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1.  Antihypertensive Medication Use and Change in Kidney Function in Elderly Adults: A Marginal Structural Model Analysis 
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.
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.
The mean annual decline in eGFR was 2.41 ± 4.91 mL/min/1.73 m2. 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 m2 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 m2 per year slower decline in eGFR.
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.
PMCID: PMC3204667  PMID: 22049266
aged; kidney function; hypertension; marginal structural model
2.  Measures of Blood Pressure and Cognition in Dialysis Patients 
There are few reports on the relationship of blood pressure with cognitive function in maintenance dialysis patients.
The Cognition and Dialysis Study is an ongoing investigation of cognitive function and its risk factors in 6 Boston area hemodialysis units. In this analysis we evaluated the relationship between different domains of cognitive function with systolic and diastolic blood pressure, pulse pressure, and intradialytic changes in systolic blood pressure, using univariate and multivariable linear regression models adjusted for age, sex, race, education and primary cause of end stage renal disease (ESRD).
Among 314 participants, mean age was 63 years; 47% were female, 22% African American and 48% had diabetes. Mean (SD) of systolic blood pressure, diastolic blood pressure, pulse pressure and intradialytic change in systolic blood pressure were 141 (21), 73 (12), 68 (15) and -10 (24) mm Hg, respectively. In univariate analyses, the performance on cognitive tests primarily assessing executive function and processing speeds was worse among participants with lower diastolic blood pressure and higher pulse pressure. These relationships were not statistically significant, however, in multivariable analyses. There was no association between cognitive function and systolic blood pressure or intradialytic change in systolic blood pressure in either univariate or multivariable analyses.
We found no association between different measures of blood pressure and cognitive function in cross sectional analysis. Longitudinal studies are needed to confirm these results.
PMCID: PMC4076621  PMID: 22716218
Blood pressure; Cognition; Dialysis
3.  The Relationship between Non-Traditional Risk Factors and Outcomes in Individuals with Stage 3-4 CKD 
Chronic kidney disease is associated with an increased risk for cardiovascular disease and mortality. Both traditional and non-traditional cardiovascular disease risk factors may contribute.
Study Design
Settings & Participants
Community-based adult population of the Atherosclerosis Risk in Communities and Cardiovascular Health Studies with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2
Non-traditional cardiovascular disease risk factors including body mass index, diastolic blood pressure, triglycerides, albumin, uric acid, fibrinogen, c-reactive protein, and hemoglobin
Composite of myocardial infarction, stroke and all-cause mortality. Secondary outcomes included individual components of the composite.
Among 1,678 individuals with reduced eGFR (mean 51.1±8.5 mL/min/1.73m2), 891 (53%) reached the composite endpoint during median follow-up of 108 months; 23% had a cardiac event, 45% died and 14% experienced a stroke. Serum albumin levels below 3.9 g/dL [Hazard Ratio (HR)=0.68 (95% confidence interval 0.60,0.77) for every 0.3 g/dL decrease], elevated serum triglycerides [HR=1.07 (1.02,1.12) for every 50 mg/dL increase], C-reactive protein [HR=1.15 (1.07,1.24) per log-unit increase], and fibrinogen [HR=1.12 (1.07,1.18) per 50 mg/dL increase] independently predicted composite events. Both reduced (<14.5 g/dL) and elevated (>14.5 g/dL) hemoglobin level predicted composite events. Serum albumin levels below 3.9 g/dL and elevated serum fibrinogen independently predicted cardiac events. For serum albumin and hemoglobin, the relationship with composite and mortality outcomes was non-linear (p<0.001).
Single assessment of eGFR. No albuminuria data.
Several non-traditional cardiovascular disease risk factors predict adverse outcomes in individuals with stage 3-4 chronic kidney disease. The relationship between risk factors and outcomes is often non-linear.
PMCID: PMC4083633  PMID: 18215699
Chronic kidney disease; cardiovascular disease; risk factors; inflammation; cholesterol
4.  Inflammation and Cardiovascular Events in Individuals with and without Chronic Kidney Disease 
Kidney international  2008;73(12):1406-1412.
Inflammation and chronic kidney disease (CKD) predict cardiovascular events. Little is known about the interaction of inflammation and CKD. We evaluated inflammation markers (fibrinogen, albumin, white blood cell (WBC) count) in individuals with and without CKD to assess: 1) inflammation as a risk factor for adverse events; 2) synergy between inflammation and CKD; and 3) prognostic ability of these markers relative to c-reactive protein (CRP).
Using Atherosclerosis Risk in Communities and Cardiovascular Health Study data, inflammation was defined by 2 of 3 criteria: lowest albumin quartile and highest fibrinogen and race-specific WBC quartiles. CKD was defined as estimated glomerular filtration rate of 0.25-1 mL/sec/1.73m2. In Cox models, inflammation was assessed as a risk factor for a composite of cardiac events, stroke and mortality as well as components of this composite.
Among 20,413 individuals, mean WBC count was 6.2±2.0/L3, albumin 41±3 g/L, and fibrinogen 9.1±1.9 µmol/L. Inflammation was defined in 3,594 subjects and CKD in 1,649. In multivariable analyses, while both inflammation and CKD predicted all outcomes, their interaction was non-significant. In those with CRP measurements (Cardiovascular Health Study only, n=5,597), inflammation and elevated CRP had similar hazard ratios. When focusing only on worst quartile of WBC and albumin, results remained consistent.
CKD and inflammation are associated with an increased risk of adverse events but do not exhibit synergy. The composite of albumin, WBC count and fibrinogen as well as the composite of only albumin and WBC count have a similar association with adverse events as CRP.
PMCID: PMC4083694  PMID: 18401337
5.  Waist to Hip Ratio, Body Mass Index and Subsequent Kidney Disease and Death 
Chronic kidney disease (CKD) and obesity are important public health concerns. We examined the association between anthropomorphic measures and incident CKD and mortality.
Setting and Participants
Individual patient data pooled from the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study
Waist to hip ratio (WHR), body mass index (BMI)
Incident CKD defined as serum creatinine rise of >0.4 mg/dL with baseline creatinine ≤1.4 mg/dL in men and 1.2 mg/dL in women and final creatinine above these levels, and, in separate analyses, as estimated glomerular filtration rate (eGFR) decline ≥15 mL/min/1.73m2 with baseline eGFR ≥60 and final eGFR <60 mL/min/1.73m2.
Multivariable logistic regression to determine the association between waist to hip ratio (WHR), body mass index (BMI) and outcomes. Cox models to evaluate a secondary composite outcome of all-cause mortality and incident CKD.
Among 13,324 individuals, mean WHR was 0.96 in men and 0.89 in women and mean BMI was 27.2 kg/m2 in both men and women. Over 9.3 years, 300 (2.3%) in creatinine-based models and 710 (5.5%) in eGFR-based models developed CKD. In creatinine-based models, each standard deviation increase in WHR was associated with an increased risk of incident CKD [Odds ratio=1.22 (1.05, 1.43)] and the composite outcome [Hazard ratio=1.12 (1.06, 1.18)], while each standard deviation increase in BMI was not associated with CKD [Odds ratio=1.05 (0.93, 1.20)] and appeared protective for the composite outcome [Hazard ratio=0.94 (0.90, 0.99)]. Results of eGFR-based models were similar.
Single measures of creatinine, no albuminuria data.
WHR but not BMI is associated with incident CKD and mortality. Assessment of CKD risk should utilize WHR rather than BMI as an anthropomorphic measure of obesity.
PMCID: PMC4052757  PMID: 18511168
6.  Cardiovascular disease in CKD in 2012 
Nature reviews. Nephrology  2013;9(2):69-70.
During 2012, an observational study confirmed the high risk of cardiovascular disease ascribed to chronic kidney disease (CKD) and again raised the question of whether CKD should be considered a cardiovascular disease risk equivalent. Several other studies evaluated methods to mitigate cardiovascular risk in CKD. Although the results of these studies have advanced the field they have also raised more questions
PMCID: PMC4037697  PMID: 23296300
7.  Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension: a meta-analysis 
Lancet  2012;380(9854):1649-1661.
Hypertension is the most prevalent comorbidity in individuals with chronic kidney disease (CKD). It is unknown, however, whether the association of the CKD measures, estimated glomerular filtration rate (eGFR) and albuminuria, with mortality or end-stage renal disease (ESRD) differs by hypertensive status.
We performed a meta-analysis of 45 cohorts (25 general population, 7 high-risk and 13 CKD cohorts), including 1,127,656 participants (364,344 with hypertension). Adjusted hazard ratios (HRs) for all-cause mortality (84,078 deaths from 40 cohorts) and ESRD (7,587 events from 21 cohorts) by hypertensive status were obtained for each study and pooled using random-effects models.
Low eGFR and high albuminuria were associated with mortality in both non-hypertensive and hypertensive individuals in the general population and high-risk cohorts. Mortality risk was higher in hypertensives as compared to non-hypertensives at preserved eGFR but a steeper relative risk gradient among non-hypertensives than hypertensives at eGFR range 45-75 ml/min/1.73m2 led to similar mortality risk at lower eGFR. With a reference eGFR of 95 mL/min/1.73m2 in each group to explicitly assess interaction, adjusted HR for all-cause mortality at eGFR 45 mL/min/1.73m2 was 1.77 (95% CI, 1.57-1.99) in non-hypertensives versus 1.24 (1.11-1.39) in hypertensives (P for overall interaction =0.0003). Similarly, for albumin-creatinine ratio (ACR) of 300 mg/g (vs. 5 mg/g), HRs were 2.30 (1.98-2.68) in non-hypertensives versus 2.08 (1.84-2.35) in hypertensives (P for overall interaction=0.019). Similar results were observed for cardiovascular mortality. The associations of eGFR and albuminuria with ESRD, however, did not differ by hypertensive status. Results in CKD cohorts were comparable to results in general and high-risk population cohorts.
Low eGFR and elevated albuminuria were more strongly associated with mortality among individuals without hypertension than in those with hypertension, but the associations with ESRD were similar. CKD should be considered at least an equally relevant risk factor for mortality and ESRD in non-hypertensive as it is in hypertensive individuals.
The US National Kidney Foundation (sources include Abbott and Amgen).
PMCID: PMC3993095  PMID: 23013600
8.  Anatomic Brain Disease in Hemodialysis Patients: A Cross-sectional Study 
Although dialysis patients are at high risk for stroke and have a high burden of cognitive impairment, there are few reports on anatomic brain findings in the hemodialysis population. Using brain magnetic resonance imaging (MRI), we compared the prevalence of brain abnormalities in hemodialysis patients to a control population without known kidney disease.
Study Design
Cross-sectional cohort.
Setting & Participants
45 maintenance hemodialysis patients and 67 controls without reported kidney disease, both without prior history of known stroke.
The primary predictor was dialysis status. Covariates included demographics (age, race, sex), vascular risk factors (diabetes and hypertension) and cardiovascular disease (coronary artery disease, congestive heart failure).
Brain MRI features including severity of white matter disease and cerebral atrophy (sulcal prominence and ventricular atrophy), hippocampal size, and small/large vessel infarcts.
Semi-quantitative scale (0-9 for white matter disease and cerebral atrophy, 0-3 for hippocampal size) and infarct prevalence.
The mean age of hemodialysis patients and controls was 55 ± 17 (SD) and 53 ± 13 years, respectively. In comparison with controls, hemodialysis patients had more severe white matter disease (1.6 v 0.7) and cerebral atrophy (sulcal prominence = 2.3 v 0.6; ventricular enlargement = 2.3 v 0.9; hippocampal size = 1.3 v 1.0) with all p-values <0.001. In multivariable analyses, hemodialysis status was independently associated with worse white matter disease and atrophy grades. Hemodialysis patients also had a higher prevalence of small (17.8%) and large (7.8%) vessel infarcts than controls (combined 22% vs 0%, p<0.001).
The dialysis cohort is likely healthier than the overall US hemodialysis population, partly limiting generalizability.
Hemodialysis patients have more white matter disease and cerebral atrophy compared to controls without known kidney disease. Hemodialysis patients also have a high prevalence of unrecognized infarcts.
PMCID: PMC3546146  PMID: 23040011
Hemodialysis; brain abnormalities; cerebral atrophy; white matter disease; magnetic resonance imaging (MRI)
9.  Frequency of and risk factors for poor cognitive performance in hemodialysis patients 
Neurology  2013;80(5):471-480.
There are few detailed data on cognition in patients undergoing dialysis. We evaluated the frequency of and risk factors for poor cognitive performance using detailed neurocognitive testing.
In this cross-sectional cohort study, 314 hemodialysis patients from 6 Boston-area hemodialysis units underwent detailed cognitive assessment. The neuropsychological battery assessed a broad range of functions, with established age-, sex-, and education-matched normative scores. Principal component analysis was used to derive composite scores for memory and executive function domains. Risk factors for each domain were evaluated using linear regression adjusting for age, sex, race, and education status. Analyses were repeated in those with Mini-Mental State Examination (MMSE) score ≥24.
Compared with population norms, patients on dialysis had significantly poorer executive function but not memory performance, a finding that persisted in the subgroup with MMSE score ≥24. In adjusted analyses, vascular risk factors and vascular disease were associated with lower executive function (p < 0.01).
There is a high frequency of poor cognitive performance in hemodialysis patients, primarily affecting executive function. Risk factors for worse executive function include vascular risk factors as well as vascular disease. Normal performance on the MMSE does not preclude impaired cognitive function, because individuals with MMSE score ≥24 also have a high frequency of poor cognitive performance.
PMCID: PMC3590049  PMID: 23303848
10.  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
11.  Apolipoprotein E and kidney function in older adults 
Clinical nephrology  2012;78(3):174-180.
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).
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.
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.
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.
PMCID: PMC3874583  PMID: 22874105
apolipoprotein E; chronic kidney disease; kidney function; elderly
12.  Long-term Assessment of Inflammation and Healthy Aging in Late Life: The Cardiovascular Health Study All Stars 
Associations of inflammation with age-related pathologies are documented; however, it is not understood how changes in inflammation over time impact healthy aging.
We examined associations of long-term change in C-reactive protein (CRP) and interleukin-6 (IL-6) with concurrent onset of physical and cognitive impairment, subsequent cardiovascular disease (CVD), and mortality in 1,051 participants in the Cardiovascular Health Study All Stars Study. Biomarkers were measured in 1996–1997 and 2005–2006.
In 2005–2006, median age was 84.9 years, 63% were women and 17% non-white; 21% had at least a doubling in CRP over time and 23% had at least a doubling in IL-6. Adjusting for demographics, CVD risk factors, and 1996–1997 CRP level, each doubling in CRP change over 9 years was associated with higher risk of physical or cognitive impairment (odds ratio 1.29; 95% confidence interval 1.15, 1.45). Results were similar for IL-6 (1.45; 1.20, 1.76). A doubling in IL-6 change over time, but not CRP, was associated with incident CVD events; hazard ratio (95% confidence interval) 1.34 (1.03, 1.75). Doubling in change in each biomarker was individually associated with mortality (CRP: 1.12 [1.03, 1.22]; IL-6 1.39 [1.16, 1.65]). In models containing both change and 2005–2006 level, only level was associated with CVD events and mortality.
Although increases in inflammation markers over 9 years were associated with higher concurrent risk of functional impairment and subsequent CVD events and mortality, final levels of each biomarker appeared to be more important in determining risk of subsequent events than change over time.
PMCID: PMC3436091  PMID: 22367431
Inflammation; Aging; Physical function; Cognitive function
13.  The Kidney Disease Quality of Life Cognitive Function Subscale and Cognitive Performance in Maintenance Hemodialysis Patients 
Cognitive impairment is common but often undiagnosed in patients with end-stage renal disease, in part reflecting limited validated and easily administered tools to assess cognitive function in dialysis patients. Accordingly, we assessed the utility of the Kidney Disease Quality of Life Cognitive Function (KDQOL-CF) scale in comparison to an extensive neuropsychological battery, building on a prior assessment of this potential cognitive screen.
Study Design
Cross-sectional cohort.
Setting & Participants
Maintenance hemodialysis patients at 6 Boston area dialysis units were administered an extensive neurocognitive battery and the KDQOL-CF at the beginning of a hemodialysis session.
KDQOL-CF score, depression symptom burden, and demographic and clinical characteristics.
Neurocognitive performance classified into executive function and memory domains, determined using principal components analysis.
Univariate and multivariable linear regression models adjusting for age, sex, race, and end-stage renal disease cause were used to evaluate the association between KDQOL-CF score and cognitive performance, and test metrics were determined for a KDQOL-CF cutoff score of 60 or less from a maximum score of 100.
For 168 prevalent hemodialysis patients, KDQOL-CF score was 76 ± 19 and 40 (24%) had scores of 60 or less, consistent with self-identified worse cognitive performance. There was no significant correlation between KDQOL-CF score and either memory (P = 0.2 and P = 0.3) or executive function (P = 0.1 and P = 0.4) in univariate and multivariable models, respectively. There was a strong correlation between higher KDQOL-CF score and fewer depression symptoms (P <0.001). Sensitivity of the KDQOL-CF was poor (range, 0.28–0.36), with modest specificity (range, 0.77–0.81) for identifying worse executive function and memory.
Cross-sectional study, modest population size, and abbreviated gold-standard cognitive battery.
The KDQOL-CF is a poor determinant of neurocognitive performance in hemodialysis patients, with limited sensitivity. To assess cognitive impairment in hemodialysis patients, better screening tests are essential.
PMCID: PMC3547669  PMID: 22425261
Dialysis; dementia; cognitive impairment; screening; depression; quality of life
14.  Obesity, anthropometric measures and chronic kidney disease complications 
American journal of nephrology  2012;36(3):219-227.
Anthropometric measures such as body mass index (BMI) and waist circumference (WC) have differential associations with incident chronic kidney disease (CKD) and mortality. We examined the associations of BMI and WC with various CKD complications.
We conducted a cross-sectional analysis of 2853 adult participants with CKD in the National Health and Nutrition Examination Surveys 1999-2006. The associations of BMI and WC (both as categorical and continuous variables) with CKD complications such as anemia, secondary hyperparathyroidism, hyperphosphatemia, metabolic acidosis, hypoalbuminemia, and hypertension were examined using logistic regression models while adjusting for relevant confounding variables.
When examined as a continuous variable, an increase in BMI by 2 kg/m2 and WC by 5 cm was associated with higher odds of secondary hyperparathyroidism, hypoalbuminemia, and hypertension among those with CKD. CKD participants with a BMI ≥30 kg/m2 have higher odds of hypoalbuminemia and hypertension than CKD participants with BMI <30 kg/m2. CKD participants with a high WC (>102 cm in men and >88 cm in women) have higher odds of hypoalbuminemia and hypertension and lower odds of having anemia than CKD participants with a low WC. CKD participants with BMI <30 kg/m2 and high WC (vs. BMI <30 kg/m2 and low WC) was not associated with CKD complications.
Anthropometric measures such as BMI and WC are associated with secondary hyperparathyroidism, hypoalbuminemia, and hypertension among adults with CKD. Higher WC among those with BMI <30 kg/m2 is not associated with CKD complications.
PMCID: PMC3542766  PMID: 22948230
Obesity; body mass index; waist circumference; chronic kidney disease
15.  Effects of intensive blood pressure lowering on the progression of chronic kidney disease: a systematic review and meta-analysis 
Recent guidelines suggest lowering the target blood pressure for patients with chronic kidney disease, although the strength of evidence for this suggestion has been uncertain. We sought to assess the renal and cardiovascular effects of intensive blood pressure lowering in people with chronic kidney disease.
We performed a systematic review and meta-analysis of all relevant reports published between 1950 and July 2011 identified in a search of MEDLINE, Embase and the Cochrane Library. We included randomized trials that assigned patients with chronic kidney disease to different target blood pressure levels and reported kidney failure or cardiovascular events. Two reviewers independently identified relevant articles and extracted data.
We identified 11 trials providing information on 9287 patients with chronic kidney disease and 1264 kidney failure events (defined as either a composite of doubling of serum creatinine level and 50% decline in glomerular filtration rate, or end-stage kidney disease). Compared with standard regimens, a more intensive blood pressure–lowering strategy reduced the risk of the composite outcome (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.68–0.98) and end-stage kidney disease (HR 0.79, 95% CI 0.67–0.93). Subgroup analysis showed effect modification by baseline proteinuria (p = 0.006) and markers of trial quality. Intensive blood pressure lowering reduced the risk of kidney failure (HR 0.73, 95% CI 0.62–0.86), but not in patients without proteinuria at baseline (HR 1.12, 95% CI 0.67–1.87). There was no clear effect on the risk of cardiovascular events or death.
Intensive blood pressure lowering appears to provide protection against kidney failure events in patients with chronic kidney disease, particularly among those with proteinuria. More data are required to determine the effects of such a strategy among patients without proteinuria.
PMCID: PMC3735743  PMID: 23798459
16.  Serum triglycerides and risk for death in Stage 3 and Stage 4 chronic kidney disease 
Nephrology Dialysis Transplantation  2012;27(8):3228-3234.
An elevated triglyceride level is associated with cardiovascular and all-cause mortality in the general population. The associations between serum triglyceride and all-cause mortality among patients with chronic kidney disease (CKD) are unclear.
Patients with Stage 3 and Stage 4 CKD (estimated glomerular filtration rate 15–59 mL/min/1.73 m2) who had serum triglycerides measured prior to being classified as CKD were included. We examined the associations of serum triglyceride levels with all-cause mortality among 25 641 Stage 3 and Stage 4 CKD patients using Cox proportional hazard models and Kaplan–Meier survival curves.
In the Cox model, after adjusting for relevant covariates including other lipid parameters, serum triglyceride level 150–199 mg/dL was not associated with death [hazard ratio (HR) 1.00, 95% confidence interval (95% CI) 0.92–1.10] relative to serum triglyceride <150 mg/dL while serum triglyceride ≥200 mg/dL was associated with a 11% increased hazard for death (95% CI 1.01–1.22). Age modified the association between serum triglyceride levels ≥200 mg/dL and mortality with patients <65 years having a 38% higher hazard for death (95% CI 1.15–1.65) and ≥65 years with no increased risk for death (HR 0.97, 95% CI 0.88–1.08, P for interaction <0.001). When serum triglycerides were examined as a continuous log-transformed variable, similar associations with mortality were noted.
Serum triglyceride ≥200 mg/dL was independently associated with all-cause mortality in Stage 3 and Stage 4 CKD patients aged <65 years but not among patients of age ≥65 years. Future studies should confirm these findings and examine the mechanisms that may explain these associations.
PMCID: PMC3408940  PMID: 22553369
chronic kidney disease; mortality; serum triglycerides
17.  Fibroblast Growth Factor-23 and Death, Heart Failure, and Cardiovascular Events in Community-Living Individuals: the Cardiovascular Health Study 
To determine the associations of FGF23 with death, HF, and CVD and investigate the influence of CKD in a general community-living population.
FGF23 increases renal phosphorus excretion and inhibits vitamin D activation. In ESRD, high FGF23 levels are associated with mortality. The associations of FGF23 with death, heart failure (HF), and cardiovascular disease (CVD) in teh general population are unknown.
Plasma FGF23 was measured in 3,107 community-living persons ≥ 65 years in 1996–97, and participants were followed through 2008. HF and CVD events were adjudicated by a panel of experts. Associations of FGF23 with each outcome were evaluated using Cox proportional hazards models, and we tested whether associations differed by CKD status.
Both lower eGFR and higher urine ACR were associated with high FGF23 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 FGF23 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 FGF23 quartile had adjusted hazards ratios (HR) of 1.87 (1.47, 2.38) for all-cause death, 1.94 (1.32, 2.83) for incident HF, and 1.49 (1.02, 2.18) for incident CVD events compared to the lowest quartile. Corresponding HRs in those without CKD (n=1,979) were 1.29 (1.05, 1.59), 1.37 (0.99, 1.89), and 1.07 (0.79, 1.45).
FGF23, 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.
PMCID: PMC3396791  PMID: 22703926
Fibroblast growth factor-23; kidney disease; mineral metabolism; cardiovascular disease; heart failure; elderly
18.  The Risk of Infection-Related Hospitalization With Decreased Kidney Function 
Moderate kidney disease may predispose to infection. We sought to determine whether decreased kidney function, as estimated by serum cystatin C, was associated with the risk of infection-related hospitalization in older individuals.
Study Design
Cohort Study.
Setting & Participants
5,142 Cardiovascular Health Study participants with measured serum creatinine and cystatin C and without eGFR <15 ml/min/1.73 m2 at enrollment.
The primary exposure of interest was estimated glomerular filtration rate using serum cystatin C (eGFRSCysC).
Infection-related hospitalizations during a median follow-up of 11.5 years.
In adjusted analyses, eGFRSCysC categories of 60–89, 45–59, and 15–44 ml/min/1.73 m2 were associated with 16%, 37%, and 64% greater risk of all-cause infection-related hospitalization, respectively, compared with an eGFRSCysC ≥90 ml/min/1.73 m2. When cause specific infection was examined, an eGFRSCysC of 15–44 ml/min/1.73 m2 was associated with an 80% greater risk of pulmonary and 160% greater risk of genitourinary infection compared with an eGFRSCysC ≥90 ml/min/1.73 m2.
No measures of urinary protein, study limited to principal discharge diagnosis.
Lower kidney function, estimated using cystatin C, was associated with a linear and graded risk of infection-related hospitalization. These findings highlight that even moderate degrees of reduced kidney function are associated with clinically significant higher risks of serious infection in older individuals.
PMCID: PMC3288732  PMID: 21906862
renal disease; chronic kidney disease; infection; clinical epidemiology
19.  Retinal Microvascular Signs and Disability in the Cardiovascular Health Study 
Archives of ophthalmology  2011;130(3):350-356.
Retinal microvascular signs are associated with systemic conditions and cognitive decline. We studied the associations of microvascular changes, measured by retinal signs, with disability in performing activities of daily living (ADL).
Prospective cohort study.
1487 participants in the Cardiovascular Health Study (mean age 78 years) who were free of ADL disability and had available data on retinal signs and carotid intima-media thickness (IMT) at the 1998–99 visit.
Main Outcome Measure
Incident ADL disability, defined as self-reported difficulty in performing any ADLs, by the presence of retinal signs and advanced carotid atherosclerosis, defined by carotid IMT ≥ 80th percentile or ≥ 25% stenosis; and potential mediation by cerebral microvascular disease on brain imaging or by executive dysfunction, slow gait, and depressive mood that are symptoms of frontal subcortical dysfunction.
During the median follow-up of 3.1 years (maximum 7.8 years), participants with ≥ 2 retinal signs had a higher rate of disability than those with < 2 retinal signs (10.1% versus 7.1%; adjusted hazards ratio, 1.45; 95% confidence interval, 1.24–1.69; P < 0.001). There was no evidence of interaction by advanced carotid atherosclerosis (P > 0.10). The association seemed to be partially mediated by executive dysfunction, slow gait, and depressive symptoms, but not by cerebral microvascular disease on brain imaging.
These results provide further support for the pathophysiologic and prognostic significance of microvascular disease in age-related disability. However, it remains to be determined how to best utilize retinal photography in the clinical risk prediction.
PMCID: PMC3520093  PMID: 22084159
20.  Association of Pulse Pressure, Arterial Elasticity, and Endothelial Function With Kidney Function Decline Among Adults With Estimated GFR > 60 mL/min/1.73 m2: The Multi-Ethnic Study of Atherosclerosis 
The association of subclinical vascular disease and early declines in kidney function has not been well studied.
Study Design
Prospective cohort study
Setting & Participants
MESA participants with eGFR ≥60 ml/min/1.73m2 with follow-up of 5 years
Pulse pressure (pulse pressure), small and large arterial elasticity (SAE, LAE), and flow mediated dilation.
kidney function decline
SAE and LAE were measured by pulse contour analysis of the radial artery. Kidney function was measured by serum creatinine- and cystatin C-based eGFR.
Among 4,853 adults, higher pulse pressure and lower SAE and LAE had independent and linear associations with faster rates of kidney function decline. Compared to persons with pulse pressure 40–50mmHg, eGFRSCysC decline was 0.29 (p=0.006), 0.56 (p<0.001), and 0.91 (p<0.001) ml/min/1.73m2/year faster among persons with pulse pressure 50–60, 60–70, and >70mmHg, respectively. Compared to the highest quartile of SAE (most elastic), eGFRSCysC decline was 0.26 (p=0.009), 0.35 (p=0.001), and 0.70 (p<0.001) ml/min/1.73m2/year faster for the second, third and fourth quartiles respectively. For LAE, compared to the highest quartile, eGFRSCysC decline was 0.28 (p=0.004), 0.58 (p<0.001), and 0.83 (p<0.001) ml/min/1.73m2/year faster for each decreasing quartile of LAE. Findings were similar with creatinine-based eGFR. In contrast, among 2,997 adults with flow-mediated dilation and kidney function measures, flow-mediated dilation was not significantly associated with kidney function decline. For every 1-SD greater flow-mediated dilation, eGFRSCysC and eGFRSCr changed by 0.05 ml/min/1.73m2/year (p=0.3) and 0.06 ml/min/1.73m2/year (p=0.04), respectively.
We had no direct measure of GFR, in common with nearly all large population based studies.
Higher pulse pressure and lower arterial elasticity, but not flow-mediated dilation, were linearly and independently associated with faster kidney function decline among persons with eGFR ≥60 ml/min/1.73m2. Future studies investigate whether treatments to lower stiffness of large and small arteries may slow the rate of kidney function loss.
PMCID: PMC3242889  PMID: 22000727
kidney function; arterial elasticity; chronic kidney disease; atherosclerosis
21.  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
22.  Cardiovascular Disease and Cognitive Function in Maintenance Hemodialysis Patients 
Cardiovascular disease (CVD) and cognitive impairment are common in dialysis patients. Given the proposed role of microvascular disease on cognitive function, particularly cognitive domains that incorporate executive functions, we hypothesized that prevalent systemic CVD would be associated with worse cognitive performance in hemodialysis patients.
Cross-sectional cohort
Setting and Participants
200 maintenance hemodialysis patients without prior stroke from 5 Boston-area hemodialysis units
CVD, defined by history of coronary disease or peripheral vascular disease
Performance on a detailed neurocognitive battery. Primary analyses quantified cognitive performance using principal components analysis to reduce cognitive tests to a processing speed/executive function domain and a memory domain. Multivariable linear regression models adjusted for age, sex, education, race and other clinical and demographic characteristics.
Mean (SD) age of participants was 62 (18) years and 75 (38%) had CVD. Individuals with CVD were older, more likely to be men, diabetic, and current or former smokers. In adjusted models, individuals with CVD performed 0.50 standard deviations worse (p<0.001) on tests assessing processing speed/executive function, while there was no difference in performance on tests of memory. Similar results were seen when assessing individual tests, with performance on the block design, digit symbol coding and Trail Making Tests A and B significantly associated with CVD in age, sex, education and race-adjusted analyses and approaching toward significance in fully adjusted models.
CVD ascertainment dependent on patient recall and dialysis unit documentation. No brain imaging.
The presence of CVD is associated with worse cognitive performance on tests of processing speed and executive functioning in hemodialysis patients and identifies a high risk population for greater difficulty with complex tasks.
PMCID: PMC3199371  PMID: 21778003
23.  Association of Cystatin C with Adverse Outcomes 
Purpose of Review
To discuss recent studies which have evaluated determinants of cystatin C and to focus on the relationship of cystatin C with mortality, cardiovascular disease (CVD) and non-cardiovascular outcomes.
Recent Findings
In the Chronic Kidney Disease Epidemiology Study cystatin C was associated with demographic characteristics independent of measured glomerular filtration rate (GFR), although this was to a smaller extent than creatinine. In patients with established CKD, cystatin C was strongly and inversely correlated with measured GFR, suggesting that although cystatin C may have other determinants, it is primarily a measure of kidney function. Several cohort studies, particularly in older adults, have now demonstrated that cystatin C is linearly associated with mortality, CVD and non-CVD outcomes, whereas creatinine is primarily associated with risk in individuals with more advanced kidney disease. A recent study has also shown that changes in kidney function as ascertained by cystatin C, even within the relatively normal range, are associated with subsequent CVD and all-cause mortality among older adults.
Cystatin C appears to capture an association of mild kidney disease with increased risk of mortality, CVD and non-CVD outcomes. Future studies should evaluate whether cystatin C can improve medical decision-making and lead to favorable patient outcomes.
PMCID: PMC2890263  PMID: 19374014
cystatin C; kidney disease; cardiovascular disease; mortality
Vitamin D deficiency and parathyroid hormone (PTH) excess are common among older adults and may adversely impact cardiovascular health. We evaluated associations of 25-hydroxyvitamin D (25-OHD) and PTH concentrations, separately, and in combination, with incident cardiovascular events and mortality during 14 years of follow-up in the Cardiovascular Health Study.
Methods and results
We studied 2,312 participants who were free of cardiovascular disease at baseline. We measured 25-OHD and intact PTH from previously frozen serum using mass spectrometry and a two-site immunoassay. Outcomes were adjudicated cases of myocardial infarction, heart failure, cardiovascular death, and all cause mortality. There were 384 participants (17%) who had serum 25-OHD concentrations <15 ng/ml and 570 (25%) who had serum PTH concentrations ≥ 65 pg/ml. After adjustment, each 10-ng/ml lower 25-OHD concentration was associated with a 9% greater (95% 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 of mortality. Serum PTH concentrations ≥ 65 pg/ml were associated with a 30% greater risk of 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.
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.
PMCID: PMC3210558  PMID: 21939825
Vitamin D; parathyroid hormone; myocardial infarction; cardiovascular death; heart failure; mortality; mineral metabolism

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