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1.  Antihypertensive Medication Use and Change in Kidney Function in Elderly Adults: A Marginal Structural Model Analysis 
Background:
The evidence for the effectiveness of antihypertensive medication use for slowing decline in kidney function in older persons is sparse. We addressed this research question by the application of novel methods in a marginal structural model.
Methods:
Change in kidney function was measured by two or more measures of cystatin C in 1,576 hypertensive participants in the Cardiovascular Health Study over 7 years of follow-up (1989–1997 in four U.S. communities). The exposure of interest was antihypertensive medication use. We used a novel estimator in a marginal structural model to account for bias due to confounding and informative censoring.
Results:
The mean annual decline in eGFR was 2.41 ± 4.91 mL/min/1.73 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.
Conclusion:
In summary, estimates from a marginal structural model suggested that antihypertensive therapy was associated with preserved kidney function in hypertensive elderly adults. Confirmatory studies may provide power to determine the strength and validity of the findings.
doi:10.2202/1557-4679.1320
PMCID: PMC3204667  PMID: 22049266
aged; kidney function; hypertension; marginal structural model
2.  A Meta-analysis of the Association of Estimated GFR, Albuminuria, Age, Race, and Sex With Acute Kidney Injury 
Background
Acute kidney injury (AKI) is a serious global public health problem. We aimed to quantify the risk of AKI associated with estimated glomerular filtration rate (eGFR), albuminuria (albumin-creatinine ratio [ACR]), age, sex, and race (African American and Caucasian).
Study Design
Collaborative meta-analysis.
Setting & Population
8 general population cohorts (1,285,049 participants) and 5 chronic kidney disease (CKD) cohorts (79,519 participants).
Selection Criteria for Studies
Available eGFR, ACR, and ≥50 AKI events.
Predictors
Age, sex, race, eGFR, urine ACR, and interactions.
Outcome
Hospitalized with or for AKI, using Cox proportional hazards models to estimate HRs of AKI and random effects meta-analysis to pool results.
Results
16,480 (1.3%) general population cohort participants had AKI over a mean follow-up of 4 years; 2,087 (2.6%) CKD participants had AKI over mean follow-up of 1 year. Lower eGFR and higher ACR were strongly associated with AKI. Compared with eGFR 80 ml/min/1.73 m2, the adjusted HR of AKI at eGFR 45 ml/min/1.73 m2 was 3.35 (95% CI, 2.75–4.07). Compared with ACR 5 mg/g, the risk of AKI at ACR 300 mg/g was 2.73 (95% CI, 2.18–3.43). Older age was associated with higher risk of AKI, but this effect was attenuated in lower eGFR or higher ACR. Male sex was associated with higher risk of AKI, with a slight attenuation in lower eGFR but not in higher ACR. African Americans had higher AKI risk at higher levels of eGFR and most levels of ACR.
Limitations
Only 2 general population cohorts could contribute to analyses by race; AKI identified by diagnostic code.
Conclusions
Reduced eGFR and increased ACR are consistent, strong risk factors for AKI whereas the associations of AKI with age, sex, and race may be weaker in more advanced stages of CKD.
doi:10.1053/j.ajkd.2015.02.337
PMCID: PMC4584180  PMID: 25943717
estimated glomerular filtration rate (eGFR); renal function; albuminuria; albumin-creatinine ratio (ACR); proteinuria; age; race/ethnicity; sex; acute kidney injury (AKI); acute renal failure (ARF); Chronic Kidney Disease Prognosis Consortium; meta-analysis
3.  Chronic Kidney Disease Progression and Cardiovascular Outcomes Following Cardiac Catheterization—A Population‐Controlled Study 
Background
Studies of kidney disease associated with cardiac catheterization typically rely on billing records rather than laboratory data. We examined the associations between percutaneous coronary interventions, acute kidney injury, and chronic kidney disease progression using comprehensive Veterans Affairs clinical and laboratory databases.
Methods and Results
Patients undergoing percutaneous coronary interventions between 2005 and 2010 (N=24 405) were identified in the Veterans Affairs Clinical Assessment, Reporting, and Tracking registry and examined for associated acute kidney injury and chronic kidney disease development or progression relative to 24 405 matched population controls. Secondary outcomes analyzed included dialysis, acute myocardial infarction, and mortality. The incidence of chronic kidney disease progression following percutaneous coronary interventions complicated by acute kidney injury, following uncomplicated coronary interventions, and in matched controls were 28.66, 11.15, and 6.81 per 100 person‐years, respectively. Percutaneous coronary intervention also increased the likelihood of chronic kidney disease progression in both the presence and absence of acute injury relative to controls in adjusted analyses (hazard ratio [HR], 5.02 [95% CI, 4.68–5.39]; and HR, 1.76 [95% CI, 1.70–1.86]). Among patients with estimated glomerular filtration rate <60 mL/min per 1.73 m2, acute kidney injury increased the likelihood of disease progression by 8‐fold. Similar results were observed for all secondary outcomes.
Conclusions
Acute kidney injury following percutaneous coronary intervention was associated with increased chronic kidney disease development and progression and mortality.
doi:10.1161/JAHA.116.003812
PMCID: PMC5121483  PMID: 27742616
angioplasty; contrast media; kidney; morbidity; survival; Mortality/Survival; Percutaneous Coronary Intervention; Quality and Outcomes; Epidemiology; Nephrology and Kidney
4.  Microvascular and Macrovascular Abnormalities, and Cognitive and Physical Function In Older Adults: Cardiovascular Health Study 
Objectives
To evaluate and compare the associations of microvascular and macrovascular abnormalities with cognitive and physical function
Design
Cross-sectional analysis of the Cardiovascular Health Study (1998–1999)
Setting
Community
Participants
2452 participants (mean age 79.5 years) with available data on ≥3 of 5 microvascular abnormalities (brain, retina, kidney) and ≥3 of 6 macrovascular abnormalities (brain, carotid artery, heart, peripheral artery)
Measurements
Standardized composite scores derived from 3 cognitive tests (Modified Mini-Mental State Examination, digit-symbol substitution test, trail making test) and 3 physical tests (gait speed, grip strength, 5-times sit-to-stands)
Results
Compared with individuals with low microvascular and macrovascular burden, those with high microvascular and macrovascular burden had the worst cognitive function (mean score difference [95% confidence interval]: −0.30 [−0.37, −0.24]) and physical function (−0.32 [−0.38, −0.26]). Individuals with high microvascular burden alone had similarly lower scores as those with high macrovascular burden alone (cognitive function: −0.16 [−0.24, −0.08] versus −0.13 [−0.20, −0.06], respectively; physical function: −0.15 [−0.22, −0.08] versus −0.12 [−0.18, −0.06], respectively). Psychomotor speed and working memory, assessed by trail making test, were only impaired in the presence of high microvascular burden. Of the 11 vascular abnormalities considered, white matter hyperintensity, cystatin C-based glomerular filtration rate, large brain infarct, and ankle-arm index were independently associated with both cognitive and physical function.
Conclusion
Microvascular and macrovascular abnormalities assessed from non-invasive tests of the brain, kidney, and peripheral artery were independently associated with poor cognitive and physical function in older adults. Future research should evaluate the usefulness of these tests in prognostication.
doi:10.1111/jgs.13594
PMCID: PMC4578971  PMID: 26338279
Vascular disease; microvascular disease; cognitive function; physical function
5.  Relationship of dietary phosphate intake with risk of end stage renal disease and mortality in chronic kidney disease stage 3-5: A Modification of Diet in Renal Disease study 
Kidney international  2016;89(1):176-184.
KDIGO guidelines recommend dietary phosphate restriction to lower serum phosphate levels in CKD stage 3-5. Recent studies suggest that dietary phosphate intake is only weakly linked to its serum concentration, and the relationship of phosphate intake with adverse outcomes is uncertain. To further evaluate this, we used Cox proportional hazards models to assess associations of baseline 24 hour urine phosphate excretion with risk of end stage renal disease (ESRD), all-cause mortality, and mortality subtypes (cardiovascular disease (CVD) and non-CVD) using the Modification of Diet in Renal Disease data. Models were adjusted for demographics, CVD risk factors, iothalamate GFR, and urine protein and nitrogen excretion. Phosphate excretion was modestly inversely correlated with serum phosphate concentrations. There was no association of 24 hour urinary phosphate excretion with risk of ESRD, CVD-, non-CVD- or all-cause mortality. For comparison, higher serum phosphate concentrations were associated with all-cause mortality (hazard ratio per 0.7 mg/dL higher, 1.15 [95% CI 1.01, 1.30]). Thus, phosphate intake is not tightly linked with serum phosphate concentrations in CKD stage 3-5, and there was no evidence that greater phosphate intake, assessed by 24 hour phosphate excretion, is associated with ESRD, CVD-, non CVD-, or all-cause mortality in CKD stage 3-5. Hence, factors other than dietary intake may be key determinants of serum phosphate concentrations and require additional investigation.
doi:10.1038/ki.2015.284
PMCID: PMC4814358  PMID: 26422502
Mineral metabolism; cardiovascular disease; nutrition; USRDS
6.  Association of Uric Acid With Vascular Stiffness in the Framingham Heart Study 
American Journal of Hypertension  2014;28(7):877-883.
BACKGROUND
Uric acid is associated with increased risk of cardiovascular disease and arterial stiffness in patients with hypertension or stroke. It remains unknown if uric acid is associated with arterial stiffness in the general population.
METHODS
We analyzed the association between serum uric acid levels and measures of arterial stiffness such as carotid-femoral pulse wave velocity (CF PWV), carotid-radial pulse wave velocity (CR PWV) and augmentation index (AI) in 4,140 participants from the Generation 3 Framingham cohort using linear regression.
RESULTS
Mean (SD) age was 40.0 (8.8) years and mean (SD) serum uric acid levels were 5.3 (1.5) mg/dl. Mean (SD) CF PWV was 7.0 (1.4) m/s. Individuals in the highest quartile of uric acid were more likely to be male, have a higher prevalence of hypertension, higher BMI, fasting glucose and insulin, and lower estimated glomerular filtration rate (eGFR). Multivariate adjusted means of CF PWV were 6.90, 6.94, 7.06, and 7.15 m/s for uric acid quartile 1, 2, 3, and 4 respectively. In unadjusted analysis each 1mg/dl increase in uric acid was associated with higher CF-PWV (β = 0.27; 95% CI = 0.25, 0.29; P < 0.0001). This was attenuated but remained significant after adjusting for age, sex, smoking, hypertension, BMI, fasting glucose, insulin, animal protein intake, and eGFR (β= 0.06; 95% CI = 0.02, 0.09; P < 0.0007). There was no association between serum uric acid levels and AI upon adjustment for cardiovascular risk factors.
CONCLUSIONS
Serum uric acid levels are significantly associated with CF PWV and CR PWV in a younger Caucasian population.
doi:10.1093/ajh/hpu253
PMCID: PMC4542908  PMID: 25552515
blood pressure; hypertension; uric acid; vascular stiffness.
7.  Fibroblast Growth Factor 23 and Sudden Versus Nonsudden Cardiac Death: The Cardiovascular Health Study 
Background
Elevated fibroblast growth factor 23 (FGF-23) concentrations are associated with greater risk of cardiovascular events and mortality, especially among people with chronic kidney disease (CKD). Since individuals with CKD are at an increased risk of sudden cardiac death (SCD), we sought to understand whether FGF-23 is a stronger risk factor for SCD versus non-SCD.
Study Design
Cohort study.
Setting & Participants
3,244 participants in the community-based Cardiovascular Health Study, aged 65 years or older.
Predictor
Plasma FGF-23 concentrations.
Outcomes
We assessed SCD and non-SCD in these analyses. SCD was rigorously adjudicated and was defined as a sudden pulseless condition of cardiac origin in a previously stable person occurring out of hospital or in emergency department.
Measurements
We estimated associations of baseline FGF-23 concentrations with SCD and non-SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, comorbidities, and kidney function. We also tested whether associations differed by CKD status.
Results
During a median follow-up of 8.1 years, there were 118 adjudicated SCD and 570 non-SCD events. After multivariable adjustment for demographics, cardiovascular risk factors, comorbidities, and parameters of kidney function, higher FGF-23 concentrations were an independent risk factor for non-SCD (HR [per doubling], 1.17; 95% CI, 1.06-1.30). Elevated FGF-23 concentrations, however, were not independently associated with SCD (HR [per doubling], 1.07; 95% CI, 0.85-1.35). In stratified analysis by CKD status (36.5% of cohort), doubling of FGF-23 concentrations was independently associated with non-SCD (adjusted HR, 1.26; 95% CI, 1.10-1.45). A similar magnitude of association was observed between FGF-23 and SCD among the CKD subgroup; however, it was not significant (HR, 1.20; 95% CI, 0.89-1.62).
Limitations
Limited power to detect moderate-sized effects between FGF-23 and SCD in both the primary and stratified analyses.
Conclusions
In this population-based study, FGF-23 elevations were independently associated with non-SCD. Among individuals with CKD, the associations between FGF-23 and SCD and non-SCD were similar.
doi:10.1053/j.ajkd.2014.10.025
PMCID: PMC4485528  PMID: 25572028
fibroblast growth factor 23 (FGF-23); chronic kidney disease (CKD); sudden cardiac death (SCD); non-SCD; cardiovascular event; cardiovascular mortality; fatal arrhythmic event; renal function; Cardiovascular Health Study (CHS); cohort study
8.  Urinary uromodulin, kidney function and cardiovascular disease in elderly adults 
Kidney international  2015;88(5):1126-1134.
Urinary uromodulin (uUMOD) is the most common secreted tubular protein in healthy adults. However, the relationship between uUMOD and clinical outcomes is still unclear. Here we measured uUMOD in 192 participants of the Cardiovascular Health Study with over a 30% decline in estimated glomerular filtration rate (eGFR) over 9 years, 54 with incident end stage renal disease (ESRD), and in a random sub-cohort of 958 participants. The association of uUMOD with eGFR decline was evaluated using logistic regression and with incident ESRD, cardiovascular disease, heart failure and mortality using Cox proportional regression. Mean age was 78 years and median uUMOD was 25.8 μg/mL. In a case-control study evaluating eGFR decline (192 cases and 231 controls), each standard deviation higher uUMOD was associated with a 23% lower odds of eGFR decline (odds ratio 0.77, (95% CI 0.62, 0.96)) and a 10% lower risk of mortality (hazard ratio 0.90, (95% CI 0.83, 0.98)) after adjusting for demographics, eGFR, albumin/creatinine ratio and other risk factors. There was no risk association of uUMOD with ESRD, cardiovascular disease or heart failure after multivariable adjustment. Thus, low uUMOD levels may identify persons at risk of progressive kidney disease and mortality above and beyond established markers of kidney disease, namely eGFR and the albumin/creatinine ratio. Future studies need to confirm these results and evaluate whether uUMOD is a marker of tubular health and/or whether it plays a causal role in preserving kidney function.
doi:10.1038/ki.2015.192
PMCID: PMC4653069  PMID: 26154925
uromodulin; tamm-horsfall protein; chronic kidney disease; cardiovascular disease; urinary biomarkers
9.  How Do Centers Begin the Process To Prevent CI-AKI: A Report from a New Regional Collaborative 
BMJ quality & safety  2011;21(1):54-62.
Objectives
This study evaluates the variation in practice patterns associated with contrast-induced acute kidney injury (CI-AKI) and identifies clinical practices that have been associated with a reduction in CI-AKI.
Background
Contrast-induced acute kidney injury (AKI) is a recognized as a complication of invasive cardiovascular procedures and is associated with cardiovascular events, prolonged hospitalization, end-stage renal disease, and all-cause mortality. Reducing the risk of CI-AKI is a patient safety objective set by the National Quality Forum.
Methods
We prospectively collected quantitative and qualitative data from 10 centers, which participate in the Northern New England Cardiovascular Disease Study Group PCI Registry. Quantitative data were collected from the PCI registry. Qualitative data were obtained through clinical team meetings to map care processes related to CI-AKI and focus groups to understand attitudes towards CI-AKI prophylaxis. Fixed and random effects modeling were conducted to test the differences across centers.
Results
Significant variation in rates of CI-AKI were found across ten medical centers. Both fixed effects and mixed effects logistic regression demonstrated significant variabiltiy across centers even after adjustment for baseline co-variates (p<0.001 for both modeling approaches). We found patterns in reported processes and clinical leadership that were attributable to centers with lower rates of CI-AKI. These included: reducing NPO time to 4 hours prior to case, and standardizing volume administration protocols in combination with administering 3–4 high doses of N-acetylcysteine (1200 mg) for each patient.
Conclusions
These data suggest that clinical leadership and institution-focused efforts to standardize preventive practices can help reduce the incidence of CI-AKI.
doi:10.1136/bmjqs-2011-000041
PMCID: PMC4872501  PMID: 21890755
Contrast Media; acute kidney injury; patient safety; quality improvement
10.  Reducing Contrast-Induced Acute Kidney Injury Using a Regional Multicenter Quality Improvement Intervention 
Background
Contrast-induced acute kidney injury (CI-AKI) is associated with increased morbidity and mortality following percutaneous coronary interventions (PCI) and is a patient safety objective of the National Quality Forum. However, no formal quality improvement program to prevent CI-AKI has been conducted. Therefore, we sought to determine if a six-year regional multi-center quality improvement intervention could reduce CI-AKI following PCI.
Methods and Results
We conducted a prospective multi-center quality improvement study to prevent CI-AKI (serum creatinine increase ≥0.3 mg/dL within 48 hours or ≥50% during hospitalization) among 21,067 non-emergent patients undergoing PCI at ten hospitals between 2007 and 2012. Six ‘intervention’ hospitals participated in the quality improvement intervention. Two hospitals with significantly lower baseline rates of CI-AKI, which served as “benchmark” sites and were used to develop the intervention and two hospitals not receiving the intervention were used as controls. Using time series analysis and multilevel poisson regression clustering to the hospital-level we calculated adjusted risk ratios (RR) for CI-AKI comparing the intervention period to baseline. Adjusted rates of CI-AKI were significantly reduced in hospitals receiving the intervention by 21% (RR 0.79; 95%CI: 0.67 to 0.93; p=0.005) for all patients and by 28% in patients with baseline eGFR<60 ml/min/1.73 m2 (RR 0.72; 95%CI: 0.56 to 0.91; p=0.007). Benchmark hospitals had no significant changes in CI-AKI. Key qualitative system factors associated with improvement included: multidisciplinary teams, limiting contrast volume, standardized fluid orders, intravenous fluid bolus, and patient education about oral hydration.
Conclusions
Simple cost-effective quality improvement interventions can prevent up to one in five CI-AKI events in patients with undergoing non-emergent PCI.
doi:10.1161/CIRCOUTCOMES.114.000903
PMCID: PMC4869689  PMID: 25074372
quality improvement; contrast-induced nephropathy; contrast media; PCI
11.  Cognitive Function and All-Cause Mortality in Maintenance Hemodialysis Patients 
Background
Cognitive impairment is common in hemodialysis patients and associated with significant morbidity. Limited information exists on whether cognitive impairment is associated with survival, and whether type of cognitive impairment is important.
Study Design
Longitudinal cohort.
Setting & Participants
Cognitive function was assessed at baseline and yearly using a comprehensive battery of cognitive tests in 292 prevalent hemodialysis patients.
Predictor
Using principal component analysis, individual test results were reduced into 2 domain scores, representing memory and executive function. By definition, each score carried a mean of 0 and SD of 1.
Outcomes
Association of each score with all-cause mortality was assessed using Cox proportional hazards models adjusted for demographics as well as dialysis and cardiovascular (CV) risk factors.
Results
Mean age of participants was 63 years, 53% were male, 23% were African American and 90% had at least a high school education. During median follow up of 2.1 (IQR, 1.1–3.7) years, 145 deaths occurred. Each 1-SD better executive function score was associated with 35% lower hazard of mortality (HR, 0.65; 95% CI, 0.55–0.76). In models adjusting for demographics and dialysis-related factors, this relationship was partially attenuated but remained significant (HR, 0.81; 95% CI, 0.67–0.98), while adjustment for CV disease and heart failure further attenuated it (HR, 0.87; 95% CI, 0.72–1.06). Use of time-dependent models showed a similar unadjusted association (HR, 0.62; 95% CI, 0.54–0.72), with the relationship remaining significant after adjustment for demographics, dialysis, and CV risk factors (HR, 0.79; 95% CI, 0.66–0.94). Better memory was associated with lower mortality in univariate analysis (HR per 1 SD, 0.82 [95% CI, 0.69–0.96]), but not when adjusting for demographics (HR, 1.00; 95% CI, 0.83–1.19).
Limitations
Patients with dementia were excluded from the full battery, perhaps underestimating strength of the association.
Conclusions
Worse executive function and memory are associated with increased risk of mortality. For memory, this association is explained by patient demographics, while for executive function this relationship may be partly explained by CV disease burden.
doi:10.1053/j.ajkd.2014.07.009
PMCID: PMC4305473  PMID: 25240262
cognition; cognitive impairment; executive function; memory; neurocognitive testing; cardiovascular disease; mortality; hemodialysis; end-stage renal disease (ESRD)
12.  Association of Albumin-Creatinine Ratio and Cystatin C With Change in Ankle-Brachial Index: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Low ankle-brachial index (ABI) is a reflection of atherosclerotic disease, and high ABI is an indicator of calcified vessels. The associations of albuminuria and cystatin C with incidence of either low or high ABI are unknown.
Study Design
Prospective longitudinal cohort study.
Setting & Participants
The Multi-Ethnic Study of Atherosclerosis (MESA) enrolled community-dwelling adults (N=6,814) aged 45–84 years who were free of clinical cardiovascular disease (CVD) at baseline.
Predictors
Baseline albumin-creatinine ratio (ACR) and serum cystatin C levels.
Outcomes
Development of low (< 0.90), and high (> 1.40) ABI using multinomial regression among persons with ABI 0.90–1.40 at baseline.
Results
During 9.8 years of follow up, 221 and 89 participants progressed to low and high ABI, respectively. Baseline ACR and cystatin C were higher among progressors compared to non-progressors. In multivariable analyses, doubling of ACR was associated with increased risk of progression to low (OR, 1.08; 95% CI, 0.99–1.20) and high (OR, 1.16; 95% CI, 1.01–1.32) ABI. Compared to the lowest quintile, the highest quintile of ACR had a significantly increased risk of progression to low (OR, 1.79; 95% CI, 1.03–3.12) and high (OR, 2.76; 95% CI, 1.32–5.77) ABI. Higher cystatin C levels were associated with progression to low (OR per 1-SD greater, 1.12; 95% CI, 1.00–1.26) but not high (OR per 1-SD greater, 1.01; 95% CI, 0.81–1.25) ABI, but the highest quintile of cystatin C was not independently associated with either outcome.
Limitations
Single measure of albuminuria and low number of progressors to high ABI.
Conclusions
In adults free of clinical CVD, albuminuria was a strong, independent risk factor for the development of both high and low ABI, important and different measures of peripheral artery disease.
doi:10.1053/j.ajkd.2014.05.014
PMCID: PMC4272615  PMID: 24998036
Cystatin C; albuminuria; albumin-creatinine ratio (ACR); peripheral artery disease (PAD); ankle-brachial index (ABI); chronic kidney disease (CKD); cardiovascular disease (CVD); atherosclerotic disease
13.  Association of Frailty based on self-reported physical function with directly measured kidney function and mortality 
BMC Nephrology  2015;16:203.
Background
Use of serum creatinine to estimate GFR may lead to underestimation of the association between self-reported frailty and kidney function. Our objectives were to evaluate the association of measured GFR (mGFR) with self-reported frailty among patients with CKD and to determine whether self-reported frailty was associated with death after adjusting for mGFR.
Methods
Participants in the Modification of Diet in Renal Disease study (1989–1993) had GFR measured using iothalamate clearance (mGFR), and GFR was estimated based on the CKD-EPI creatinine (eGFRcr) and cystatin C (eGFRcys) equations. We defined self-reported frailty as three or more of: exhaustion, poor physical function, low physical activity, and low body weight. Death was ascertained through 2007 using the National Death Index and the United States Renal Data System.
Results
Eight hundred twelve MDRD participants (97 %) had complete data on self-reported frailty (16 % prevalence, N = 130) and mGFR (mean (SD) 33.1 ± 11.7 ml/min/1.73 m2). Higher GFR was associated with lower odds of self-reported frailty based on mGFR, (OR 0.71, 95 % CI 0.60–0.86 per 10 ml/min/1.73 m2), eGFRcr (OR 0.80, 95 % CI 0.67–0.94 per 10 ml/min/1.73 m2), and eGFRcys (OR 0.75, 95 % CI 0.62–0.90 per 10 ml/min/1.73 m2). Median follow-up was 17 (IQR 11–18) years, with 371 deaths. Self-reported frailty was associated with a higher risk of death (HR 1.71, 95 % CI 1.26–2.30), which was attenuated to a similar degree when mGFR (HR 1.48, 95 % CI 1.08–2.00), eGFRcr (HR 1.57, 95 % CI 1.15–2.10), or eGFRcys (HR 1.51, 95 % CI 1.10–2.10) was included as an indicator of kidney function.
Conclusions
We found an inverse association between kidney function and self-reported frailty that was similar for mGFR, eGFR and eGFRcys. In this relatively healthy cohort of clinical trial participants with CKD, using serum creatinine to estimate GFR did not substantially alter the association of GFR with self-reported frailty or of self-reported frailty with death.
doi:10.1186/s12882-015-0202-6
PMCID: PMC4673778  PMID: 26645070
Self-report frailty; Kidney function and mortality
14.  Serum Urate Levels and the Risk of Hip Fractures: Data from the Cardiovascular Health Study 
Purpose
Uric acid inhibits vitamin D activation experimentally and higher serum urate levels are associated with higher parathyroid hormone levels in humans suggesting a link between uric acid and bone health. We hypothesized that hyperuricemia may increase the risk of fractures in older adults.
Methods
1963 men and 2729 women ≥ 65 years of age who participated in the Cardiovascular Health Study and had baseline serum urate levels were included in the study. The primary outcome was incident hip fracture, assessed prospectively through June, 2008 by inpatient and outpatient records. The analysis was stratified by sex apriori.
Results
There was a U- shaped relationship between serum urate levels and hip fractures in men. Men in the lowest and the highest urate quartiles (<4.88 and ≥6.88 mg/dL respectively) had a significantly higher rate of fractures in unadjusted analysis. However, upon multivariate adjustment, only the HR for hip fracture in highest quartile versus the reference remained significant (HR 1.9; 95% C.I. 1.1, 3.1; p value 0.02). High serum urate levels were not associated with hip fractures in women.
Conclusion
In this large prospective cohort of community-dwelling older adults, increased serum urate levels were associated with an increased risk of hip fractures in men. Further studies are needed to confirm these findings and to understand the mechanisms that underlie them.
doi:10.1016/j.metabol.2014.11.006
PMCID: PMC4312534  PMID: 25491429
urate; fractures; bone health
15.  Prognostic Implications of Microvascular and Macrovascular Abnormalities in Older Adults: Cardiovascular Health Study 
Background.
Microvascular and macrovascular abnormalities are frequently found on noninvasive tests performed in older adults. Their prognostic implications on disability and life expectancy have not been collectively assessed.
Methods.
This prospective study included 2,452 adults (mean age: 79.5 years) with available measures of microvascular (brain, retina, kidney) and macrovascular abnormalities (brain, carotid, coronary, peripheral artery) in the Cardiovascular Health Study. The burden of microvascular and macrovascular abnormalities was examined in relation to total, activity-of-daily-living disability-free, and severe disability-free life expectancies in the next 10 years (1999–2009).
Results.
At 75 years, individuals with low burden of both abnormalities lived, on average, 8.71 years (95% confidence interval: 8.29, 9.12) of which 7.67 years (7.16, 8.17) were without disability. In comparison, individuals with high burden of both abnormalities had shortest total life expectancy (6.95 years [6.52, 7.37]; p < .001) and disability-free life expectancy (5.60 years [5.10, 6.11]; p < .001). Although total life expectancy was similarly reduced for those with high burden of either type of abnormalities (microvascular: 7.96 years [7.50, 8.42] vs macrovascular: 8.25 years [7.80, 8.70]; p = .10), microvascular abnormalities seemed to have larger impact than macrovascular abnormalities on disability-free life expectancy (6.45 years [5.90, 6.99] vs 6.96 years [6.43, 7.48]; p = .016). These results were consistent for severe disability-free life expectancy and in individuals without clinical cardiovascular disease.
Conclusions.
Considering both microvascular and macrovascular abnormalities from multiple noninvasive tests may provide additional prognostic information on how older adults spend their remaining life. Optimal clinical use of this information remains to be determined.
doi:10.1093/gerona/glu074
PMCID: PMC4271022  PMID: 24864308
Cardiovascular; Epidemiology; Longevity; Disablement process.
16.  Risk Factors for Cardiovascular Disease across the Spectrum of Older Age: The Cardiovascular Health Study 
Atherosclerosis  2014;237(1):336-342.
Objective
The associations of some risk factors with cardiovascular disease (CVD) are attenuated in older age; whereas others appear robust. The present study aimed to compare CVD risk factors across older age.
Methods
Participants (n=4,883) in the Cardiovascular Health Study free of prevalent CVD, were stratified into three age groups: 65–74, 75–84, 85+ years. Traditional risk factors included systolic blood pressure (BP), LDL-cholesterol, HDL-cholesterol, obesity, and diabetes. Novel risk factors included kidney function, C-reactive protein (CRP), and N-terminal pro-B-type natriuretic peptide (NT pro-BNP).
Results
There were 1,498 composite CVD events (stroke, myocardial infarction, and cardiovascular death) over 5 years. The associations of high systolic BP and diabetes appeared strongest, though both were attenuated with age (p-values for interaction = 0.01 and 0.002, respectively). The demographic-adjusted hazard ratios (HR) for elevated systolic BP were 1.79 (95% confidence interval: 1.49, 2.15), 1.59 (1.37, 1.85) and 1.10 (0.86, 1.41) in participants aged 65–74, 75–84, 85+, and for diabetes, 2.36 (1.89, 2.95), 1.55 (1.27, 1.89), 1.51 (1.10, 2.09). The novel risk factors had consistent associations with the outcome across the age spectrum; low kidney function: 1.69 (1.31, 2.19), 1.61 (1.36, 1.90), and 1.57 (1.16, 2.14) for 65–74, 75–84, and 85+ years, respectively; elevated CRP: 1.54 (1.28, 1.87), 1.33 (1.13, 1.55), and 1.51 (1.15, 1.97); elevated NT pro-BNP: 2.67 (1.96, 3.64), 2.71 (2.25, 3.27), and 2.18 (1.43, 3.45).
Conclusions
The associations of most traditional risk factors with CVD were minimal in the oldest old, whereas diabetes, eGFR, CRP, and NT pro-BNP were associated with CVD across older age.
doi:10.1016/j.atherosclerosis.2014.09.012
PMCID: PMC4254262  PMID: 25303772
aging; epidemiology; risk factors
17.  Association of sleep disturbances with cognitive impairment and depression in maintenance hemodialysis patients 
Journal of nephrology  2013;26(1):101-110.
Background
There are few data on the relationship of sleep with measures of cognitive function and symptoms of depression in dialysis patients.
Methods
We evaluated the relationship of sleep with cognitive function and symptoms of depression in 168 hemodialysis patients, using multivariable linear and logistic regression. Sleep disturbances were assessed using the sleep subscale battery of the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) Health Experience Questionnaire. The cognitive battery assessed a broad range of functioning including global ability, verbal intelligence, supraspan learning, auditory retention, visual retention, attention/mental processing speed, visual construction/fluid reasoning and motor speed. Depressive symptoms were assessed using the Center for Epidemiological Studies of Depression (CESD) Scale, with depression indicated by a CESD score ≥ 16.
Results
Mean (SD) age of participants was 62 (17) years, 49% were women, 30% were African American and 33% had diabetes. There was no significant relationship between sleep score and performance on any neurocognitive test (p>0.13, for all multivariable analyses). The prevalence of depression increased from 16% in the highest quartile (best) of sleep score, to 31% in the lowest quartile (worst) of sleep score. In multivariable analyses, each 1 SD increase in sleep score was associated with a 2.18 (95% confidence interval, 1.07–3.29, p<0.001) lower CESD score. Results were consistent when considering individual components of both the CESD and sleep score.
Conclusions
Disturbances in sleep are associated with symptoms of depression but not measures of cognitive function. Dialysis patients with disturbances in sleep should be screened for depression.
doi:10.5301/jn.5000131
PMCID: PMC4447083  PMID: 22641565
Cognitive function; Depression; Hemodi-alysis; Sleep
18.  A meta-analysis of the association of estimated GFR, albuminuria, diabetes mellitus, and hypertension with AKI 
Background
Diabetes mellitus and hypertension are risk factors for acute kidney injury (AKI). Whether estimated glomerular filtration rate (eGFR) and urine albumin creatinine ratio (ACR) remain risk factors for AKI in the presence and absence of these conditions is uncertain.
Study Design
Meta-analysis of cohort studies.
Setting & Population
8 general population (1,285,045 participants) and 5 CKD (79,519 participants) cohorts.
Selection Criteria for Studies
Cohorts participating in the CKD Prognosis Consortium.
Predictors
Diabetes and hypertension status, eGFR by the CKD Epidemiology Collaboration 2009 creatinine equation, urine ACR, and interactions.
Outcome
Hospitalization with AKI, using Cox proportional hazards models to estimate hazard ratios (HR) of AKI and random effects meta-analysis to pool results.
Results
Over a mean follow-up period of 4 years, there were 16,480 episodes of AKI in the general population and 2,087 episodes in the CKD cohorts. Low eGFR and high ACR were associated with higher risks of AKI in individuals with or without diabetes and with or without hypertension. When compared to a common reference of eGFR 80 mL/min/1.73m2 in non-diabetic patients, HRs for AKI were generally higher in diabetic patients at any level of eGFR. The same was true for diabetic patients at all levels of ACR compared to non-diabetic patients. The risk gradient for AKI with lower eGFR was greater in those without diabetes than with diabetes, but similar with higher ACR in those without versus with diabetes. Those with hypertension had a higher risk of AKI at eGFR greater than 60 ml/min/1.73m2 than those without hypertension. However, the risk gradients for AKI with both lower eGFR and higher ACR were greater for those without than with hypertension.
Limitations
AKI identified by diagnostic code.
Conclusions
Lower eGFR and higher ACR are associated with higher risks of AKI among individuals with or without either diabetes or hypertension.
doi:10.1053/j.ajkd.2015.02.338
PMCID: PMC4594211  PMID: 25975964
eGFR; albuminuria; diabetes; hypertension; acute kidney injury
19.  Cognitive Performance before and during Hemodialysis: A Randomized Cross-Over Trial 
Nephron. Clinical practice  2013;124(0):151-158.
Background and Aims
Hemodialysis (HD) patients are educated and counseled during the HD procedure. There are few studies assessing whether cognitive performance varies with dialysis.
Methods
Using a randomized cross-over design, 40 patients were assigned to one of two sequences: testing 1 h before dialysis followed 1 month later by testing during the first hour of dialysis (n = 21) versus testing during the first hour of dialysis followed 1 month later by 1 h before dialysis (n = 19). Cognitive tests were administered at each testing period. Mixed regression models evaluated for a dialysis effect (difference between test performance before vs. during dialysis) while adjusting for potential learning (difference between first and second tests).
Results
In models accounting for period of testing, there was no difference in test performance between 1 h before versus during the first hour of HD for all administered cognitive tests (p > 0.05). A learning effect was detected between first and second test administration in two tests, specifically, the Word List Learning and the Digit Symbol Substitution Test.
Conclusions
We found no difference in cognitive performance depending on the time of testing, suggesting that cognitive tests performed during the first hour of dialysis are a valid assessment of cognitive performance.
doi:10.1159/000356393
PMCID: PMC4440830  PMID: 24335582
Cognition; Hemodialysis; Randomized cross-over trial
20.  Low Serum Bicarbonate and Kidney Function Decline: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Among populations with established chronic kidney disease (CKD), metabolic acidosis is associated with more rapid progression of kidney disease. The association of serum bicarbonate concentrations with early declines in kidney function is less clear.
Study Design
Retrospective cohort study.
Setting & Participants
6380 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) with a baseline estimated glomerular filtration rate (eGFR) >60 mL/min/1.73m2 using the CKD-EPI (CKD Epidemiology Collaboration) creatinine–cystatin C equation.
Predictors
Serum bicarbonate concentrations.
Outcomes
Rapid kidney function decline (eGFR decline >5% per year) and incident reduced eGFR (eGFR<60 mL/min/1.73 m2 with minimum rate of eGFR loss of 1 mL/min/1.73 m2 per year).
Results
The average bicarbonate concentration was 23.2 ± 1.8 mEq/L. 1730 (33%) participants had rapid kidney function decline, and 487 had incident reduced eGFR during follow-up. Each 1-SD lower baseline bicarbonate concentration was associated with 12% higher adjusted odds of rapid kidney function decline (95% CI, 6%–20%) and higher risk of incident reduced eGFR (adjusted incidence rate ratio, 1.11; 95% CI, 1.03–1.20) in models adjusting for demographics, baseline eGFR, albuminuria, and CKD risk factors. The OR for the associations of bicarbonate <21mEq/L relative to 23–24 mEq/L was 1.35 (95% CI, 1.05–1.73) for rapid kidney function decline, and the incidence rate ratio was 1.16 (95% CI, 0.83–1.62) for incident reduced eGFR.
Limitations
Etiology of metabolic acidosis cannot be determined in this study.
Conclusions
Lower serum bicarbonate concentrations are independently associated with rapid kidney function decline independent of eGFR or albuminuria in community-living persons with a baseline eGFR >60 mL/min/1.73 m2. If confirmed, our findings suggest that metabolic acidosis may indicate either early kidney disease that is not captured by eGFR or albuminuria, or may have a causal role in the development of an eGFR <60 mL/min/1.73 m2.
doi:10.1053/j.ajkd.2014.05.008
PMCID: PMC4177290  PMID: 24953891
serum bicarbonate; metabolic acidosis; chronic kidney disease (CKD); kidney function; renal disease; disease progression; kidney disease trajectory
21.  Serum Bicarbonate Concentrations and Kidney Disease Progression in Community-Living Elders: The Health, Aging, and Body Composition (Health ABC) Study 
Background
In populations with prevalent chronic kidney disease (CKD), lower serum bicarbonate is associated with more rapid CKD progression, but whether lower bicarbonate is also associated with risk of incident estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 and progression among community-living persons with predominantly preserved kidney function is unknown.
Study Design
Longitudinal observational cohort study.
Setting & Participants
Well functioning community living elders aged 70–79 years at inception.
Predictor
Serum bicarbonate measured at the time of collection by arterialized venous blood sample using an arterial blood gas analyzer.
Outcomes
Change in eGFR, and new eGFR < 60 ml/min/1.73m2 and loss of ≥1 ml/min/1.73m2 per year at follow-up.
Measurements
Linear and logistic regressions were used to evaluate associations of baseline serum bicarbonate with change in eGFR and incident eGFR <60 mL/min/1.73m2.
Results
At baseline, mean eGFR was 84±16 (SD) mL/min/1.73m2, and serum bicarbonate was 25.2±1.9 mmol/L. Compared to participants with higher bicarbonate concentrations (23.0–28.0 mmol/L), those with bicarbonate concentrations < 23 mmol/L (n=85 [8%]) lost eGFR 0.55 (95%CI, 0.13–0.97) mL/min/1.73m2 per year faster in models adjusted for demographics, CKD risk factors, baseline eGFR, and urine albumin-creatinine ratio. Among the 989 (92%) participants with baseline eGFR>60 mL/min/1.73m2, 252 (25%) developed incident eGFR <60 mL/min/1.73m2 at follow-up. Adjusting for the same covariates, participants with bicarbonate concentrations < 23 mmol/L had nearly 2-fold greater odds of incident eGFR <60 mL/min/1.73m2 (OR, 1.72; 95% CI, 0.97–3.07) compared to those with higher bicarbonate concentrations.
Limitations
Only two measurements of kidney function separated by seven years and loss to follow up due to intervening mortality in this elderly population.
Conclusions
Lower serum bicarbonate concentrations are independently associated with decline in eGFR and incident eGFR <60 mL/min/1.73m2 in community-living older persons. If confirmed, serum bicarbonate levels may give insights into kidney tubule health among persons with preserved eGFR and suggest a possible new target for intervention to prevent CKD development.
doi:10.1053/j.ajkd.2014.05.009
PMCID: PMC4177317  PMID: 24953890
Acidosis; alkalosis; kidney disease; aging; risk factor; renal disease; disease progression; kidney disease trajectory
22.  Fibroblast Growth Factor 23, the Ankle-Brachial Index, and Incident Peripheral Artery Disease in the Cardiovascular Health Study 
Atherosclerosis  2014;233(1):91-96.
Background
Fibroblast growth factor 23 (FGF23) has emerged as a novel risk factor for mortality and cardiovascular events. Its association with the ankle-brachial index (ABI) and clinical peripheral artery disease (PAD) is less known.
Methods
Using data (N=3,143) from the Cardiovascular Health Study (CHS), a cohort of community dwelling adults > 65 years of age, we analyzed the cross sectional association of FGF23 with ABI and its association with incident clinical PAD events during 9.8 years of follow up using multinomial logistic regression and Cox proportional hazards models respectively.
Results
The prevalence of cardiovascular disease (CVD) and traditional risk factors like diabetes, coronary artery disease, and heart failure increased across higher quartiles of FGF23. Compared to those with ABI of 1.1–1.4, FGF23 at baseline was associated with prevalent PAD (ABI<0.9) although this association was attenuated after adjusting for CVD risk factors, and kidney function (OR 0.91, 95% CI 0.76–1.08). FGF23 was not associated with high ABI (>1.4) (OR 1.06, 95% CI 0.75–1.51). Higher FGF23 was associated with incidence of PAD events in unadjusted, demographic adjusted, and CVD risk factor adjusted models (HR 2.26, 95% CI 1.28–3.98; highest versus lowest quartile). The addition of estimated glomerular filtration and urine albumin to creatinine ratio to the model however, attenuated these findings (HR 1.46, 95% CI, 0.79–2.70).
Conclusions
In community dwelling older adults, FGF23 was not associated with baseline low or high ABI or incident PAD events after adjusting for confounding variables. These results suggest that FGF23 may primarily be associated with adverse cardiovascular outcomes through non atherosclerotic mechanisms.
doi:10.1016/j.atherosclerosis.2013.12.015
PMCID: PMC3927151  PMID: 24529128
Fibroblast growth factor; peripheral artery disease; ankle-brachial index; chronic kidney disease; cardiovascular disease
23.  Urinary sodium excretion and kidney failure in non-diabetic chronic kidney disease 
Kidney international  2014;86(3):582-588.
Current guidelines recommend under 2g/day sodium intake in chronic kidney disease, but there are few studies relating sodium intake to long-term outcomes. Here we evaluated the association of mean baseline 24-hour urinary sodium excretion with kidney failure and a composite outcome of kidney failure or all-cause mortality using Cox regression in 840 participants enrolled in the Modification of Diet in Renal Disease Study. Mean 24-hour urinary sodium excretion was 3.46 g/day. Kidney failure developed in 617 and the composite outcome was reached in 723. In the primary analyses there was no association between 24-hour urine sodium and kidney failure [HR 0.99 (95% CI 0.91–1.08)] nor on the composite outcome [HR 1.01 (95% CI 0.93–1.09),] each per 1g/day higher urine sodium. In exploratory analyses there was a significant interaction of baseline proteinuria and sodium excretion with kidney failure. Using a 2-slope model, when urine sodium was under 3g/day, higher urine sodium was associated with increased risk of kidney failure in those with baseline proteinuria under 1g/day, and lower risk of kidney failure in those with baseline proteinuria of 1g/day or more. There was no association between urine sodium and kidney failure when urine sodium was 3g/day or more. Results were consistent using first baseline and time-dependent urine sodium. Thus, we noted no association of urine sodium with kidney failure. Results of the exploratory analyses need to be verified in additional studies and the mechanism explored.
doi:10.1038/ki.2014.59
PMCID: PMC4149837  PMID: 24646858
24-h urinary sodium excretion; kidney failure; CKD
24.  Kidney Function and Mortality in Octogenarians: Cardiovascular Health Study All Stars 
OBJECTIVES:
To examine the association between kidney function and all-cause mortality in octogenarians.
DESIGN:
Retrospective analysis of prospectively collected data.
SETTING:
Community.
PARTICIPANTS:
Serum creatinine and cystatin C were measured in 1,053 Cardiovascular Health Study (CHS) All Stars participants.
MEASUREMENTS:
Estimated glomerular filtration rate (eGFR) was determined using the Chronic Kidney Disease Epidemiology Collaboration creatinine (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.
RESULTS:
Mean age of the participants was 85, 64% were female, 66% had hypertension, 14% had diabetes mellitus, and 39% had prevalent cardiovascular disease. There were 154 deaths over a median follow-up of 2.6 years. The association between 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).
CONCLUSION:
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.
doi:10.1111/j.1532-5415.2012.04046.x
PMCID: PMC3902776  PMID: 22724391
octogenarians; kidney function; mortality
25.  Kidney Function and Cognitive Health in Older Adults: The Cardiovascular Health Study 
American Journal of Epidemiology  2014;180(1):68-75.
Recent evidence has demonstrated the importance of kidney function in healthy aging. We examined the association between kidney function and change in cognitive function in 3,907 participants in the Cardiovascular Health Study who were recruited from 4 US communities and studied from 1992 to 1999. Kidney function was measured by cystatin C–based estimated glomerular filtration rate (eGFRcys). Cognitive function was assessed using the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test, which were administered up to 7 times during annual visits. There was an association between eGFRcys and change in cognitive function after adjustment for confounders; persons with an eGFRcys of less than 60 mL/minute/1.73 m2 had a 0.64 (95% confidence interval: 0.51, 0.77) points/year faster decline in Modified Mini-Mental State Examination score and a 0.42 (95% confidence interval: 0.28, 0.56) points/year faster decline in Digit Symbol Substitution Test score compared with persons with an eGFRcys of 90 or more mL/minute/1.73 m2. Additional adjustment for intermediate cardiovascular events modestly affected these associations. Participants with an eGFRcys of less than 60 mL/minute/1.73 m2 had fewer cognitive impairment–free life-years on average compared with those with eGFRcys of 90 or more mL/minute/1.73 m2, independent of confounders and mediating cardiovascular events (mean difference = −0.44, 95% confidence interval: −0.62, −0.26). Older adults with lower kidney function are at higher risk of worsening cognitive function.
doi:10.1093/aje/kwu102
PMCID: PMC4070934  PMID: 24844846
aging; chronic kidney disease; cognitive function; congestive heart failure; myocardial infarction; prospective study; stroke; successful aging

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