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1.  Antihypertensive Medication Use and Change in Kidney Function in Elderly Adults: A Marginal Structural Model Analysis 
The evidence for the effectiveness of antihypertensive medication use for slowing decline in kidney function in older persons is sparse. We addressed this research question by the application of novel methods in a marginal structural model.
Change in kidney function was measured by two or more measures of cystatin C in 1,576 hypertensive participants in the Cardiovascular Health Study over 7 years of follow-up (1989–1997 in four U.S. communities). The exposure of interest was antihypertensive medication use. We used a novel estimator in a marginal structural model to account for bias due to confounding and informative censoring.
The mean annual decline in eGFR was 2.41 ± 4.91 mL/min/1.73 m2. In unadjusted analysis, antihypertensive medication use was not associated with annual change in kidney function. Traditional multivariable regression did not substantially change these estimates. Based on a marginal structural analysis, persons on antihypertensives had slower declines in kidney function; participants had an estimated 0.88 (0.13, 1.63) ml/min/1.73 m2 per year slower decline in eGFR compared with persons on no treatment. In a model that also accounted for bias due to informative censoring, the estimate for the treatment effect was 2.23 (−0.13, 4.59) ml/min/1.73 m2 per year slower decline in eGFR.
In summary, estimates from a marginal structural model suggested that antihypertensive therapy was associated with preserved kidney function in hypertensive elderly adults. Confirmatory studies may provide power to determine the strength and validity of the findings.
PMCID: PMC3204667  PMID: 22049266
aged; kidney function; hypertension; marginal structural model
2.  Kidney Function and Mortality in Octogenarians: Cardiovascular Health Study All Stars 
To examine the association between kidney function and all-cause mortality in octogenarians.
Retrospective analysis of prospectively collected data.
Serum creatinine and cystatin C were measured in 1,053 Cardiovascular Health Study (CHS) All Stars participants.
Estimated glomerular filtration rate (eGFR) was determined using the Chronic Kidney Disease Epidemiology Collaboration creatinine (eGFRCR) and cystatin C one-variable (eGFRCYS) equations. The association between quintiles of kidney function and all-cause mortality was analyzed using unadjusted and adjusted Cox proportional hazards models.
Mean age of the participants was 85, 64% were female, 66% had hypertension, 14% had diabetes mellitus, and 39% had prevalent cardiovascular disease. There were 154 deaths over a median follow-up of 2.6 years. The association between eGFRCR and all-cause mortality was U-shaped. In comparison with the reference quintile (64–75 mL/min per 1.73 m2), the highest (≥75 mL/min per 1.73 m2) and lowest (≤43 mL/min per 1.73 m2) quintiles of eGFRCR were independently associated with mortality (hazard ratio (HR) = 2.49, 95% confidence interval (CI) = 1.36–4.55; HR = 2.28, 95% CI = 1.26–4.10, respectively). The association between eGFRCYS and all-cause mortality was linear in those with eGFRCYS of less than 60 mL/min per 1.73 m2, and in the multivariate analyses, the lowest quintile of eGFRCYS (<52 mL/min per 1.73 m2) was significantly associated with mortality (HR = 2.04, 95% CI = 1.12–3.71) compared with the highest quintile (>0.88 mL/min per 1.73 m2).
Moderate reduction in kidney function is a risk factor for all-cause mortality in octogenarians. The association between eGFRCR and all-cause mortality differed from that observed with eGFRCYS; the relationship was U-shaped for eGFRCR, whereas the risk was primarily present in the lowest quintile for eGFRCYS. J Am Geriatr Soc 2012.
PMCID: PMC3902776  PMID: 22724391
octogenarians; kidney function; mortality
3.  Measures of Blood Pressure and Cognition in Dialysis Patients 
There are few reports on the relationship of blood pressure with cognitive function in maintenance dialysis patients.
The Cognition and Dialysis Study is an ongoing investigation of cognitive function and its risk factors in 6 Boston area hemodialysis units. In this analysis we evaluated the relationship between different domains of cognitive function with systolic and diastolic blood pressure, pulse pressure, and intradialytic changes in systolic blood pressure, using univariate and multivariable linear regression models adjusted for age, sex, race, education and primary cause of end stage renal disease (ESRD).
Among 314 participants, mean age was 63 years; 47% were female, 22% African American and 48% had diabetes. Mean (SD) of systolic blood pressure, diastolic blood pressure, pulse pressure and intradialytic change in systolic blood pressure were 141 (21), 73 (12), 68 (15) and -10 (24) mm Hg, respectively. In univariate analyses, the performance on cognitive tests primarily assessing executive function and processing speeds was worse among participants with lower diastolic blood pressure and higher pulse pressure. These relationships were not statistically significant, however, in multivariable analyses. There was no association between cognitive function and systolic blood pressure or intradialytic change in systolic blood pressure in either univariate or multivariable analyses.
We found no association between different measures of blood pressure and cognitive function in cross sectional analysis. Longitudinal studies are needed to confirm these results.
PMCID: PMC4076621  PMID: 22716218
Blood pressure; Cognition; Dialysis
4.  Influence of Urine Creatinine Concentrations on the Relation of Albumin-Creatinine Ratio With Cardiovascular Disease Events: The Multi-Ethnic Study of Atherosclerosis (MESA) 
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.
Spot urine albumin, the reciprocal of the urine creatinine concentration (1/UCr), and ACR.
Incident CVD events.
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).
We lacked 24-hour urine data.
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.
PMCID: PMC3783582  PMID: 23830183
5.  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) 
Obesity is associated with higher end-stage renal disease incidence, but associations with earlier forms of kidney disease remain incompletely characterized.
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.
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.
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
6.  Cystatin C versus Creatinine in Determining Risk Based on Kidney Function 
The New England journal of medicine  2013;369(10):932-943.
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.
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.
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.
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.)
PMCID: PMC3993094  PMID: 24004120
7.  Blood Pressure Components and Decline in Kidney Function in Community-Living Older Adults: The Cardiovascular Health Study 
American Journal of Hypertension  2013;26(8):1037-1044.
Although hypertension contributes to kidney dysfunction in the general population, the contributions of elevated systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) to kidney function decline in community-dwelling older adults are unknown.
We used linear and logistic regression to examine the separate and combined associations of SBP, DBP, and PP at baseline with kidney function decline among 4,365 older adults in the Cardiovascular Health Study. We used cystatin C to estimate glomerular filtration rate on 3 occasions over 7 years of follow-up. We defined rapid decline ≥ 3ml/min/year.
Average age was 72.2 and mean (standard deviation) SBP, DBP, and PP were 135 (21), 71 (11), and 65 (18) mm Hg, respectively. SBP and PP, rather than DBP, were most significantly associated with kidney function decline. In adjusted linear models, each 10-mm Hg increment in SBP and PP was associated with 0.13ml/min/year (–0.19, –0.08, P < 0.001) and 0.15-ml/min/year faster decline (–0.21, –0.09, P < 0.001), respectively. Each 10-mm Hg increment in DBP was associated with a nonsignificant 0.10-ml/min/year faster decline (95% confidence interval, –0.20, 0.01). In adjusted logistic models, SBP had the strongest associations with rapid decline, with 14% increased hazard of rapid decline (95% confidence interval, 10% to 17%, P < 0.01) per 10mm Hg. In models combining BP components, only SBP consistently had independent associations with rapid decline.
Our findings suggest that elevated BP, particularly SBP, contributes to declining kidney function in older adults.
PMCID: PMC3816322  PMID: 23709568
blood pressure; cystatin C; diastolic blood pressure; elderly; hypertension; kidney function; systolic blood pressure.
8.  The Association of Chronic Kidney Disease Complications by Glomerular Filtration Rate and Albuminuria: A Cross-sectional Analysis 
Clinical nephrology  2013;80(1):29-39.
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
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.
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.
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).
Limited generalizability; lack of data on other complications that may be related to CKD.
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
9.  The Relationship between Non-Traditional Risk Factors and Outcomes in Individuals with Stage 3-4 CKD 
Chronic kidney disease is associated with an increased risk for cardiovascular disease and mortality. Both traditional and non-traditional cardiovascular disease risk factors may contribute.
Study Design
Settings & Participants
Community-based adult population of the Atherosclerosis Risk in Communities and Cardiovascular Health Studies with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2
Non-traditional cardiovascular disease risk factors including body mass index, diastolic blood pressure, triglycerides, albumin, uric acid, fibrinogen, c-reactive protein, and hemoglobin
Composite of myocardial infarction, stroke and all-cause mortality. Secondary outcomes included individual components of the composite.
Among 1,678 individuals with reduced eGFR (mean 51.1±8.5 mL/min/1.73m2), 891 (53%) reached the composite endpoint during median follow-up of 108 months; 23% had a cardiac event, 45% died and 14% experienced a stroke. Serum albumin levels below 3.9 g/dL [Hazard Ratio (HR)=0.68 (95% confidence interval 0.60,0.77) for every 0.3 g/dL decrease], elevated serum triglycerides [HR=1.07 (1.02,1.12) for every 50 mg/dL increase], C-reactive protein [HR=1.15 (1.07,1.24) per log-unit increase], and fibrinogen [HR=1.12 (1.07,1.18) per 50 mg/dL increase] independently predicted composite events. Both reduced (<14.5 g/dL) and elevated (>14.5 g/dL) hemoglobin level predicted composite events. Serum albumin levels below 3.9 g/dL and elevated serum fibrinogen independently predicted cardiac events. For serum albumin and hemoglobin, the relationship with composite and mortality outcomes was non-linear (p<0.001).
Single assessment of eGFR. No albuminuria data.
Several non-traditional cardiovascular disease risk factors predict adverse outcomes in individuals with stage 3-4 chronic kidney disease. The relationship between risk factors and outcomes is often non-linear.
PMCID: PMC4083633  PMID: 18215699
Chronic kidney disease; cardiovascular disease; risk factors; inflammation; cholesterol
10.  Inflammation and Cardiovascular Events in Individuals with and without Chronic Kidney Disease 
Kidney international  2008;73(12):1406-1412.
Inflammation and chronic kidney disease (CKD) predict cardiovascular events. Little is known about the interaction of inflammation and CKD. We evaluated inflammation markers (fibrinogen, albumin, white blood cell (WBC) count) in individuals with and without CKD to assess: 1) inflammation as a risk factor for adverse events; 2) synergy between inflammation and CKD; and 3) prognostic ability of these markers relative to c-reactive protein (CRP).
Using Atherosclerosis Risk in Communities and Cardiovascular Health Study data, inflammation was defined by 2 of 3 criteria: lowest albumin quartile and highest fibrinogen and race-specific WBC quartiles. CKD was defined as estimated glomerular filtration rate of 0.25-1 mL/sec/1.73m2. In Cox models, inflammation was assessed as a risk factor for a composite of cardiac events, stroke and mortality as well as components of this composite.
Among 20,413 individuals, mean WBC count was 6.2±2.0/L3, albumin 41±3 g/L, and fibrinogen 9.1±1.9 µmol/L. Inflammation was defined in 3,594 subjects and CKD in 1,649. In multivariable analyses, while both inflammation and CKD predicted all outcomes, their interaction was non-significant. In those with CRP measurements (Cardiovascular Health Study only, n=5,597), inflammation and elevated CRP had similar hazard ratios. When focusing only on worst quartile of WBC and albumin, results remained consistent.
CKD and inflammation are associated with an increased risk of adverse events but do not exhibit synergy. The composite of albumin, WBC count and fibrinogen as well as the composite of only albumin and WBC count have a similar association with adverse events as CRP.
PMCID: PMC4083694  PMID: 18401337
11.  Anatomic Brain Disease in Hemodialysis Patients: A Cross-sectional Study 
Although dialysis patients are at high risk for stroke and have a high burden of cognitive impairment, there are few reports on anatomic brain findings in the hemodialysis population. Using brain magnetic resonance imaging (MRI), we compared the prevalence of brain abnormalities in hemodialysis patients to a control population without known kidney disease.
Study Design
Cross-sectional cohort.
Setting & Participants
45 maintenance hemodialysis patients and 67 controls without reported kidney disease, both without prior history of known stroke.
The primary predictor was dialysis status. Covariates included demographics (age, race, sex), vascular risk factors (diabetes and hypertension) and cardiovascular disease (coronary artery disease, congestive heart failure).
Brain MRI features including severity of white matter disease and cerebral atrophy (sulcal prominence and ventricular atrophy), hippocampal size, and small/large vessel infarcts.
Semi-quantitative scale (0-9 for white matter disease and cerebral atrophy, 0-3 for hippocampal size) and infarct prevalence.
The mean age of hemodialysis patients and controls was 55 ± 17 (SD) and 53 ± 13 years, respectively. In comparison with controls, hemodialysis patients had more severe white matter disease (1.6 v 0.7) and cerebral atrophy (sulcal prominence = 2.3 v 0.6; ventricular enlargement = 2.3 v 0.9; hippocampal size = 1.3 v 1.0) with all p-values <0.001. In multivariable analyses, hemodialysis status was independently associated with worse white matter disease and atrophy grades. Hemodialysis patients also had a higher prevalence of small (17.8%) and large (7.8%) vessel infarcts than controls (combined 22% vs 0%, p<0.001).
The dialysis cohort is likely healthier than the overall US hemodialysis population, partly limiting generalizability.
Hemodialysis patients have more white matter disease and cerebral atrophy compared to controls without known kidney disease. Hemodialysis patients also have a high prevalence of unrecognized infarcts.
PMCID: PMC3546146  PMID: 23040011
Hemodialysis; brain abnormalities; cerebral atrophy; white matter disease; magnetic resonance imaging (MRI)
12.  Waist to Hip Ratio, Body Mass Index and Subsequent Kidney Disease and Death 
Chronic kidney disease (CKD) and obesity are important public health concerns. We examined the association between anthropomorphic measures and incident CKD and mortality.
Setting and Participants
Individual patient data pooled from the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study
Waist to hip ratio (WHR), body mass index (BMI)
Incident CKD defined as serum creatinine rise of >0.4 mg/dL with baseline creatinine ≤1.4 mg/dL in men and 1.2 mg/dL in women and final creatinine above these levels, and, in separate analyses, as estimated glomerular filtration rate (eGFR) decline ≥15 mL/min/1.73m2 with baseline eGFR ≥60 and final eGFR <60 mL/min/1.73m2.
Multivariable logistic regression to determine the association between waist to hip ratio (WHR), body mass index (BMI) and outcomes. Cox models to evaluate a secondary composite outcome of all-cause mortality and incident CKD.
Among 13,324 individuals, mean WHR was 0.96 in men and 0.89 in women and mean BMI was 27.2 kg/m2 in both men and women. Over 9.3 years, 300 (2.3%) in creatinine-based models and 710 (5.5%) in eGFR-based models developed CKD. In creatinine-based models, each standard deviation increase in WHR was associated with an increased risk of incident CKD [Odds ratio=1.22 (1.05, 1.43)] and the composite outcome [Hazard ratio=1.12 (1.06, 1.18)], while each standard deviation increase in BMI was not associated with CKD [Odds ratio=1.05 (0.93, 1.20)] and appeared protective for the composite outcome [Hazard ratio=0.94 (0.90, 0.99)]. Results of eGFR-based models were similar.
Single measures of creatinine, no albuminuria data.
WHR but not BMI is associated with incident CKD and mortality. Assessment of CKD risk should utilize WHR rather than BMI as an anthropomorphic measure of obesity.
PMCID: PMC4052757  PMID: 18511168
13.  Cardiovascular disease in CKD in 2012 
Nature reviews. Nephrology  2013;9(2):69-70.
During 2012, an observational study confirmed the high risk of cardiovascular disease ascribed to chronic kidney disease (CKD) and again raised the question of whether CKD should be considered a cardiovascular disease risk equivalent. Several other studies evaluated methods to mitigate cardiovascular risk in CKD. Although the results of these studies have advanced the field they have also raised more questions
PMCID: PMC4037697  PMID: 23296300
14.  Apolipoprotein E and kidney function in older adults 
Clinical nephrology  2012;78(3):174-180.
Previous studies suggest that the ε4 and ε2 alleles of apolipoprotein E (APOE) may be associated with decreased and increased risks of CKD, respectively, but there are limited data in older adults. We evaluated the associations of apolipoprotein E alleles with kidney function among older adults in the cardiovascular health study (CHS).
Caucasian participants had APOE allelic analysis and serum creatinine and cystatin C measured at baseline (n = 3,844 for cross sectional analysis) and in follow up (n = 3,226 for longitudinal analysis). APOE variation was evaluated as an additive model with number of ε2, ε3 and ε4 alleles. GFR was estimated using the CKD epidemiology equation (eGFRcreat) and the cystatin C demographic equation (eGFRcys). The primary outcome was CKD defined by eGFR < 60 ml/min/1.73 m2. The secondary outcome was rapid progression defined by annual loss of eGFR > 3 ml/min/1.73 m2.
Mean eGFRcreat was 72 ml/min/1.73 m2 (25% CKD). Compared with the ε3 allele, the APOE ε4 allele was associated with reduced risk of CKD by eGFRcreat: unadjusted odds ratio (OR) and 95% confidence interval (CI) 0.79 (0.67 – 0.93) per allele, fully adjusted OR (95% CI) 0.80 (0.68 – 0.96) per allele. Results were consistent using eGFRcys. There was no association of the ε2 allele with CKD or between the apolipoprotein E gene with rapid progression.
The apolipoprotein ε4 allele was associated with lower odds of CKD in elderly Caucasian individuals. Future research should confirm these findings in other races and explore mechanisms to explain these results.
PMCID: PMC3874583  PMID: 22874105
apolipoprotein E; chronic kidney disease; kidney function; elderly
15.  Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension: a meta-analysis 
Lancet  2012;380(9854):1649-1661.
Hypertension is the most prevalent comorbidity in individuals with chronic kidney disease (CKD). It is unknown, however, whether the association of the CKD measures, estimated glomerular filtration rate (eGFR) and albuminuria, with mortality or end-stage renal disease (ESRD) differs by hypertensive status.
We performed a meta-analysis of 45 cohorts (25 general population, 7 high-risk and 13 CKD cohorts), including 1,127,656 participants (364,344 with hypertension). Adjusted hazard ratios (HRs) for all-cause mortality (84,078 deaths from 40 cohorts) and ESRD (7,587 events from 21 cohorts) by hypertensive status were obtained for each study and pooled using random-effects models.
Low eGFR and high albuminuria were associated with mortality in both non-hypertensive and hypertensive individuals in the general population and high-risk cohorts. Mortality risk was higher in hypertensives as compared to non-hypertensives at preserved eGFR but a steeper relative risk gradient among non-hypertensives than hypertensives at eGFR range 45-75 ml/min/1.73m2 led to similar mortality risk at lower eGFR. With a reference eGFR of 95 mL/min/1.73m2 in each group to explicitly assess interaction, adjusted HR for all-cause mortality at eGFR 45 mL/min/1.73m2 was 1.77 (95% CI, 1.57-1.99) in non-hypertensives versus 1.24 (1.11-1.39) in hypertensives (P for overall interaction =0.0003). Similarly, for albumin-creatinine ratio (ACR) of 300 mg/g (vs. 5 mg/g), HRs were 2.30 (1.98-2.68) in non-hypertensives versus 2.08 (1.84-2.35) in hypertensives (P for overall interaction=0.019). Similar results were observed for cardiovascular mortality. The associations of eGFR and albuminuria with ESRD, however, did not differ by hypertensive status. Results in CKD cohorts were comparable to results in general and high-risk population cohorts.
Low eGFR and elevated albuminuria were more strongly associated with mortality among individuals without hypertension than in those with hypertension, but the associations with ESRD were similar. CKD should be considered at least an equally relevant risk factor for mortality and ESRD in non-hypertensive as it is in hypertensive individuals.
The US National Kidney Foundation (sources include Abbott and Amgen).
PMCID: PMC3993095  PMID: 23013600
16.  Hypertension and Low HDL-Cholesterol were Associated with Reduced Kidney Function Across the Age Spectrum: A Collaborative Study 
Annals of epidemiology  2013;23(3):106-111.
To determine if the associations among established risk factors and reduced kidney function vary by age.
We pooled cross-sectional data from 14,788 non-diabetics aged 40–100 years in 4 studies: Cardiovascular Health Study, Health, Aging, and Body Composition Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-Stage Disease cohort.
Hypertension and low HDL-cholesterol were associated with reduced cystatin C-based estimated glomerular filtration rate (eGFR) across the age spectrum. In adjusted analyses, hypertension was associated with a 2.3 (95% CI 0.1, 4.4), 5.1 (4.1, 6.1), and 6.9 (3.0, 10.4) mL/min/1.73 m2 lower eGFR in participants 40–59, 60–79, and 80+ years, respectively (p-value for interaction <0.001). The association of low HDL-cholesterol with reduced kidney function was also greater in the older age groups: 4.9 (3.5, 6.3), 7.1 (CI 6.0, 8.3), 8.9 (CI 5.4, 11.9) mL/min/1.73 m2 (p-value for interaction <0.001). Smoking and obesity were associated with reduced kidney function in participants under 80 years. All estimates of the potential population impact of the risk factors were modest.
Hypertension, obesity, smoking, and low HDL-cholesterol are modestly associated with reduced kidney function in non-diabetics. The associations of hypertension and HDL-cholesterol with reduced kidney function appear stronger in older adults.
PMCID: PMC3570601  PMID: 23313266
Chronic kidney insufficiency; aged; hypertension; cholesterol; obesity; smoking
17.  Frequency of and risk factors for poor cognitive performance in hemodialysis patients 
Neurology  2013;80(5):471-480.
There are few detailed data on cognition in patients undergoing dialysis. We evaluated the frequency of and risk factors for poor cognitive performance using detailed neurocognitive testing.
In this cross-sectional cohort study, 314 hemodialysis patients from 6 Boston-area hemodialysis units underwent detailed cognitive assessment. The neuropsychological battery assessed a broad range of functions, with established age-, sex-, and education-matched normative scores. Principal component analysis was used to derive composite scores for memory and executive function domains. Risk factors for each domain were evaluated using linear regression adjusting for age, sex, race, and education status. Analyses were repeated in those with Mini-Mental State Examination (MMSE) score ≥24.
Compared with population norms, patients on dialysis had significantly poorer executive function but not memory performance, a finding that persisted in the subgroup with MMSE score ≥24. In adjusted analyses, vascular risk factors and vascular disease were associated with lower executive function (p < 0.01).
There is a high frequency of poor cognitive performance in hemodialysis patients, primarily affecting executive function. Risk factors for worse executive function include vascular risk factors as well as vascular disease. Normal performance on the MMSE does not preclude impaired cognitive function, because individuals with MMSE score ≥24 also have a high frequency of poor cognitive performance.
PMCID: PMC3590049  PMID: 23303848
18.  Urinary Markers of Kidney Injury and Kidney Function Decline in HIV-Infected Women 
HIV-infected persons have substantially higher risk of kidney failure than persons without HIV, but serum creatinine levels are insensitive for detecting declining kidney function. We hypothesized that urine markers of kidney injury would be associated with declining kidney function among HIV-infected women.
In the Women's Interagency HIV Study (WIHS), we measured concentrations of albumin-to-creatinine ratio (ACR), interleukin-18 (IL-18), kidney injury marker-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) from stored urine among 908 HIV-infected and 289 uninfected participants. Primary analyses used cystatin C based estimated glomerular filtration rate (CKD-EPI eGFRcys) as the outcome, measured at baseline and two follow-up visits over eight years; secondary analyses used creatinine (CKD-EPI eGFRcr). Each urine biomarker was categorized into tertiles, and kidney decline was modeled with both continuous and dichotomized outcomes.
Compared with the lowest tertiles, the highest tertiles of ACR (−0.15ml/min/1.73m2, p<0.0001), IL-18 (−0.09ml/min/1.73m2, p<0.0001) and KIM-1 (−0.06ml/min/1.73m2, p<0.001) were independently associated with faster eGFRcys decline after multivariate adjustment including all three biomarkers among HIV-infected women. Among these biomarkers, only IL-18 was associated with each dichotomized eGFRcys outcome: ≥3% (Relative Risk 1.40; 95%CI 1.04-1.89); ≥5% (1.88; 1.30-2.71); and ≥10% (2.16; 1.20-3.88) for the highest versus lowest tertile. In alternative models using eGFRcr, the high tertile of KIM-1 had independent associations with 5% (1.71; 1.25-2.33) and 10% (1.78; 1.07-2.96) decline, and the high IL-18 tertile with 10% decline (1.97; 1.00-3.87).
Among HIV-infected women in the WIHS cohort, novel urine markers of kidney injury detect risk for subsequent declines in kidney function.
PMCID: PMC3509242  PMID: 23023103
HIV; KIM-1; NGAL; IL-18; albumin-to-creatinine ratio; cystatin C; kidney injury
19.  Long-term Assessment of Inflammation and Healthy Aging in Late Life: The Cardiovascular Health Study All Stars 
Associations of inflammation with age-related pathologies are documented; however, it is not understood how changes in inflammation over time impact healthy aging.
We examined associations of long-term change in C-reactive protein (CRP) and interleukin-6 (IL-6) with concurrent onset of physical and cognitive impairment, subsequent cardiovascular disease (CVD), and mortality in 1,051 participants in the Cardiovascular Health Study All Stars Study. Biomarkers were measured in 1996–1997 and 2005–2006.
In 2005–2006, median age was 84.9 years, 63% were women and 17% non-white; 21% had at least a doubling in CRP over time and 23% had at least a doubling in IL-6. Adjusting for demographics, CVD risk factors, and 1996–1997 CRP level, each doubling in CRP change over 9 years was associated with higher risk of physical or cognitive impairment (odds ratio 1.29; 95% confidence interval 1.15, 1.45). Results were similar for IL-6 (1.45; 1.20, 1.76). A doubling in IL-6 change over time, but not CRP, was associated with incident CVD events; hazard ratio (95% confidence interval) 1.34 (1.03, 1.75). Doubling in change in each biomarker was individually associated with mortality (CRP: 1.12 [1.03, 1.22]; IL-6 1.39 [1.16, 1.65]). In models containing both change and 2005–2006 level, only level was associated with CVD events and mortality.
Although increases in inflammation markers over 9 years were associated with higher concurrent risk of functional impairment and subsequent CVD events and mortality, final levels of each biomarker appeared to be more important in determining risk of subsequent events than change over time.
PMCID: PMC3436091  PMID: 22367431
Inflammation; Aging; Physical function; Cognitive function
20.  The Kidney Disease Quality of Life Cognitive Function Subscale and Cognitive Performance in Maintenance Hemodialysis Patients 
Cognitive impairment is common but often undiagnosed in patients with end-stage renal disease, in part reflecting limited validated and easily administered tools to assess cognitive function in dialysis patients. Accordingly, we assessed the utility of the Kidney Disease Quality of Life Cognitive Function (KDQOL-CF) scale in comparison to an extensive neuropsychological battery, building on a prior assessment of this potential cognitive screen.
Study Design
Cross-sectional cohort.
Setting & Participants
Maintenance hemodialysis patients at 6 Boston area dialysis units were administered an extensive neurocognitive battery and the KDQOL-CF at the beginning of a hemodialysis session.
KDQOL-CF score, depression symptom burden, and demographic and clinical characteristics.
Neurocognitive performance classified into executive function and memory domains, determined using principal components analysis.
Univariate and multivariable linear regression models adjusting for age, sex, race, and end-stage renal disease cause were used to evaluate the association between KDQOL-CF score and cognitive performance, and test metrics were determined for a KDQOL-CF cutoff score of 60 or less from a maximum score of 100.
For 168 prevalent hemodialysis patients, KDQOL-CF score was 76 ± 19 and 40 (24%) had scores of 60 or less, consistent with self-identified worse cognitive performance. There was no significant correlation between KDQOL-CF score and either memory (P = 0.2 and P = 0.3) or executive function (P = 0.1 and P = 0.4) in univariate and multivariable models, respectively. There was a strong correlation between higher KDQOL-CF score and fewer depression symptoms (P <0.001). Sensitivity of the KDQOL-CF was poor (range, 0.28–0.36), with modest specificity (range, 0.77–0.81) for identifying worse executive function and memory.
Cross-sectional study, modest population size, and abbreviated gold-standard cognitive battery.
The KDQOL-CF is a poor determinant of neurocognitive performance in hemodialysis patients, with limited sensitivity. To assess cognitive impairment in hemodialysis patients, better screening tests are essential.
PMCID: PMC3547669  PMID: 22425261
Dialysis; dementia; cognitive impairment; screening; depression; quality of life
21.  Obesity, anthropometric measures and chronic kidney disease complications 
American journal of nephrology  2012;36(3):219-227.
Anthropometric measures such as body mass index (BMI) and waist circumference (WC) have differential associations with incident chronic kidney disease (CKD) and mortality. We examined the associations of BMI and WC with various CKD complications.
We conducted a cross-sectional analysis of 2853 adult participants with CKD in the National Health and Nutrition Examination Surveys 1999-2006. The associations of BMI and WC (both as categorical and continuous variables) with CKD complications such as anemia, secondary hyperparathyroidism, hyperphosphatemia, metabolic acidosis, hypoalbuminemia, and hypertension were examined using logistic regression models while adjusting for relevant confounding variables.
When examined as a continuous variable, an increase in BMI by 2 kg/m2 and WC by 5 cm was associated with higher odds of secondary hyperparathyroidism, hypoalbuminemia, and hypertension among those with CKD. CKD participants with a BMI ≥30 kg/m2 have higher odds of hypoalbuminemia and hypertension than CKD participants with BMI <30 kg/m2. CKD participants with a high WC (>102 cm in men and >88 cm in women) have higher odds of hypoalbuminemia and hypertension and lower odds of having anemia than CKD participants with a low WC. CKD participants with BMI <30 kg/m2 and high WC (vs. BMI <30 kg/m2 and low WC) was not associated with CKD complications.
Anthropometric measures such as BMI and WC are associated with secondary hyperparathyroidism, hypoalbuminemia, and hypertension among adults with CKD. Higher WC among those with BMI <30 kg/m2 is not associated with CKD complications.
PMCID: PMC3542766  PMID: 22948230
Obesity; body mass index; waist circumference; chronic kidney disease
22.  Effects of intensive blood pressure lowering on the progression of chronic kidney disease: a systematic review and meta-analysis 
Recent guidelines suggest lowering the target blood pressure for patients with chronic kidney disease, although the strength of evidence for this suggestion has been uncertain. We sought to assess the renal and cardiovascular effects of intensive blood pressure lowering in people with chronic kidney disease.
We performed a systematic review and meta-analysis of all relevant reports published between 1950 and July 2011 identified in a search of MEDLINE, Embase and the Cochrane Library. We included randomized trials that assigned patients with chronic kidney disease to different target blood pressure levels and reported kidney failure or cardiovascular events. Two reviewers independently identified relevant articles and extracted data.
We identified 11 trials providing information on 9287 patients with chronic kidney disease and 1264 kidney failure events (defined as either a composite of doubling of serum creatinine level and 50% decline in glomerular filtration rate, or end-stage kidney disease). Compared with standard regimens, a more intensive blood pressure–lowering strategy reduced the risk of the composite outcome (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.68–0.98) and end-stage kidney disease (HR 0.79, 95% CI 0.67–0.93). Subgroup analysis showed effect modification by baseline proteinuria (p = 0.006) and markers of trial quality. Intensive blood pressure lowering reduced the risk of kidney failure (HR 0.73, 95% CI 0.62–0.86), but not in patients without proteinuria at baseline (HR 1.12, 95% CI 0.67–1.87). There was no clear effect on the risk of cardiovascular events or death.
Intensive blood pressure lowering appears to provide protection against kidney failure events in patients with chronic kidney disease, particularly among those with proteinuria. More data are required to determine the effects of such a strategy among patients without proteinuria.
PMCID: PMC3735743  PMID: 23798459
23.  Serum triglycerides and risk for death in Stage 3 and Stage 4 chronic kidney disease 
Nephrology Dialysis Transplantation  2012;27(8):3228-3234.
An elevated triglyceride level is associated with cardiovascular and all-cause mortality in the general population. The associations between serum triglyceride and all-cause mortality among patients with chronic kidney disease (CKD) are unclear.
Patients with Stage 3 and Stage 4 CKD (estimated glomerular filtration rate 15–59 mL/min/1.73 m2) who had serum triglycerides measured prior to being classified as CKD were included. We examined the associations of serum triglyceride levels with all-cause mortality among 25 641 Stage 3 and Stage 4 CKD patients using Cox proportional hazard models and Kaplan–Meier survival curves.
In the Cox model, after adjusting for relevant covariates including other lipid parameters, serum triglyceride level 150–199 mg/dL was not associated with death [hazard ratio (HR) 1.00, 95% confidence interval (95% CI) 0.92–1.10] relative to serum triglyceride <150 mg/dL while serum triglyceride ≥200 mg/dL was associated with a 11% increased hazard for death (95% CI 1.01–1.22). Age modified the association between serum triglyceride levels ≥200 mg/dL and mortality with patients <65 years having a 38% higher hazard for death (95% CI 1.15–1.65) and ≥65 years with no increased risk for death (HR 0.97, 95% CI 0.88–1.08, P for interaction <0.001). When serum triglycerides were examined as a continuous log-transformed variable, similar associations with mortality were noted.
Serum triglyceride ≥200 mg/dL was independently associated with all-cause mortality in Stage 3 and Stage 4 CKD patients aged <65 years but not among patients of age ≥65 years. Future studies should confirm these findings and examine the mechanisms that may explain these associations.
PMCID: PMC3408940  PMID: 22553369
chronic kidney disease; mortality; serum triglycerides
24.  Fibroblast Growth Factor-23 and Death, Heart Failure, and Cardiovascular Events in Community-Living Individuals: the Cardiovascular Health Study 
To determine the associations of FGF23 with death, HF, and CVD and investigate the influence of CKD in a general community-living population.
FGF23 increases renal phosphorus excretion and inhibits vitamin D activation. In ESRD, high FGF23 levels are associated with mortality. The associations of FGF23 with death, heart failure (HF), and cardiovascular disease (CVD) in teh general population are unknown.
Plasma FGF23 was measured in 3,107 community-living persons ≥ 65 years in 1996–97, and participants were followed through 2008. HF and CVD events were adjudicated by a panel of experts. Associations of FGF23 with each outcome were evaluated using Cox proportional hazards models, and we tested whether associations differed by CKD status.
Both lower eGFR and higher urine ACR were associated with high FGF23 at baseline. During 10.5 years (median) follow-up, there were 1,730 deaths, 697 incident HF events, and 797 incident CVD events. Although high FGF23 concentrations were associated with each outcome in combined analyses, the associations were consistently stronger for those with CKD (P interactions all < 0.006). In the CKD group (n=1,128), the highest FGF23 quartile had adjusted hazards ratios (HR) of 1.87 (1.47, 2.38) for all-cause death, 1.94 (1.32, 2.83) for incident HF, and 1.49 (1.02, 2.18) for incident CVD events compared to the lowest quartile. Corresponding HRs in those without CKD (n=1,979) were 1.29 (1.05, 1.59), 1.37 (0.99, 1.89), and 1.07 (0.79, 1.45).
FGF23, a hormone involved in phosphorous and vitamin D homeostasis, is independently associated with all-cause death and incident HF in community-living older persons. These associations appear stronger in persons with CKD.
PMCID: PMC3396791  PMID: 22703926
Fibroblast growth factor-23; kidney disease; mineral metabolism; cardiovascular disease; heart failure; elderly
25.  Cystatin C and Albuminuria as Risk Factors for Development of CKD Stage 3: The Multi-Ethnic Study of Atherosclerosis (MESA) 
The growing burden and morbidity of chronic kidney disease (CKD) warrant effective strategies for identifying those at increased risk. We examined the association of cystatin C and albuminuria with development of CKD stage 3.
Study Design
Prospective observational study.
Setting and Participants
5,422 participants from the Multi-Ethnic Study of Atherosclerosis with estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73m2.
Participants were categorized into four mutually exclusive groups: presence or absence of microalbuminuria (albumin-creatinine ratio >17 and > 25 µg/mg in men and women, respectively) in those with or without cystatin C ≥ 1.0 mg/L.
Outcomes and Measurements
Incident CKD stage 3 was defined as eGFR < 60 ml/min/1.73m2 at the 3rd or 4th visit and an annual decline of > 1 ml/min/1.73 m2. Poisson regression was used to evaluate incident rate ratios in unadjusted and adjusted analyses that include baseline eGFR.
Mean age was 61 years, 49% were men, 38% white, 11% had diabetes, 13.7% had cystatin C ≥ 1mg/L, 8.4% had microalbuminuria, and 2.7 % had cystatin C ≥ 1 mg/L with microalbuminuria. 554 (10%) participants developed CKD stage 3 over a median follow-up of 4.7 years and the adjusted incidence rate ratios (95% CI) were 1.57 (1.19–2.07), 1.37 (1.13–1.66), and 2.12 (1.61–2.80) in those with microalbuminuria, cystatin C ≥ 1 mg/L, and both, respectively, compared to those with neither.
Relatively short follow up and absence of measured GFR.
Cystatin C and microalbuminuria are independent risk factors for incident CKD stage 3 and could be useful as screening tools to identify those at increased risk.
PMCID: PMC3090544  PMID: 21296473

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