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1.  Kidney Function and Mortality in Octogenarians: Cardiovascular Health Study All Stars 
To examine the association between kidney function and all-cause mortality in octogenarians.
Retrospective analysis of prospectively collected data.
Serum creatinine and cystatin C were measured in 1,053 Cardiovascular Health Study (CHS) All Stars participants.
Estimated glomerular filtration rate (eGFR) was determined using the Chronic Kidney Disease Epidemiology Collaboration creatinine (eGFRCR) and cystatin C one-variable (eGFRCYS) equations. The association between quintiles of kidney function and all-cause mortality was analyzed using unadjusted and adjusted Cox proportional hazards models.
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 eGFRCR and all-cause mortality was U-shaped. In comparison with the reference quintile (64–75 mL/min per 1.73 m2), the highest (≥75 mL/min per 1.73 m2) and lowest (≤43 mL/min per 1.73 m2) quintiles of eGFRCR 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 eGFRCYS and all-cause mortality was linear in those with eGFRCYS of less than 60 mL/min per 1.73 m2, and in the multivariate analyses, the lowest quintile of eGFRCYS (<52 mL/min per 1.73 m2) 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 m2).
Moderate reduction in kidney function is a risk factor for all-cause mortality in octogenarians. The association between eGFRCR and all-cause mortality differed from that observed with eGFRCYS; the relationship was U-shaped for eGFRCR, whereas the risk was primarily present in the lowest quintile for eGFRCYS. J Am Geriatr Soc 2012.
PMCID: PMC3902776  PMID: 22724391
octogenarians; kidney function; mortality
2.  Blood Pressure Components and Decline in Kidney Function in Community-Living Older Adults: The Cardiovascular Health Study 
American Journal of Hypertension  2013;26(8):1037-1044.
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.
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.
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.
Our findings suggest that elevated BP, particularly SBP, contributes to declining kidney function in older adults.
PMCID: PMC3816322  PMID: 23709568
blood pressure; cystatin C; diastolic blood pressure; elderly; hypertension; kidney function; systolic blood pressure.
3.  Risk Factors for ESRD in Individuals With Preserved Estimated GFR With and Without Albuminuria: Results From the Kidney Early Evaluation Program (KEEP) 
Given the increasing costs and poor outcomes of end-stage renal disease (ESRD), we sought to identify risk factors for ESRD in people with preserved estimated glomerular filtration rate (eGFR), with or without albuminuria, who were at high risk of ESRD.
This cohort study included participants in the National Kidney Foundation’s Kidney Early Evaluation Program (KEEP) with eGFR ≥60 mL/min/1.73 m2 at baseline stratified by the presence or absence of albuminuria. The Chronic Kidney Disease Epidemiology Collaboration equation was used to calculate eGFR. Urine was tested for albuminuria by semiquantitative dipstick. The outcome was the development of treated chronic kidney failure, defined as initiation of maintenance dialysis therapy or kidney transplantation, determined by linkage to the US Renal Data System. We used a Cox model with the Fine-Gray method to assess risk factors for treated chronic kidney failure while accounting for the competing risk of death.
During a median follow-up of 4.8 years, 126 of 13,923 participants with albuminuria (16/10,000 patient-years) and 56 of 109,135 participants without albuminuria (1.1/10,000 patient-years) developed treated chronic kidney failure. Diabetes was a strong risk factor for developing treated chronic kidney failure in participants with and without albuminuria (adjusted HRs of 9.3 [95% CI, 5.7–15.3] and 7.8 [95% CI, 4.1–14.8], respectively). Black race, lower eGFR, and higher systolic blood pressure also were associated with higher adjusted risks of developing treated chronic kidney failure.
In a diverse high-risk cohort of KEEP participants with preserved eGFR, we showed that diabetes, higher systolic blood pressure, lower eGFR, and black race were risk factors for developing treated chronic kidney failure irrespective of albuminuria status, although the absolute risk of kidney failure in participants without albuminuria was very low. Our findings support testing for kidney disease in high-risk populations, which often have otherwise unrecognized kidney disease.
PMCID: PMC4117734  PMID: 23507268
Albuminuria; blood pressure; chronic kidney disease; diabetes; dialysis risk factors; end-stage renal disease; public health
4.  Correlates of insulin resistance in older individuals with and without kidney disease 
Nephrology Dialysis Transplantation  2011;26(9):2814-2819.
Background. Chronic kidney disease (CKD) is associated with insulin resistance (IR). Prior studies have found that in individuals with CKD, leptin is associated with fat mass but resistin is not and the associations with adiponectin are conflicting. This suggests that the mechanism and factors associated with IR in CKD may differ.
Methods. Of the 2418 individuals without reported diabetes at baseline, participating in the Health, Aging and Body Composition study, a study in older individuals aged 70–79 years, 15.6% had CKD defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 based on cystatin C. IR was defined as the upper quartile of the homeostasis model assessment. The association of visceral and subcutaneous abdominal fat, percent body fat, muscle fat, lipids, inflammatory markers and adiponectin were tested with logistic regression. Interactions were checked to assess whether the factors associated with IR were different in those with and without CKD.
Results. Individuals with IR had a lower eGFR (80.7 ± 20.9 versus 75.6 ± 19.6, P < 0.001). After multivariable adjustment, eGFR (odds ratio per 10 mL/min/1.73m2 0.92, 95% confidence interval 0.87–0.98) and CKD (1.41, 1.04–1.92) remained independently associated with IR. In individuals with and without CKD, the significant predictors of IR were male sex, black race, higher visceral fat, abdominal subcutaneous fat and triglycerides. In individuals without CKD, IR was associated with lower high-density lipoprotein and current nonsmoking status in multivariate analysis. In contrast, among individuals with CKD, interleukin-6 (IL-6) was independently associated with IR. There was a significant interaction of eGFR with race and IL-6 with a trend for adionectin but no significant interactions with CKD (P > 0.1). In the fully adjusted model, there was a trend for an interaction with adiponectin for eGFR (P = 0.08) and significant for CKD (P = 0.04 ), where adiponectin was associated with IR in those without CKD but not in those with CKD.
Conclusions. In mainly Stage 3 CKD, kidney function is associated with IR; except for adiponectin, the correlates of IR are similar in those with and without CKD.
PMCID: PMC3203409  PMID: 21248294
chronic kidney disease; cystatin C; insulin resistance; subcutaneous fat
5.  Hypertension and Low HDL-Cholesterol were Associated with Reduced Kidney Function Across the Age Spectrum: A Collaborative Study 
Annals of epidemiology  2013;23(3):106-111.
To determine if the associations among established risk factors and reduced kidney function vary by age.
We pooled cross-sectional data from 14,788 non-diabetics aged 40–100 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.
Hypertension and low 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% CI 0.1, 4.4), 5.1 (4.1, 6.1), and 6.9 (3.0, 10.4) mL/min/1.73 m2 lower eGFR in participants 40–59, 60–79, and 80+ years, respectively (p-value for interaction <0.001). The association of low HDL-cholesterol with reduced kidney function was also greater in the older age groups: 4.9 (3.5, 6.3), 7.1 (CI 6.0, 8.3), 8.9 (CI 5.4, 11.9) mL/min/1.73 m2 (p-value for interaction <0.001). 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.
Hypertension, obesity, smoking, and low HDL-cholesterol are modestly associated with reduced kidney function in non-diabetics. The associations of hypertension and HDL-cholesterol with reduced kidney function appear stronger in older adults.
PMCID: PMC3570601  PMID: 23313266
Chronic kidney insufficiency; aged; hypertension; cholesterol; obesity; smoking
6.  Endothelial Cell Autoantibodies in Predicting Declining Renal Function, End-Stage Renal Disease, or Death in Adult Type 2 Diabetic Nephropathy 
Albuminuria is a strong predictor of diabetic nephropathy chronic kidney disease outcomes. Yet, therapeutic albuminuria-lowering has not consistently translated into a reduction in clinical events suggesting the involvement of additional pathogenic factors. Our hypothesis is that anti-endothelial cell autoantibodies play a role in development and progression in diabetic nephropathy. We determined anti-endothelial cell antibody (AECA) bioactivity in protein A-elutes of baseline plasma in 305 participants in the VA NEPHRON-D study, a randomized trial of angiotensin receptor blocker (ARB) or dual ARB plus angiotensin-converting enzyme inhibitor therapy in type 2 diabetes with proteinuric nephropathy. Thirty-eight percent (117/305) of participants had significantly reduced endothelial cell survival ( ≤80%) in the IgG fraction of plasma. A VA NEPHRON-D primary endpoint [end-stage renal disease (ESRD), significant reduction in estimated glomerular filtration rate, or death] was experienced by 58 individuals. In adjusted Cox regression analysis, there was a significant interaction effect of baseline anti-endothelial cell-mediated cell survival and albuminuria on the hazard rate (HR) for primary composite endpoint (P = 0.017). Participants lacking strongly inhibitory antibodies with albuminuria ≥1 g/g creatinine had a significantly increased primary event hazard ratio, 3.41 – 95% confidence intervals (CI 1.84–6.33; P < 0.001) compared to those lacking strongly inhibitory antibodies with lower baseline albuminuria ( <1 g/g creatinine). These results suggest that anti-endothelial cell antibodies interact significantly with albuminuria in predicting the composite endpoint of death, ESRD, or substantial decline in renal function in older, adult type 2 diabetic nephropathy.
PMCID: PMC4127944  PMID: 25157242
endothelium; autoantibodies; type 2 diabetes; nephropathy; chronic kidney disease
7.  Hemoglobin Decline, Function and Mortality in the Elderly: The Cardiovascular Health Study 
American journal of hematology  2012;88(1):10.1002/ajh.23336.
While anemia is associated with poor functional and mortality outcomes in the elderly, the impact of hemoglobin decline is less studied.
We evaluated the determinants and consequences of hemoglobin decline in 3.758 non-anemic participants from the Cardiovascular Health Study, a prospective cohort of community-dwelling elderly ≥65 years old at baseline and followed for up to 16 years. Hemoglobin was measured at baseline and 3 years later and anemia defined by World Health Organization (WHO) criteria. We modeled hemoglobin decline in two ways: 1) per each 1g/dL decrease in hemoglobin and 2) development of anemia by the WHO criteria.
Among participants without baseline anemia, hemoglobin decreased by 0.4g/dL and 9% developed anemia over 3 years. Baseline increasing age, female sex, diabetes, and kidney disease predicted hemoglobin decline over 3 years. Baseline increasing age, being African-American, and kidney disease predicted anemia development over 3 years. Hemoglobin decline was associated with subsequent worse cognitive function in men and anemia development with subsequent worse cognitive function in women. Both anemia development (HR 1.39, 95% CI 1.15, 1.69) and hemoglobin decline (HR 1.11, 95% CI 1.04, 1.18 per 1g/dL decrease) predicted subsequent mortality in men and women.
Hemoglobin decreases identified a large group of elderly individuals at risk for subsequent adverse outcomes who would not be identified using the WHO anemia criteria. These data may allow clinicians to identify at-risk elderly individuals for early intervention to improve the quality and quantity of life.
PMCID: PMC3860593  PMID: 23044913
Anemia; Hemoglobin; Elderly; Mortality; Function; Epidemiology
8.  Change in Cardiovascular Risk Factors with Progression of Kidney Disease 
American Journal of Nephrology  2008;29(4):334-341.
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.
Individuals with an increase in serum creatinine ≥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.
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.
Cardiovascular risk factors and kidney function may change concurrently. This could lead to an increased risk of cardiovascular disease as kidney function worsens.
PMCID: PMC2786019  PMID: 18948687
Cardiovascular risk factors; Chronic kidney disease; Disease progression; Inflammation; Lipids
9.  Insulin Resistance, Cystatin C, and Mortality Among Older Adults 
Diabetes Care  2012;35(6):1355-1360.
Insulin resistance is a risk factor for cardiovascular and noncardiovascular diseases. Impaired kidney function is linked with insulin resistance and may affect relationships of insulin resistance with health outcomes.
We performed a cohort study of 3,138 Cardiovascular Health Study participants (age ≥65 years) without diabetes. Insulin sensitivity index (ISI) was calculated from fasting and 2-h postload insulin and glucose concentrations. Associations of ISI and fasting insulin concentration with all-cause mortality were tested using Cox proportional hazards models, adjusting for demographic variables, prevalent cardiovascular disease, lifestyle variables, waist circumference, and LDL cholesterol. Subsequent models were additionally adjusted for or stratified by glomerular filtration rate estimated using serum cystatin C (eGFR).
A total of 1,810 participants died during the 14.7-year median follow-up. Compared with the highest quartile of ISI, the lowest quartile (most insulin resistant) was associated with 21% (95% CI 6–41) and 11% (−3 to 29) higher risks of death without and with adjustment for eGFR, respectively. Compared with the lowest quartile of fasting insulin concentration, the highest quartile was associated with 22% (4–43) and 4% (−12 to 22) higher risks of death without and with adjustment for eGFR, respectively. Similar attenuation by eGFR was observed when blood pressure, triglycerides, HDL cholesterol, and C-reactive protein were included in models.
Insulin resistance measured as ISI or fasting insulin concentration is associated with increased risk of death among older adults, adjusting for conventional confounding characteristics. Impaired kidney function may mediate or confound this relationship.
PMCID: PMC3357240  PMID: 22432118
10.  Leukocyte Telomere Length Is Associated With Noninvasively Measured Age-Related Disease: The Cardiovascular Health Study 
Most studies of leukocyte telomere length (LTL) focus on diagnosed disease in one system. A more encompassing depiction of health is disease burden, defined here as the sum of noninvasively measured markers of structure or function in different organ systems. We determined if (a) shorter LTL is associated with greater age-related disease burden and (b) shorter LTL is less strongly associated with disease in individual systems or diagnosed chronic conditions (cardiovascular disease, stroke, pulmonary disease, diabetes, kidney disease, arthritis, or depression).
LTL was measured by Southern blots of terminal restriction fragment length. Age-related disease was measured noninvasively and included carotid intima–media thickness, lung vital capacity, white matter grade, cystatin-C, and fasting glucose; each graded 0 (best tertile), 1 (middle tertile), or 2 (worst tertile) and summed (0 to 10) to estimate disease burden. Of 419 participants randomly selected for LTL measurement, 236 had disease burden assessed (mean [SD] age 74.2 [4.9] years, 42.4% male, 86.8% white, and 13.2% black).
Mean (SD) LTL was 6,312 (615) bp, and disease score was 4.7 (2.1) points. An SD higher disease score (β [SE] = −132 [47] bp, p < .01), age (β [SE] = −107 [46], p = .02) or carotid thickness (β [SE] = −95 [40] bp, p = .02) was associated with shorter LTL, but diagnosed conditions or number of conditions were not associated with LTL. Disease score attenuated the effect of age on LTL by 35%.
LTL was associated with a characterization of age-related disease burden across multiple physiologic systems, which was comparable to, but independent of, its association with age.
PMCID: PMC3309872  PMID: 21934123
Leukocyte telomere length; Disease burden; Noninvasive measurements; Aging
11.  Perceived Discrimination Predicts Longer Time to be Accepted for Kidney Transplant 
Transplantation  2012;93(4):423-429.
Although end-stage kidney disease (ESKD) in African Americans (AAs) is four times greater than in Whites, AAs are less than half as likely to undergo kidney transplantation (KT). This racial disparity has been found even after controlling for clinical factors such as co-morbid conditions, dialysis vintage and type, and availability of potential living donors. Therefore, studying non-medical factors is critical to understanding disparities in KT.
Design, Setting, and Participants
We conducted a longitudinal cohort study with 127 AA and White patients with ESKD undergoing evaluation for KT (12/06 – 7/07) to determine whether, after controlling for medical factors, differences in time to acceptance for transplant is explained by patients’ cultural factors (e.g., perceived racism and discrimination, medical mistrust, religious objections to living donor KT), psychosocial characteristics (e.g., social support, anxiety, depression), or transplant knowledge. Participants completed 2 telephone interviews (shortly after initiation of transplant evaluation and after being accepted or found ineligible for transplant).
Results indicated that AA patients reported higher levels of the cultural factors than did Whites. We found no differences in co-morbidity or availability of potential living donors. AAs took significantly longer to get accepted for transplant than did Whites (HR=1.49, p=0.005). After adjustment for demographic, psychosocial, and cultural factors, the association of race with longer time for listing was no longer significant.
We suggest that interventions to address racial disparities in KT incorporate key non-medical risk factors in patients.
PMCID: PMC3275654  PMID: 22228417
kidney transplantation; disparities; discrimination
12.  Aging and antihypertensive medication-related complications in the chronic kidney disease patient 
Purpose of review
We have reviewed the recent literature to describe the potential medication errors and adverse drug events (ADEs) associated with antihypertensives among older adults with chronic kidney disease (CKD).
Recent findings
Overall, few studies have been published describing ADEs in older adults with CKD. Several examined hyperkalemia associated with angiotensin-converting enzyme (ACE)-inhibitor/angiotensin II receptor blocker (ARB), diuretic (potassium-sparing), and β-blocker use. Additional studies described acute kidney injury (AKI) most commonly with ACE-inhibitor/ARB therapy. Finally, orthostatic hypotension was evaluated in those taking ACE-inhibitor/ARB, β-blocker, or calcium-channel blocker therapy. In the absence of robust literature examining these events in this understudied population, one must consider age-related antihypertensive pharmacokinetic/pharmacodynamic profiles concomitantly with the patient’s comorbidities and other medications in order to minimize the risk for potential medication errors, drug–drug interactions, and ADEs.
Some of the most common ADEs associated with antihypertensive use in older adults with CKD include hyperkalemia, AKI, and orthostatic hypotension. Diligent monitoring of laboratory data, vital signs, and potential drug–drug interactions may mitigate serious ADEs caused by antihypertensives in this high-risk patient population.
PMCID: PMC3531992  PMID: 21670671
adverse drug events; aging; antihypertensives; chronic kidney disease; older adults
13.  Vitamin D, Parathyroid Hormone and Sudden Cardiac Death: Results from the Cardiovascular Health Study 
Hypertension  2011;58(6):1021-1028.
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 2,312 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 10,000 for 25-OHD ≥ 20 ng/ml and 4 events per 10,000 for 25-OHD < 20 ng/ml. Similarly, SCD incidence was greater among subjects who had higher PTH concentrations: 2 events per 10,000 for PTH ≤ 65 pg/ml and 4 events per 10,000 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 more than 2-fold risk of SCD after adjustment (hazard ratio 2.19, 95% confidence interval 1.17, 4.10, p=0.017) compared to 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.
PMCID: PMC3337033  PMID: 22068871
Sudden cardiac death; Vitamin D; Parathyroid hormone; Elderly; Risk Factors
14.  Potential Explanatory Factors for Higher Incident Hip Fracture Risk in Older Diabetic Adults 
Type 2 diabetes is associated with higher fracture risk. Diabetes-related conditions may account for this risk. Cardiovascular Health Study participants (N = 5641; 42.0% men; 15.5% black; 72.8±5.6 years) were followed 10.9 ± 4.6 years. Diabetes was defined as hypoglycemic medication use or fasting glucose (FG) ≥126 mg/dL. Peripheral artery disease (PAD) was defined as ankle-arm index <0.9. Incident hip fractures were from medical records. Crude hip fracture rates (/1000 person-years) were higher for diabetic vs. non-diabetic participants with BMI <25 (13.6, 95% CI: 8.9–20.2 versus 11.4, 95% CI: 10.1–12.9) and BMI ≥25 to <30 (8.3, 95% CI: 5.7–11.9 versus 6.6, 95% CI: 5.6–7.7), but similar for BMI ≥30. Adjusting for BMI, sex, race, and age, diabetes was related to fractures (HR = 1.34; 95% CI: 1.01–1.78). PAD (HR = 1.25 (95% CI: 0.92–1.57)) and longer walk time (HR = 1.07 (95% CI: 1.04–1.10)) modified the fracture risk in diabetes (HR = 1.17 (95% CI: 0.87–1.57)). Diabetes was associated with higher hip fracture risk after adjusting for BMI though this association was modified by diabetes-related conditions.
PMCID: PMC3152969  PMID: 21837239
15.  Markers of Mineral Metabolism Are Not Associated With Aortic Pulse Wave Velocity in Community-Living Elderly Persons: The Health Aging and Body Composition Study 
American journal of hypertension  2011;24(7):755-761.
Disorders in mineral metabolism are associated with risk for cardiovascular disease (CVD) events in patients with kidney disease as well as in the general population. This risk is thought to be mediated, in part, through the mechanism of stiffening of the arteries.
The objective of this study was to evaluate the relationships between serum calcium, phosphorus, intact parathyroid hormone (iPTH), and 25-hydroxyvitamin D levels and arterial pulse wave velocity (aPWV) among 2,229 community-dwelling elderly persons participating in the Health Aging and Body Composition (Health ABC) study.
The mean age of the participants was 72 years; 52% were woman, 39% were black, and 17% had chronic kidney disease (CKD) (estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2). In parallel unadjusted analyses, the following associations were observed: 2.86% greater aPWV per 12 ng/ml (s.d.) lower 25-hydroxyvitamin D (95% confidence interval −4.38%, −1.31%), 3.04% greater aPWV per 28 pg/ml (s.d.) higher iPTH (95% confidence interval 1.42–4.68%), and 2.37% lower aPWV per 0.5 mg/dl (s.d.) higher phosphorus (95% confidence interval −3.90% to − 0.81%). Except for phosphorus, these associations were attenuated and rendered no longer statistically significant after adjustment for demographic risk factors, clinical site, season, medications and other CVD risk factors. The results were similar in men and women and were not dependent on the presence of CKD.
Among well-functioning community-dwelling elderly persons, only serum phosphorus was associated with aPWV; and this association was in the opposite direction of the one hypothesized. Factors other than vascular stiffening may mediate the relationship between disordered mineral metabolism and CVD events in community-living elders.
PMCID: PMC3117915  PMID: 21436791
arterial stiffness; blood pressure; cardiovascular disease; hypertension; kidney disease; mineral metabolism; PWV
16.  Association between Baseline Kidney Function and Change in CRP: An Analysis of the Cardiovascular Health Study 
Nephron. Clinical Practice  2010;115(2):c114-c121.
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.
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.
The mean (SD) age of the cohort was 72 (5.2) years; mean (SD) eGFRcys was 78.9 (18.4) ml/min/1.73 m2. 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).
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.
PMCID: PMC2892648  PMID: 20413990
Inflammation; Cystatin C; Kidney function; Epidemiology
17.  Albuminuria, impaired kidney function and cardiovascular outcomes or mortality in the elderly 
Nephrology Dialysis Transplantation  2009;25(5):1560-1567.
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 m2); preclinical kidney disease (cystatin C level > 1.0 mg/l but eGFR > 60 mL/min/1.73 m2); and chronic kidney disease (CKD) (eGFR < 60 mL/min/1.73 m2). 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.
PMCID: PMC3307251  PMID: 20008829
albuminuria; aging; cardiovascular diseases; kidney function; mortality
18.  Cystatin C and Sudden Cardiac Death Risk in the Elderly 
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. 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 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: [HR = 2.72, 95% CI (1.44–5.16) in tertile 2 and HR = 2.67, 95% CI (1.33–5.35) 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.
Impaired kidney function, as measured by cystatin C, has an independent association with SCD risk among elderly persons without clinical cardiovascular disease.
PMCID: PMC2871673  PMID: 20233980
Cystatin C; kidney; sudden cardiac death; epidemiology
19.  Cystatin C and Carotid Intima-Media Thickness in Asymptomatic Adults: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Persons with early kidney disease have an increased risk of cardiovascular events and mortality, but the importance of accelerated atherosclerosis in promoting these outcomes is unclear. We therefore explored whether serum cystatin C level is associated with carotid intima-media thickness (IMT) in ambulatory adults without clinical heart disease.
Study Design
Cross-sectional study.
Setting & Participants
We evaluated 6,557 ethnically diverse persons free of clinical cardiovascular disease aged 45 to 84 years at the baseline visit of the Multi-Ethnic Study of Atherosclerosis.
Kidney function was estimated by using 2 methods: serum cystatin C level and estimated glomerular filtration rate, based on creatinine and cystatin C levels.
Outcomes & Measurements
Study outcomes were internal and common carotid IMT, measured by using high-resolution B-mode ultrasound. Multivariate linear and logistic regressions were used to evaluate the independent association of kidney function with carotid IMT.
In unadjusted linear analysis, each SD (0.23 mg/L) greater cystatin C level was associated with 0.091-mm greater internal carotid IMT (P < 0.001), but this association was diminished by 70% after adjustment for age, sex, and race/ethnicity (0.027 mm; P < 0.001) and was no longer significant after adjustment for cardiovascular risk factors (0.005 mm; P = 0.5). Similarly, the strong unadjusted associations of cystatin C level with common carotid IMT disappeared after adjustment. Chronic kidney disease, defined by using either creatinine level or cystatin C–based estimated glomerular filtration rate less than 60 mL/min/1.73 m2, had no independent association with internal and common carotid IMT.
There were few participants with severe kidney disease.
Cystatin C level had no independent association with carotid IMT in a population free of clinical heart disease. This observation suggests that accelerated atherosclerosis is unlikely to be the primary mechanism explaining the independent association of cystatin C level with cardiovascular risk.
PMCID: PMC3046734  PMID: 18823684
Cystatin C; intima-media thickness (IMT); atherosclerosis; cardiovascular diseases; kidney
20.  Differences in Kidney Function and Incident Hypertension: The Multi-Ethnic Study of Atherosclerosis 
Annals of internal medicine  2008;148(7):501-508.
Kidney disease and hypertension commonly coexist, yet the direction of their association is still debated.
To evaluate whether early kidney dysfunction, measured by serum cystatin C levels and urinary albumin excretion, predates hypertension in adults without clinically recognized kidney or cardiovascular disease.
Observational cohort study using data from 2000 to 2005.
The MESA (Multi-Ethnic Study of Atherosclerosis), a community-based study of subclinical cardiovascular disease in adults age 45 to 84 years.
2767 MESA participants without prevalent hypertension, cardiovascular disease, or clinically recognized kidney disease (an estimated glomerular filtration rate <60 mL/min per 1.73 m2 or microalbuminuria).
Cystatin C was measured by using a nephelometer, and urinary albumin and creatinine were measured from a spot morning collection. The primary outcome was incident hypertension, defined as systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, or use of an antihypertensive medication.
During a median follow-up of 3.1 years, 19.7% of the cohort (545 participants) developed hypertension. After adjustment for established hypertension risk factors, each 15-nmol/L increase in cystatin C was associated with a statistically significant 15% greater incidence of hypertension (P = 0.017). The highest sex-specific quartile of urinary albumin–creatinine ratio was associated with a statistically insignificant 16% greater incidence of hypertension (P = 0.192) compared with the lowest quartile. No statistical evidence suggested a multiplicative interaction.
Unmeasured characteristics may have confounded observed associations of kidney markers with hypertension. Follow-up was relatively short. Hypertension that may have occurred between study visits or hypertension that was not captured by standard cuff measurements may have been missed.
Differences in kidney function, indicated by cystatin C levels, are associated with incident hypertension among individuals without clinical kidney or cardiovascular disease. These population-based findings complement experimental work implicating early kidney damage in the pathogenesis of essential hypertension.
PMCID: PMC3044648  PMID: 18378946
21.  Age and cystatin C in healthy adults: a collaborative study 
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.
PMCID: PMC2904248  PMID: 19749145
ageing; chronic kidney disease; cystatin C; epidemiology
22.  Kidney function and multiple hemostatic markers: cross sectional associations in the multi-ethnic study of atherosclerosis 
BMC Nephrology  2011;12:3.
Defined as estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2, chronic kidney disease (CKD) is strongly and independently associated with cardiovascular and overall mortality. We hypothesized that reduced kidney function would be characterized by abnormalities of hemostasis.
We tested cross-sectional associations between (eGFR) and multiple hemostatic markers among 6751 participants representing a broad spectrum of kidney function in the Multi-Ethnic Study of Atherosclerosis (MESA). Kidney function was measured using cystatin C (eGFRcys) or creatinine, using CKD Epidemiology Collaboration (eGFRcr). Hemostatic markers included soluble thrombomodulin (sTM), soluble tissue factor (sTF), D-Dimer, von Willebrand factor (vWF), factor VIII, plasmin-antiplasmin complex (PAP), tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor-1 (PAI-1), and fibrinogen. Associations were tested using multivariable linear regression with adjustment for demographics and comorbidities.
In comparison to persons with eGFRcys >90 ml/min/1.73 m2, subjects with eGFRcys < 60 ml/min/1.73 m2 had adjusted levels of sTM, sTF, D-Dimer, PAP, Factor VIII, TFPI, vWF and fibrinogen that were respectively 86%, 68%, 44%, 22%, 17%, 15%, 12% and 6% higher. Subjects with eGFRcys 60-90 ml/min/1.73 m2 had adjusted levels that were respectively 16%, 14%, 12%, 6%, 6%, 6%, 11% and 4% higher (p < 0.05 for all). Percent differences were not significantly different when groups were categorized by eGFRcr.
Throughout a broad spectrum of kidney function, lower eGFR was associated with higher levels of hemostatic markers. Dysregulation of hemostasis may be a mechanism by which reduced kidney function promotes higher cardiovascular risk.
PMCID: PMC3037849  PMID: 21269477
23.  Inflammatory biomarkers and decline in kidney function in the elderly: the Cardiovascular Health Study 
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 (eGFRcysC) was estimated, and rapid kidney function decline was defined as an annual loss of eGFRcysC >3 mL/min/1.73 m2. 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.
PMCID: PMC2910326  PMID: 19734138
cystatin C; inflammation; inflammatory biomarkers; kidney
24.  Obesity and Change in Estimated GFR Among Older Adults 
The prevalence of chronic kidney disease is growing most rapidly among older adults, but determinants of impaired kidney function in this population are not well understood. Obesity assessed in mid-life has been associated with chronic kidney disease.
Study design
Cohort study.
Setting & Participants
4,295 participants in the community-based Cardiovascular Health Study, ages >=65 years.
Body mass index, waist circumference, and fat mass measured using bioelectrical impedance.
Change in glomerular filtration rate (GFR) over 7 years of follow-up.
Longitudinal estimates of GFR calculated with the 4-variable Modification of Diet in Renal Disease Study equation.
Estimated GFR declined by an average of 0.4 +/− 3.6 mL/min/1.73m2/year, and rapid GFR loss (> 3 mL/min/1.73m2/year) occurred in 693 participants (16%). Baseline body mass index, waist circumference, and fat mass were each associated with increased risk of rapid GFR loss: odds ratios (95% confidence intervals) 1.19 (1.09, 1.30) per 5 kg/m2, 1.25 (1.16, 1.36) per 12 cm, and 1.14 (1.05, 1.24) per 10 kg, respectively, after adjustment for age, sex, race, and smoking. Magnitude of increased risk was larger for participants with estimated GFR < 60 mL/min/1.73m2 at baseline (p for interaction < 0.05). Associations were substantially attenuated by further adjustment for diabetes, hypertension, and C-reactive protein. Obesity measurements were not associated with change in GFR estimated using serum cystatin C.
Few participants with advanced chronic kidney disease at baseline, no direct GFR measurements.
Obesity may be a modifiable risk factor for the development and progression of kidney disease among older adults.
PMCID: PMC2787647  PMID: 19782454
25.  Cystatin C, Albuminuria, and Mortality Among Older Adults With Diabetes 
Diabetes Care  2009;32(10):1833-1838.
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.
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.
Of 691 participants, 378 died over 10 years of follow-up. Cystatin C–estimated GFR <60 ml/min per 1.73 m2, creatinine-based estimated GFR <60 ml/min per 1.73 m2, and urine ACR ≥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.
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.
PMCID: PMC2752913  PMID: 19587367

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