.43, 95% CI [1.11-1.84] in quartile 3; and HR=1.88, 95% CI [1.47-2.41] in quartile 4); however, after multivariate adjustment, these findings were no longer significant. An estimated GFR <60 mL.min.1.73m(2) was associated with prevalent and incident AF in unadjusted, but not multivariate analyses.

CONCLUSIONS: Impaired kidney function, as measured by cystatin C, is an independent marker of prevalent AF; however, neither cystatin C nor eGFR are predictors of incident AF.

VL - 16 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20123319?dopt=Abstract ER - TY - JOUR T1 - Inflammatory biomarkers and decline in kidney function in the elderly: the Cardiovascular Health Study. JF - Nephrol Dial Transplant Y1 - 2010 A1 - Keller, Christopher A1 - Katz, Ronit A1 - Sarnak, Mark J A1 - Fried, Linda F A1 - Kestenbaum, Bryan A1 - Cushman, Mary A1 - Shlipak, Michael G KW - Aged KW - Biomarkers KW - C-Reactive Protein KW - Cohort Studies KW - Cystatin C KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Inflammation KW - Intercellular Adhesion Molecule-1 KW - Interleukin-6 KW - Kidney KW - Logistic Models KW - Longitudinal Studies KW - Male KW - Prospective Studies KW - Serum Albumin AB -

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.

VL - 25 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19734138?dopt=Abstract ER - TY - JOUR T1 - New loci associated with kidney function and chronic kidney disease. JF - Nat Genet Y1 - 2010 A1 - Köttgen, Anna A1 - Pattaro, Cristian A1 - Böger, Carsten A A1 - Fuchsberger, Christian A1 - Olden, Matthias A1 - Glazer, Nicole L A1 - Parsa, Afshin A1 - Gao, Xiaoyi A1 - Yang, Qiong A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Li, Man A1 - Schmidt, Helena A1 - Tanaka, Toshiko A1 - Isaacs, Aaron A1 - Ketkar, Shamika A1 - Hwang, Shih-Jen A1 - Johnson, Andrew D A1 - Dehghan, Abbas A1 - Teumer, Alexander A1 - Paré, Guillaume A1 - Atkinson, Elizabeth J A1 - Zeller, Tanja A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Tönjes, Anke A1 - Hayward, Caroline A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Rampersaud, Evadnie A1 - Mitchell, Braxton D A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Struchalin, Maksim A1 - Cavalieri, Margherita A1 - Singleton, Andrew A1 - Giallauria, Francesco A1 - Metter, Jeffrey A1 - de Boer, Ian H A1 - Haritunians, Talin A1 - Lumley, Thomas A1 - Siscovick, David A1 - Psaty, Bruce M A1 - Zillikens, M Carola A1 - Oostra, Ben A A1 - Feitosa, Mary A1 - Province, Michael A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Schillert, Arne A1 - Ziegler, Andreas A1 - Wild, Philipp S A1 - Schnabel, Renate B A1 - Wilde, Sandra A1 - Munzel, Thomas F A1 - Leak, Tennille S A1 - Illig, Thomas A1 - Klopp, Norman A1 - Meisinger, Christa A1 - Wichmann, H-Erich A1 - Koenig, Wolfgang A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Kolcic, Ivana A1 - Minelli, Cosetta A1 - Hu, Frank B A1 - Johansson, Asa A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Schreiber, Stefan A1 - Aulchenko, Yurii S A1 - Felix, Janine F A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Imboden, Medea A1 - Nitsch, Dorothea A1 - Brandstätter, Anita A1 - Kollerits, Barbara A1 - Kedenko, Lyudmyla A1 - Mägi, Reedik A1 - Stumvoll, Michael A1 - Kovacs, Peter A1 - Boban, Mladen A1 - Campbell, Susan A1 - Endlich, Karlhans A1 - Völzke, Henry A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Völker, Uwe A1 - Polasek, Ozren A1 - Vitart, Veronique A1 - Badola, Sunita A1 - Parker, Alexander N A1 - Ridker, Paul M A1 - Kardia, Sharon L R A1 - Blankenberg, Stefan A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Franke, Andre A1 - Rochat, Thierry A1 - Paulweber, Bernhard A1 - Prokopenko, Inga A1 - Wang, Wei A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - Shlipak, Michael G A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Krämer, Bernhard K A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Witteman, Jacqueline C A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Hastie, Nick A1 - Chasman, Daniel I A1 - Kao, W H A1 - Heid, Iris M A1 - Fox, Caroline S KW - Cohort Studies KW - Creatinine KW - Cystatin C KW - Diet KW - Europe KW - Genetic Markers KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Models, Genetic KW - Risk Factors AB -

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.

VL - 42 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20383146?dopt=Abstract ER - TY - JOUR T1 - Antihypertensive medication use and change in kidney function in elderly adults: a marginal structural model analysis. JF - Int J Biostat Y1 - 2011 A1 - Odden, Michelle C A1 - Tager, Ira B A1 - van der Laan, Mark J A1 - Delaney, Joseph A C A1 - Peralta, Carmen A A1 - Katz, Ronit A1 - Sarnak, Mark J A1 - Psaty, Bruce M A1 - Shlipak, Michael G KW - Aged KW - Antihypertensive Agents KW - Cystatin C KW - Data Interpretation, Statistical KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Hypertension KW - Kidney KW - Longitudinal Studies KW - Male KW - Models, Statistical AB -

BACKGROUND: The evidence for the effectiveness of antihypertensive medication use for slowing decline in kidney function in older persons is sparse. We addressed this research question by the application of novel methods in a marginal structural model.

METHODS: Change in kidney function was measured by two or more measures of cystatin C in 1,576 hypertensive participants in the Cardiovascular Health Study over 7 years of follow-up (1989-1997 in four U.S. communities). The exposure of interest was antihypertensive medication use. We used a novel estimator in a marginal structural model to account for bias due to confounding and informative censoring.

RESULTS: The mean annual decline in eGFR was 2.41 ± 4.91 mL/min/1.73 m(2). In unadjusted analysis, antihypertensive medication use was not associated with annual change in kidney function. Traditional multivariable regression did not substantially change these estimates. Based on a marginal structural analysis, persons on antihypertensives had slower declines in kidney function; participants had an estimated 0.88 (0.13, 1.63) ml/min/1.73 m(2) per year slower decline in eGFR compared with persons on no treatment. In a model that also accounted for bias due to informative censoring, the estimate for the treatment effect was 2.23 (-0.13, 4.59) ml/min/1.73 m(2) per year slower decline in eGFR.

CONCLUSION: In summary, estimates from a marginal structural model suggested that antihypertensive therapy was associated with preserved kidney function in hypertensive elderly adults. Confirmatory studies may provide power to determine the strength and validity of the findings.

VL - 7 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22049266?dopt=Abstract ER - TY - JOUR T1 - Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD. JF - PLoS Genet Y1 - 2011 A1 - Böger, Carsten A A1 - Gorski, Mathias A1 - Li, Man A1 - Hoffmann, Michael M A1 - Huang, Chunmei A1 - Yang, Qiong A1 - Teumer, Alexander A1 - Krane, Vera A1 - O'Seaghdha, Conall M A1 - Kutalik, Zoltán A1 - Wichmann, H-Erich A1 - Haak, Thomas A1 - Boes, Eva A1 - Coassin, Stefan A1 - Coresh, Josef A1 - Kollerits, Barbara A1 - Haun, Margot A1 - Paulweber, Bernhard A1 - Köttgen, Anna A1 - Li, Guo A1 - Shlipak, Michael G A1 - Powe, Neil A1 - Hwang, Shih-Jen A1 - Dehghan, Abbas A1 - Rivadeneira, Fernando A1 - Uitterlinden, Andre A1 - Hofman, Albert A1 - Beckmann, Jacques S A1 - Krämer, Bernhard K A1 - Witteman, Jacqueline A1 - Bochud, Murielle A1 - Siscovick, David A1 - Rettig, Rainer A1 - Kronenberg, Florian A1 - Wanner, Christoph A1 - Thadhani, Ravi I A1 - Heid, Iris M A1 - Fox, Caroline S A1 - Kao, W H KW - Adaptor Proteins, Signal Transducing KW - Adult KW - Aged KW - Chronic Disease KW - Creatinine KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Genetic Association Studies KW - Humans KW - Kidney Diseases KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Receptor, Epidermal Growth Factor KW - Uromodulin AB -

Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.

VL - 7 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21980298?dopt=Abstract ER - TY - JOUR T1 - Chronic kidney disease and the risk of end-stage renal disease versus death. JF - J Gen Intern Med Y1 - 2011 A1 - Dalrymple, Lorien S A1 - Katz, Ronit A1 - Kestenbaum, Bryan A1 - Shlipak, Michael G A1 - Sarnak, Mark J A1 - Stehman-Breen, Catherine A1 - Seliger, Stephen A1 - Siscovick, David A1 - Newman, Anne B A1 - Fried, Linda KW - Aged KW - Aged, 80 and over KW - Cause of Death KW - Cohort Studies KW - Female KW - Follow-Up Studies KW - Humans KW - Kidney Failure, Chronic KW - Longitudinal Studies KW - Male KW - Prospective Studies KW - Renal Insufficiency, Chronic KW - Risk Factors KW - Treatment Outcome AB -

BACKGROUND: Among older adults with chronic kidney disease (CKD), the comparative event rates of end-stage renal disease (ESRD) and cause-specific death are unknown.

OBJECTIVE: To compare the rates of ESRD, cardiovascular and non-cardiovascular death and examine risk factors for ESRD and all-cause mortality in Cardiovascular Health Study (CHS) participants.

DESIGN: The CHS is a longitudinal cohort study of community-dwelling adults aged 65 years and older.

PARTICIPANTS: 1,268 participants with an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m(2) were followed until the time of first event (ESRD, cardiovascular or non-cardiovascular death) or until March 31, 2003.

MAIN MEASURES: The outcomes were ESRD, cardiovascular- and non-cardiovascular death. Rates of each event were calculated, and a Cox Proportional Hazards Model with a competing risk framework was used to examine risk factors for ESRD as compared with death. Predictors included age, gender, race, BMI, hypertension, diabetes, cardiovascular disease, heart failure, tobacco use, eGFR, and total cholesterol.

KEY RESULTS: During 9.7 years of follow-up, 5% of the cohort progressed to ESRD, and 61% of the cohort died. The rate (per 100 person-years) was 0.5 for ESRD and 6.8 for all-cause mortality (3.0 for cardiovascular and 3.8 for non-cardiovascular mortality). In the competing risk framework, lower eGFR, male gender, African-American race, and higher BMI were associated with an increased risk of ESRD.

CONCLUSIONS: Older adults with CKD are 13-fold more likely to die from any cause than progress to ESRD and are 6-fold more likely to die from cardiovascular causes than develop ESRD.

VL - 26 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20853156?dopt=Abstract ER - TY - JOUR T1 - Chronic kidney disease in octogenarians. JF - Clin J Am Soc Nephrol Y1 - 2011 A1 - Shastri, Shani A1 - Tighiouart, Hocine A1 - Katz, Ronit A1 - Rifkin, Dena E A1 - Fried, Linda F A1 - Shlipak, Michael G A1 - Newman, Anne B A1 - Sarnak, Mark J KW - Age Factors KW - Aged, 80 and over KW - Analysis of Variance KW - Biomarkers KW - Cardiovascular Diseases KW - Chi-Square Distribution KW - Chronic Disease KW - Creatinine KW - Cross-Sectional Studies KW - Cystatin C KW - Diabetes Mellitus KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Diseases KW - Logistic Models KW - Male KW - Models, Biological KW - Prevalence KW - Risk Assessment KW - Risk Factors KW - United States AB -

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.

VL - 6 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21511839?dopt=Abstract ER - TY - JOUR T1 - CUBN is a gene locus for albuminuria. JF - J Am Soc Nephrol Y1 - 2011 A1 - Böger, Carsten A A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Olden, Matthias A1 - Köttgen, Anna A1 - de Boer, Ian H A1 - Fuchsberger, Christian A1 - O'Seaghdha, Conall M A1 - Pattaro, Cristian A1 - Teumer, Alexander A1 - Liu, Ching-Ti A1 - Glazer, Nicole L A1 - Li, Man A1 - O'Connell, Jeffrey R A1 - Tanaka, Toshiko A1 - Peralta, Carmen A A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Zhao, Jing Hua A1 - Hwang, Shih-Jen A1 - Akylbekova, Ermeg A1 - Kramer, Holly A1 - van der Harst, Pim A1 - Smith, Albert V A1 - Lohman, Kurt A1 - de Andrade, Mariza A1 - Hayward, Caroline A1 - Kollerits, Barbara A1 - Tönjes, Anke A1 - Aspelund, Thor A1 - Ingelsson, Erik A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Shuldiner, Alan R A1 - Mitchell, Braxton D A1 - Arking, Dan E A1 - Franceschini, Nora A1 - Boerwinkle, Eric A1 - Egan, Josephine A1 - Hernandez, Dena A1 - Reilly, Muredach A1 - Townsend, Raymond R A1 - Lumley, Thomas A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Kestenbaum, Bryan A1 - Haritunians, Talin A1 - Bergmann, Sven A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Mooser, Vincent A1 - Waterworth, Dawn A1 - Johnson, Andrew D A1 - Florez, Jose C A1 - Meigs, James B A1 - Lu, Xiaoning A1 - Turner, Stephen T A1 - Atkinson, Elizabeth J A1 - Leak, Tennille S A1 - Aasarød, Knut A1 - Skorpen, Frank A1 - Syvänen, Ann-Christine A1 - Illig, Thomas A1 - Baumert, Jens A1 - Koenig, Wolfgang A1 - Krämer, Bernhard K A1 - Devuyst, Olivier A1 - Mychaleckyj, Josyf C A1 - Minelli, Cosetta A1 - Bakker, Stephan J L A1 - Kedenko, Lyudmyla A1 - Paulweber, Bernhard A1 - Coassin, Stefan A1 - Endlich, Karlhans A1 - Kroemer, Heyo K A1 - Biffar, Reiner A1 - Stracke, Sylvia A1 - Völzke, Henry A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Campbell, Harry A1 - Vitart, Veronique A1 - Hastie, Nicholas D A1 - Gudnason, Vilmundur A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Polasek, Ozren A1 - Curhan, Gary A1 - Kronenberg, Florian A1 - Prokopenko, Inga A1 - Rudan, Igor A1 - Arnlöv, Johan A1 - Hallan, Stein A1 - Navis, Gerjan A1 - Parsa, Afshin A1 - Ferrucci, Luigi A1 - Coresh, Josef A1 - Shlipak, Michael G A1 - Bull, Shelley B A1 - Paterson, Nicholas J A1 - Wichmann, H-Erich A1 - Wareham, Nicholas J A1 - Loos, Ruth J F A1 - Rotter, Jerome I A1 - Pramstaller, Peter P A1 - Cupples, L Adrienne A1 - Beckmann, Jacques S A1 - Yang, Qiong A1 - Heid, Iris M A1 - Rettig, Rainer A1 - Dreisbach, Albert W A1 - Bochud, Murielle A1 - Fox, Caroline S A1 - Kao, W H L KW - African Continental Ancestry Group KW - Albuminuria KW - European Continental Ancestry Group KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Humans KW - Mutation, Missense KW - Receptors, Cell Surface AB -

Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.

VL - 22 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21355061?dopt=Abstract ER - TY - JOUR T1 - Cystatin C identifies chronic kidney disease patients at higher risk for complications. JF - J Am Soc Nephrol Y1 - 2011 A1 - Peralta, Carmen A A1 - Katz, Ronit A1 - Sarnak, Mark J A1 - Ix, Joachim A1 - Fried, Linda F A1 - de Boer, Ian A1 - Palmas, Walter A1 - Siscovick, David A1 - Levey, Andrew S A1 - Shlipak, Michael G KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Cardiovascular Diseases KW - Chronic Disease KW - Creatinine KW - Cystatin C KW - Disease Progression KW - Female KW - Glomerular Filtration Rate KW - Heart Failure KW - Humans KW - Kidney Diseases KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Predictive Value of Tests KW - Retrospective Studies KW - Risk Factors AB -

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.

VL - 22 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21164029?dopt=Abstract ER - TY - JOUR T1 - Genetic association for renal traits among participants of African ancestry reveals new loci for renal function. JF - PLoS Genet Y1 - 2011 A1 - Liu, Ching-Ti A1 - Garnaas, Maija K A1 - Tin, Adrienne A1 - Köttgen, Anna A1 - Franceschini, Nora A1 - Peralta, Carmen A A1 - de Boer, Ian H A1 - Lu, Xiaoning A1 - Atkinson, Elizabeth A1 - Ding, Jingzhong A1 - Nalls, Michael A1 - Shriner, Daniel A1 - Coresh, Josef A1 - Kutlar, Abdullah A1 - Bibbins-Domingo, Kirsten A1 - Siscovick, David A1 - Akylbekova, Ermeg A1 - Wyatt, Sharon A1 - Astor, Brad A1 - Mychaleckjy, Josef A1 - Li, Man A1 - Reilly, Muredach P A1 - Townsend, Raymond R A1 - Adeyemo, Adebowale A1 - Zonderman, Alan B A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Mosley, Thomas H A1 - Harris, Tamara B A1 - Rotimi, Charles N A1 - Liu, Yongmei A1 - Kardia, Sharon L R A1 - Evans, Michele K A1 - Shlipak, Michael G A1 - Kramer, Holly A1 - Flessner, Michael F A1 - Dreisbach, Albert W A1 - Goessling, Wolfram A1 - Cupples, L Adrienne A1 - Kao, W Linda A1 - Fox, Caroline S KW - Adaptor Proteins, Vesicular Transport KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Animals KW - Female KW - Gene Knockdown Techniques KW - Genetic Association Studies KW - Genetic Loci KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - KCNQ1 Potassium Channel KW - Kidney KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Neoplasm Proteins KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Zebrafish AB -

Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m(2)), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10(-7)) and FNDC1 (p-value = 3.0×10(-7)) for UACR, and KCNQ1 with eGFR (p = 3.6×10(-6)). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.

VL - 7 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21931561?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele. JF - Hum Mol Genet Y1 - 2011 A1 - Tin, Adrienne A1 - Woodward, Owen M A1 - Kao, Wen Hong Linda A1 - Liu, Ching-Ti A1 - Lu, Xiaoning A1 - Nalls, Michael A A1 - Shriner, Daniel A1 - Semmo, Mariam A1 - Akylbekova, Ermeg L A1 - Wyatt, Sharon B A1 - Hwang, Shih-Jen A1 - Yang, Qiong A1 - Zonderman, Alan B A1 - Adeyemo, Adebowale A A1 - Palmer, Cameron A1 - Meng, Yan A1 - Reilly, Muredach A1 - Shlipak, Michael G A1 - Siscovick, David A1 - Evans, Michele K A1 - Rotimi, Charles N A1 - Flessner, Michael F A1 - Köttgen, Michael A1 - Cupples, L Adrienne A1 - Fox, Caroline S A1 - Köttgen, Anna KW - Adult KW - African Americans KW - Aged KW - Animals KW - CHO Cells KW - Cricetinae KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Gout KW - Humans KW - Loss of Heterozygosity KW - Male KW - Middle Aged KW - Organic Anion Transporters KW - Organic Cation Transport Proteins KW - Polymorphism, Single Nucleotide KW - Uric Acid KW - Young Adult AB -

Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using (14)C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P< 5.0 × 10(-8)): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P= 1.0 × 10(-9)), and two loci previously identified in EA participants, SLC2A9 (P= 3.8 × 10(-32)) and SLC22A12 (P= 2.1 × 10(-10)). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta -1.19 mg/dl, P= 2.7 × 10(-16)). (14)C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants.

VL - 20 IS - 20 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21768215?dopt=Abstract ER - TY - JOUR T1 - Serum 25-hydroxyvitamin D and change in estimated glomerular filtration rate. JF - Clin J Am Soc Nephrol Y1 - 2011 A1 - de Boer, Ian H A1 - Katz, Ronit A1 - Chonchol, Michel A1 - Ix, Joachim H A1 - Sarnak, Mark J A1 - Shlipak, Michael G A1 - Siscovick, David S A1 - Kestenbaum, Bryan KW - Aged KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney Diseases KW - Male KW - Prospective Studies KW - Vitamin D AB -

BACKGROUND AND OBJECTIVES: Mounting evidence suggests that 1,25-dihydroxyvitamin D prevents the progression of chronic kidney disease (CKD). It is not clear whether "nutritional" forms of vitamin D affect GFR.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We tested whether serum 25-hydroxyvitamin D concentration (25(OH)D), a measure of total vitamin D intake from cutaneous synthesis and dietary consumption, is associated with loss of estimated GFR among 1705 older adults with predominantly normal baseline kidney function participating in the Cardiovascular Health Study. Baseline 25(OH)D was measured by HPLC-tandem mass spectrometry. GFR was estimated at baseline and 4 years later using the CKD-EPI formula, with rapid GFR loss defined as 12 ml/min per 1.73 m(2) or more over 4 years.

RESULTS: Rapid GFR loss was observed for 207 participants (12%). Each 10 ng/ml lower 25(OH)D was associated with a 25% greater risk of rapid GFR loss (95% confidence interval [CI] 5%, 49%, P = 0.01), adjusting for potential confounding characteristics. Compared with 25(OH)D ≥30 ng/ml, 25(OH)D concentrations 15 to 29 ng/ml and <15 ng/ml were associated with 29% (95% CI -13%, 91%) and 68% (95% CI 1%, 177%) greater adjusted risks of rapid GFR loss, respectively. Magnitudes of association were largest among participants with diabetes.

RESULTS: were similar evaluating a composite outcome of rapid GFR loss, end stage renal disease, and death. Conclusions Insufficient 25(OH)D may be a modifiable risk factor for early GFR loss. We recommend clinical trials to determine whether vitamin D supplementation prevents the development and progression of CKD.

VL - 6 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21836148?dopt=Abstract ER - TY - JOUR T1 - Vitamin D, parathyroid hormone, and cardiovascular events among older adults. JF - J Am Coll Cardiol Y1 - 2011 A1 - Kestenbaum, Bryan A1 - Katz, Ronit A1 - de Boer, Ian A1 - Hoofnagle, Andy A1 - Sarnak, Mark J A1 - Shlipak, Michael G A1 - Jenny, Nancy S A1 - Siscovick, David S KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Follow-Up Studies KW - Humans KW - Male KW - Parathyroid Hormone KW - Prospective Studies KW - Vitamin D AB -

OBJECTIVES: The aim of this study was to evaluate associations of 25-hydroxyvitamin D (25-OHD) and parathyroid hormone (PTH) concentrations separately and in combination with incident cardiovascular events and mortality during 14 years of follow-up in the CHS (Cardiovascular Health Study).

BACKGROUND: Vitamin D deficiency and PTH excess are common in older adults and may adversely affect cardiovascular health.

METHODS: A total of 2,312 participants who were free of cardiovascular disease at baseline were studied. Vitamin D and intact PTH were measured from previously frozen serum using mass spectrometry and a 2-site immunoassay. Outcomes were adjudicated cases of myocardial infarction, heart failure, cardiovascular death, and all-cause mortality.

RESULTS: There were 384 participants (17%) with serum 25-OHD concentrations <15 ng/ml and 570 (25%) with serum PTH concentrations ≥ 65 pg/ml. After adjustment, each 10 ng/ml lower 25-OHD concentration was associated with a 9% greater (95% confidence interval [CI]: 2% to 17% greater) relative hazard of mortality and a 25% greater (95% CI: 8% to 44% greater) relative hazard of myocardial infarction. Serum 25-OHD concentrations <15 ng/ml were associated with a 29% greater (95% CI: 5% to 55% greater) risk for mortality. Serum PTH concentrations ≥ 65 pg/ml were associated with a 30% greater risk for heart failure (95% CI: 6% to 61% greater) but not other outcomes. There was no evidence of an interaction between serum 25-OHD and PTH concentrations and cardiovascular events.

CONCLUSIONS: Among older adults, 25-OHD deficiency is associated with myocardial infarction and mortality; PTH excess is associated with heart failure. Vitamin D and PTH might influence cardiovascular risk through divergent pathways.

VL - 58 IS - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21939825?dopt=Abstract ER - TY - JOUR T1 - Vitamin D, parathyroid hormone, and sudden cardiac death: results from the Cardiovascular Health Study. JF - Hypertension Y1 - 2011 A1 - Deo, Rajat A1 - Katz, Ronit A1 - Shlipak, Michael G A1 - Sotoodehnia, Nona A1 - Psaty, Bruce M A1 - Sarnak, Mark J A1 - Fried, Linda F A1 - Chonchol, Michel A1 - de Boer, Ian H A1 - Enquobahrie, Daniel A1 - Siscovick, David A1 - Kestenbaum, Bryan KW - Aged KW - Cardiovascular Diseases KW - Comorbidity KW - Death, Sudden, Cardiac KW - Diabetes Mellitus KW - Female KW - Follow-Up Studies KW - Humans KW - Hypertension KW - Incidence KW - Kidney KW - Male KW - Middle Aged KW - Minerals KW - Parathyroid Hormone KW - Proportional Hazards Models KW - Risk Factors KW - Socioeconomic Factors KW - United States KW - Vitamin D AB -

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.

VL - 58 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22068871?dopt=Abstract ER - TY - JOUR T1 - Apolipoprotein E and kidney function in older adults. JF - Clin Nephrol Y1 - 2012 A1 - Seshasai, Rebecca Kurnik A1 - Katz, Ronit A1 - de Boer, Ian H A1 - Siscovick, David A1 - Shlipak, Michael G A1 - Rifkin, Dena E A1 - Sarnak, Mark J KW - Aged KW - Aged, 80 and over KW - Alleles KW - Apolipoproteins E KW - Confidence Intervals KW - Creatinine KW - Cross-Sectional Studies KW - Cystatin C KW - Disease Progression KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genotype KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Male KW - Odds Ratio KW - Renal Insufficiency, Chronic KW - Risk Factors AB -

BACKGROUND: Previous studies suggest that the ε4 and ε2 alleles of apolipoprotein E (APOE) may be associated with decreased and increased risks of CKD, respectively, but there are limited data in older adults. We evaluated the associations of apolipoprotein E alleles with kidney function among older adults in the cardiovascular health study (CHS).

METHODS: Caucasian participants had APOE allelic analysis and serum creatinine and cystatin C measured at baseline (n = 3,844 for cross sectional analysis) and in follow up (n = 3,226 for longitudinal analysis). APOE variation was evaluated as an additive model with number of ε2, ε3 and ε4 alleles. GFR was estimated using the CKD epidemiology equation (eGFRcreat) and the cystatin C demographic equation (eGFRcys). The primary outcome was CKD defined by eGFR < 60 ml/min/1.73 m2. The secondary outcome was rapid progression defined by annual loss of eGFR > 3 ml/min/1.73 m2.

RESULTS: Mean eGFRcreat was 72 ml/min/1.73 m2 (25% CKD). Compared with the ε3 allele, the APOE ε4 allele was associated with reduced risk of CKD by eGFRcreat: unadjusted odds ratio (OR) and 95% confidence interval (CI) 0.79 (0.67 - 0.93) per allele, fully adjusted OR (95% CI) 0.80 (0.68 - 0.96) per allele. Results were consistent using eGFRcys. There was no association of the ε2 allele with CKD or between the apolipoprotein E gene with rapid progression.

CONCLUSIONS: The apolipoprotein ε4 allele was associated with lower odds of CKD in elderly Caucasian individuals. Future research should confirm these findings in other races and explore mechanisms to explain these results.

VL - 78 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22874105?dopt=Abstract ER - TY - JOUR T1 - Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study). JF - J Am Coll Cardiol Y1 - 2012 A1 - Ix, Joachim H A1 - Katz, Ronit A1 - Kestenbaum, Bryan R A1 - de Boer, Ian H A1 - Chonchol, Michel A1 - Mukamal, Kenneth J A1 - Rifkin, Dena A1 - Siscovick, David S A1 - Sarnak, Mark J A1 - Shlipak, Michael G KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Female KW - Fibroblast Growth Factors KW - Heart Failure KW - Humans KW - Kidney Function Tests KW - Male KW - Mortality KW - Renal Insufficiency, Chronic KW - United States AB -

OBJECTIVES: This study sought to determine the association of fibroblast growth factor (FGF)-23 with death, heart failure (HF), and cardiovascular disease (CVD) in the general population, as well as the influence of chronic kidney disease (CKD) in this setting.

BACKGROUND: FGF-23 increases renal phosphorus excretion and inhibits vitamin D activation. In end-stage renal disease, high FGF-23 levels are associated with mortality. The association of FGF-23 with death, HF, and CVD in the general population, and the influence of CKD in this setting, are unknown.

METHODS: Plasma FGF-23 was measured in 3,107 community-living persons ≥ 65 years of age in 1996 and 1997, and participants were followed through 2008. HF and CVD events were adjudicated by a panel of experts. Associations of FGF-23 with each outcome were evaluated using Cox proportional hazards models, and we tested whether associations differed by CKD status.

RESULTS: Both lower estimated glomerular filtration rate and higher urine albumin to creatinine ratios were associated with high FGF-23 at baseline. During 10.5 years (median) follow-up, there were 1,730 deaths, 697 incident HF events, and 797 incident CVD events. Although high FGF-23 concentrations were associated with each outcome in combined analyses, the associations were consistently stronger for those with CKD (p interactions all <0.006). In the CKD group (n = 1,128), the highest FGF-23 quartile had adjusted hazards ratios (HR) of 1.87 (95% confidence interval [CI]: 1.47 to 2.38) for all-cause death, 1.94 (95% CI: 1.32 to 2.83) for incident HF, and 1.49 (95% CI: 1.02 to 2.18) for incident CVD events compared with the lowest quartile. Corresponding HRs in those without CKD (n = 1,979) were 1.29 (95% CI: 1.05 to 1.59), 1.37 (95% CI: 0.99 to 1.89), and 1.07 (95% CI: 0.79 to 1.45).

CONCLUSIONS: FGF-23, a hormone involved in phosphorous and vitamin D homeostasis, is independently associated with all-cause death and incident HF in community-living older persons. These associations appear stronger in persons with CKD.

VL - 60 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22703926?dopt=Abstract ER - TY - JOUR T1 - Kidney function and mortality in octogenarians: Cardiovascular Health Study All Stars. JF - J Am Geriatr Soc Y1 - 2012 A1 - Shastri, Shani A1 - Katz, Ronit A1 - Rifkin, Dena E A1 - Fried, Linda F A1 - Odden, Michelle C A1 - Peralta, Carmen A A1 - Chonchol, Michel A1 - Siscovick, David A1 - Shlipak, Michael G A1 - Newman, Anne B A1 - Sarnak, Mark J KW - Aged, 80 and over KW - Analysis of Variance KW - Cardiovascular Diseases KW - Chi-Square Distribution KW - Creatinine KW - Cystatin C KW - Diabetes Mellitus KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Hypertension KW - Kidney Diseases KW - Male KW - Prevalence KW - Proportional Hazards Models KW - Retrospective Studies KW - Risk Factors KW - United States AB -

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) .

VL - 60 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22724391?dopt=Abstract ER - TY - JOUR T1 - The risk of infection-related hospitalization with decreased kidney function. JF - Am J Kidney Dis Y1 - 2012 A1 - Dalrymple, Lorien S A1 - Katz, Ronit A1 - Kestenbaum, Bryan A1 - de Boer, Ian H A1 - Fried, Linda A1 - Sarnak, Mark J A1 - Shlipak, Michael G KW - Aged KW - Cohort Studies KW - Female KW - Glomerular Filtration Rate KW - Hospitalization KW - Humans KW - Infection KW - Kidney KW - Male KW - Risk Factors AB -

BACKGROUND: Moderate kidney disease may predispose to infection. We sought to determine whether decreased kidney function, estimated by serum cystatin C level, was associated with the risk of infection-related hospitalization in older individuals.

STUDY DESIGN: Cohort study.

SETTING & PARTICIPANTS: 5,142 Cardiovascular Health Study (CHS) participants with measured serum creatinine and cystatin C and without estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m(2) at enrollment.

PREDICTOR: The primary exposure of interest was eGFR using serum cystatin C level (eGFR(SCysC)).

OUTCOME: Infection-related hospitalizations during a median follow-up of 11.5 years.

RESULTS: In adjusted analyses, eGFR(SCysC) categories of 60-89, 45-59, and 15-44 mL/min/1.73 m(2) were associated with 16%, 37%, and 64% greater risk of all-cause infection-related hospitalization, respectively, compared with eGFR(SCysC) ≥90 mL/min/1.73 m(2). When cause-specific infection was examined, eGFR(SCysC) of 15-44 mL/min/1.73 m(2) was associated with an 80% greater risk of pulmonary and 160% greater risk of genitourinary infection compared with eGFR(SCysC) ≥90 mL/min/1.73 m(2).

LIMITATIONS: No measures of urinary protein, study limited to principal discharge diagnosis.

CONCLUSIONS: Lower kidney function, estimated using cystatin C level, was associated with a linear and graded risk of infection-related hospitalization. These findings highlight that even moderate degrees of decreased kidney function are associated with clinically significant higher risks of serious infection in older individuals.

VL - 59 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21906862?dopt=Abstract ER - TY - JOUR T1 - Blood pressure components and decline in kidney function in community-living older adults: the Cardiovascular Health Study. JF - Am J Hypertens Y1 - 2013 A1 - Rifkin, Dena E A1 - Katz, Ronit A1 - Chonchol, Michel A1 - Shlipak, Michael G A1 - Sarnak, Mark J A1 - Fried, Linda F A1 - Newman, Anne B A1 - Siscovick, David S A1 - Peralta, Carmen A KW - Aged KW - Blood Pressure KW - Cohort Studies KW - Cystatin C KW - Diastole KW - Disease Progression KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Hypertension KW - Logistic Models KW - Longitudinal Studies KW - Male KW - Pulse KW - Renal Insufficiency, Chronic KW - Systole AB -

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.

VL - 26 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23709568?dopt=Abstract ER - TY - JOUR T1 - Cystatin C versus creatinine in determining risk based on kidney function. JF - N Engl J Med Y1 - 2013 A1 - Shlipak, Michael G A1 - Matsushita, Kunihiro A1 - Arnlöv, Johan A1 - Inker, Lesley A A1 - Katz, Ronit A1 - Polkinghorne, Kevan R A1 - Rothenbacher, Dietrich A1 - Sarnak, Mark J A1 - Astor, Brad C A1 - Coresh, Josef A1 - Levey, Andrew S A1 - Gansevoort, Ron T KW - Creatinine KW - Cystatin C KW - Glomerular Filtration Rate KW - Humans KW - Kidney Failure, Chronic KW - Kidney Function Tests KW - Reference Standards KW - Renal Insufficiency, Chronic KW - Risk KW - Risk Assessment AB -

BACKGROUND: Adding the measurement of cystatin C to that of serum creatinine to determine the estimated glomerular filtration rate (eGFR) improves accuracy, but the effect on detection, staging, and risk classification of chronic kidney disease across diverse populations has not been determined.

METHODS: We performed a meta-analysis of 11 general-population studies (with 90,750 participants) and 5 studies of cohorts with chronic kidney disease (2960 participants) for whom standardized measurements of serum creatinine and cystatin C were available. We compared the association of the eGFR, as calculated by the measurement of creatinine or cystatin C alone or in combination with creatinine, with the rates of death (13,202 deaths in 15 cohorts), death from cardiovascular causes (3471 in 12 cohorts), and end-stage renal disease (1654 cases in 7 cohorts) and assessed improvement in reclassification with the use of cystatin C.

RESULTS: In the general-population cohorts, the prevalence of an eGFR of less than 60 ml per minute per 1.73 m(2) of body-surface area was higher with the cystatin C-based eGFR than with the creatinine-based eGFR (13.7% vs. 9.7%). Across all eGFR categories, the reclassification of the eGFR to a higher value with the measurement of cystatin C, as compared with creatinine, was associated with a reduced risk of all three study outcomes, and reclassification to a lower eGFR was associated with an increased risk. The net reclassification improvement with the measurement of cystatin C, as compared with creatinine, was 0.23 (95% confidence interval [CI], 0.18 to 0.28) for death and 0.10 (95% CI, 0.00 to 0.21) for end-stage renal disease. Results were generally similar for the five cohorts with chronic kidney disease and when both creatinine and cystatin C were used to calculate the eGFR.

CONCLUSIONS: The use of cystatin C alone or in combination with creatinine strengthens the association between the eGFR and the risks of death and end-stage renal disease across diverse populations. (Funded by the National Kidney Foundation and others.).

VL - 369 IS - 10 ER - TY - JOUR T1 - Fibroblast growth factor 23, bone mineral density, and risk of hip fracture among older adults: the cardiovascular health study. JF - J Clin Endocrinol Metab Y1 - 2013 A1 - Jovanovich, Anna A1 - Bůzková, Petra A1 - Chonchol, Michel A1 - Robbins, John A1 - Fink, Howard A A1 - de Boer, Ian H A1 - Kestenbaum, Bryan A1 - Katz, Ronit A1 - Carbone, Laura A1 - Lee, Jennifer A1 - Laughlin, Gail A A1 - Mukamal, Kenneth J A1 - Fried, Linda F A1 - Shlipak, Michael G A1 - Ix, Joachim H KW - Aged KW - Aged, 80 and over KW - Bone Density KW - Female KW - Fibroblast Growth Factors KW - Hip Fractures KW - Humans KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Prospective Studies KW - Risk KW - Spinal Fractures AB -

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 ± 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.

VL - 98 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23771921?dopt=Abstract ER - TY - JOUR T1 - Fibroblast growth factor 23, left ventricular mass, and left ventricular hypertrophy in community-dwelling older adults. JF - Atherosclerosis Y1 - 2013 A1 - Jovanovich, Anna A1 - Ix, Joachim H A1 - Gottdiener, John A1 - McFann, Kim A1 - Katz, Ronit A1 - Kestenbaum, Bryan A1 - de Boer, Ian H A1 - Sarnak, Mark A1 - Shlipak, Michael G A1 - Mukamal, Kenneth J A1 - Siscovick, David A1 - Chonchol, Michel KW - Aged KW - Female KW - Fibroblast Growth Factors KW - Heart Ventricles KW - Humans KW - Hypertrophy, Left Ventricular KW - Longitudinal Studies KW - Male KW - Renal Insufficiency, Chronic KW - Risk Factors KW - Ultrasonography AB -

OBJECTIVES: In chronic kidney disease (CKD), high FGF23 concentrations are associated with left ventricular hypertrophy (LVH), cardiovascular events, and death. The associations of FGF23 with left ventricular mass (LVM) and LVH in the general population and the influence of CKD remains uncertain.

METHODS: C-terminal plasma FGF23 concentrations were measured, and LVM and LVH evaluated by echocardiogram among 2255 individuals ≥65 years in the Cardiovascular Health Study. Linear regression analysis adjusting for demographics, cardiovascular, and kidney related risk factors examined the associations of FGF23 concentrations with LVM. Analyses were stratified by CKD status and adjusted linear and logistic regression analysis explored the associations of FGF23 with LVM and LVH.

RESULTS: Among the entire cohort, higher FGF23 concentrations were associated with greater LVM in adjusted analyses (β = 6.71 [95% CI 4.35-9.01] g per doubling of FGF23). 32% (n = 624) had CKD (eGFR <60 mL/min/1.73 m(2) and/or urine albumin-to-creatinine ratio >30 mg/g). Associations were stronger among participants with CKD (p interaction = 0.006): LVM β = 9.71 [95% CI 5.86-13.56] g per doubling of FGF23 compared to those without CKD (β = 3.44 [95% CI 0.77, 6.11] g per doubling of FGF23). While there was no significant interaction between FGF23 and CKD for LVH (p interaction = 0.25), the OR (1.46 95% CI [1.20-1.77]) in the CKD group was statistically significant and of larger magnitude than the OR for in the no CKD group (1.12 [95% CI 0.97-1.48]).

CONCLUSION: In a large cohort of older community-dwelling adults, higher FGF23 concentrations were associated with greater LVM and LVH with stronger relationships in participants with CKD.

VL - 231 IS - 1 ER - TY - JOUR T1 - Hypertension and low HDL cholesterol were associated with reduced kidney function across the age spectrum: a collaborative study. JF - Ann Epidemiol Y1 - 2013 A1 - Odden, Michelle C A1 - Tager, Ira B A1 - Gansevoort, Ron T A1 - Bakker, Stephan J L A1 - Fried, Linda F A1 - Newman, Anne B A1 - Katz, Ronit A1 - Satterfield, Suzanne A1 - Harris, Tamara B A1 - Sarnak, Mark J A1 - Siscovick, David A1 - Shlipak, Michael G KW - Adult KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Aging KW - Causality KW - Cholesterol, LDL KW - Cohort Studies KW - Comorbidity KW - Cross-Sectional Studies KW - Cystatin C KW - Female KW - Humans KW - Hypertension KW - Kidney Function Tests KW - Male KW - Netherlands KW - Obesity KW - Prevalence KW - Renal Insufficiency, Chronic KW - Risk Factors KW - Smoking KW - United States AB -

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.

VL - 23 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23313266?dopt=Abstract ER - TY - JOUR T1 - Kidney function and prevalent and incident frailty. JF - Clin J Am Soc Nephrol Y1 - 2013 A1 - Dalrymple, Lorien S A1 - Katz, Ronit A1 - Rifkin, Dena E A1 - Siscovick, David A1 - Newman, Anne B A1 - Fried, Linda F A1 - Sarnak, Mark J A1 - Odden, Michelle C A1 - Shlipak, Michael G KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Aging KW - Biomarkers KW - Creatinine KW - Cross-Sectional Studies KW - Cystatin C KW - Fatigue KW - Female KW - Frail Elderly KW - Geriatric Assessment KW - Glomerular Filtration Rate KW - Humans KW - Incidence KW - Independent Living KW - Kidney KW - Kidney Diseases KW - Logistic Models KW - Male KW - Motor Activity KW - Multivariate Analysis KW - Muscle Weakness KW - Odds Ratio KW - Phenotype KW - Prevalence KW - Prospective Studies KW - Risk Factors KW - Time Factors KW - United States KW - Weight Loss AB -

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.

VL - 8 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24178972?dopt=Abstract ER - TY - JOUR T1 - Association of a cystatin C gene variant with cystatin C levels, CKD, and risk of incident cardiovascular disease and mortality. JF - Am J Kidney Dis Y1 - 2014 A1 - O'Seaghdha, Conall M A1 - Tin, Adrienne A1 - Yang, Qiong A1 - Katz, Ronit A1 - Liu, Yongmei A1 - Harris, Tamara A1 - Astor, Brad A1 - Coresh, Josef A1 - Fox, Caroline S A1 - Kao, W H Linda A1 - Shlipak, Michael G KW - Aged KW - Bias KW - Biomarkers KW - Cardiovascular Diseases KW - Creatinine KW - Cystatin C KW - Female KW - Genetic Variation KW - Glomerular Filtration Rate KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Renal Insufficiency, Chronic KW - Risk Assessment KW - Risk Factors KW - Severity of Illness Index KW - Statistics as Topic KW - Survival Rate AB -

BACKGROUND: Carriers of the T allele of the single-nucleotide polymorphism rs13038305 tend to have lower cystatin C levels and higher cystatin C-based estimated glomerular filtration rate (eGFRcys). Adjusting for this genetic effect on cystatin C concentrations may improve GFR estimation, reclassify cases of chronic kidney disease (CKD), and strengthen risk estimates for cardiovascular disease (CVD) and mortality.

STUDY DESIGN: Observational.

SETTING & POPULATION: 4 population-based cohorts: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health (CHS), Framingham Heart (FHS), and Health, Aging, and Body Composition (Health ABC) studies.

PREDICTORS: We estimated the association of rs13038305 with eGFRcys and serum creatinine-based eGFR (eGFRcr) and performed longitudinal analyses of the associations of eGFRcys with mortality and cardiovascular events following adjustment for rs13038305.

OUTCOMES: We assessed reclassification by genotype-adjusted eGFRcys across CKD categories: <45, 45-59, 60-89, and ≥ 90 mL/min/1.73 m(2). We compared mortality and CVD outcomes in those reclassified to a worse eGFRcys category with those unaffected. Results were combined using fixed-effect inverse-variance meta-analysis.

RESULTS: In 14,645 participants, each copy of the T allele of rs13038305 (frequency, 21%) was associated with a 6.4% lower cystatin C concentration, 5.5-mL/min/1.73 m(2) higher eGFRcys, and 36% [95% CI, 29%-41%] lower odds of CKD. Associations with CVD (HR, 1.17; 95% CI, 1.14-1.20) and mortality (HR, 1.22; 95% CI, 1.19-1.24) per 10-mL/min/1.73 m(2) lower eGFRcys were similar with or without rs13038305 adjustment. 1,134 (7.7%) participants were reclassified to a worse CKD category following rs13038305 adjustment, and rates of CVD and mortality were higher in individuals who were reclassified. However, the overall net reclassification index was not significant for either outcome, at 0.009 (95% CI, -0.003 to 0.022) for mortality and 0.014 (95% CI, 0.0 to 0.028) for CVD.

LIMITATIONS: rs13038305 explains only a small proportion of cystatin C variation.

CONCLUSIONS: Statistical adjustment can correct a genetic bias in GFR estimates based on cystatin C in carriers of the T allele of rs13038305 and result in changes in disease classification. However, on a population level, the effects on overall reclassification of CKD status are modest.

VL - 63 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23932088?dopt=Abstract ER - TY - JOUR T1 - Association of kidney disease measures with ischemic versus hemorrhagic strokes: pooled analyses of 4 prospective community-based cohorts. JF - Stroke Y1 - 2014 A1 - Mahmoodi, Bakhtawar K A1 - Yatsuya, Hiroshi A1 - Matsushita, Kunihiro A1 - Sang, Yinying A1 - Gottesman, Rebecca F A1 - Astor, Brad C A1 - Woodward, Mark A1 - Longstreth, W T A1 - Psaty, Bruce M A1 - Shlipak, Michael G A1 - Folsom, Aaron R A1 - Gansevoort, Ron T A1 - Coresh, Josef KW - Aged KW - Albuminuria KW - Brain Ischemia KW - Comorbidity KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Intracranial Hemorrhages KW - Kidney Diseases KW - Male KW - Middle Aged KW - Netherlands KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Stroke KW - United States AB -

BACKGROUND AND PURPOSE: Although low glomerular filtration rate (GFR) and albuminuria are associated with increased risk of stroke, few studies compared their contribution to risk of ischemic versus hemorrhagic stroke separately. We contrasted the association of these kidney measures with ischemic versus hemorrhagic stroke.

METHODS: We pooled individual participant data from 4 community-based cohorts: 3 from the United States and 1 from The Netherlands. GFR was estimated using both creatinine and cystatin C, and albuminuria was quantified by urinary albumin-to-creatinine ratio (ACR). Associations of estimated GFR and ACR were compared for each stroke type (ischemic versus intraparenchymal hemorrhagic) using study-stratified Cox regression.

RESULTS: Among 29,595 participants (mean age, 61 [SD 12.5] years; 46% men; 17% black), 1261 developed stroke (12% hemorrhagic) during 280,549 person-years. Low estimated GFR was significantly associated with increased risk of ischemic stroke, but not hemorrhagic stroke, whereas high ACR was associated with both stroke types. Adjusted hazard ratios for ischemic and hemorrhagic stroke at estimated GFR of 45 (versus 95) mL/min per 1.73 m2 were 1.30 (95% confidence interval, 1.01-1.68) and 0.92 (0.47-1.81), respectively. In contrast, the corresponding hazard ratios for ACR of 300 (versus 5) mg/g were 1.62 (1.27-2.07) for ischemic and 2.57 (1.37-4.83) for hemorrhagic stroke, with significantly stronger association with hemorrhagic stroke (P=0.04). For hemorrhagic stroke, the association of elevated ACR was of similar magnitude as that of elevated systolic blood pressure.

CONCLUSIONS: Whereas albuminuria showed significant association with both stroke types, the association of decreased estimated GFR was only significant for ischemic stroke. The strong association of albuminuria with both stroke types warrants clinical attention and further investigations.

VL - 45 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24876078?dopt=Abstract ER - TY - JOUR T1 - Fibroblast growth factor 23, the ankle-brachial index, and incident peripheral artery disease in the Cardiovascular Health Study. JF - Atherosclerosis Y1 - 2014 A1 - Garimella, Pranav S A1 - Ix, Joachim H A1 - Katz, Ronit A1 - Chonchol, Michel B A1 - Kestenbaum, Bryan R A1 - de Boer, Ian H A1 - Siscovick, David S A1 - Shastri, Shani A1 - Hiramoto, Jade S A1 - Shlipak, Michael G A1 - Sarnak, Mark J KW - Aged KW - Ankle Brachial Index KW - Cardiovascular Diseases KW - Cross-Sectional Studies KW - Fibroblast Growth Factors KW - Humans KW - Incidence KW - Peripheral Arterial Disease KW - Risk Factors AB -

BACKGROUND: Fibroblast growth factor 23 (FGF23) has emerged as a novel risk factor for mortality and cardiovascular events. Its association with the ankle-brachial index (ABI) and clinical peripheral artery disease (PAD) is less known.

METHODS: Using data (N = 3143) from the Cardiovascular Health Study (CHS), a cohort of community dwelling adults >65 years of age, we analyzed the cross-sectional association of FGF23 with ABI and its association with incident clinical PAD events during 9.8 years of follow up using multinomial logistic regression and Cox proportional hazards models respectively.

RESULTS: The prevalence of cardiovascular disease (CVD) and traditional risk factors like diabetes, coronary artery disease, and heart failure increased across higher quartiles of FGF23. Compared to those with ABI of 1.1-1.4, FGF23 per doubling at baseline was associated with prevalent PAD (ABI < 0.9) although this association was attenuated after adjusting for CVD risk factors, and kidney function (OR 0.91, 95% CI 0.76-1.08). FGF23 was not associated with high ABI (>1.4) (OR 1.06, 95% CI 0.75-1.51). Higher FGF23 was associated with incidence of PAD events in unadjusted, demographic adjusted, and CVD risk factor adjusted models (HR 2.26, 95% CI 1.28-3.98; highest versus lowest quartile). The addition of estimated glomerular filtration and urine albumin to creatinine ratio to the model however, attenuated these findings (HR 1.46, 95% CI, 0.79-2.70).

CONCLUSIONS: In community dwelling older adults, FGF23 was not associated with baseline low or high ABI or incident PAD events after adjusting for confounding variables. These results suggest that FGF23 may primarily be associated with adverse cardiovascular outcomes through non atherosclerotic mechanisms.

VL - 233 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24529128?dopt=Abstract ER - TY - JOUR T1 - Kidney function and cognitive health in older adults: the Cardiovascular Health Study. JF - Am J Epidemiol Y1 - 2014 A1 - Darsie, Brendan A1 - Shlipak, Michael G A1 - Sarnak, Mark J A1 - Katz, Ronit A1 - Fitzpatrick, Annette L A1 - Odden, Michelle C KW - Aged KW - Cardiovascular Diseases KW - Cognition KW - Cognition Disorders KW - Cystatin C KW - Female KW - Glomerular Filtration Rate KW - Health Status KW - Humans KW - Kidney KW - Kidney Diseases KW - Male KW - Neuropsychological Tests AB -

Recent evidence has demonstrated the importance of kidney function in healthy aging. We examined the association between kidney function and change in cognitive function in 3,907 participants in the Cardiovascular Health Study who were recruited from 4 US communities and studied from 1992 to 1999. Kidney function was measured by cystatin C-based estimated glomerular filtration rate (eGFRcys). Cognitive function was assessed using the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test, which were administered up to 7 times during annual visits. There was an association between eGFRcys and change in cognitive function after adjustment for confounders; persons with an eGFRcys of less than 60 mL/minute/1.73 m(2) had a 0.64 (95% confidence interval: 0.51, 0.77) points/year faster decline in Modified Mini-Mental State Examination score and a 0.42 (95% confidence interval: 0.28, 0.56) points/year faster decline in Digit Symbol Substitution Test score compared with persons with an eGFRcys of 90 or more mL/minute/1.73 m(2). Additional adjustment for intermediate cardiovascular events modestly affected these associations. Participants with an eGFRcys of less than 60 mL/minute/1.73 m(2) had fewer cognitive impairment-free life-years on average compared with those with eGFRcys of 90 or more mL/minute/1.73 m(2), independent of confounders and mediating cardiovascular events (mean difference = -0.44, 95% confidence interval: -0.62, -0.26). Older adults with lower kidney function are at higher risk of worsening cognitive function.

VL - 180 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24844846?dopt=Abstract ER - TY - JOUR T1 - Risk factors for cardiovascular disease across the spectrum of older age: the Cardiovascular Health Study. JF - Atherosclerosis Y1 - 2014 A1 - Odden, Michelle C A1 - Shlipak, Michael G A1 - Whitson, Heather E A1 - Katz, Ronit A1 - Kearney, Patricia M A1 - deFilippi, Chris A1 - Shastri, Shani A1 - Sarnak, Mark J A1 - Siscovick, David S A1 - Cushman, Mary A1 - Psaty, Bruce M A1 - Newman, Anne B KW - Aged KW - Aged, 80 and over KW - Blood Pressure KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Diabetes Complications KW - Diabetes Mellitus KW - Female KW - Humans KW - Inflammation KW - Kidney KW - Kidney Diseases KW - Lipids KW - Male KW - Natriuretic Peptide, Brain KW - Obesity KW - Peptide Fragments KW - Risk Factors AB -

OBJECTIVE: The associations of some risk factors with cardiovascular disease (CVD) are attenuated in older age; whereas others appear robust. The present study aimed to compare CVD risk factors across older age.

METHODS: Participants (n = 4883) in the Cardiovascular Health Study free of prevalent CVD, were stratified into three age groups: 65-74, 75-84, 85+ years. Traditional risk factors included systolic blood pressure (BP), LDL-cholesterol, HDL-cholesterol, obesity, and diabetes. Novel risk factors included kidney function, C-reactive protein (CRP), and N-terminal pro-B-type natriuretic peptide (NT pro-BNP).

RESULTS: There were 1498 composite CVD events (stroke, myocardial infarction, and cardiovascular death) over 5 years. The associations of high systolic BP and diabetes appeared strongest, though both were attenuated with age (p-values for interaction = 0.01 and 0.002, respectively). The demographic-adjusted hazard ratios (HR) for elevated systolic BP were 1.79 (95% confidence interval: 1.49, 2.15), 1.59 (1.37, 1.85) and 1.10 (0.86, 1.41) in participants aged 65-74, 75-84, 85+, and for diabetes, 2.36 (1.89, 2.95), 1.55 (1.27, 1.89), 1.51 (1.10, 2.09). The novel risk factors had consistent associations with the outcome across the age spectrum; low kidney function: 1.69 (1.31, 2.19), 1.61 (1.36, 1.90), and 1.57 (1.16, 2.14) for 65-74, 75-84, and 85+ years, respectively; elevated CRP: 1.54 (1.28, 1.87), 1.33 (1.13, 1.55), and 1.51 (1.15, 1.97); elevated NT pro-BNP: 2.67 (1.96, 3.64), 2.71 (2.25, 3.27), and 2.18 (1.43, 3.45).

CONCLUSIONS: The associations of most traditional risk factors with CVD were minimal in the oldest old, whereas diabetes, eGFR, CRP, and NT pro-BNP were associated with CVD across older age.

VL - 237 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25303772?dopt=Abstract ER - TY - JOUR T1 - Development and validation of a model to predict 5-year risk of death without ESRD among older adults with CKD. JF - Clin J Am Soc Nephrol Y1 - 2015 A1 - Bansal, Nisha A1 - Katz, Ronit A1 - de Boer, Ian H A1 - Peralta, Carmen A A1 - Fried, Linda F A1 - Siscovick, David S A1 - Rifkin, Dena E A1 - Hirsch, Calvin A1 - Cummings, Steven R A1 - Harris, Tamara B A1 - Kritchevsky, Stephen B A1 - Sarnak, Mark J A1 - Shlipak, Michael G A1 - Ix, Joachim H KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Albuminuria KW - Continental Population Groups KW - Creatinine KW - Diabetes Mellitus KW - Female KW - Glomerular Filtration Rate KW - Heart Failure KW - Humans KW - Male KW - Proportional Hazards Models KW - Regression Analysis KW - Renal Insufficiency, Chronic KW - Risk Factors KW - Sex Factors KW - Smoking KW - Stroke AB -

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 (±5.6) years and an eGFR of 47 (±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 (±2.8) years and an eGFR of 50 (±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.

VL - 10 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25710804?dopt=Abstract ER - TY - JOUR T1 - Fibroblast growth factor 23 and sudden versus non-sudden cardiac death: the Cardiovascular Health Study. JF - Am J Kidney Dis Y1 - 2015 A1 - Deo, Rajat A1 - Katz, Ronit A1 - de Boer, Ian H A1 - Sotoodehnia, Nona A1 - Kestenbaum, Bryan A1 - Mukamal, Kenneth J A1 - Chonchol, Michel A1 - Sarnak, Mark J A1 - Siscovick, David A1 - Shlipak, Michael G A1 - Ix, Joachim H KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Comorbidity KW - Death, Sudden, Cardiac KW - Electrocardiography KW - Female KW - Fibroblast Growth Factors KW - Follow-Up Studies KW - Heart Arrest KW - Heart Diseases KW - Humans KW - Kaplan-Meier Estimate KW - Male KW - Prospective Studies KW - Renal Insufficiency, Chronic KW - Risk Factors KW - Sympathetic Nervous System KW - United States AB -

BACKGROUND: Elevated fibroblast growth factor 23 (FGF-23) concentrations are associated with greater risk of cardiovascular events and mortality, especially among people with chronic kidney disease (CKD). Because individuals with CKD are at an increased risk of sudden cardiac death (SCD), we sought to understand whether FGF-23 level is a stronger risk factor for SCD versus non-SCD.

STUDY DESIGN: Cohort study.

SETTING & PARTICIPANTS: 3,244 participants 65 years or older in the community-based Cardiovascular Health Study.

PREDICTOR: Plasma FGF-23 concentrations.

OUTCOMES: We assessed SCD and non-SCD in these analyses. SCD was adjudicated rigorously and was defined as a sudden pulseless condition of cardiac origin in a previously stable person occurring out of hospital or in the emergency department.

MEASUREMENTS: We estimated associations of baseline FGF-23 concentrations with SCD and non-SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, comorbid conditions, and kidney function. We also tested whether associations differed by CKD status.

RESULTS: During a median follow-up of 8.1 years, there were 118 adjudicated SCD and 570 non-SCD events. After multivariable adjustment for demographics, cardiovascular risk factors, comorbid conditions, and parameters of kidney function, higher FGF-23 concentrations were an independent risk factor for non-SCD (HR [per doubling], 1.17; 95% CI, 1.06-1.30). However, elevated FGF-23 concentrations were not associated independently with SCD (HR [per doubling], 1.07; 95% CI, 0.85-1.35). In stratified analysis by CKD status (36.5% of cohort), doubling of FGF-23 concentrations was associated independently with non-SCD (adjusted HR, 1.26; 95% CI, 1.10-1.45). A similar magnitude of association was observed between FGF-23 level and SCD in the CKD subgroup; however, it was not significant (HR, 1.20; 95% CI, 0.89-1.62).

LIMITATIONS: Limited power to detect moderate-sized effects between FGF-23 level and SCD in both the primary and stratified analyses.

CONCLUSIONS: In this population-based study, FGF-23 level elevations were associated independently with non-SCD. Among individuals with CKD, the associations between FGF-23 level and SCD and non-SCD were similar.

VL - 66 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25572028?dopt=Abstract ER - TY - JOUR T1 - Urinary uromodulin, kidney function, and cardiovascular disease in elderly adults. JF - Kidney Int Y1 - 2015 A1 - Garimella, Pranav S A1 - Biggs, Mary L A1 - Katz, Ronit A1 - Ix, Joachim H A1 - Bennett, Michael R A1 - Devarajan, Prasad A1 - Kestenbaum, Bryan R A1 - Siscovick, David S A1 - Jensen, Majken K A1 - Shlipak, Michael G A1 - Chaves, Paulo H M A1 - Sarnak, Mark J KW - Aged KW - Aged, 80 and over KW - Albuminuria KW - Biomarkers KW - Cardiovascular Diseases KW - Case-Control Studies KW - Creatinine KW - Disease Progression KW - Female KW - Glomerular Filtration Rate KW - Heart Failure KW - Humans KW - Incidence KW - Kidney Failure, Chronic KW - Male KW - Proportional Hazards Models KW - Uromodulin AB -

Urinary uromodulin (uUMOD) is the most common secreted tubular protein in healthy adults. However, the relationship between uUMOD and clinical outcomes is still unclear. Here we measured uUMOD in 192 participants of the Cardiovascular Health Study with over a 30% decline in estimated glomerular filtration rate (eGFR) over 9 years, 54 with incident end-stage renal disease (ESRD), and in a random subcohort of 958 participants. The association of uUMOD with eGFR decline was evaluated using logistic regression and with incident ESRD, cardiovascular disease, heart failure, and mortality using Cox proportional regression. Mean age was 78 years and median uUMOD was 25.8 μg/ml. In a case-control study evaluating eGFR decline (192 cases and 231 controls), each 1-s.d. higher uUMOD was associated with a 23% lower odds of eGFR decline (odds ratio 0.77 (95% CI 0.62-0.96)) and a 10% lower risk of mortality (hazard ratio 0.90 (95% CI 0.83-0.98)) after adjusting for demographics, eGFR, albumin/creatinine ratio, and other risk factors. There was no risk association of uUMOD with ESRD, cardiovascular disease, or heart failure after multivariable adjustment. Thus, low uUMOD levels may identify persons at risk of progressive kidney disease and mortality above and beyond established markers of kidney disease, namely eGFR and the albumin/creatinine ratio. Future studies need to confirm these results and evaluate whether uUMOD is a marker of tubular health and/or whether it plays a causal role in preserving kidney function.

VL - 88 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26154925?dopt=Abstract ER - TY - JOUR T1 - Urine Collagen Fragments and CKD Progression-The Cardiovascular Health Study. JF - J Am Soc Nephrol Y1 - 2015 A1 - Ix, Joachim H A1 - Biggs, Mary L A1 - Mukamal, Kenneth A1 - Djoussé, Luc A1 - Siscovick, David A1 - Tracy, Russell A1 - Katz, Ronit A1 - Delaney, Joseph A A1 - Chaves, Paulo A1 - Rifkin, Dena E A1 - Hughes-Austin, Jan M A1 - Garimella, Pranav S A1 - Sarnak, Mark J A1 - Shlipak, Michael G A1 - Kizer, Jorge R KW - Aged KW - Cardiovascular Diseases KW - Case-Control Studies KW - Disease Progression KW - Female KW - Heart Failure KW - Humans KW - Kidney Failure, Chronic KW - Male KW - Peptide Fragments KW - Procollagen KW - Prospective Studies KW - Renal Insufficiency, Chronic AB -

Tubulointerstitial fibrosis is common with ageing and strongly prognostic for ESRD but is poorly captured by eGFR or urine albumin to creatinine ratio (ACR). Higher urine levels of procollagen type III N-terminal propeptide (PIIINP) mark the severity of tubulointerstitial fibrosis in biopsy studies, but the association of urine PIIINP with CKD progression is unknown. Among community-living persons aged ≥65 years, we measured PIIINP in spot urine specimens from the 1996 to 1997 Cardiovascular Health Study visit among individuals with CKD progression (30% decline in eGFR over 9 years, n=192) or incident ESRD (n=54) during follow-up, and in 958 randomly selected participants. We evaluated associations of urine PIIINP with CKD progression and incident ESRD. Associations of urine PIIINP with cardiovascular disease, heart failure, and death were evaluated as secondary end points. At baseline, mean age (±SD) was 78±5 years, mean eGFR was 63±18 ml/min per 1.73 m(2), and median urine PIIINP was 2.6 (interquartile range, 1.4-4.2) μg/L. In a case-control study (192 participants, 231 controls), each doubling of urine PIIINP associated with 22% higher odds of CKD progression (adjusted odds ratio, 1.22; 95% confidence interval, 1.00 to 1.49). Higher urine PIIINP level was also associated with incident ESRD, but results were not significant in fully adjusted models. In a prospective study among the 958 randomly selected participants, higher urine PIIINP was significantly associated with death, but not with incident cardiovascular disease or heart failure. These data suggest higher urine PIIINP levels associate with CKD progression independently of eGFR and ACR in older individuals.

VL - 26 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25655067?dopt=Abstract ER - TY - JOUR T1 - Development and Validation of a Sudden Cardiac Death Prediction Model for the General Population. JF - Circulation Y1 - 2016 A1 - Deo, Rajat A1 - Norby, Faye L A1 - Katz, Ronit A1 - Sotoodehnia, Nona A1 - Adabag, Selcuk A1 - deFilippi, Christopher R A1 - Kestenbaum, Bryan A1 - Chen, Lin Y A1 - Heckbert, Susan R A1 - Folsom, Aaron R A1 - Kronmal, Richard A A1 - Konety, Suma A1 - Patton, Kristen K A1 - Siscovick, David A1 - Shlipak, Michael G A1 - Alonso, Alvaro AB -

BACKGROUND: Most sudden cardiac death (SCD) events occur in the general population among persons who do not have any prior history of clinical heart disease. We sought to develop a predictive model of SCD among US adults.

METHODS: We evaluated a series of demographic, clinical, laboratory, electrocardiographic, and echocardiographic measures in participants in the ARIC study (Atherosclerosis Risk in Communities) (n=13 677) and the CHS (Cardiovascular Health Study) (n=4207) who were free of baseline cardiovascular disease. Our initial objective was to derive a SCD prediction model using the ARIC cohort and validate it in CHS. Independent risk factors for SCD were first identified in the ARIC cohort to derive a 10-year risk model of SCD. We compared the prediction of SCD with non-SCD and all-cause mortality in both the derivation and validation cohorts. Furthermore, we evaluated whether the SCD prediction equation was better at predicting SCD than the 2013 American College of Cardiology/American Heart Association Cardiovascular Disease Pooled Cohort risk equation.

RESULTS: There were a total of 345 adjudicated SCD events in our analyses, and the 12 independent risk factors in the ARIC study included age, male sex, black race, current smoking, systolic blood pressure, use of antihypertensive medication, diabetes mellitus, serum potassium, serum albumin, high-density lipoprotein, estimated glomerular filtration rate, and QTc interval. During a 10-year follow-up period, a model combining these risk factors showed good to excellent discrimination for SCD risk (c-statistic 0.820 in ARIC and 0.745 in CHS). The SCD prediction model was slightly better in predicting SCD than the 2013 American College of Cardiology/American Heart Association Pooled Cohort risk equations (c-statistic 0.808 in ARIC and 0.743 in CHS). Only the SCD prediction model, however, demonstrated similar and accurate prediction for SCD using both the original, uncalibrated score and the recalibrated equation. Finally, in the echocardiographic subcohort, a left ventricular ejection fraction <50% was present in only 1.1% of participants and did not enhance SCD prediction.

CONCLUSIONS: Our study is the first to derive and validate a generalizable risk score that provides well-calibrated, absolute risk estimates across different risk strata in an adult population of white and black participants without a clinical diagnosis of cardiovascular disease.

VL - 134 IS - 11 ER - TY - JOUR T1 - Fibroblast Growth Factor-23 and Frailty in Elderly Community-Dwelling Individuals: The Cardiovascular Health Study. JF - J Am Geriatr Soc Y1 - 2016 A1 - Beben, Tomasz A1 - Ix, Joachim H A1 - Shlipak, Michael G A1 - Sarnak, Mark J A1 - Fried, Linda F A1 - Hoofnagle, Andrew N A1 - Chonchol, Michel A1 - Kestenbaum, Bryan R A1 - de Boer, Ian H A1 - Rifkin, Dena E KW - Aged KW - Anthropometry KW - Biomarkers KW - Cardiovascular Diseases KW - Cross-Sectional Studies KW - Enzyme-Linked Immunosorbent Assay KW - Female KW - Fibroblast Growth Factors KW - Frail Elderly KW - Glomerular Filtration Rate KW - Humans KW - Independent Living KW - Longitudinal Studies KW - Male KW - Phenotype KW - Risk Factors KW - Surveys and Questionnaires AB -

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 ± 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 ± 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.

VL - 64 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26889836?dopt=Abstract ER - TY - JOUR T1 - Galectin-3 and Soluble ST2 and Kidney Function Decline in Older Adults: The Cardiovascular Health Study (CHS). JF - Am J Kidney Dis Y1 - 2016 A1 - Bansal, Nisha A1 - Katz, Ronit A1 - Seliger, Stephen A1 - DeFilippi, Christopher A1 - Sarnak, Mark J A1 - Delaney, Joseph A A1 - Christenson, Robert A1 - de Boer, Ian H A1 - Kestenbaum, Bryan A1 - Robinson-Cohen, Cassianne A1 - Ix, Joachim H A1 - Shlipak, Michael G KW - Aged KW - Cohort Studies KW - Creatinine KW - Cystatin C KW - Female KW - Galectin 3 KW - Glomerular Filtration Rate KW - Humans KW - Interleukin-1 Receptor-Like 1 Protein KW - Logistic Models KW - Longitudinal Studies KW - Male KW - Prognosis KW - Renal Insufficiency, Chronic VL - 67 IS - 6 ER - TY - JOUR T1 - Urinary Uromodulin and Risk of Urinary Tract Infections: The Cardiovascular Health Study. JF - Am J Kidney Dis Y1 - 2016 A1 - Garimella, Pranav S A1 - Bartz, Traci M A1 - Ix, Joachim H A1 - Chonchol, Michel A1 - Shlipak, Michael G A1 - Devarajan, Prasad A1 - Bennett, Michael R A1 - Sarnak, Mark J AB -

BACKGROUND: Laboratory studies suggest that urinary uromodulin, the most common protein in the urine of healthy adults, may protect against urinary tract infection (UTI). Epidemiologic studies evaluating this relationship in humans are lacking.

STUDY DESIGN: Prospective longitudinal cohort study.

SETTING & PARTICIPANTS: 953 participants enrolled in the Cardiovascular Health Study.

PREDICTOR: Uromodulin assayed using enzyme-linked immunosorbent assay in spot urine samples.

OUTCOMES: Composite of outpatient UTI events or UTI-related hospitalizations and each of them individually identified using International Classification of Diseases, Ninth Revision (ICD-9) codes using negative binomial regression with robust standard errors adjusted for age, race, sex, body mass index, diabetes, estimated glomerular filtration rate, and urinary albumin and urinary creatinine excretion.

RESULTS: Median uromodulin level was 25.9 (IQR, 17.3-38.9) μg/mL, mean age of participants was 78 years, 61% were women, and 15% were black. There were 331 outpatient UTI events and 87 UTI-related hospitalizations among 186 participants during a median 9.9 years of follow-up. Persons in the highest quartile (>38.93μg/mL) of uromodulin concentration had a significantly lower risk for the composite outcome (incidence rate ratio [IRR], 0.47; 95% CI, 0.29-0.79) compared with those in the lowest quartile (≤17.26μg/mL). This association remained significant for outpatient UTI events (highest vs lowest quartile even after excluding those with prior UTI: IRR, 0.42; 95% CI, 0.23-0.77). The direction of association with UTI hospitalization was similar, but not statistically significant (IRR, 0.78; 95% CI, 0.39-1.58).

LIMITATIONS: Use of ICD-9 codes to identify outcomes and lack of generalizability to younger populations.

CONCLUSIONS: High urinary uromodulin levels are associated with lower risk for UTI in older community-dwelling adults independent of traditional UTI risk factors. This finding supports prior laboratory data indicating a protective role of uromodulin against UTI. Further research is needed to understand if this may lead to new treatments to prevent or treat UTI.

ER - TY - JOUR T1 - Absolute Rates of Heart Failure, Coronary Heart Disease, and Stroke in Chronic Kidney Disease: An Analysis of 3 Community-Based Cohort Studies. JF - JAMA Cardiol Y1 - 2017 A1 - Bansal, Nisha A1 - Katz, Ronit A1 - Robinson-Cohen, Cassianne A1 - Odden, Michelle C A1 - Dalrymple, Lorien A1 - Shlipak, Michael G A1 - Sarnak, Mark J A1 - Siscovick, David S A1 - Zelnick, Leila A1 - Psaty, Bruce M A1 - Kestenbaum, Bryan A1 - Correa, Adolfo A1 - Afkarian, Maryam A1 - Young, Bessie A1 - de Boer, Ian H AB -

Importance: Cardiovascular disease is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). Understanding the relative contributions of cardiovascular disease event types to the excess burden of cardiovascular disease is important for developing effective strategies to improve outcomes.

Objective: To determine absolute rates and risk differences of incident heart failure (HF), coronary heart disease (CHD), and stroke in participants with vs without CKD.

Design, Setting and Participants: We pooled participants without prevalent cardiovascular disease from 3 community-based cohort studies: the Jackson Heart Study, Cardiovascular Health Study, and Multi-Ethnic Study of Atherosclerosis. The Jackson Heart Study was conducted between 2000 and 2010, the Cardiovascular Health Study was conducted between 1989 and 2003, and the Multi-Ethnic Study of Atherosclerosis was conducted between 2000 and 2012.

Exposures: Chronic kidney disease was defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m2, calculated using the combined creatinine-cystatin C CKD-Epidemiology Collaboration Equation.

Main Outcomes and Measures: Poisson regression was used to calculate incidence rates (IRs) and risk differences of adjudicated incident HF, CHD, and stroke, comparing participants with vs without CKD.

Results: Among 14 462 participants, the mean (SD) age was 63 (12) years, 59% (n = 8533) were women, and 44% (n = 6363) were African American. Overall, 1461 (10%) had CKD (mean [SD] estimated glomerular filtration rate, 49 [10] mL/min/1.73 m2). Unadjusted IRs for participants with and without CKD, respectively, were 22.0 (95% CI, 19.3-24.8) and 6.2 (95% CI, 5.8-6.7) per 1000 person-years for HF; 24.5 (95% CI, 21.6-27.5) and 8.4 (95% CI, 7.9-9.0) per 1000 person-years for CHD; and 13.4 (95% CI, 11.3-15.5) and 4.8 (95% CI, 4.4-5.3) for stroke. Adjusting for demographics, cohort, hypertension, diabetes, hyperlipidemia, and tobacco use, risk differences comparing participants with vs without CKD (per 1000 person-years) were 2.3 (95% CI, 1.2-3.3) for HF, 2.3 (95% CI, 1.2-3.4) for CHD, and 0.8 (95% CI, 0.09-1.5) for stroke. Among African American and Hispanic participants, adjusted risk differences comparing participants with vs without CKD for HF were 3.5 (95% CI, 1.5-5.5) and 7.8 (95% CI, 2.2-13.3) per 1000 person-years, respectively.

Conclusions and Relevance: Among 3 diverse community-based cohorts, CKD was associated with an increased risk of HF that was similar in magnitude to CHD and greater than stroke. The excess risk of HF associated with CKD was particularly large among African American and Hispanic individuals. Efforts to improve health outcomes for patients with CKD should prioritize HF in addition to CHD prevention.

VL - 2 IS - 3 ER - TY - JOUR T1 - Association of Blood Pressure Trajectory With Mortality, Incident Cardiovascular Disease, and Heart Failure in the Cardiovascular Health Study. JF - Am J Hypertens Y1 - 2017 A1 - Smitson, Christopher C A1 - Scherzer, Rebecca A1 - Shlipak, Michael G A1 - Psaty, Bruce M A1 - Newman, Anne B A1 - Sarnak, Mark J A1 - Odden, Michelle C A1 - Peralta, Carmen A AB -

BACKGROUND: Common blood pressure (BP) trajectories are not well established in elderly persons, and their association with clinical outcomes is uncertain.

METHODS: We used hierarchical cluster analysis to identify discrete BP trajectories among 4,067 participants in the Cardiovascular Health Study using repeated BP measures from years 0 to 7. We then evaluated associations of each BP trajectory cluster with all-cause mortality, incident cardiovascular disease (CVD, defined as stroke or myocardial infarction) (N = 2,837), and incident congestive heart failure (HF) (N = 3,633) using Cox proportional hazard models.

RESULTS: Median age was 77 years at year 7. Over a median 9.3 years of follow-up, there were 2,475 deaths, 659 CVD events, and 1,049 HF events. The cluster analysis identified 3 distinct trajectory groups. Participants in cluster 1 (N = 1,838) had increases in both systolic (SBP) and diastolic (DBP) BPs, whereas persons in cluster 2 (N = 1,109) had little change in SBP but declines in DBP. Persons in cluster 3 (N = 1,120) experienced declines in both SBP and DBP. After multivariable adjustment, clusters 2 and 3 were associated with increased mortality risk relative to cluster 1 (hazard ratio = 1.21, 95% confidence interval: 1.06-1.37 and hazard ratio = 1.20, 95% confidence interval: 1.05-1.36, respectively). Compared to cluster 1, cluster 3 had higher rates of incident CVD but associations were not statistically significant in demographic-adjusted models (hazard ratio = 1.16, 95% confidence interval: 0.96-1.39). Findings were similar when stratified by use of antihypertensive therapy.

CONCLUSIONS: Among community-dwelling elders, distinct BP trajectories were identified by integrating both SBP and DBP. These clusters were found to have differential associations with outcomes.

ER - TY - JOUR T1 - eGFR and Albuminuria in Relation to Risk of Incident Atrial Fibrillation: A Meta-Analysis of the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study. JF - Clin J Am Soc Nephrol Y1 - 2017 A1 - Bansal, Nisha A1 - Zelnick, Leila R A1 - Alonso, Alvaro A1 - Benjamin, Emelia J A1 - de Boer, Ian H A1 - Deo, Rajat A1 - Katz, Ronit A1 - Kestenbaum, Bryan A1 - Mathew, Jehu A1 - Robinson-Cohen, Cassianne A1 - Sarnak, Mark J A1 - Shlipak, Michael G A1 - Sotoodehnia, Nona A1 - Young, Bessie A1 - Heckbert, Susan R AB -

BACKGROUND AND OBJECTIVES: The incidence of atrial fibrillation is high in ESRD, but limited data are available on the incidence of atrial fibrillation across a broad range of kidney function. Thus, we examined the association of eGFR and urine albumin-to-creatinine ratio with risk of incident atrial fibrillation.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We meta-analyzed three prospective cohorts: the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study. Cox regression models were performed examining the association of eGFR and urine albumin-to-creatinine ratio with incident atrial fibrillation adjusting for demographics and comorbidity. In additional analyses, we adjusted for measures of subclinical cardiovascular disease (by electrocardiogram and cardiac imaging) and interim heart failure and myocardial infarction events.

RESULTS: In the meta-analyzed study population of 16,769 participants without prevalent atrial fibrillation, across categories of decreasing eGFR (eGFR>90 [reference], 60-89, 45-59, 30-44, and <30 ml/min per 1.73 m(2)), there was a stepwise increase in the adjusted risk of incident atrial fibrillation: hazard ratios (95% confidence intervals) were 1.00, 1.09 (0.97 to 1.24), 1.17 (1.00 to 1.38), 1.59 (1.28 to 1.98), and 2.03 (1.40 to 2.96), respectively. There was a stepwise increase in the adjusted risk of incident atrial fibrillation across categories of increasing urine albumin-to-creatinine ratio (urine albumin-to-creatinine ratio <15 [reference], 15-29, 30-299, and ≥300 mg/g): hazard ratios (95% confidence intervals) were 1.00, 1.04 (0.83 to 1.30), 1.47 (1.20 to 1.79), and 1.76 (1.18 to 2.62), respectively. The associations were consistent after adjustment for subclinical cardiovascular disease measures and interim heart failure and myocardial infarction events.

CONCLUSIONS: In this meta-analysis of three cohorts, reduced eGFR and elevated urine albumin-to-creatinine ratio were significantly associated with greater risk of incident atrial fibrillation, highlighting the need for further studies to understand mechanisms linking kidney disease with atrial fibrillation.

VL - 12 IS - 9 ER - TY - JOUR T1 - Fibroblast Growth Factor 23 and the Risk of Infection-Related Hospitalization in Older Adults. JF - J Am Soc Nephrol Y1 - 2017 A1 - Nowak, Kristen L A1 - Bartz, Traci M A1 - Dalrymple, Lorien A1 - de Boer, Ian H A1 - Kestenbaum, Bryan A1 - Shlipak, Michael G A1 - Garimella, Pranav S A1 - Ix, Joachim H A1 - Chonchol, Michel AB -

Within monocytes, 1,25-dihydroxyvitamin D [1,25(OH)2D] is important for production of cathelicidins, which in turn, are critical for antibacterial action. Fibroblast growth factor 23 (FGF23) decreases 1,25(OH)2D production and thus, could increase infection risk. We examined this possibility in 3141 community-dwelling adults ages ≥65 years old at baseline in the Cardiovascular Health Study using Cox proportional hazards models to examine the association between FGF23 concentrations and first infection-related hospitalizations and determine whether associations differed by the presence of CKD (eGFR<60 ml/min per 1.73 m(2) [n=832] or urine albumin-to-creatinine ratio >30 mg/g [n=577]). Mean±SD age of participants was 78±5 years old, 60% of participants were women, and the median plasma FGF23 concentration was 70 (interquartile range, 53-99) relative units per milliliter. In fully adjusted models, higher FGF23 concentrations associated with higher risk of first infection-related hospitalization (hazard ratio [HR], 1.11; 95% confidence interval [95% CI], 1.03 to 1.20 per doubling of FGF23) during a median follow-up of 8.6 years. In participants with or without CKD (defined by eGFR), FGF23 concentration associated with first infection-related hospitalization with HRs of 1.24 (95% CI, 1.08 to 1.42) and 1.06 (95% CI, 0.97 to 1.17) per doubling of FGF23, respectively (P=0.13 for interaction). Associations did not differ between groups when stratified by urine albumin-to-creatinine ratio. In sensitivity analyses, the addition of serum calcium, phosphorus, 25-hydroxyvitamin D, intact parathyroid hormone, and 24,25-dihydroxyvitamin D did not meaningfully change the estimates. In conclusion, in community-dwelling older adults, higher plasma FGF23 concentrations independently associated with the risk of first infection-related hospitalization.

VL - 28 IS - 4 ER - TY - JOUR T1 - Measures of chronic kidney disease and risk of incident peripheral artery disease: a collaborative meta-analysis of individual participant data. JF - Lancet Diabetes Endocrinol Y1 - 2017 A1 - Matsushita, Kunihiro A1 - Ballew, Shoshana H A1 - Coresh, Josef A1 - Arima, Hisatomi A1 - Arnlöv, Johan A1 - Cirillo, Massimo A1 - Ebert, Natalie A1 - Hiramoto, Jade S A1 - Kimm, Heejin A1 - Shlipak, Michael G A1 - Visseren, Frank L J A1 - Gansevoort, Ron T A1 - Kovesdy, Csaba P A1 - Shalev, Varda A1 - Woodward, Mark A1 - Kronenberg, Florian AB -

BACKGROUND: Some evidence suggests that chronic kidney disease is a risk factor for lower-extremity peripheral artery disease. We aimed to quantify the independent and joint associations of two measures of chronic kidney disease (estimated glomerular filtration rate [eGFR] and albuminuria) with the incidence of peripheral artery disease.

METHODS: In this collaborative meta-analysis of international cohorts included in the Chronic Kidney Disease Prognosis Consortium (baseline measurements obtained between 1972 and 2014) with baseline measurements of eGFR and albuminuria, at least 1000 participants (this criterion not applied to cohorts exclusively enrolling patients with chronic kidney disease), and at least 50 peripheral artery disease events, we analysed adult participants without peripheral artery disease at baseline at the individual patient level with Cox proportional hazards models to quantify associations of creatinine-based eGFR, urine albumin-to-creatinine ratio (ACR), and dipstick proteinuria with the incidence of peripheral artery disease (including hospitalisation with a diagnosis of peripheral artery disease, intermittent claudication, leg revascularisation, and leg amputation). We assessed discrimination improvement through c-statistics.

FINDINGS: We analysed 817 084 individuals without a history of peripheral artery disease at baseline from 21 cohorts. 18 261 cases of peripheral artery disease were recorded during follow-up across cohorts (median follow-up was 7·4 years [IQR 5·7-8·9], range 2·0-15·8 years across cohorts). Both chronic kidney disease measures were independently associated with the incidence of peripheral artery disease. Compared with an eGFR of 95 mL/min per 1·73 m2, adjusted hazard ratios (HRs) for incident study-specific peripheral artery disease was 1·22 (95% CI 1·14-1·30) at an eGFR of 45 mL/min per 1·73 m2 and 2·06 (1·70-2·48) at an eGFR of 15 mL/min per 1·73 m2. Compared with an ACR of 5 mg/g, the adjusted HR for incident study-specific peripheral artery disease was 1·50 (1·41-1·59) at an ACR of 30 mg/g and 2·28 (2·12-2·44) at an ACR of 300 mg/g. The adjusted HR at an ACR of 300 mg/g versus 5 mg/g was 3·68 (95% CI 3·00-4·52) for leg amputation. eGFR and albuminuria contributed multiplicatively (eg, adjusted HR 5·76 [4·90-6·77] for incident peripheral artery disease and 10·61 [5·70-19·77] for amputation in eGFR <30 mL/min per 1·73 m2 plus ACR ≥300 mg/g or dipstick proteinuria 2+ or higher vs eGFR ≥90 mL/min per 1·73 m2 plus ACR <10 mg/g or dipstick proteinuria negative). Both eGFR and ACR significantly improved peripheral artery disease risk discrimination beyond traditional predictors, with a substantial improvement prediction of amputation with ACR (difference in c-statistic 0·058, 95% CI 0·045-0·070). Patterns were consistent across clinical subgroups.

INTERPRETATION: Even mild-to-moderate chronic kidney disease conferred increased risk of incident peripheral artery disease, with a strong association between albuminuria and amputation. Clinical attention should be paid to the development of peripheral artery disease symptoms and signs in people with any stage of chronic kidney disease.

FUNDING: American Heart Association, US National Kidney Foundation, and US National Institute of Diabetes and Digestive and Kidney Diseases.

VL - 5 IS - 9 ER - TY - JOUR T1 - The Relation of Serum Potassium Concentration with Cardiovascular Events and Mortality in Community-Living Individuals. JF - Clin J Am Soc Nephrol Y1 - 2017 A1 - Hughes-Austin, Jan M A1 - Rifkin, Dena E A1 - Beben, Tomasz A1 - Katz, Ronit A1 - Sarnak, Mark J A1 - Deo, Rajat A1 - Hoofnagle, Andrew N A1 - Homma, Shunichi A1 - Siscovick, David S A1 - Sotoodehnia, Nona A1 - Psaty, Bruce M A1 - de Boer, Ian H A1 - Kestenbaum, Bryan A1 - Shlipak, Michael G A1 - Ix, Joachim H AB -

BACKGROUND AND OBJECTIVES: Hyperkalemia is associated with adverse outcomes in patients with CKD and in hospitalized patients with acute medical conditions. Little is known regarding hyperkalemia, cardiovascular disease (CVD), and mortality in community-living populations. In a pooled analysis of two large observational cohorts, we investigated associations between serum potassium concentrations and CVD events and mortality, and whether potassium-altering medications and eGFR<60 ml/min per 1.73 m(2) modified these associations.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 9651 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS), who were free of CVD at baseline (2000-2002 in the MESA and 1989-1993 in the CHS), we investigated associations between serum potassium categories (<3.5, 3.5-3.9, 4.0-4.4, 4.5-4.9, and ≥5.0 mEq/L) and CVD events, mortality, and mortality subtypes (CVD versus non-CVD) using Cox proportional hazards models, adjusting for demographics, time-varying eGFR, traditional CVD risk factors, and use of potassium-altering medications.

RESULTS: Compared with serum potassium concentrations between 4.0 and 4.4 mEq/L, those with concentrations ≥5.0 mEq/L were at higher risk for all-cause mortality (hazard ratio, 1.41; 95% confidence interval, 1.12 to 1.76), CVD death (hazard ratio, 1.50; 95% confidence interval, 1.00 to 2.26), and non-CVD death (hazard ratio, 1.40; 95% confidence interval, 1.07 to 1.83) in fully adjusted models. Associations of serum potassium with these end points differed among diuretic users (Pinteraction<0.02 for all), such that participants who had serum potassium ≥5.0 mEq/L and were concurrently using diuretics were at higher risk of each end point compared with those not using diuretics.

CONCLUSIONS: Serum potassium concentration ≥5.0 mEq/L was associated with all-cause mortality, CVD death, and non-CVD death in community-living individuals; associations were stronger in diuretic users. Whether maintenance of potassium within the normal range may improve clinical outcomes requires future study.

VL - 12 IS - 2 ER - TY - JOUR T1 - Visit-to-Visit Blood Pressure Variability and Mortality and Cardiovascular Outcomes Among Older Adults: The Health, Aging, and Body Composition Study. JF - Am J Hypertens Y1 - 2017 A1 - Wu, Chenkai A1 - Shlipak, Michael G A1 - Stawski, Robert S A1 - Peralta, Carmen A A1 - Psaty, Bruce M A1 - Harris, Tamara B A1 - Satterfield, Suzanne A1 - Shiroma, Eric J A1 - Newman, Anne B A1 - Odden, Michelle C KW - Aged KW - Aging KW - Blood Pressure KW - Blood Pressure Determination KW - Body Composition KW - California KW - Cohort Studies KW - Female KW - Health Status KW - Humans KW - Hypertension KW - Incidence KW - Longitudinal Studies KW - Male KW - Myocardial Infarction KW - Office Visits KW - Prognosis KW - Retrospective Studies KW - Risk Factors KW - Stroke KW - Survival Rate AB -

BACKGROUND: Level of blood pressure (BP) is strongly associated with cardiovascular (CV) events and mortality. However, it is questionable whether mean BP can fully capture BP-related vascular risk. Increasing attention has been given to the value of visit-to-visit BP variability.

METHODS: We examined the association of visit-to-visit BP variability with mortality, incident myocardial infarction (MI), and incident stroke among 1,877 well-functioning elders in the Health, Aging, and Body Composition Study. We defined visit-to-visit diastolic BP (DBP) and systolic BP (SBP) variability as the root-mean-square error of person-specific linear regression of BP as a function of time. Alternatively, we counted the number of considerable BP increases and decreases (separately; 10mm Hg for DBP and 20mm Hg for SBP) between consecutive visits for each individual.

RESULTS: Over an average follow-up of 8.5 years, 623 deaths (207 from CV disease), 153 MIs, and 156 strokes occurred. The median visit-to-visit DBP and SBP variability was 4.96 mmHg and 8.53 mmHg, respectively. After multivariable adjustment, visit-to-visit DBP variability was related to higher all-cause (hazard ratio (HR) = 1.18 per 1 SD, 95% confidence interval (CI) = 1.01-1.37) and CV mortality (HR = 1.35, 95% CI = 1.05-1.73). Additionally, individuals having more considerable decreases of DBP (≥10mm Hg between 2 consecutive visits) had higher risk of all-cause (HR = 1.13, 95% CI = 0.99-1.28) and CV mortality (HR = 1.30, 95% CI = 1.05-1.61); considerable increases of SBP (≥20mm Hg) were associated with higher risk of all-cause (HR = 1.18, 95% CI = 1.03-1.36) and CV mortality (HR = 1.37, 95% CI = 1.08-1.74).

CONCLUSIONS: Visit-to-visit DBP variability and considerable changes in DBP and SBP were risk factors for mortality in the elderly.

VL - 30 IS - 2 ER - TY - JOUR T1 - The 24,25 to 25-hydroxyvitamin D ratio and fracture risk in older adults: The cardiovascular health study. JF - Bone Y1 - 2018 A1 - Ginsberg, Charles A1 - Katz, Ronit A1 - de Boer, Ian H A1 - Kestenbaum, Bryan R A1 - Chonchol, Michel A1 - Shlipak, Michael G A1 - Sarnak, Mark J A1 - Hoofnagle, Andrew N A1 - Rifkin, Dena E A1 - Garimella, Pranav S A1 - Ix, Joachim H AB -

25-hydroxyvitamin D [25(OH)D] may not optimally indicate vitamin D receptor activity. Higher concentrations of its catabolic product 24,25-dihydroxyvitmin D [24,25(OH)2D] and a higher ratio of 24,25(OH)2D to 25(OH)D (the vitamin D metabolite ratio [VMR]) may provide additional information on receptor activity. We compared the strength of associations of these markers with serum PTH concentrations, hip bone mineral density (BMD), and risk of incident hip fracture in community-living older participants in the Cardiovascular Health Study. Among 890 participants, the mean age was 78years, 60% were women, and the mean 25(OH)D was 28±11ng/ml. In cross-sectional analysis, the strength of association of each vitamin D measure with PTH was similar; a 1% higher 25(OH)D, 24,25(OH)2D, and VMR were associated with 0.32%, 0.25%, and 0.26% lower PTH, respectively (p<0.05 for all). Among 358 participants with available BMD data, we found no associations of 25(OH)D or VMR with BMD, whereas higher 24,25(OH)2D was modestly associated with greater hip BMD (1% higher 24,25(OH)2D associated with 0.04% [95% CI 0.01-0.08%] higher BMD). Risk of incident hip fracture risk was evaluated using a case-cohort design. There were 289 hip fractures during a mean follow up time of 8.4years. Both higher 24,25(OH)2D and VMR were associated with lower risk of hip fracture (HR per SD higher, 0.73 [0.61, 0.87] and 0.74 [0.61, 0.88], respectively) whereas 25(OH)D was not associated with hip fracture (HR 0.93 [0.79, 1.10]). We conclude that evaluating vitamin D status by incorporating assessment of 24,25(OH)D and the VMR provides information on bone health above and beyond 25(OH)D alone.

VL - 107 ER - TY - JOUR T1 - Low thyroid function is not associated with an accelerated deterioration in renal function. JF - Nephrol Dial Transplant Y1 - 2018 A1 - Meuwese, Christiaan L A1 - van Diepen, Merel A1 - Cappola, Anne R A1 - Sarnak, Mark J A1 - Shlipak, Michael G A1 - Bauer, Douglas C A1 - Fried, Linda P A1 - Iacoviello, Massimo A1 - Vaes, Bert A1 - Degryse, Jean A1 - Khaw, Kay-Tee A1 - Luben, Robert N A1 - Asvold, Bjørn O A1 - Bjøro, Trine A1 - Vatten, Lars J A1 - de Craen, Anton J M A1 - Trompet, Stella A1 - Iervasi, Giorgio A1 - Molinaro, Sabrina A1 - Ceresini, Graziano A1 - Ferrucci, Luigi A1 - Dullaart, Robin P F A1 - Bakker, Stephan J L A1 - Jukema, J Wouter A1 - Kearney, Patricia M A1 - Stott, David J A1 - Peeters, Robin P A1 - Franco, Oscar H A1 - Völzke, Henry A1 - Walsh, John P A1 - Bremner, Alexandra A1 - Sgarbi, José A A1 - Maciel, Rui M B A1 - Imaizumi, Misa A1 - Ohishi, Waka A1 - Dekker, Friedo W A1 - Rodondi, Nicolas A1 - Gussekloo, Jacobijn A1 - den Elzen, Wendy P J AB -

Background: Chronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups.

Methods: Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models.

Results: A total of 72 856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95% confidence interval) -4.07 (-6.37 to -1.78) and -2.40 (-3.78 to -1.02) mL/min/1.73 m2 lower eGFR as compared with euthyroid subjects (n = 66 542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50-4.52) mL/min/1.73 m2 higher. During 329 713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function.

Conclusions: Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations.

ER - TY - JOUR T1 - Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities: An Individual Participant Data Meta-analysis in a Global Consortium. JF - Am J Kidney Dis Y1 - 2018 A1 - Inker, Lesley A A1 - Grams, Morgan E A1 - Levey, Andrew S A1 - Coresh, Josef A1 - Cirillo, Massimo A1 - Collins, John F A1 - Gansevoort, Ron T A1 - Gutierrez, Orlando M A1 - Hamano, Takayuki A1 - Heine, Gunnar H A1 - Ishikawa, Shizukiyo A1 - Jee, Sun Ha A1 - Kronenberg, Florian A1 - Landray, Martin J A1 - Miura, Katsuyuki A1 - Nadkarni, Girish N A1 - Peralta, Carmen A A1 - Rothenbacher, Dietrich A1 - Schaeffner, Elke A1 - Sedaghat, Sanaz A1 - Shlipak, Michael G A1 - Zhang, Luxia A1 - van Zuilen, Arjan D A1 - Hallan, Stein I A1 - Kovesdy, Csaba P A1 - Woodward, Mark A1 - Levin, Adeera AB -

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework.

STUDY DESIGN: Cross-sectional individual participant-level analyses in a global consortium.

SETTING & STUDY POPULATIONS: 17 CKD and 38 general population and high-risk cohorts.

SELECTION CRITERIA FOR STUDIES: Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension.

DATA EXTRACTION: Data were obtained and analyzed between July 2015 and January 2018.

ANALYTICAL APPROACH: We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses.

RESULTS: The CKD cohorts (n=254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n=1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59mL/min/1.73m), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30mg/g).

LIMITATIONS: Variations in study era, health care delivery system, typical diet, and laboratory assays.

CONCLUSIONS: Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD.

ER - TY - JOUR T1 - Association of serum and urinary uromodulin and their correlates in older adults-The Cardiovascular Health Study. JF - Nephrology (Carlton) Y1 - 2019 A1 - Steubl, Dominik A1 - Bůzková, Petra A1 - Ix, Joachim H A1 - Devarajan, Prasad A1 - Bennett, Michael R A1 - Chaves, Paolo H M A1 - Shlipak, Michael G A1 - Bansal, Nisha A1 - Sarnak, Mark J A1 - Garimella, Pranav S AB -

Uromodulin is released into serum (sUMOD) and urine (uUMOD) exclusively by renal tubular cells. Both sUMOD and uUMOD are correlated with estimated glomerular filtration rate (eGFR), and associated with mortality and cardiovascular disease (CVD). However, no study to our knowledge has measured both sUMOD and uUMOD in the same population, thus the relationship of sUMOD with uUMOD with one another, and their respective correlates have not been evaluated simultaneously. We evaluated the correlations of sUMOD, uUMOD with eGFR in a random sub-cohort (n = 933) of the Cardiovascular Health Study and their associations with demographic and laboratory parameters and CVD risk factors using multi-variable linear regression analysis. The mean age of the cohort was 78 years, 40% were male and 15% were Black. The mean sUMOD level was 127 ng/mL, uUMOD was 30 500 ng/mL and eGFR was 63 mL/min/1.73 m . Correlation between sUMOD and uUMOD, adjusted for eGFR was moderate (r = 0.27 [95% confidence interval = 0.21-0.33]). The correlation of eGFR with sUMOD (r = 0.44 [0.39-0.49]) was stronger than with uUMOD (r = 0.21 [0.15-0.27]). In multi-variable analysis adjusting sUMOD for uUMOD and vice versa, sUMOD was independently associated with eGFR (β = 1.3 [1.1-1.6]), log2 C-reactive protein (β = -4.2 [-6.8 to -1.6]) and male sex (β = -13.6 [-22.7 to -4.5]). In contrast, male sex was associated with higher uUMOD (β = 3700 [400-7000]), while diabetes (β = -6400 [-10 600 to -2100]) and hypertension (-4300 [-7500 to -1100]) were associated with lower uUMOD levels. We conclude that sUMOD is more strongly associated with eGFR compared with uUMOD. Correlates of sUMOD and uUMOD differ substantially, suggesting that apical and basolateral secretion may be differentially regulated.

ER - TY - JOUR T1 - Association of serum uromodulin with mortality and cardiovascular disease in the elderly-the Cardiovascular Health Study. JF - Nephrol Dial Transplant Y1 - 2019 A1 - Steubl, Dominik A1 - Bůzková, Petra A1 - Garimella, Pranav S A1 - Ix, Joachim H A1 - Devarajan, Prasad A1 - Bennett, Michael R A1 - Chaves, Paulo H M A1 - Shlipak, Michael G A1 - Bansal, Nisha A1 - Sarnak, Mark J AB -

BACKGROUND: Uromodulin (UMOD) is released by renal tubular cells into the serum (sUMOD) and urine. Lower urine UMOD has been linked to mortality and cardiovascular disease but much less is known about sUMOD. We evaluated the association of sUMOD with these outcomes in community-dwelling older adults.

METHODS: We measured sUMOD in a random subcohort of 933 participants enrolled in the Cardiovascular Health Study. The associations of sUMOD with all-cause mortality, incident heart failure (HF) and incident cardiovascular disease (CVD; myocardial infarction, stroke and mortality due to coronary disease or stroke) were evaluated using multivariable Cox regression, adjusting for study participants' demographics, estimated glomerular filtration rate (eGFR), albuminuria and CVD risk factors. Generalized additive models with splines were used to address the functional form of sUMOD with outcomes. Due to nonlinear associations of sUMOD with all outcomes, 2.5% of the values on either end of the sUMOD distribution were excluded from the analyses, limiting the range of sUMOD to 34.3-267.1 ng/mL.

RESULTS: The mean age was 78 ± 5 years, 40% were male, sUMOD level was 127 ± 64 ng/mL, eGFR was 63 mL/min/1.73 m2 and 42% had CKD defined as eGFR <60 mL/min/1.73 m2. Patients in the lower sUMOD quartiles had lower eGFR and higher albuminuria (P < 0.01, respectively). During a median follow-up of 9.9 years, 805 patients died, 283 developed HF and 274 developed CVD. In multivariable analysis, higher sUMOD was significantly associated with a lower hazard for mortality {hazard ratio [HR] 0.89 [95% confidence interval (CI) 0.80-0.99] per 1 standard deviation (SD) higher sUMOD}, CVD [HR 0.80 (95% CI 0.67-0.96)] and the composite endpoint [HR 0.88 (95% CI 0.78-0.99)]; the association with HF was not statistically significant [HR 0.84 (95% CI 0.70-1.01)].

CONCLUSION: Higher sUMOD is independently associated with a lower risk for mortality and CVD in older adults.

ER - TY - JOUR T1 - Heterogeneous Exposure Associations in Observational Cohort Studies: The Example of Blood Pressure in Older Adults. JF - Am J Epidemiol Y1 - 2019 A1 - Odden, Michelle C A1 - Rawlings, Andreea M A1 - Khodadadi, Abtin A1 - Fern, Xiaoli A1 - Shlipak, Michael G A1 - Bibbins-Domingo, Kirsten A1 - Covinsky, Kenneth A1 - Kanaya, Alka M A1 - Lee, Anne A1 - Haan, Mary N A1 - Newman, Anne B A1 - Psaty, Bruce M A1 - Peralta, Carmen A AB -

Heterogeneous exposure associations (HEAs) can be defined as differences in the association of a exposure with an outcome among subgroups that differ by a set of characteristics. This manuscript intends to foster discussion of HEAs in the epidemiological literature, and present a variant of the random forest algorithm that can be used to identify HEAs. We demonstrate the use of this algorithm in the setting of the association of systolic blood pressure and death in older adults. The training set included pooled data from the baseline examination of the Cardiovascular Health Study (1989-1993), the Health, Aging, and Body Composition study (1997-1998), and the Sacramento Area Latino Study on Aging (1998-1999). The test set included data from the National Health and Nutrition Examination Survey (1999-2002). The hazard ratios ranged from 1.25 (95% CI: 1.13, 1.37) per 10 mmHg higher systolic blood pressure in men aged ≤67 years with diastolic blood pressure >80 mmHg, to 1.00 (0.96, 1.03) in women with creatinine <0.7 mg/dL and a history of hypertension. HEAs have the potential to improve our understanding of disease mechanisms in diverse populations, and guide the design of randomized controlled trials to control exposures in heterogeneous populations.

ER - TY - JOUR T1 - The Difference Between Cystatin C and Creatinine-Based Estimated GFR and Incident Frailty: An Analysis of the Cardiovascular Health Study (CHS). JF - Am J Kidney Dis Y1 - 2020 A1 - Potok, O Alison A1 - Phil, Ronit Katz D A1 - Bansal, Nisha A1 - Siscovick, David S A1 - Odden, Michelle A1 - Ix, Joachim H A1 - Shlipak, Michael G A1 - Rifkin, Dena E ER - TY - JOUR T1 - Hospitalization Rates in Older Adults with Albuminuria: The Cardiovascular Health Study. JF - J Gerontol A Biol Sci Med Sci Y1 - 2020 A1 - Barzilay, Joshua I A1 - Bůzková, Petra A1 - Shlipak, Michael G A1 - Bansal, Nisha A1 - Garimella, Pranav A1 - Mukamal, Kenneth J AB -

BACKGROUND: Albuminuria is highly prevalent among older adults, especially those with diabetes. It is associated with several chronic diseases, but its overall impact on the health of older adults, as measured by hospitalization, has not been quantified.

METHODS: We followed 3110 adults, mean age 78 years, for a median 9.75 years, of whom 654 (21%) had albuminuria (>30 mg albumin / gram creatinine) at baseline. Poisson regression models, adjusted for cardiovascular, renal and demographic factors, were used to evaluate association of albuminuria with all-cause and cause-specific hospitalizations, as defined by ICD, version 9, categories.

RESULTS: The rates of hospitalization per 100 patient-years were 65.85 for participants with albuminuria and 37.55 for participants without albuminuria. After adjustment for covariates, participants with albuminuria were more likely to be hospitalized for any cause than participants without albuminuria (incident rate ratio [IRR], 1.39 [95% confidence intervals, 1.27. 1.53] and to experience more days in hospital (IRR 1.56 [1.37, 1.76]). The association of albuminuria with hospitalization was similar among participants with and without diabetes (adjusted IRR for albuminuria vs no albuminuria: diabetes 1.37 [1.11, 1.70], no diabetes 1.40 [1.26, 1.55]; p interaction NS). Albuminuria was significantly associated with hospitalization for circulatory, endocrine, genitourinary, respiratory, and injury categories.

CONCLUSIONS: Albuminuria in older adults is associated with an increased risk of hospitalization for a broad range of illnesses. Albuminuria in the presence or absence of diabetes appears to mark a generalized vulnerability to diseases of aging among older adults.

ER - TY - JOUR T1 - Intact and C-Terminal FGF23 Assays-Do Kidney Function, Inflammation, and Low Iron Influence Relationships With Outcomes? JF - J Clin Endocrinol Metab Y1 - 2020 A1 - Sharma, Shilpa A1 - Katz, Ronit A1 - Bullen, Alexander L A1 - Chaves, Paulo H M A1 - de Leeuw, Peter W A1 - Kroon, Abraham A A1 - Houben, Alfons J H M A1 - Shlipak, Michael G A1 - Ix, Joachim H AB -

CONTEXT: Higher fibroblast growth factor-23 (FGF23) concentrations are associated with heart failure and mortality in diverse populations, but the strengths of associations differ markedly depending up on which assay is used.

OBJECTIVE: We sought to evaluate whether iron deficiency, inflammation, or kidney function account for differences in the strengths of associations between these 2 FGF23 assays with clinical outcomes.

DESIGN: Case cohort study from the Cardiovascular Health Study.

SETTING: A total of 844 community-dwelling individuals aged 65 years or older with and without chronic kidney disease were followed for 10 years.

OUTCOMES: Outcomes included death, incident heart failure (HF), and incident myocardial infarction (MI). Exposure was baseline intact and C-terminal FGF23. Using modified Cox models, adjusting sequentially we tested whether observed associations of each assay with outcomes were attenuated by iron status, inflammation, kidney function, or their combinations.

RESULTS: FGF23 measured by either assay was associated with mortality in unadjusted analysis (intact FGF23 hazard ratio [HR] per 2-fold higher 1.45; 95% CI, 1.25-1.68; C-terminal FGF23 HR 1.38; 95% CI, 1.26-1.50). Adjustment for kidney function completely attenuated associations of intact FGF23 with mortality (HR 1.00; 95% CI, 0.85-1.17), but had much less influence on the association of C-terminal FGF23, for which results remained significant after adjustment (HR 1.15; 95% CI, 1.04-1.28). Attenuation was much less with adjustment for iron status or inflammation. Results were similar for the HF end point. Neither C-terminal or intact FGF23 was associated with MI risk.

CONCLUSIONS: The relationship of FGF23 with clinical end points is markedly different depending on the type of FGF23 assay used. The associations of biologically active FGF23 with clinical end points may be confounded by kidney disease, and thus much weaker than previously thought.

VL - 105 IS - 12 ER - TY - JOUR T1 - Level and change in N-terminal pro B-type Natriuretic Peptide and kidney function and survival to age 90. JF - J Gerontol A Biol Sci Med Sci Y1 - 2020 A1 - Häberle, Astrid D A1 - Biggs, Mary L A1 - Cushman, Mary A1 - Psaty, Bruce M A1 - Newman, Anne B A1 - Shlipak, Michael G A1 - Gottdiener, John A1 - Wu, Chenkai A1 - Gardin, Julius M A1 - Bansal, Nisha A1 - Odden, Michelle C AB -

BACKGROUND: Many traditional cardiovascular risk factors do not predict survival to very old age. Studies have shown associations of estimated glomerular filtration rate (eGFR) and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) with cardiovascular disease and mortality in older populations. This study aimed to evaluate the associations of the level and change in eGFR and NT-pro-BNP with longevity to age 90 years.

METHODS: The population included participants (n=3,645) in the Cardiovascular Health Study, aged between 67-75 at baseline. The main exposures were eGFR, calculated with the Berlin Initiative Study equation (BIS2), and NT-pro-BNP, and the main outcome was survival to age 90. Mixed models were used to estimate level and change of the main exposures.

RESULTS: There was an association between baseline level and change of both eGFR and NT-pro-BNP and survival to 90, and this association persisted after adjustment for covariates. Each 10 ml/min per 1.73 m2 higher eGFR level was associated with an adjusted odds ratio (OR) of 1.23 (95% CI: 1.13, 1.34) of survival to 90, and a 0.5 ml/min/ 1.73 m2 slower decline in eGFR was associated with an OR of 1.51 (95% CI: 1.31, 1.74). A 2-fold higher level of NT-pro-BNP level had an adjusted OR of 0.67 (95% CI: 0.61, 0.73), and a 1.05-fold increase per year in NT-pro-BNP had an OR of 0.53 (95% CI: 0.43, 0.65) for survival to age 90.

CONCLUSION: eGFR and NT-pro-BNP appear to be important risk factors for longevity to age 90.

ER - TY - JOUR T1 - Urine creatinine concentration and clinical outcomes in older adults: The Cardiovascular Health Study. JF - J Am Geriatr Soc Y1 - 2021 A1 - Barzilay, Joshua I A1 - Bůzková, Petra A1 - Shlipak, Michael G A1 - Lyles, Mary F A1 - Bansal, Nisha A1 - Garimella, Pranav S A1 - Ix, Joachim H A1 - Kizer, Jorge R A1 - Strotmeyer, Elsa S A1 - Djoussé, Luc A1 - Biggs, Mary L A1 - Siscovick, David A1 - Mukamal, Kenneth J AB -

PURPOSE: Loss of muscle mass and strength are associated with long-term adverse health outcomes in older adults. Urine creatinine concentrations (Ucr; mg/dl) are a measure of muscle tissue mass and turnover. This study assessed the associations of a spot Ucr level with muscle mass and with risk of hospitalization, mortality, and diabetes mellitus in older adults.

METHODS: We examined 3424 participants from the Cardiovascular Health Study who provided spot urine samples in 1996-1997 and who were followed through June 2015. All participants underwent baseline measurement of grip strength. In a sub-cohort, 1331 participants underwent dual energy X-ray absorptiometry (DEXA) scans, from which lean muscle mass was derived. Participants were followed for a median of 10 years for hospitalizations and mortality, and 9 years for diabetes mellitus.

RESULTS: In linear regression analysis, a one standard deviation higher Ucr concentration (64.6 mg/dl) was associated with greater grip strength (kg force) β = 0.44 [0.16, 0.72]; p = 0.002) and higher lean muscle mass (kg) (β = 0.43 [0.08, 0.78]; p = 0.02). In Cox regression analyses, each standard deviation greater Ucr concentration was associated with lower rates of hospitalizations (0.94 [95% confidence interval, 0.90, 0.98]; p < 0.001) and lower mortality risk (0.92 [0.88, 0.97]; p < 0.001), while a one standard deviation increase in muscle mass derived from DEXA had no such significant association. Ucr levels were not associated with incident diabetes mellitus risk (0.97 [0.85, 1.11]; p = 0.65).

CONCLUSION: A higher spot Ucr concentration was favorably associated with muscle mass and strength and with health outcomes in older community-living adults. The ease of obtaining a spot Ucr makes it an attractive analyte to use for gauging the health of older adults.

ER - TY - JOUR T1 - Cardiac Mechanics and Kidney Function Decline in the Cardiovascular Health Study. JF - Kidney360 Y1 - 2023 A1 - Mehta, Rupal A1 - Bůzková, Petra A1 - Patel, Harnish A1 - Cheng, Jeanette A1 - Kizer, Jorge R A1 - Gottdiener, John S A1 - Psaty, Bruce A1 - Khan, Sadiya S A1 - Ix, Joachim H A1 - Isakova, Tamara A1 - Shlipak, Michael G A1 - Bansal, Nisha A1 - Shah, Sanjiv J AB -

BACKGROUND: Clinical heart failure frequently coexists with chronic kidney disease (CKD) and may precipitate kidney function decline. However, whether earlier-stage myocardial dysfunction assessable by speckle tracking echocardiography is a contributor to kidney function decline remains unknown.

METHODS: We studied 2135 Cardiovascular Health Study (CHS) participants who were free of clinical heart failure and had Year 2-baseline 2D speckle tracking echocardiography and two measurements of estimated glomerular filtration rate (eGFR) (Year 2 and Year 9). "Archival" speckle tracking of digitized echocardiogram videotapes was utilized to measure left ventricular longitudinal strain (LVLS), LV early diastolic strain rate (EDSR), left atrial reservoir strain (LARS), right ventricular free wall strain (RVFWS), and mitral annular velocity (e'). Multivariable Poisson regression models that adjusted for demographics and cardiovascular risk factors were used to investigate the independent associations of cardiac mechanics indices and decline in kidney function defined as a 30% decline in eGFR over 7 years.

RESULTS: In risk factor (RF) models LVLS, EDSR, RVFWS, and e' were all significantly associated with the prevalence of kidney disease. After multivariable adjustment, left atrial dysfunction (RR 1.18 [95% CI 1.01, 1.38] per SD lower LARS] and left ventricular diastolic dysfunction (RR 1.21 [95% CI 1.04, 1.41] per SD lower EDSR) were each significantly associated with 30% decline in eGFR.

CONCLUSIONS: Subclinical myocardial dysfunction suggesting abnormal diastolic function detected by 2D speckle-tracking echocardiography was independently associated with decline in kidney function over time. Further studies are needed to understand the mechanisms of these associations and to test whether interventions that may improve subclinical myocardial dysfunction can prevent decline of kidney function.

ER - TY - JOUR T1 - Evaluation of plasma sphingolipids as mediators of the relationship between kidney disease and cardiovascular events. JF - EBioMedicine Y1 - 2023 A1 - Lidgard, Benjamin A1 - Bansal, Nisha A1 - Zelnick, Leila R A1 - Hoofnagle, Andrew N A1 - Fretts, Amanda M A1 - Longstreth, William T A1 - Shlipak, Michael G A1 - Siscovick, David S A1 - Umans, Jason G A1 - Lemaitre, Rozenn N AB -

BACKGROUND: Sphingolipids are a family of circulating lipids with regulatory and signaling roles that are strongly associated with both eGFR and cardiovascular disease. Patients with chronic kidney disease (CKD) are at high risk for cardiovascular events, and have different plasma concentrations of certain plasma sphingolipids compared to patients with normal kidney function. We hypothesize that circulating sphingolipids partially mediate the associations between eGFR and cardiovascular events.

METHODS: We measured the circulating concentrations of 8 sphingolipids, including 4 ceramides and 4 sphingomyelins with the fatty acids 16:0, 20:0, 22:0, and 24:0, in plasma from 3,463 participants in a population-based cohort (Cardiovascular Health Study) without prevalent cardiovascular disease. We tested the adjusted mediation effects by these sphingolipids of the associations between eGFR and incident cardiovascular disease via quasi-Bayesian Monte Carlo method with 2,000 simulations, using a Bonferroni correction for significance.

FINDINGS: The mean (±SD) eGFR was 70 (±16) mL/min/1.73 m; 62% of participants were women. Lower eGFR was associated with higher plasma ceramide-16:0 and sphingomyelin-16:0, and lower ceramides and sphingomyelins-20:0 and -22:0. Lower eGFR was associated with risk of incident heart failure and ischemic stroke, but not myocardial infarction. Five of eight sphingolipids partially mediated the association between eGFR and heart failure. The sphingolipids associated with the greatest proportion mediated were ceramide-16:0 (proportion mediated 13%, 95% CI 8-22%) and sphingomyelin-16:0 (proportion mediated 10%, 95% CI 5-17%). No sphingolipids mediated the association between eGFR and ischemic stroke.

INTERPRETATION: Plasma sphingolipids partially mediated the association between lower eGFR and incident heart failure. Altered sphingolipids metabolism may be a novel mechanism for heart failure in patients with CKD.

FUNDING: This study was supported by T32 DK007467 and a KidneyCure Ben J. Lipps Research Fellowship (Dr. Lidgard). Sphingolipid measurements were supported by R01 HL128575 (Dr. Lemaitre) and R01 HL111375 (Dr. Hoofnagle) from the National Heart, Lung, and Blood Institute (NHLBI).

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