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.
aged; kidney function; hypertension; marginal structural model
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.
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.
Hemodialysis; brain abnormalities; cerebral atrophy; white matter disease; magnetic resonance imaging (MRI)
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.
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.
octogenarians; kidney function; mortality
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.
apolipoprotein E; chronic kidney disease; kidney function; elderly
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.
Inflammation; Aging; Physical function; Cognitive function
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.
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.
Dialysis; dementia; cognitive impairment; screening; depression; quality of life
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.
Obesity; body mass index; waist circumference; chronic kidney disease
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.
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.
chronic kidney disease; mortality; serum triglycerides
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.
Fibroblast growth factor-23; kidney disease; mineral metabolism; cardiovascular disease; heart failure; elderly
Moderate kidney disease may predispose to infection. We sought to determine whether decreased kidney function, as estimated by serum cystatin C, was associated with the risk of infection-related hospitalization in older individuals.
Setting & Participants
5,142 Cardiovascular Health Study participants with measured serum creatinine and cystatin C and without eGFR <15 ml/min/1.73 m2 at enrollment.
The primary exposure of interest was estimated glomerular filtration rate using serum cystatin C (eGFRSCysC).
Infection-related hospitalizations during a median follow-up of 11.5 years.
In adjusted analyses, eGFRSCysC categories of 60–89, 45–59, and 15–44 ml/min/1.73 m2 were associated with 16%, 37%, and 64% greater risk of all-cause infection-related hospitalization, respectively, compared with an eGFRSCysC ≥90 ml/min/1.73 m2. When cause specific infection was examined, an eGFRSCysC of 15–44 ml/min/1.73 m2 was associated with an 80% greater risk of pulmonary and 160% greater risk of genitourinary infection compared with an eGFRSCysC ≥90 ml/min/1.73 m2.
No measures of urinary protein, study limited to principal discharge diagnosis.
Lower kidney function, estimated using cystatin C, was associated with a linear and graded risk of infection-related hospitalization. These findings highlight that even moderate degrees of reduced kidney function are associated with clinically significant higher risks of serious infection in older individuals.
renal disease; chronic kidney disease; infection; clinical epidemiology
Retinal microvascular signs are associated with systemic conditions and cognitive decline. We studied the associations of microvascular changes, measured by retinal signs, with disability in performing activities of daily living (ADL).
Prospective cohort study.
1487 participants in the Cardiovascular Health Study (mean age 78 years) who were free of ADL disability and had available data on retinal signs and carotid intima-media thickness (IMT) at the 1998–99 visit.
Main Outcome Measure
Incident ADL disability, defined as self-reported difficulty in performing any ADLs, by the presence of retinal signs and advanced carotid atherosclerosis, defined by carotid IMT ≥ 80th percentile or ≥ 25% stenosis; and potential mediation by cerebral microvascular disease on brain imaging or by executive dysfunction, slow gait, and depressive mood that are symptoms of frontal subcortical dysfunction.
During the median follow-up of 3.1 years (maximum 7.8 years), participants with ≥ 2 retinal signs had a higher rate of disability than those with < 2 retinal signs (10.1% versus 7.1%; adjusted hazards ratio, 1.45; 95% confidence interval, 1.24–1.69; P < 0.001). There was no evidence of interaction by advanced carotid atherosclerosis (P > 0.10). The association seemed to be partially mediated by executive dysfunction, slow gait, and depressive symptoms, but not by cerebral microvascular disease on brain imaging.
These results provide further support for the pathophysiologic and prognostic significance of microvascular disease in age-related disability. However, it remains to be determined how to best utilize retinal photography in the clinical risk prediction.
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.
Chronic kidney insufficiency; aged; hypertension; cholesterol; obesity; smoking
The association of subclinical vascular disease and early declines in kidney function has not been well studied.
Prospective cohort study
Setting & Participants
MESA participants with eGFR ≥60 ml/min/1.73m2 with follow-up of 5 years
Pulse pressure (pulse pressure), small and large arterial elasticity (SAE, LAE), and flow mediated dilation.
kidney function decline
SAE and LAE were measured by pulse contour analysis of the radial artery. Kidney function was measured by serum creatinine- and cystatin C-based eGFR.
Among 4,853 adults, higher pulse pressure and lower SAE and LAE had independent and linear associations with faster rates of kidney function decline. Compared to persons with pulse pressure 40–50mmHg, eGFRSCysC decline was 0.29 (p=0.006), 0.56 (p<0.001), and 0.91 (p<0.001) ml/min/1.73m2/year faster among persons with pulse pressure 50–60, 60–70, and >70mmHg, respectively. Compared to the highest quartile of SAE (most elastic), eGFRSCysC decline was 0.26 (p=0.009), 0.35 (p=0.001), and 0.70 (p<0.001) ml/min/1.73m2/year faster for the second, third and fourth quartiles respectively. For LAE, compared to the highest quartile, eGFRSCysC decline was 0.28 (p=0.004), 0.58 (p<0.001), and 0.83 (p<0.001) ml/min/1.73m2/year faster for each decreasing quartile of LAE. Findings were similar with creatinine-based eGFR. In contrast, among 2,997 adults with flow-mediated dilation and kidney function measures, flow-mediated dilation was not significantly associated with kidney function decline. For every 1-SD greater flow-mediated dilation, eGFRSCysC and eGFRSCr changed by 0.05 ml/min/1.73m2/year (p=0.3) and 0.06 ml/min/1.73m2/year (p=0.04), respectively.
We had no direct measure of GFR, in common with nearly all large population based studies.
Higher pulse pressure and lower arterial elasticity, but not flow-mediated dilation, were linearly and independently associated with faster kidney function decline among persons with eGFR ≥60 ml/min/1.73m2. Future studies investigate whether treatments to lower stiffness of large and small arteries may slow the rate of kidney function loss.
kidney function; arterial elasticity; chronic kidney disease; atherosclerosis
Recent studies have demonstrated greater risks of cardiovascular events and mortality among persons who have lower 25-hydroxyvitamin D (25-OHD) and higher parathyroid hormone (PTH) levels. We sought to evaluate the association between markers of mineral metabolism and sudden cardiac death (SCD) among the 2,312 participants from the Cardiovascular Health Study who were free of clinical cardiovascular disease at baseline. We estimated associations of baseline 25-OHD and PTH concentrations individually and in combination with SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, and kidney function. During a median follow-up of 14 years, there were 73 adjudicated SCD events. The annual incidence of SCD was greater among subjects who had lower 25-OHD concentrations: 2 events per 10,000 for 25-OHD ≥ 20 ng/ml and 4 events per 10,000 for 25-OHD < 20 ng/ml. Similarly, SCD incidence was greater among subjects who had higher PTH concentrations: 2 events per 10,000 for PTH ≤ 65 pg/ml and 4 events per 10,000 for PTH > 65 pg/ml. Multivariate adjustment attenuated associations of 25-OHD and PTH with SCD. Finally, 267 participants (11.7% of the cohort) had high PTH and low 25-OHD concentrations. This combination was associated with a more than 2-fold risk of SCD after adjustment (hazard ratio 2.19, 95% confidence interval 1.17, 4.10, p=0.017) compared to participants with normal levels of PTH and 25-OHD. The combination of lower 25-OHD and higher PTH concentrations appears to be associated independently with SCD risk among older adults without cardiovascular disease.
Sudden cardiac death; Vitamin D; Parathyroid hormone; Elderly; Risk Factors
Cardiovascular disease (CVD) and cognitive impairment are common in dialysis patients. Given the proposed role of microvascular disease on cognitive function, particularly cognitive domains that incorporate executive functions, we hypothesized that prevalent systemic CVD would be associated with worse cognitive performance in hemodialysis patients.
Setting and Participants
200 maintenance hemodialysis patients without prior stroke from 5 Boston-area hemodialysis units
CVD, defined by history of coronary disease or peripheral vascular disease
Performance on a detailed neurocognitive battery. Primary analyses quantified cognitive performance using principal components analysis to reduce cognitive tests to a processing speed/executive function domain and a memory domain. Multivariable linear regression models adjusted for age, sex, education, race and other clinical and demographic characteristics.
Mean (SD) age of participants was 62 (18) years and 75 (38%) had CVD. Individuals with CVD were older, more likely to be men, diabetic, and current or former smokers. In adjusted models, individuals with CVD performed 0.50 standard deviations worse (p<0.001) on tests assessing processing speed/executive function, while there was no difference in performance on tests of memory. Similar results were seen when assessing individual tests, with performance on the block design, digit symbol coding and Trail Making Tests A and B significantly associated with CVD in age, sex, education and race-adjusted analyses and approaching toward significance in fully adjusted models.
CVD ascertainment dependent on patient recall and dialysis unit documentation. No brain imaging.
The presence of CVD is associated with worse cognitive performance on tests of processing speed and executive functioning in hemodialysis patients and identifies a high risk population for greater difficulty with complex tasks.
Vitamin D deficiency and parathyroid hormone (PTH) excess are common among older adults and may adversely impact cardiovascular health. We evaluated associations of 25-hydroxyvitamin D (25-OHD) and PTH concentrations, separately, and in combination, with incident cardiovascular events and mortality during 14 years of follow-up in the Cardiovascular Health Study.
Methods and results
We studied 2,312 participants who were free of cardiovascular disease at baseline. We measured 25-OHD and intact PTH from previously frozen serum using mass spectrometry and a two-site immunoassay. Outcomes were adjudicated cases of myocardial infarction, heart failure, cardiovascular death, and all cause mortality. There were 384 participants (17%) who had serum 25-OHD concentrations <15 ng/ml and 570 (25%) who had serum PTH concentrations ≥ 65 pg/ml. After adjustment, each 10-ng/ml lower 25-OHD concentration was associated with a 9% greater (95% CI 2% to 17% greater) relative hazard of mortality and a 25% greater (95% CI 8% to 44% greater) relative hazard of myocardial infarction. Serum 25-OHD concentrations <15 ng/ml, were associated with a 29% greater (95% CI 5% to 55% greater) risk of mortality. Serum PTH concentrations ≥ 65 pg/ml were associated with a 30% greater risk of heart failure (95% CI 6% to 61% greater), but not other outcomes. There was no evidence of an interaction between serum 25-OHD and PTH concentrations and cardiovascular events.
Among older adults, 25-OHD deficiency is associated with myocardial infarction and mortality; PTH excess is associated with heart failure. Vitamin D and PTH might influence cardiovascular risk through divergent pathways.
Vitamin D; parathyroid hormone; myocardial infarction; cardiovascular death; heart failure; mortality; mineral metabolism
Purpose of Review
To discuss recent studies which have evaluated determinants of cystatin C and to focus on the relationship of cystatin C with mortality, cardiovascular disease (CVD) and non-cardiovascular outcomes.
In the Chronic Kidney Disease Epidemiology Study cystatin C was associated with demographic characteristics independent of measured glomerular filtration rate (GFR), although this was to a smaller extent than creatinine. In patients with established CKD, cystatin C was strongly and inversely correlated with measured GFR, suggesting that although cystatin C may have other determinants, it is primarily a measure of kidney function. Several cohort studies, particularly in older adults, have now demonstrated that cystatin C is linearly associated with mortality, CVD and non-CVD outcomes, whereas creatinine is primarily associated with risk in individuals with more advanced kidney disease. A recent study has also shown that changes in kidney function as ascertained by cystatin C, even within the relatively normal range, are associated with subsequent CVD and all-cause mortality among older adults.
Cystatin C appears to capture an association of mild kidney disease with increased risk of mortality, CVD and non-CVD outcomes. Future studies should evaluate whether cystatin C can improve medical decision-making and lead to favorable patient outcomes.
cystatin C; kidney disease; cardiovascular disease; mortality
Background. Cardiovascular disease is the leading cause of premature mortality in autosomal dominant polycystic kidney disease (ADPKD). We examined peripheral augmentation index (AIx) as a measure of systemic vascular function and circulating markers of vascular inflammation in patients with ADPKD.
Methods. Fifty-two ADPKD patients with hypertension and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, 50 ADPKD patients with hypertension and eGFR ≥60 mL/min/1.73 m2, 42 normotensive ADPKD patients with eGFR ≥60 mL/min/1.73 m2 and 51 normotensive healthy controls were enrolled in this study. AIx was measured from peripheral artery tone recordings using finger plethysmography. Serum levels of soluble intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule-1, P-selectin, E-selectin, soluble Fas (sFas) and Fas ligand (FasL) were measured as markers of vascular inflammation.
Results. AIx was higher in all three patient groups with ADPKD compared to healthy controls (P < 0.05). AIx was similar between the normotensive ADPKD patients with eGFR ≥60 mL/min/1.73 m2 and hypertensive ADPKD patients with eGFR <60 mL/min/1.73 m2 (P > 0.05). ICAM, P-selectin, E-selectin and sFas were higher and FasL lower in all ADPKD groups compared to controls (P < 0.05). ICAM, P-selectin and E-selectin were similar between the normotensive ADPKD patients with eGFR ≥60 mL/min/1.73 m2 and hypertensive ADPKD patients with eGFR < 60 mL/min/1.73 m2 (P > 0.05). According to multiple regression analysis, predictors of AIx in ADPKD included age, height, heart rate and mean arterial pressure (P < 0.05). Vascular inflammatory markers were not predictors of AIx in ADPKD.
Conclusions. Systemic vascular dysfunction, manifesting as an increase in AIx and vascular inflammation is evident in young normotensive ADPKD patients with preserved renal function. Vascular inflammation is not associated with elevated AIx in ADPKD.
hypertension; inflammation; kidney disease; vascular function
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.
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.
Background and Purpose
We hypothesized that retinal microvascular signs are associated with executive dysfunction, slow gait, and depressive mood that are characteristic features of microvascular disease affecting frontal subcortical regions of the brain.
In the Cardiovascular Health Study, 1744 participants (mean age 78) free of stroke had retinal photographs and carotid ultrasound during the 1997–1998 visit. We examined the cross-sectional association of retinal signs with the digit-symbol substitution test (DSST) score, gait speed, the Center for Epidemiologic Studies – Depression (CES-D) score, and depressive mood, defined as CES-D score > 9 or antidepressant use.
After adjusting for potential confounders, retinal signs were associated with lower DSST score (generalized arteriolar narrowing and arteriovenous nicking), slower gait (retinopathy), and depressive mood (generalized arteriolar narrowing). A higher number of retinal signs was associated with lower DSST score (−0.76 and −2.79 points for 1 sign and ≥ 2 signs versus none; P < 0.001) and slower gait (−0.009 and −0.083 m/sec; P = 0.047), but not with the square root of CES-D score (0.079 and −0.208; P = 0.072). In addition, coexistence of retinal signs (generalized arteriolar narrowing and arteriovenous nicking) and carotid atherosclerosis was associated with lower DSST score compared with either process alone (P for interaction < 0.01). Notably, further adjustment for ventricular size, white matter disease, and infarcts on magnetic resonance imaging did not attenuate the association.
Retinal signs are associated with executive dysfunction and slow gait, and possibly with depressive mood, suggesting a common process involving small vessels.
Retinal Microvascular Signs; Executive Function; Gait Speed; Depression
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.
HIV; KIM-1; NGAL; IL-18; albumin-to-creatinine ratio; cystatin C; kidney injury
Cognitive impairment is common in hemodialysis patients and may be impacted by multiple patient and treatment characteristics. The impact of dialysis dose on cognitive function remains uncertain, particularly in the current era of increased dialysis dose and flux.
We explored the cross-sectional relationship between dialysis adequacy and cognitive function in a cohort of maintenance hemodialysis patients. Adequacy was defined as the average of the 3 most proximate single pool Kt/V assessments. A detailed neurocognitive battery was administered during the 1st hour of dialysis. Multivariable linear regression models were adjusted for age, sex, education, race and other clinical and demographic characteristics.
Among 273 patients who underwent cognitive testing, the mean (SD) age was 63 (17) years and the median dialysis duration was 13 months, 47% were woman, 22% were African American, and 48% had diabetes. The mean (SD) Kt/V was 1.51 (0.24). In univariate, parsimonious and multivariable models, there were no significant relationships between decreased cognitive function and lower Kt/V.
In contrast to several older studies, there is no association between lower Kt/V and worse cognitive performance in the current era of increased dialysis dose. Future studies should address the longitudinal relationship between adequacy of dialysis and cognitive function to confirm these findings.
Cognitive function; Dialysis adequacy; Chronic kidney disease