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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.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  Depression and All-Cause Mortality in Hemodialysis Patients 
American journal of nephrology  2014;40(1):12-18.
Background
There are limited data regarding the relationship between depression and mortality in hemodialysis patients.
Methods
Among 323 maintenance hemodialysis patients, depression symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale, with a score of ≥16 consistent with depression. Adjusted Cox proportional hazards models, with additional analyses incorporating antidepressant medication use, were used to evaluate the association between depression and mortality. Baseline CES-D scores were used for primary analyses, while secondary time dependent analyses incorporated subsequent CES-D results.
Results
Mean age was 62.9 ± 16.5 years, 46% were women and 22% African American. Mean baseline CES-D score was 10.7 ± 8.3, and 83 (26%) participants had CES-D scores ≥16. During median (25th, 75th) follow-up of 25 (13, 43) months, 154 participants died. After adjusting for age, sex, race, primary cause of kidney failure, dialysis vintage and access, baseline depression was associated with an increased risk of all-cause mortality [HR (95% CI)=1.51 (1.06, 2.17)]. This attenuated with further adjustment for cardiovascular disease, smoking, Kt/V, serum albumin, log CRP and antidepressant use [HR=1.21 (0.82, 1.80)]. When evaluating time-dependent CES-D, depression remained associated with increased mortality risk in the fully adjusted model [HR=1.44 (1.00, 2.06)].
Conclusions
Greater symptoms of depression are associated with an increased risk of mortality in hemodialysis patients, particularly when accounting for the most proximate assessment. This relationship was attenuated with adjustment for comorbid conditions, suggesting a complex relationship between clinical characteristics and depression symptoms. Future studies should evaluate whether treatment for depression impacts mortality among HD patients.
doi:10.1159/000363539
PMCID: PMC4128686  PMID: 24969267
All-cause mortality; antidepressant medication use; depression; hemodialysis
9.  FGF-23 and cognitive performance in hemodialysis patients 
Although cognitive impairment is common in hemodialysis patients, the etiology of and risk factors for its development remain unclear. Fibroblast growth factor 23 (FGF-23) levels are elevated in hemodialysis patients and are associated with increased mortality and left ventricular hypertrophy. Despite FGF-23 being found within the brain, there are no prior studies assessing whether FGF-23 levels are associated with cognitive performance. We measured FGF-23 in 263 prevalent hemodialysis patients in whom comprehensive neurocognitive testing was also performed. The cross-sectional association between patient characteristics and FGF-23 levels was assessed. Principal factor analysis was used to derive two factors from cognitive test scores, representing memory and executive function, which carried a mean of 0 and a standard deviation of 1. Multivariable linear regression adjusting for age, sex, education status, and other relevant covariates was used to explore the relationship between FGF-23 and each factor. Mean age was 63 years, 46% were women and 22% were African American. The median FGF-23 level was 3098 RU/mL. Younger age, lower prevalence of diabetes, longer dialysis vintage, and higher calcium and phosphorus were independently associated with higher FGF-23 levels. Higher FGF-23 was independently associated with a lower memory score (per doubling of FGF-23, β = −0.08 SD [95% confidence interval, CI: −0.16, −0.01]) and highest quartile vs. lowest quartile (β = −0.42 SD [−0.82, −0.02]). There was no definite association of FGF 23 with executive function when examined as a continuous variable (β = −0.03 SD [−0.10, 0.04]); however, there was a trend in the quartile analysis (β = −0.28 SD [−0.63, 0.07], P = 0.13, for 4th quartile vs. 1st quartile). FGF-23 was associated with worse performance on a composite memory score, including after adjustment for measures of mineral metabolism. High FGF-23 levels in hemodialysis patients may contribute to cognitive impairment.
doi:10.1111/hdi.12100
PMCID: PMC4443906  PMID: 24164913
Cognition; FGF-23; hemodialysis
10.  Urinary Biomarkers of Kidney Injury Are Associated with All-Cause Mortality in the Women’s Interagency HIV Study (WIHS) 
HIV medicine  2013;15(5):291-300.
Objectives
Chronic kidney disease (CKD) is common in HIV; CKD is associated with mortality. Urinary markers of tubular injury have been associated with future kidney disease risk, but associations with mortality are unknown.
Methods
We evaluated the association of urinary interleukin-18(IL-18), liver fatty acid binding protein(L-FABP), kidney injury molecule-1(KIM-1), neutrophil gelatinase-associated lipocalin(NGAL), albumin-to-creatinine ratio(ACR) with 10-year, all-cause death in 908 HIV-infected women. Kidney function was estimated using cystatin C (eGFRcys).
Results
There were 201 deaths during 9,269 person-years of follow-up. After demographic adjustment, compared to the lowest tertile, highest tertiles of IL-18 (HR 2.54,95%CI 1.75–3.68), KIM-1 (2.04,1.44–2.89), NGAL(1.50,1.05–2.14), and ACR(1.63,1.13–2.36) were associated with higher mortality. After multivariable adjustment including eGFRcys, only the highest tertiles of IL-18, (1.88,1.29–2.74) and ACR (1.46,1.01–2.12) remained independently associated with mortality. Findings with KIM-1 were borderline (1.41, 0.99–2.02). We found a J-shaped association between L-FABP and mortality. Compared to persons in the lowest tertile, HR for middle tertile of L-FABP was 0.67 (0.46–0.98) after adjustment. Findings were stronger when IL-18, ACR and L-FABP were simultaneously included in models.
Conclusions
Among HIV-infected women, some urinary markers of tubular injury are associated with mortality risk, independently of eGFRcys and ACR. These markers represent potential tools to identify early kidney injury in persons with HIV.
doi:10.1111/hiv.12113
PMCID: PMC3975680  PMID: 24313986
HIV; IL-18; KIM-1; L-FABP; NGAL; urinary biomarkers
11.  Measures of Blood Pressure and Cognition in Dialysis Patients 
Background
There are few reports on the relationship of blood pressure with cognitive function in maintenance dialysis patients.
Methods
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).
Results
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.
Conclusion
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.
doi:10.1111/j.1542-4758.2012.00718.x
PMCID: PMC4076621  PMID: 22716218
Blood pressure; Cognition; Dialysis
12.  Anatomic Brain Disease in Hemodialysis Patients: A Cross-sectional Study 
Background
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.
Predictor
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).
Outcomes
Brain MRI features including severity of white matter disease and cerebral atrophy (sulcal prominence and ventricular atrophy), hippocampal size, and small/large vessel infarcts.
Measurements
Semi-quantitative scale (0-9 for white matter disease and cerebral atrophy, 0-3 for hippocampal size) and infarct prevalence.
Results
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).
Limitations
The dialysis cohort is likely healthier than the overall US hemodialysis population, partly limiting generalizability.
Conclusions
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.
doi:10.1053/j.ajkd.2012.08.035
PMCID: PMC3546146  PMID: 23040011
Hemodialysis; brain abnormalities; cerebral atrophy; white matter disease; magnetic resonance imaging (MRI)
13.  Apolipoprotein E and kidney function in older adults 
Clinical nephrology  2012;78(3):174-180.
Background
Previous studies suggest that the ε4 and ε2 alleles of apolipoprotein E (APOE) may be associated with decreased and increased risks of CKD, respectively, but there are limited data in older adults. We evaluated the associations of apolipoprotein E alleles with kidney function among older adults in the cardiovascular health study (CHS).
Methods
Caucasian participants had APOE allelic analysis and serum creatinine and cystatin C measured at baseline (n = 3,844 for cross sectional analysis) and in follow up (n = 3,226 for longitudinal analysis). APOE variation was evaluated as an additive model with number of ε2, ε3 and ε4 alleles. GFR was estimated using the CKD epidemiology equation (eGFRcreat) and the cystatin C demographic equation (eGFRcys). The primary outcome was CKD defined by eGFR < 60 ml/min/1.73 m2. The secondary outcome was rapid progression defined by annual loss of eGFR > 3 ml/min/1.73 m2.
Results
Mean eGFRcreat was 72 ml/min/1.73 m2 (25% CKD). Compared with the ε3 allele, the APOE ε4 allele was associated with reduced risk of CKD by eGFRcreat: unadjusted odds ratio (OR) and 95% confidence interval (CI) 0.79 (0.67 – 0.93) per allele, fully adjusted OR (95% CI) 0.80 (0.68 – 0.96) per allele. Results were consistent using eGFRcys. There was no association of the ε2 allele with CKD or between the apolipoprotein E gene with rapid progression.
Conclusions
The apolipoprotein ε4 allele was associated with lower odds of CKD in elderly Caucasian individuals. Future research should confirm these findings in other races and explore mechanisms to explain these results.
PMCID: PMC3874583  PMID: 22874105
apolipoprotein E; chronic kidney disease; kidney function; elderly
14.  Influence of Urine Creatinine Concentrations on the Relation of Albumin-Creatinine Ratio With Cardiovascular Disease Events: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Higher urine albumin-creatinine ratio (ACR) is associated with cardiovascular disease (CVD) events, an association that is stronger than that between spot urine albumin on its own and CVD. Urine creatinine is correlated with muscle mass, and low muscle mass is also associated with CVD. Whether low urine creatinine in the denominator of the ACR contributes to the association of ACR with CVD is uncertain.
Study Design
Prospective cohort study.
Setting & Participants
6,770 community-living individuals without CVD.
Predictors
Spot urine albumin, the reciprocal of the urine creatinine concentration (1/UCr), and ACR.
Outcome
Incident CVD events.
Results
During a mean of 7.1 years’ follow-up, 281 CVD events occurred. Geometric means for spot urine creatinine, urine albumin and ACR were 95 ± 2 (SD) mg/dl, 0.7 ± 3.7 mg/dl and 7.0 ± 3.1 mg/g. Adjusted HRs per 2-fold higher increment in each urinary measures with CVD events were similar (1/UCr: 1.07 [95% CI, 0.94-1.22]; urine albumin: 1.08 [95% CI, 1.01-1.14]; and ACR: 1.11 [95% CI, 1.04-1.18]). Urine creatinine was lower in older, female, and low weight individuals. ACR ≥10 mg/g was more strongly associated with CVD events in individuals with low weight (HR for lowest vs. highest tertile: 4.34 vs. 1.97; p for interaction=0.006). Low weight also modified the association of urine albumin with CVD (p for interaction=0.06), but 1/urine creatinine did not (p for interaction=0.9).
Limitations
We lacked 24-hour urine data.
Conclusions
While ACR is more strongly associated with CVD events among persons with low body weight, this association is not driven by differences in spot urine creatinine. Overall, the associations of ACR with CVD events appear to be driven primarily by urine albumin and less by urine creatinine.
doi:10.1053/j.ajkd.2013.05.010
PMCID: PMC3783582  PMID: 23830183
15.  Association of Obesity and Kidney Function Decline among Non-Diabetic Adults with eGFR > 60 ml/min/1.73m2: Results from the Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Obesity is associated with higher end-stage renal disease incidence, but associations with earlier forms of kidney disease remain incompletely characterized.
Methods
We studied the association of body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) with rapid kidney function decline and incident chronic kidney disease in 4573 non-diabetic adults with eGFR ≥ 60 ml/min/1.73m2 at baseline from longitudinal Multi-Ethnic Study of Atherosclerosis cohort. Kidney function was estimated by creatinine and cystatin C. Multivariate analysis was adjusted for age, race, baseline eGFR, and hypertension.
Results
Mean age was 60 years old, BMI 28 kg/m2, baseline eGFRCr 82 and eGFRCys 95 ml/min/1.73m2. Over 5 years of follow up, 25% experienced rapid decline in renal function by eGFRCr and 22% by eGFRCys. Incident chronic kidney disease (CKD) developed in 3.3% by eGFRCys, 11% by eGFRCr, and 2.4% by both makers. Compared to persons with BMI < 25, overweight (BMI 25 – 30) persons had the lowest risk of rapid decline by eGFRCr (0.84, 0.71 – 0.99). In contrast, higher BMI categories were associated with stepwise higher odds of rapid decline by eGFRCys, but remained significant only when BMI ≥ 35 kg/m2 (1.87, 1.41 – 2.48). Associations of BMI with incident CKD were insignificant after adjustment. Large WC and WHR were associated with increased risk of rapid decline only by eGFRCys, and of incident CKD only when defined by both filtration markers.
Conclusions
Obesity may be a risk factor for kidney function decline, but associations vary by filtration marker used.
PMCID: PMC4157691  PMID: 25210651
Kidney Function Decline; MESA; Obesity; Waist Circumference; Waist-to-Hip Ratio
16.  Cystatin C versus Creatinine in Determining Risk Based on Kidney Function 
The New England journal of medicine  2013;369(10):932-943.
BACKGROUND
Adding the measurement of cystatin C to that of serum creatinine to determine the estimated glomerular filtration rate (eGFR) improves accuracy, but the effect on detection, staging, and risk classification of chronic kidney disease across diverse populations has not been determined.
METHODS
We performed a meta-analysis of 11 general-population studies (with 90,750 participants) and 5 studies of cohorts with chronic kidney disease (2960 participants) for whom standardized measurements of serum creatinine and cystatin C were available. We compared the association of the eGFR, as calculated by the measurement of creatinine or cystatin C alone or in combination with creatinine, with the rates of death (13,202 deaths in 15 cohorts), death from cardiovascular causes (3471 in 12 cohorts), and end-stage renal disease (1654 cases in 7 cohorts) and assessed improvement in reclassification with the use of cystatin C.
RESULTS
In the general-population cohorts, the prevalence of an eGFR of less than 60 ml per minute per 1.73 m2 of body-surface area was higher with the cystatin C–based eGFR than with the creatinine-based eGFR (13.7% vs. 9.7%). Across all eGFR categories, the reclassification of the eGFR to a higher value with the measurement of cystatin C, as compared with creatinine, was associated with a reduced risk of all three study outcomes, and reclassification to a lower eGFR was associated with an increased risk. The net reclassification improvement with the measurement of cystatin C, as compared with creatinine, was 0.23 (95% confidence interval [CI], 0.18 to 0.28) for death and 0.10 (95% CI, 0.00 to 0.21) for end-stage renal disease. Results were generally similar for the five cohorts with chronic kidney disease and when both creatinine and cystatin C were used to calculate the eGFR.
CONCLUSIONS
The use of cystatin C alone or in combination with creatinine strengthens the association between the eGFR and the risks of death and end-stage renal disease across diverse populations. (Funded by the National Kidney Foundation and others.)
doi:10.1056/NEJMoa1214234
PMCID: PMC3993094  PMID: 24004120
17.  Blood Pressure Components and Decline in Kidney Function in Community-Living Older Adults: The Cardiovascular Health Study 
American Journal of Hypertension  2013;26(8):1037-1044.
BACKGROUND
Although hypertension contributes to kidney dysfunction in the general population, the contributions of elevated systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) to kidney function decline in community-dwelling older adults are unknown.
METHODS
We used linear and logistic regression to examine the separate and combined associations of SBP, DBP, and PP at baseline with kidney function decline among 4,365 older adults in the Cardiovascular Health Study. We used cystatin C to estimate glomerular filtration rate on 3 occasions over 7 years of follow-up. We defined rapid decline ≥ 3ml/min/year.
RESULTS
Average age was 72.2 and mean (standard deviation) SBP, DBP, and PP were 135 (21), 71 (11), and 65 (18) mm Hg, respectively. SBP and PP, rather than DBP, were most significantly associated with kidney function decline. In adjusted linear models, each 10-mm Hg increment in SBP and PP was associated with 0.13ml/min/year (–0.19, –0.08, P < 0.001) and 0.15-ml/min/year faster decline (–0.21, –0.09, P < 0.001), respectively. Each 10-mm Hg increment in DBP was associated with a nonsignificant 0.10-ml/min/year faster decline (95% confidence interval, –0.20, 0.01). In adjusted logistic models, SBP had the strongest associations with rapid decline, with 14% increased hazard of rapid decline (95% confidence interval, 10% to 17%, P < 0.01) per 10mm Hg. In models combining BP components, only SBP consistently had independent associations with rapid decline.
CONCLUSIONS
Our findings suggest that elevated BP, particularly SBP, contributes to declining kidney function in older adults.
doi:10.1093/ajh/hpt067
PMCID: PMC3816322  PMID: 23709568
blood pressure; cystatin C; diastolic blood pressure; elderly; hypertension; kidney function; systolic blood pressure.
18.  The Association of Chronic Kidney Disease Complications by Glomerular Filtration Rate and Albuminuria: A Cross-sectional Analysis 
Clinical nephrology  2013;80(1):29-39.
Background
Albuminuria is strongly associated with future risk for cardiovascular and kidney outcomes, and has been proposed to be included in the classification of chronic kidney disease (CKD) along with glomerular filtration rate (GFR). Few data are available on whether albuminuria is associated with concurrent complications of CKD.
Study Design
Cross-Sectional
Setting & Participants
The Modification of Diet in Renal Disease (MDRD) Study examined the effects of dietary protein restriction and blood pressure control on the progression of kidney disease. This analysis includes 1665 participants screened for the MDRD Study.
Predictors
Urine albumin-creatinine ratio (ACR) and measured GFR using urinary clearance of iothalamate.
Outcomes & Measurements
Associations between ACR categories and GFR categories with anemia, acidosis, hyperphosphatemia and hypertension were evaluated using log-binomial regression.
Results
Mean GFR (±SD) was 39 ml/min/1.73m2 (± 21) and the median (25th–75th percentile) ACR was 161 (38–680) mg/g. In multivariable models adjusted for age, sex, race, kidney disease etiology and GFR, higher ACR levels were not associated with any complication. For example, comparing ACR > 300 mg/g versus < 30 mg/g, the prevalence ratio (95% CI) for anemia was 0.98 (0.81–1.20), acidosis 1.13 (0.86–1.48), hyperphosphatemia 1.69 (0.91–3.17) and hypertension 1.04 (0.97–1.12). Lower levels of GFR were associated with all complications. For example, GFR levels < 30 ml/min/1.73m2 versus GFR levels 60–89 ml/min/1.73m2 were associated with prevalence ratios (95% CI) of anemia 4.35 (3.18–5.96), acidosis 5.31 (3.41–8.29), hyperphosphatemia 23.8 (7.71–73.6) and hypertension 1.21 (1.10–1.32).
Limitations
Limited generalizability; lack of data on other complications that may be related to CKD.
Conclusions
Albuminuria is not associated with complications after controlling for GFR and thus would not affect clinical action plans for decisions regarding evaluation and treatment of complications.
PMCID: PMC4108165  PMID: 23803596
Albuminuria; GFR; CKD; complications
19.  The Relationship between Non-Traditional Risk Factors and Outcomes in Individuals with Stage 3-4 CKD 
Background
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
Cohort
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
Predictors
Non-traditional cardiovascular disease risk factors including body mass index, diastolic blood pressure, triglycerides, albumin, uric acid, fibrinogen, c-reactive protein, and hemoglobin
Outcomes
Composite of myocardial infarction, stroke and all-cause mortality. Secondary outcomes included individual components of the composite.
Results
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).
Limitations
Single assessment of eGFR. No albuminuria data.
Conclusions
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.
doi:10.1053/j.ajkd.2007.10.035
PMCID: PMC4083633  PMID: 18215699
Chronic kidney disease; cardiovascular disease; risk factors; inflammation; cholesterol
20.  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.
doi:10.1038/ki.2008.75
PMCID: PMC4083694  PMID: 18401337
21.  Waist to Hip Ratio, Body Mass Index and Subsequent Kidney Disease and Death 
Background
Chronic kidney disease (CKD) and obesity are important public health concerns. We examined the association between anthropomorphic measures and incident CKD and mortality.
Design
Cohort
Setting and Participants
Individual patient data pooled from the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study
Exposures
Waist to hip ratio (WHR), body mass index (BMI)
Outcomes
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.
Analysis
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.
Results
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.
Limitations
Single measures of creatinine, no albuminuria data.
Conclusions
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.
doi:10.1053/j.ajkd.2008.02.363
PMCID: PMC4052757  PMID: 18511168
22.  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
doi:10.1038/nrneph.2012.285
PMCID: PMC4037697  PMID: 23296300
23.  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.
Background
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.
Methods
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.
Findings
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.
Interpretation
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.
Funding
The US National Kidney Foundation (sources include Abbott and Amgen).
doi:10.1016/S0140-6736(12)61272-0
PMCID: PMC3993095  PMID: 23013600
24.  Apolipoprotein E and kidney function in older adults  
Clinical Nephrology  2012;78(3):174-180.
Background: Previous studies suggest that the ε4 and ε2 alleles of apolipoprotein E (APOE) may be associated with decreased and increased risks of CKD, respectively, but there are limited data in older adults. We evaluated the associations of apolipoprotein E alleles with kidney function among older adults in the cardiovascular health study (CHS). Methods: Caucasian participants had APOE allelic analysis and serum creatinine and cystatin C measured at baseline (n = 3,844 for cross sectional analysis) and in follow up (n = 3,226 for longitudinal analysis). APOE variation was evaluated as an additive model with number of ε2, ε3 and ε4 alleles. GFR was estimated using the CKD epidemiology equation (eGFRcreat) and the cystatin C demographic equation (eGFRcys). The primary outcome was CKD defined by eGFR < 60 ml/min/1.73 m2. The secondary outcome was rapid progression defined by annual loss of eGFR > 3 ml/min/1.73 m2. Results: Mean eGFRcreat was 72 ml/min/1.73 m2 (25% CKD). Compared with the ε3 allele, the APOE ε4 allele was associated with reduced risk of CKD by eGFRcreat: unadjusted odds ratio (OR) and 95% confidence interval (CI) 0.79 (0.67 – 0.93) per allele, fully adjusted OR (95% CI) 0.80 (0.68 – 0.96) per allele. Results were consistent using eGFRcys. There was no association of the ε2 allele with CKD or between the apolipoprotein E gene with rapid progression. Conclusions: The apolipoprotein ε4 allele was associated with lower odds of CKD in elderly Caucasian individuals. Future research should confirm these findings in other races and explore mechanisms to explain these results.
doi:10.5414/CN107427
PMCID: PMC3874583  PMID: 22874105
apolipoprotein E; chronic kidney disease; kidney function; elderly
25.  Hypertension and Low HDL-Cholesterol were Associated with Reduced Kidney Function Across the Age Spectrum: A Collaborative Study 
Annals of epidemiology  2013;23(3):106-111.
Purpose
To determine if the associations among established risk factors and reduced kidney function vary by age.
Methods
We pooled cross-sectional data from 14,788 non-diabetics aged 40–100 years in 4 studies: Cardiovascular Health Study, Health, Aging, and Body Composition Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-Stage Disease cohort.
Results
Hypertension and low HDL-cholesterol were associated with reduced cystatin C-based estimated glomerular filtration rate (eGFR) across the age spectrum. In adjusted analyses, hypertension was associated with a 2.3 (95% CI 0.1, 4.4), 5.1 (4.1, 6.1), and 6.9 (3.0, 10.4) mL/min/1.73 m2 lower eGFR in participants 40–59, 60–79, and 80+ years, respectively (p-value for interaction <0.001). The association of low HDL-cholesterol with reduced kidney function was also greater in the older age groups: 4.9 (3.5, 6.3), 7.1 (CI 6.0, 8.3), 8.9 (CI 5.4, 11.9) mL/min/1.73 m2 (p-value for interaction <0.001). Smoking and obesity were associated with reduced kidney function in participants under 80 years. All estimates of the potential population impact of the risk factors were modest.
Conclusions
Hypertension, obesity, smoking, and low HDL-cholesterol are modestly associated with reduced kidney function in non-diabetics. The associations of hypertension and HDL-cholesterol with reduced kidney function appear stronger in older adults.
doi:10.1016/j.annepidem.2012.12.004
PMCID: PMC3570601  PMID: 23313266
Chronic kidney insufficiency; aged; hypertension; cholesterol; obesity; smoking

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