Aspirin for Primary and Secondary Prevention of Mortality, Cardiovascular Disease, and Kidney Failure in the Chronic Renal Insufficiency Cohort (CRIC) Study.

Rationale and Objective: Chronic kidney disease is a risk enhancing factor for cardiovascular disease (CVD) and mortality, and the role of aspirin use is unclear in this population. We investigated the risk and benefits of aspirin use in primary and secondary prevention of CVD in the Chronic Renal Insufficiency Cohort Study. Study Design: Prospective observational cohort. Setting & Participants: 3,664 Chronic Renal Insufficiency Cohort participants. Exposure: Aspirin use in patients with and without preexisting CVD. Outcomes: Mortality, composite and individual CVD events (myocardial infarction, stroke, and peripheral arterial disease), kidney failure (dialysis and transplant), and major bleeding. Analytical Approach: Intention-to-treat analysis and multivariable Cox proportional hazards model to examine associations of time varying aspirin use. Results: The primary prevention group was composed of 2,578 (70.3%) individuals. Mean age was 57 ± 11 years, 46% women, 42% Black, and 47% had diabetes. The mean estimated glomerular filtration rate was 45 mL/min/1.73 m2. Median follow-up was 11.5 (IQR, 7.4-13) years. Aspirin was not associated with all-cause mortality in those without preexisting cardiovascular disease (CVD) (HR, 0.84; 95% CI, 0.7-1.01; P = 0.06) or those with CVD (HR, 0.88; 95% CI, 0.77-1.02, P = 0.08). Aspirin was not associated with a reduction of the CVD composite in primary prevention (HR, 0.97; 95% CI, 0.77-1.23; P = 0.79) and in secondary prevention because the original study design was not meant to study the effects of aspirin. Limitations: This is not a randomized controlled trial, and therefore, causality cannot be determined. Conclusions: Aspirin use in chronic kidney disease patients was not associated with reduction in primary or secondary CVD events, progression to kidney failure, or major bleeding.

Orthostatic Hypertension and Intensive Blood Pressure Control; Post-Hoc Analyses of SPRINT.

We evaluated the association between orthostatic hypertension and cardiovascular outcomes and the effect of intensive blood pressure (BP) control on cardiovascular outcomes in patients with orthostatic hypertension. Post hoc analyses of the SPRINT (Systolic Blood Pressure Intervention Trial) data were conducted; orthostatic hypertension was defined as increase in systolic BP≥20 mm Hg or increase in diastolic BP≥10 mm Hg with standing. Of 9329 participants, 1986 (21.2%) had orthostatic hypertension at baseline. Within the intensive treatment group, participants with orthostatic hypertension were at higher risk of developing the composite cardiovascular outcome (hazard ratio, 1.44 [95% CI, 1.1-1.87], P=0.007) compared with participants without orthostatic hypertension. Within the standard treatment group, there were no significant differences in cardiovascular outcome between participants with and without orthostatic hypertension. In participants with orthostatic hypertension, there was no statistically significant difference in risk of the composite cardiovascular outcome between the intensive and the standard BP treatment group (hazard ratio, 1.07 [95% CI, 0.78-1.47], P=0.68). In participants without orthostatic hypertension at baseline, the intensive treatment group was associated with a lower risk of the composite cardiovascular outcome (hazard ratio, 0.67 [95% CI, 0.56-0.79], P<0.0001). Orthostatic hypertension was associated with a higher risk of cardiovascular outcomes in the intensive and not in the standard treatment group; intensive treatment of BP did not reduce the risk of cardiovascular outcomes compared with standard treatment in patients with orthostatic hypertension. These post hoc analyses are hypothesis generating and will need to be confirmed in future studies.

Hospitalizations among adults with chronic kidney disease in the United States: A cohort study.

BACKGROUND: Adults with chronic kidney disease (CKD) are hospitalized more frequently than those without CKD, but the magnitude of this excess morbidity and the factors associated with hospitalizations are not well known. METHODS AND FINDINGS: Data from 3,939 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study between 2003 and 2008 at 7 clinical centers in the United States were used to estimate primary causes of hospitalizations, hospitalization rates, and baseline participant factors associated with all-cause, cardiovascular, and non-cardiovascular hospitalizations during a median follow up of 9.6 years. Multivariable-adjusted Poisson regression was used to identify factors associated with hospitalization rates, including demographics, blood pressure, estimated glomerular filtration rate (eGFR), and proteinuria. Hospitalization rates in CRIC were compared with rates in the Nationwide Inpatient Sample (NIS) from 2012. Of the 3,939 CRIC participants, 45.1% were female, and 41.9% identified as non-Hispanic black, with a mean age of 57.7 years, and the mean eGFR is 44.9 ml/min/1.73m2. CRIC participants had an unadjusted overall hospitalization rate of 35.0 per 100 person-years (PY) [95% CI: 34.3 to 35.6] and 11.1 per 100 PY [95% CI: 10.8 to 11.5] for cardiovascular-related causes. All-cause, non-cardiovascular, and cardiovascular hospitalizations were associated with older age (≥65 versus 45 to 64 years), more proteinuria (≥150 to <500 versus <150 mg/g), higher systolic blood pressure (≥140 versus 120 to <130 mmHg), diabetes (versus no diabetes), and lower eGFR (<60 versus ≥60 ml/min/1.73m2). Non-Hispanic black (versus non-Hispanic white) race/ethnicity was associated with higher risk for cardiovascular hospitalization [rate ratio (RR) 1.25, 95% CI: 1.16 to 1.35, p-value < 0.001], while risk among females was lower [RR 0.89, 95% CI: 0.83 to 0.96, p-value = 0.002]. Rates of cardiovascular hospitalizations were higher among those with ≥500 mg/g of proteinuria irrespective of eGFR. The most common causes of hospitalization were related to cardiovascular (31.8%), genitourinary (8.7%), digestive (8.3%), endocrine, nutritional or metabolic (8.3%), and respiratory (6.7%) causes. Hospitalization rates were higher in CRIC than the NIS, except for non-cardiovascular hospitalizations among individuals aged >65 years. Limitations of the study include possible misclassification by diagnostic codes, residual confounding, and potential bias from healthy volunteer effect due to its observational nature. CONCLUSIONS: In this study, we observed that adults with CKD had a higher hospitalization rate than the general population that is hospitalized, and even moderate reductions in kidney function were associated with elevated rates of hospitalization. Causes of hospitalization were predominantly related to cardiovascular disease, but other causes contributed, particularly, genitourinary, digestive, and endocrine, nutritional, and metabolic illnesses. High levels of proteinuria were observed to have the largest association with hospitalizations across a wide range of kidney function levels.

CKD Self-management: Phenotypes and Associations With Clinical Outcomes.

BACKGROUND: To slow chronic kidney disease (CKD) progression and its complications, patients need to engage in self-management behaviors. The objective of this study was to classify CKD self-management behaviors into phenotypes and assess the association of these phenotypes with clinical outcomes. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Adults with mild to moderate CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. 3,939 participants in the CRIC Study recruited between 2003 and 2008 served as the derivation cohort and 1,560 participants recruited between 2013 and 2015 served as the validation cohort. PREDICTORS: CKD self-management behavior phenotypes. OUTCOMES: CKD progression, atherosclerotic events, heart failure events, death from any cause. MEASUREMENTS: Latent class analysis stratified by diabetes was used to identify CKD self-management phenotypes based on measures of body mass index, diet, physical activity, blood pressure, smoking status, and hemoglobin A1c concentration (if diabetic); Cox proportional hazards models. RESULTS: 3 identified phenotypes varied according to the extent of implementation of recommended CKD self-management behaviors: phenotype I characterized study participants with the most recommended behaviors; phenotype II, participants with a mixture of recommended and not recommended behaviors; and phenotype III, participants with minimal recommended behaviors. In multivariable-adjusted models for those with and without diabetes, phenotype III was strongly associated with CKD progression (HRs of 1.82 and 1.49), death (HRs of 1.95 and 4.14), and atherosclerotic events (HRs of 2.54 and 1.90; each P < 0.05). Phenotype II was associated with atherosclerotic events and death among those with and without diabetes. LIMITATIONS: No consensus definition of CKD self-management; limited to baseline behavior data. CONCLUSIONS: There are potentially 3 CKD self-management behavior phenotypes that distinguish risk for clinical outcomes. These phenotypes may inform the development of studies and guidelines regarding optimal self-management.

Risk Factors for Heart Failure in Patients With Chronic Kidney Disease: The CRIC (Chronic Renal Insufficiency Cohort) Study.

BACKGROUND: Heart failure is common in patients with chronic kidney disease. We studied risk factors for incident heart failure among 3557 participants in the CRIC (Chronic Renal Insufficiency Cohort) Study. METHODS AND RESULTS: Kidney function was assessed by estimated glomerular filtration rate (eGFR) using serum creatinine, cystatin C, or both, and 24-hour urine albumin excretion. During an average of 6.3 years of follow-up, 452 participants developed incident heart failure. After adjustment for age, sex, race, and clinical site, hazard ratio (95% CI) for heart failure associated with 1 SD lower creatinine-based eGFR was 1.67 (1.49, 1.89), 1 SD lower cystatin C-based-eGFR was 2.43 (2.10, 2.80), and 1 SD higher log-albuminuria was 1.65 (1.53, 1.78), all P<0.001. When all 3 kidney function measures were simultaneously included in the model, lower cystatin C-based eGFR and higher log-albuminuria remained significantly and directly associated with incidence of heart failure. After adjusting for eGFR, albuminuria, and other traditional cardiovascular risk factors, anemia (1.37, 95% CI 1.09, 1.72, P=0.006), insulin resistance (1.16, 95% CI 1.04, 1.28, P=0.006), hemoglobin A1c (1.27, 95% CI 1.14, 1.41, P<0.001), interleukin-6 (1.15, 95% CI 1.05, 1.25, P=0.002), and tumor necrosis factor-α (1.10, 95% CI 1.00, 1.21, P=0.05) were all significantly and directly associated with incidence of heart failure. CONCLUSIONS: Our study indicates that cystatin C-based eGFR and albuminuria are better predictors for risk of heart failure compared to creatinine-based eGFR. Furthermore, anemia, insulin resistance, inflammation, and poor glycemic control are independent risk factors for the development of heart failure among patients with chronic kidney disease.

Predictors and Outcomes of Health-Related Quality of Life in Adults with CKD.

BACKGROUND AND OBJECTIVES: Low health-related quality of life is associated with increased mortality in patients with ESRD. However, little is known about demographic and clinical factors associated with health-related quality of life or its effect on outcomes in adults with CKD. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: Data from 3837 adult participants with mild to severe CKD enrolled in the prospective observational Chronic Renal Insufficiency Cohort and Hispanic Chronic Renal Insufficiency Cohort Studies were analyzed. Health-related quality of life was assessed at baseline with the Kidney Disease Quality of Life-36 and its five subscales: mental component summary, physical component summary, burden of kidney disease (burden), effects of kidney disease (effects), and symptoms and problems of kidney disease (symptoms). Low health-related quality of life was defined as baseline score >1 SD below the mean. Using Cox proportional hazards analysis, the relationships between low health-related quality of life and the following outcomes were examined: (1) CKD progression (50% eGFR loss or incident ESRD), (2) incident cardiovascular events, and (3) all-cause death. RESULTS: Younger age, women, low education, diabetes, vascular disease, congestive heart failure, obesity, and lower eGFR were associated with low baseline health-related quality of life (P<0.05). During a median follow-up of 6.2 years, there were 1055 CKD progression events, 841 cardiovascular events, and 694 deaths. Significantly higher crude rates of CKD progression, incident cardiovascular events, and all-cause death were observed among participants with low health-related quality of life in all subscales (P<0.05). In fully adjusted models, low physical component summary, effects, and symptoms subscales were independently associated with a higher risk of incident cardiovascular events and death, whereas low mental component summary was independently associated with a higher risk of death (P<0.05). Low health-related quality of life was not associated with CKD progression. CONCLUSIONS: Low health-related quality of life across several subscales was independently associated with a higher risk of incident cardiovascular events and death but not associated with CKD progression.

Candidate gene association study of coronary artery calcification in chronic kidney disease: findings from the CRIC study (Chronic Renal Insufficiency Cohort).

OBJECTIVES: This study sought to identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD). BACKGROUND: CKD is associated with increased CAC and subsequent coronary heart disease (CHD), but the mechanisms remain poorly defined. Genetic studies of CAC in CKD may provide a useful strategy for identifying novel pathways in CHD. METHODS: We performed a candidate gene study (∼2,100 genes; ∼50,000 single nucleotide polymorphisms [SNPs]) of CAC within the CRIC (Chronic Renal Insufficiency Cohort) study (N = 1,509; 57% European, 43% African ancestry). SNPs with preliminary evidence of association with CAC in CRIC were examined for association with CAC in the PennCAC (Penn Coronary Artery Calcification) (N = 2,560) and AFCS (Amish Family Calcification Study) (N = 784) samples. SNPs with suggestive replication were further analyzed for association with myocardial infarction (MI) in the PROMIS (Pakistan Risk of Myocardial Infarction Study) (N = 14,885). RESULTS: Of 268 SNPs reaching p < 5 × 10(-4) for CAC in CRIC, 28 SNPs in 23 loci had nominal support (p < 0.05 and in same direction) for CAC in PennCAC or AFCS. Besides chr9p21 and COL4A1, known loci for CHD, these included SNPs having reported genome-wide association study association with hypertension (e.g., ATP2B1). In PROMIS, 4 of the 23 suggestive CAC loci (chr9p21, COL4A1, ATP2B1, and ABCA4) had significant associations with MI, consistent with their direction of effect on CAC. CONCLUSIONS: We identified several loci associated with CAC in CKD that also relate to MI in a general population sample. CKD imparts a high risk of CHD and may provide a useful setting for discovery of novel CHD genes and pathways.

Risk factors for coronary artery calcium among patients with chronic kidney disease (from the Chronic Renal Insufficiency Cohort Study).

Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD). We examined the cross-sectional association between novel risk factors and coronary artery calcium (CAC) measured using electron beam computed tomography or multidetector computed tomography among 2,018 patients with CKD. Using the total Agatston scores, the participants were classified as having no (0), moderate (>0-100), or high (>100) CAC. After adjustment for age, gender, race, study sites, cigarette smoking, previous cardiovascular disease, hypertension, and diabetes, the use of lipid-lowering drugs, body mass index, waist circumference, and cystatin C, several novel risk factors were significantly associated with high CAC. For example, the odds ratios of high CAC associated with 1 SD greater level of risk factors were 1.20 (95% confidence interval 1.04 to 1.38) for serum calcium, 1.21 (95% confidence interval 1.04 to 1.41) for serum phosphate, 0.83 (95% confidence interval 0.71 to 0.97) for log (total parathyroid hormone), 1.21 (95% confidence interval 1.03 to 1.43) for log (homeostasis model assessment-insulin resistance), and 1.23 (95% confidence interval 1.04 to 1.45) for hemoglobin A1c. Additionally, the multivariate-adjusted odds ratio for 1 SD greater level of cystatin C was 1.31 (95% confidence interval 1.14 to 1.50). Serum high-sensitive C-reactive protein, interleukin-6, tumor necrosis factor-α, and homocysteine were not statistically significantly associated with high CAC. In conclusion, these data indicate that abnormal calcium and phosphate metabolism, insulin resistance, and declining kidney function are associated with the prevalence of high CAC, independent of the traditional risk factors in patients with CKD. Additional studies are warranted to examine the causal effect of these risk factors on CAC in patients with CKD.

Factors predicting erythropoietin resistance among maintenance hemodialysis patients.

BACKGROUND: Erythropoiesis-stimulating agent (ESA) resistance remains incompletely understood among hemodialysis (HD) patients. METHOD: A retrospective, multicenter study was designed to analyze data from 1,934 patients followed for up to two years. The outcome measure was the erythropoietin resistance index (ERI), defined as erythropoietin dosage over a week divided by the post-HD weight and hemoglobin value. RESULTS: Multivariate analysis revealed albumin, Kt/V, transferrin saturation, statin use and male gender to be inversely related to ERI, whereas parathyroid hormone and angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) use were associated with higher ESA resistance. ERI was statistically lower in patients with higher levels of albumin (p < 0.001) and with higher transferrin saturation levels (p < 0.05). DISCUSSION: The results allow for a better understanding of predictors of erythropoietin resistance among HD patients including not extensively studied factors such as statin and ACEI/ARB use.

Home blood pressure monitoring in clinical practice: a review.

Home blood pressure monitoring is a convenient and inexpensive technique to monitor blood pressure in hypertensive patients. There are convincing data that home blood pressure monitoring is a good predictor of future cardiovascular risk, perhaps better than office blood pressure. Home blood pressure measurement can be standardized using validated instruments and systematic protocols; normative criteria have established home blood pressure >135/85 mm Hg as hypertensive. Home blood pressure monitoring has been shown to improve compliance and blood pressure control, and to reduce health care costs. Ongoing studies are evaluating management of hypertension based on home blood pressure readings compared with traditional office-based readings. Home blood pressure monitoring is particularly useful for evaluation of white coat hypertension and masked hypertension. In this article, we discuss the methodology for measuring blood pressure at home, its comparison to the other measurement techniques, the advantages and disadvantages, cost benefit analyses, and ongoing clinical trials to help define the role of home blood pressure monitoring in the clinical management of hypertension.