Daniel E. Weiner

Chronic Kidney Disease as a Risk Factor for Cardiovascular Disease and All-Cause Mortality: A Pooled Analysis of Community-Based Studies

Chronic kidney disease (CKD) is a major public health problem. Conflicting evidence exists among community-based studies as to whether CKD is an independent risk factor for adverse cardiovascular outcomes. After subjects with a baseline history of cardiovascular disease were excluded, data from four publicly available, community-based longitudinal studies were pooled: Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Framingham Heart Study, and Framingham Offspring Study. Serum creatinine levels were indirectly calibrated across studies. CKD was defined by a GFR between 15 and 60 ml/min per 1.73 m(2). A composite of myocardial infarction, fatal coronary heart disease, stroke, and death was the primary study outcome. Cox proportional hazards models were used to adjust for study, demographic variables, educational status, and other cardiovascular risk factors. The total population included 22,634 subjects; 18.4% of the population was black, and 7.4% had CKD. There were 3262 events. In adjusted analyses, CKD was an independent risk factor for the composite study outcome (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.07-1.32), and there was a significant interaction between kidney function and race. Black individuals with CKD had an adjusted HR of 1.76 (95% CI, 1.35-2.31), whereas whites had an adjusted HR of 1.13 (95% CI, 1.02-1.26). CKD is a risk factor for the composite outcome of all-cause mortality and cardiovascular disease in the general population and a more pronounced risk factor in blacks than in whites. It is hypothesized that this effect may be due to more frequent or more severe subclinical vascular disease secondary to hypertension or diabetes in black individuals.

Uric Acid and Incident Kidney Disease in the Community

Uric acid may mediate aspects of the relationship between hypertension and kidney disease via renal vasoconstriction and systemic hypertension. To investigate the relationship between uric acid and subsequent reduced kidney function, limited-access data of 13,338 participants with intact kidney function in two community-based cohorts, the Atherosclerosis Risks in Communities and the Cardiovascular Health Study, were pooled. Mean baseline serum uric acid was 5.9 +/- 1.5 mg/dl, mean baseline serum creatinine was 0.9 +/- 0.2 mg/dl, and mean baseline estimated GFR was 90.4 +/- 19.4 ml/min/1.73 m(2). During 8.5 +/- 0.9 yr of follow-up, 712 (5.6%) had incident kidney disease defined by GFR decrease (>or=15 ml/min/1.73 m(2) with final GFR <60 ml/min/1.73 m(2)), while 302 (2.3%) individuals had incident kidney disease defined by creatinine increase (>or=0.4 mg/dl with final serum creatinine >1.4 mg/dl in men and 1.2 mg/dl in women). In GFR- and creatinine-based logistic regression models, baseline uric acid level was associated with increased risk for incident kidney disease (odds ratio 1.07 [95% confidence interval 1.01 to 1.14] and 1.11 [95% confidence interval 1.02 to 1.21] per 1-mg/dl increase in uric acid, respectively), after adjustment for age, gender, race, diabetes, systolic BP, hypertension, cardiovascular disease, left ventricular hypertrophy, smoking, alcohol use, education, lipids, albumin, hematocrit, baseline kidney function and cohort; therefore, elevated serum uric acid level is a modest, independent risk factor for incident kidney disease in the general population.

25-Hydroxyvitamin D, dementia, and cerebrovascular pathology in elders receiving home services

Background: Vitamin D deficiency has potential adverse effects on neurocognitive health and subcortical function. However, no studies have examined the association between vitamin D status, dementia, and cranial MRI indicators of cerebrovascular disease (CVD). Methods: Cross-sectional investigation of 25-hydroxyvitamin D [25(OH)D], dementia, and MRI measures of CVD in elders receiving home care (aged 65–99 years) from 2003 to 2007. Results: Among 318 participants, the mean age was 73.5 ± 8.1 years, 231 (72.6%) were women, and 109 (34.3%) were black. 25(OH)D concentrations were deficient (<10 ng/mL) in 14.5% and insufficient (10–20 ng/mL) in 44.3% of participants. There were 76 participants (23.9%) with dementia, 41 of which were classified as probable AD. Mean 25(OH)D concentrations were lower in subjects with dementia (16.8 vs 20.0 ng/mL, p < 0.01). There was a higher prevalence of dementia among participants with 25(OH)D insufficiency (≤20 ng/mL) (30.5% vs 14.5%, p < 0.01). 25(OH)D deficiency was associated with increased white matter hyperintensity volume (4.9 vs 2.9 mL, p < 0.01), grade (3.0 vs 2.2, p = 0.04), and prevalence of large vessel infarcts (10.1% vs 6.9%, p < 0.01). After adjustment for age, race, sex, body mass index, and education, 25(OH)D insufficiency (≤20 ng/mL) was associated with more than twice the odds of all-cause dementia (odds ratio [OR] = 2.3, 95% confidence interval [CI] 1.2–4.2), Alzheimer disease (OR = 2.5, 95% CI 1.1–6.1), and stroke (with and without dementia symptoms) (OR = 2.0, 95% CI 1.0–4.0). Conclusions: Vitamin D insufficiency and deficiency was associated with all-cause dementia, Alzheimer disease, stroke (with and without dementia symptoms), and MRI indicators of cerebrovascular disease. These findings suggest a potential vasculoprotective role of vitamin D.

Anemia as a Risk Factor for Cardiovascular Disease and All-Cause Mortality in Diabetes: The Impact of Chronic Kidney Disease

Anemia is a potential nontraditional risk factor for cardiovascular disease (CVD). This study evaluated whether anemia is a risk factor for adverse outcomes in people with diabetes and whether the risk is modified by the presence of chronic kidney disease (CKD). Persons with diabetes from four community-based studies were pooled: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study, and Framingham Offspring Study. Anemia was defined as a hematocrit <36% in women and <39% in men. CKD was defined as an estimated GFR of 15 to 60 ml/min per 1.73 m(2). Study outcomes included a composite of myocardial infarction (MI)/fatal coronary heart disease (CHD)/stroke/death and each outcome separately. Cox regression analysis was used to study the effect of anemia on the risk for outcomes after adjustment for potential confounders. The study population included 3015 individuals: 30.4% were black, 51.6% were women, 8.1% had anemia, and 13.8% had CKD. Median follow-up was 8.6 yr. There were 1215 composite events, 600 MI/fatal CHD outcomes, 300 strokes, and 857 deaths. In a model with a CKD-anemia interaction term, anemia was associated with the following hazard ratios (95% confidence intervals) in patients with CKD: 1.70 (1.24 to 2.34) for the composite outcome, 1.64 (1.03 to 2.61) for MI/fatal CHD, 1.81 (0.99 to 3.29) for stroke, and 1.88 (1.33 to 2.66) for all-cause mortality. Anemia was not a risk factor for any outcome in those without CKD (P > 0.2 for all outcomes). In persons with diabetes, anemia is primarily a risk factor for adverse outcomes in those who also have CKD.

KDOQI Clinical Practice Guideline for Hemodialysis Adequacy: 2015 Update

The National Kidney Foundations Kidney Disease Outcomes Quality Initiative (KDOQI) has provided evidence-based guidelines for all stages of chronic kidney disease (CKD) and related complications since 1997. The 2015 update of the KDOQI Clinical Practice Guideline for Hemodialysis Adequacy is intended to assist practitioners caring for patients in preparation for and during hemodialysis. The literature reviewed for this update includes clinical trials and observational studies published between 2000 and March 2014. New topics include high-frequency hemodialysis and risks; prescription flexibility in initiation timing, frequency, duration, and ultrafiltration rate; and more emphasis on volume and blood pressure control. Appraisal of the quality of the evidence and the strength of recommendations followed the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Limitations of the evidence are discussed and specific suggestions are provided for future research.

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. STUDY DESIGN Cohort study. SETTING & PARTICIPANTS Individual patient data pooled from the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. PREDICTORS Waist-to-hip ratio (WHR), body mass index (BMI). OUTCOMES & MEASUREMENTS Incident CKD defined as serum creatinine level increase greater than 0.4 mg/dL with baseline creatinine level of 1.4 mg/dL or less in men and 1.2 mg/dL or less in women and final creatinine level greater than these levels, and, in separate analyses, estimated glomerular filtration rate (eGFR) decrease of 15 mL/min/1.73 m(2) or greater with baseline eGFR of 60 mL/min/1.73 m(2) or greater and final eGFR less than 60 mL/min/1.73 m(2). Multivariable logistic regression to determine the association between WHR, BMI, and outcomes. Cox models to evaluate a secondary composite outcome of all-cause mortality and incident CKD. RESULTS Of 13,324 individuals, mean WHR was 0.96 in men and 0.89 in women and mean BMI was 27.2 kg/m(2) in both men and women. During 9.3 years, 300 patients (2.3%) in creatinine-based models and 710 patients (5.5%) in eGFR-based models developed CKD. In creatinine-based models, each SD increase in WHR was associated with increased risk of incident CKD (odds ratio, 1.22; 95% confidence interval [CI], 1.05 to 1.43) and the composite outcome (hazard ratio, 1.12; 95% CI, 1.06 to 1.18), whereas each SD increase in BMI was not associated with CKD (odds ratio, 1.05; 95% CI, 0.93 to 1.20) and appeared protective for the composite outcome (hazard ratio, 0.94; 95% CI, 0.90 to 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 use WHR rather than BMI as an anthropomorphic measure of obesity.

Effects of Anemia and Left Ventricular Hypertrophy on Cardiovascular Disease in Patients with Chronic Kidney Disease

Left ventricular hypertrophy (LVH) and anemia are highly prevalent in moderate chronic kidney disease (CKD). Because anemia may potentiate the adverse effects of LVH on cardiovascular outcomes, the effect of both anemia and LVH on outcomes in CKD was examined. Data from four community-based longitudinal studies were pooled: Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Framingham Heart Study, and Framingham Offspring Study. Serum creatinine levels were calibrated indirectly across studies, and GFR was estimated using the Modification of Diet in Renal Disease equation. CKD was defined as GFR between 15 and 60 ml/min per 1.73 m(2). LVH was based on electrocardiogram criteria. Anemia was defined as hematocrit <36% in women and 39% in men. The primary outcome was a composite of myocardial infarction, stroke, and death; a secondary cardiac outcome included only myocardial infarction and fatal coronary heart disease. Among 2423 patients with CKD, 96% had electrocardiogram and anemia data. Median follow-up was 102 mo. In adjusted analysis, LVH was associated with increased risk for composite and cardiac outcomes (hazard ratio [HR], 1.67 [95% confidence interval (CI), 1.34 to 2.07] and 1.62 [95% CI, 1.18 to 2.24], respectively), whereas anemia was associated with increased risk for the only composite outcome (HR, 1.51 [95% CI, 1.27 to 1.81]). The combination of anemia and LVH was associated with an increased risk for both study outcomes compared with individuals with neither risk factor (HR, 4.15 [95% CI, 2.62 to 6.56] and 3.92 [95% CI, 2.05 to 7.48]; P = 0.02 and 0.01 for interaction term, respectively). The combination of anemia and LVH in CKD identifies a high-risk population.

Albuminuria, Cognitive Functioning, and White Matter Hyperintensities in Homebound Elders

BACKGROUND Albuminuria, a kidney marker of microvascular disease, may herald microvascular disease elsewhere, including in the brain. STUDY DESIGN Cross sectional. SETTING & PARTICIPANTS Boston, MA, elders receiving home health services to maintain independent living who consented to brain magnetic resonance imaging. PREDICTOR Urine albumin-creatinine ratio (ACR). OUTCOME Performance on a cognitive battery assessing executive function and memory by using principal components analysis and white matter hyperintensity volume on brain imaging, evaluated in logistic and linear regression models. RESULTS In 335 participants, mean age was 73.4 +/- 8.1 years and 123 participants had microalbuminuria or macroalbuminuria. Each doubling of ACR was associated with worse executive function (beta = -0.05; P = 0.005 in univariate and beta = -0.07; P = 0.004 in multivariable analyses controlling for age, sex, race, education, diabetes, cardiovascular disease, hypertension, medications, and estimated glomerular filtration rate [eGFR]), but not with worse memory or working memory. Individuals with microalbuminuria or macroalbuminuria were more likely to be in the lower versus the highest tertile of executive functioning (odds ratio, 1.18; 95% confidence interval, 1.06 to 1.32; odds ratio, 1.19; 95% confidence interval, 1.05 to 1.35 per doubling of ACR in univariate and multivariable analyses, respectively). Albuminuria was associated with qualitative white matter hyperintensity grade (odds ratio, 1.13; 95% confidence interval, 1.02 to 1.25; odds ratio, 1.15; 95% confidence interval, 1.02 to 1.29 per doubling of ACR) in univariate and multivariable analyses and with quantitative white matter hyperintensity volume (beta = 0.11; P = 0.007; beta = 0.10; P = 0.01) in univariate and multivariable analyses of log-transformed data. Results were similar when excluding individuals with macroalbuminuria. LIMITATIONS Single measurement of ACR, indirect creatinine calibration, and reliance on participant recall for elements of medical history. CONCLUSIONS Albuminuria is associated with worse cognitive performance, particularly in executive functioning, as well as increased white matter hyperintensity volume. Albuminuria likely identifies greater brain microvascular disease burden.

The Relationship Between Nontraditional Risk Factors and Outcomes in Individuals With Stage 3 to 4 CKD

BACKGROUND Chronic kidney disease is associated with increased risk for cardiovascular disease and mortality. Both traditional and nontraditional 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) less than 60 mL/min/1.73 m(2). PREDICTORS Nontraditional cardiovascular disease risk factors, including body mass index, diastolic blood pressure, and triglyceride, albumin, uric acid, fibrinogen, C-reactive protein, and hemoglobin levels. OUTCOMES Composite of myocardial infarction, stroke, and all-cause mortality. Secondary outcomes included individual components of the composite. RESULTS Of 1,678 individuals with decreased eGFR (mean, 51.1 +/- 8.5 mL/min/1.73 m(2)), 891 (53%) reached the composite end point during a median follow-up of 108 months; 23% had a cardiac event, 45% died, and 14% experienced a stroke. Serum albumin level less than 3.9 g/dL (hazard ratio, 0.68 for every 0.3-g/dL decrease; 95% confidence interval, 0.60 to 0.77), increased serum triglyceride level (hazard ratio, 1.07 for every 50-mg/dL increase; 95% confidence interval, 1.02 to 1.12), C-reactive protein level (hazard ratio, 1.15 per log-unit increase; 95% confidence interval, 1.07 to 1.24), and fibrinogen level (hazard ratio, 1.12 per 50-mg/dL increase; 95% confidence interval, 1.07 to 1.18) independently predicted composite events. Both decreased (<14.5 g/dL) and increased (>14.5 g/dL) hemoglobin levels predicted composite events. Serum albumin level less than 3.9 g/dL and increased serum fibrinogen level independently predicted cardiac events. For serum albumin and hemoglobin levels, the relationship with composite and mortality outcomes was nonlinear (P < 0.001). LIMITATIONS Single assessment of eGFR. No albuminuria data. CONCLUSIONS Several nontraditional cardiovascular disease risk factors predict adverse outcomes in individuals with stage 3 to 4 chronic kidney disease. The relationship between risk factors and outcomes is often nonlinear.

Chronic Kidney Disease Associated With Environmental Toxins and Exposures

People are exposed to various potentially toxic agents and conditions in their natural and occupational environments. These agents may be physical or chemical, may enter the human body through oral, inhalational, or transdermal routes, and may exert effects on all organ systems. Several well-known as well as lesser known associations exist between chronic kidney disease (CKD) and both environmental agents and conditions, such as heavy metals, industrial chemicals, elevated ambient temperatures, and infections. The effects of these agents may be modulated by genetic susceptibility and other comorbid conditions and may lead to the development of acute and CKD. In this article, we present environmental factors that are associated with CKD.