Systematic integrated analysis of genetic and epigenetic variation in diabetic kidney disease.

Poor metabolic control and host genetic predisposition are critical for diabetic kidney disease (DKD) development. The epigenome integrates information from sequence variations and metabolic alterations. Here, we performed a genome-wide methylome association analysis in 500 subjects with DKD from the Chronic Renal Insufficiency Cohort for DKD phenotypes, including glycemic control, albuminuria, kidney function, and kidney function decline. We show distinct methylation patterns associated with each phenotype. We define methylation variations that are associated with underlying nucleotide variations (methylation quantitative trait loci) and show that underlying genetic variations are important drivers of methylation changes. We implemented Bayesian multitrait colocalization analysis (moloc) and summary data-based Mendelian randomization to systematically annotate genomic regions that show association with kidney function, methylation, and gene expression. We prioritized 40 loci, where methylation and gene-expression changes likely mediate the genotype effect on kidney disease development. Functional annotation suggested the role of inflammation, specifically, apoptotic cell clearance and complement activation in kidney disease development. Our study defines methylation changes associated with DKD phenotypes, the key role of underlying genetic variations driving methylation variations, and prioritizes methylome and gene-expression changes that likely mediate the genotype effect on kidney disease pathogenesis.

Risk of Potentially Inappropriate Medications in Adults With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Adults with chronic kidney disease (CKD) may be at increased risk of adverse effects from use of potentially inappropriate medications (PIMs). Our objective was to assess whether PIM exposure has an independent association with CKD progression, hospitalizations, mortality, or falls. STUDY DESIGN: Retrospective observational study. SETTING & PARTICIPANTS: Chronic Renal Insufficiency Cohort (CRIC) study; 3,929 adults with CKD enrolled 2003-2008 and followed prospectively until December 2011. EXPOSURE: PIM exposure was defined as prescriptions for any medications to be avoided in older adults as defined by the 2015 American Geriatrics Society Beers Criteria. OUTCOME: Hospitalization count, death, a composite kidney disease end point of CKD progression or initiation of kidney replacement therapy (KRT), KRT, and fall events assessed 1 year after PIM exposure. ANALYTICAL APPROACH: Logistic regression and Poisson regression to estimate the associations of PIM exposure with each outcome. RESULTS: The most commonly prescribed PIMs were proton pump inhibitors and α-blockers. In unadjusted models, any PIM exposure (compared to none) was associated with hospitalizations, death, and fall events. After adjustment, exposure to 1, 2, or≥3 PIMs had a graded association with a higher hospitalization rate (rate ratios of 1.09 [95% CI, 1.01-1.17], 1.18 [95% CI, 1.07-1.30], and 1.35 [95% CI, 1.19-1.53], respectively) and higher odds of mortality (odds ratios of 1.19 [95% CI, 0.91-1.54], 1.62 [95% CI, 1.21-2.17], and 1.65 [95% CI, 1.14-2.41], respectively). In a cohort subset reporting falls (n=1,109), prescriptions for≥3 PIMs were associated with an increased risk of falls (adjusted OR, 2.85 [95% CI, 1.54-5.26]). PIMs were not associated with CKD progression or KRT. Age did not modify the association between PIM count and outcomes. LIMITATIONS: Measurement bias; confounding by indication. CONCLUSIONS: Adults of any age with CKD who are prescribed PIMs have an increased risk of hospitalization, mortality, and falls with the greatest risk occurring after more than 1 PIM prescription.

Sex Differences in Cardiovascular Outcomes in CKD: Findings From the CRIC Study.

RATIONALE & OBJECTIVE: Cardiovascular events are less common in women than men in general populations; however, studies in chronic kidney disease (CKD) are less conclusive. We evaluated sex-related differences in cardiovascular events and death in adults with CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 1,778 women and 2,161 men enrolled in the Chronic Renal Insufficiency Cohort (CRIC). EXPOSURE: Sex (women vs men). OUTCOME: Atherosclerotic composite outcome (myocardial infarction, stroke, or peripheral artery disease), incident heart failure, cardiovascular death, and all-cause death. ANALYTICAL APPROACH: Cox proportional hazards regression. RESULTS: During a median follow-up period of 9.6 years, we observed 698 atherosclerotic events (women, 264; men, 434), 762 heart failure events (women, 331; men, 431), 435 cardiovascular deaths (women, 163; men, 274), and 1,158 deaths from any cause (women, 449; men, 709). In analyses adjusted for sociodemographic, clinical, and metabolic parameters, women had a lower risk of atherosclerotic events (HR, 0.71 [95% CI, 0.57-0.88]), heart failure (HR, 0.76 [95% CI, 0.62-0.93]), cardiovascular death (HR, 0.55 [95% CI, 0.42-0.72]), and death from any cause (HR, 0.58 [95% CI, 0.49-0.69]) compared with men. These associations remained statistically significant after adjusting for cardiac and inflammation biomarkers. LIMITATIONS: Assessment of sex hormones, which may play a role in cardiovascular risk, was not included. CONCLUSIONS: In a large, diverse cohort of adults with CKD, compared with men, women had lower risks of cardiovascular events, cardiovascular mortality, and mortality from any cause. These differences were not explained by measured cardiovascular risk factors.

Sex-Related Disparities in CKD Progression.

BACKGROUND: In the United States, incidence of ESRD is 1.5 times higher in men than in women, despite men's lower prevalence of CKD. Prior studies, limited by inclusion of small percentages of minorities and other factors, suggested that men have more rapid CKD progression, but this finding has been inconsistent. METHODS: In our prospective investigation of sex differences in CKD progression, we used data from 3939 adults (1778 women and 2161 men) enrolled in the Chronic Renal Insufficiency Cohort Study, a large, diverse CKD cohort. We evaluated associations between sex (women versus men) and outcomes, specifically incident ESRD (defined as undergoing dialysis or a kidney transplant), 50% eGFR decline from baseline, incident CKD stage 5 (eGFR<15 ml/min per 1.73 m2), eGFR slope, and all-cause death. RESULTS: Participants' mean age was 58 years at study entry; 42% were non-Hispanic black, and 13% were Hispanic. During median follow-up of 6.9 years, 844 individuals developed ESRD, and 853 died. In multivariable regression models, compared with men, women had significantly lower risk of ESRD, 50% eGFR decline, progression to CKD stage 5, and death. The mean unadjusted eGFR slope was -1.09 ml/min per 1.73 m2 per year in women and -1.43 ml/min per 1.73 m2 per year in men, but this difference was not significant after multivariable adjustment. CONCLUSIONS: In this CKD cohort, women had lower risk of CKD progression and death compared with men. Additional investigation is needed to identify biologic and psychosocial factors underlying these sex-related differences.

Impact of AKI on Urinary Protein Excretion: Analysis of Two Prospective Cohorts.

BACKGROUND: Prior studies of adverse renal consequences of AKI have almost exclusively focused on eGFR changes. Less is known about potential effects of AKI on proteinuria, although proteinuria is perhaps the strongest risk factor for future loss of renal function. METHODS: We studied enrollees from the Assessment, Serial Evaluation, and Subsequent Sequelae of AKI (ASSESS-AKI) study and the subset of the Chronic Renal Insufficiency Cohort (CRIC) study enrollees recruited from Kaiser Permanente Northern California. Both prospective cohort studies included annual ascertainment of urine protein-to-creatinine ratio, eGFR, BP, and medication use. For hospitalized participants, we used inpatient serum creatinine measurements obtained as part of clinical care to define an episode of AKI (i.e., peak/nadir inpatient serum creatinine ≥1.5). We performed mixed effects regression to examine change in log-transformed urine protein-to-creatinine ratio after AKI, controlling for time-updated covariates. RESULTS: At cohort entry, median eGFR was 62.9 ml/min per 1.73 m2 (interquartile range [IQR], 46.9-84.6) among 2048 eligible participants, and median urine protein-to-creatinine ratio was 0.12 g/g (IQR, 0.07-0.25). After enrollment, 324 participants experienced at least one episode of hospitalized AKI during 9271 person-years of follow-up; 50.3% of first AKI episodes were Kidney Disease Improving Global Outcomes stage 1 in severity, 23.8% were stage 2, and 25.9% were stage 3. In multivariable analysis, an episode of hospitalized AKI was independently associated with a 9% increase in the urine protein-to-creatinine ratio. CONCLUSIONS: Our analysis of data from two prospective cohort studies found that hospitalization for an AKI episode was independently associated with subsequent worsening of proteinuria.

Predictors of Net Acid Excretion in the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Higher urine net acid excretion (NAE) is associated with slower chronic kidney disease progression, particularly in patients with diabetes mellitus. To better understand potential mechanisms and assess modifiable components, we explored independent predictors of NAE in the CRIC (Chronic Renal Insufficiency Cohort) Study. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: A randomly selected subcohort of adults with chronic kidney disease enrolled in the CRIC Study with NAE measurements. PREDICTORS: A comprehensive set of variables across prespecified domains including demographics, comorbid conditions, medications, laboratory values, diet, physical activity, and body composition. OUTCOME: 24-hour urine NAE. ANALYTICAL APPROACH: NAE was defined as the sum of urine ammonium and calculated titratable acidity in a subset of CRIC participants. 22 individuals were excluded for urine pH < 4 (n = 1) or ≥7.4 (n = 19) or extreme outliers of NAE values (n = 2). From an analytic sample of 978, we identified the association of individual variables with NAE in the selected domains using linear regression. We estimated the percent variance explained by each domain using the adjusted R2 from a domain-specific model. RESULTS: Mean NAE was 33.2 ± 17.4 (SD) mEq/d. Multiple variables were associated with NAE in models adjusted for age, sex, estimated glomerular filtration rate (eGFR), race/ethnicity, and body surface area, including insulin resistance, dietary potential renal acid load, and a variety of metabolically active medications (eg, metformin, allopurinol, and nonstatin lipid agents). Body size, as indicated by body surface area, body mass index, or fat-free mass; race/ethnicity; and eGFR also were independently associated with NAE. By domains, more variance was explained by demographics, body composition, and laboratory values, which included eGFR and serum bicarbonate level. LIMITATIONS: Cross-sectional; use of stored biological samples. CONCLUSIONS: NAE relates to several clinical domains including body composition, kidney function, and diet, but also to metabolic factors such as insulin resistance and the use of metabolically active medications.

Cardiovascular Events after New-Onset Atrial Fibrillation in Adults with CKD: Results from the Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: Atrial fibrillation (AF), the most common sustained arrhythmia in CKD, is associated with poor clinical outcomes in both patients without CKD and patients with dialysis-treated ESRD. However, less is known about AF-associated outcomes in patients with CKD who do not require dialysis. METHODS: To prospectively examine the association of new-onset AF with subsequent risks of cardiovascular disease events and death among adults with CKD, we studied participants enrolled in the Chronic Renal Insufficiency Cohort Study who did not have AF at baseline. Outcomes included heart failure, myocardial infarction, stroke, and death occurring after diagnosis of AF. We used Cox regression models and marginal structural models to examine the association of incident AF with subsequent risk of cardiovascular disease events and death, adjusting for patient characteristics, laboratory values, and medication use. RESULTS: Among 3080 participants, 323 (10.5%) developed incident AF during a mean 6.1 years of follow-up. Compared with participants who did not develop AF, those who did had higher adjusted rates of heart failure (hazard ratio [HR], 5.17; 95% confidence interval [95% CI], 3.89 to 6.87), myocardial infarction (HR, 3.64; 95% CI, 2.50 to 5.31), stroke (HR, 2.66; 95% CI, 1.50 to 4.74), and death (HR, 3.30; 95% CI, 2.65 to 4.12). These associations remained robust with additional adjustment for biomarkers of inflammation, cardiac stress, and mineral metabolism; left ventricular mass; ejection fraction; and left atrial diameter. CONCLUSIONS: Incident AF is independently associated with two- to five-fold increased rates of developing subsequent heart failure, myocardial infarction, stroke, or death in adults with CKD. These findings have important implications for cardiovascular risk reduction.

Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system.

BACKGROUND & AIMS: Medications are a major cause of acute liver failure (ALF) in the United States, but no population-based studies have evaluated the incidence of ALF from drug-induced liver injury. We aimed to determine the incidence and outcomes of drug-induced ALF in an integrated health care system that approximates a population-based cohort. METHODS: We performed a retrospective cohort study using data from the Kaiser Permanente Northern California (KPNC) health care system between January 1, 2004, and December 31, 2010. We included all KPNC members age 18 years and older with 6 months or more of membership and hospitalization for potential ALF. The primary outcome was drug-induced ALF (defined as coagulopathy and hepatic encephalopathy without underlying chronic liver disease), determined by hepatologists who reviewed medical records of all KPNC members with inpatient diagnostic and laboratory criteria suggesting potential ALF. RESULTS: Among 5,484,224 KPNC members between 2004 and 2010, 669 had inpatient diagnostic and laboratory criteria indicating potential ALF. After medical record review, 62 (9.3%) were categorized as having definite or possible ALF, and 32 (51.6%) had a drug-induced etiology (27 definite, 5 possible). Acetaminophen was implicated in 18 events (56.3%), dietary/herbal supplements in 6 events (18.8%), antimicrobials in 2 events (6.3%), and miscellaneous medications in 6 events (18.8%). One patient with acetaminophen-induced ALF died (5.6%; 0.06 events/1,000,000 person-years) compared with 3 patients with non-acetaminophen-induced ALF (21.4%; 0.18/1,000,000 person-years). Overall, 6 patients (18.8%) underwent liver transplantation, and 22 patients (68.8%) were discharged without transplantation. The incidence rates of any definite drug-induced ALF and acetaminophen-induced ALF were 1.61 events/1,000,000 person-years (95% confidence interval, 1.06-2.35) and 1.02 events/1,000,000 person-years (95% confidence interval, 0.59-1.63), respectively. CONCLUSIONS: Drug-induced ALF is uncommon, but over-the-counter products and dietary/herbal supplements are its most common causes.

Antiretroviral Refill Adherence Correlates with, But Poorly Predicts Retention in HIV Care.

If antiretroviral refill adherence could predict non-retention in care, it could be clinically useful. In a retrospective cohort study of HIV-infected adults in Philadelphia between October 2012 and April 2013, retention in care was measured by show versus no-show at an index visit. Three measures of adherence were defined per person: (1) percent of doses taken for two refills nearest index visit, (2) days late for last refill before index visit, and (3) longest gap between any two refills. Of 393 patients, 108 (27.4 %) no-showed. Adherence was higher in the show group on all measures with longest gap having the greatest difference: 40 days (IQR 33-56) in the show versus 47 days (IQR 38-69) in the no-show group, p < 0.001. Yet, no cut-points of adherence adequately predicted show versus no-show. Antiretroviral adherence being associated, but a poor predictor of retention suggests that these two behaviors are related but distinct phenomena.

Risk of Acute Liver Failure in Patients With Drug-Induced Liver Injury: Evaluation of Hy's Law and a New Prognostic Model.

BACKGROUND & AIMS: Few studies have evaluated the ability of laboratory tests to predict risk of acute liver failure (ALF) among patients with drug-induced liver injury (DILI). We aimed to develop a highly sensitive model to identify DILI patients at increased risk of ALF. We compared its performance with that of Hy's Law, which predicts severity of DILI based on levels of alanine aminotransferase or aspartate aminotransferase and total bilirubin, and validated the model in a separate sample. METHODS: We conducted a retrospective cohort study of 15,353 Kaiser Permanente Northern California members diagnosed with DILI from 2004 through 2010, liver aminotransferase levels above the upper limit of normal, and no pre-existing liver disease. Thirty ALF events were confirmed by medical record review. Logistic regression was used to develop prognostic models for ALF based on laboratory results measured at DILI diagnosis. External validation was performed in a sample of 76 patients with DILI at the University of Pennsylvania. RESULTS: Hy's Law identified patients that developed ALF with a high level of specificity (0.92) and negative predictive value (0.99), but low level of sensitivity (0.68) and positive predictive value (0.02). The model we developed, comprising data on platelet count and total bilirubin level, identified patients with ALF with a C statistic of 0.87 (95% confidence interval [CI], 0.76-0.96) and enabled calculation of a risk score (Drug-Induced Liver Toxicity ALF Score). We found a cut-off score that identified patients at high risk patients for ALF with a sensitivity value of 0.91 (95% CI, 0.71-0.99) and a specificity value of 0.76 (95% CI, 0.75-0.77). This cut-off score identified patients at high risk for ALF with a high level of sensitivity (0.89; 95% CI, 0.52-1.00) in the validation analysis. CONCLUSIONS: Hy's Law identifies patients with DILI at high risk for ALF with low sensitivity but high specificity. We developed a model (the Drug-Induced Liver Toxicity ALF Score) based on platelet count and total bilirubin level that identifies patients at increased risk for ALF with high sensitivity.

Validity of diagnostic codes and laboratory tests of liver dysfunction to identify acute liver failure events.

PURPOSE: Identification of acute liver failure (ALF) is important for post-marketing surveillance of medications, but the validity of using ICD-9 diagnoses and laboratory data to identify these events within electronic health records is unknown. We examined positive predictive values (PPVs) of hospital ICD-9 diagnoses and laboratory tests of liver dysfunction for identifying ALF within a large, community-based integrated care organization. METHODS: We identified Kaiser Permanente Northern California health plan members (2004-2010) with a hospital diagnosis suggesting ALF (ICD-9 570, 572.2, 572.4, 572.8, 573.3, 573.8, or V42.7) plus an inpatient international normalized ratio ≥1.5 (off warfarin) and total bilirubin ≥5.0 mg/dL. Hospital records were reviewed by hepatologists to adjudicate ALF events. PPVs for confirmed outcomes were determined for individual ICD-9 diagnoses, diagnoses plus prescriptions for hepatic encephalopathy treatment, and combinations of diagnoses in the setting of coagulopathy and hyperbilirubinemia. RESULTS: Among 669 members with no pre-existing liver disease, chart review confirmed ALF in 62 (9%). Despite the presence of co-existing coagulopathy and hyperbilirubinemia, individual ICD-9 diagnoses had low PPVs (range, 5-15%); requiring prescriptions for encephalopathy treatment did not increase PPVs of these diagnoses (range, 2-23%). Hospital diagnoses of other liver disorders (ICD-9 573.8) plus hepatic coma (ICD-9 572.2) had high PPV (67%; 95%CI, 9-99%) but only identified two (3%) ALF events. CONCLUSIONS: Algorithms comprising relevant hospital diagnoses, laboratory evidence of liver dysfunction, and prescriptions for hepatic encephalopathy treatment had low PPVs for confirmed ALF events. Studies of ALF will need to rely on medical records to confirm this outcome.

Simulation study of instrumental variable approaches with an application to a study of the antidiabetic effect of bezafibrate.

PURPOSE: We studied the application of the generalized structural mean model (GSMM) of instrumental variable (IV) methods in estimating treatment odds ratios (ORs) for binary outcomes in pharmacoepidemiologic studies and evaluated the bias of GSMM compared to other IV methods. METHODS: Because of the bias of standard IV methods, including two-stage predictor substitution (2SPS) and two-stage residual inclusion (2SRI) with binary outcomes, we implemented another IV approach based on the GSMM of Vansteelandt and Goetghebeur. We performed simulations under the principal stratification setting and evaluated whether GSMM provides approximately unbiased estimates of the causal OR and compared its bias and mean squared error to that of 2SPS and 2SRI. We then applied different IV methods to a study comparing bezafibrate versus other fibrates on the risk of diabetes. RESULTS: Our simulations showed that unlike the standard logistic, 2SPS, and 2SRI procedures, our implementation of GSMM provides an approximately unbiased estimate of the causal OR even under unmeasured confounding. However, for the effect of bezafibrate versus other fibrates on the risk of diabetes, the GSMM and two-stage approaches yielded similarly attenuated and statistically non-significant OR estimates. The attenuation of the OR by the two-stage and GSMM IV approaches suggests unmeasured confounding, although violations of the IV assumptions or differences in the parameters estimated could be playing a role. CONCLUSION: The GSMM IV approach provides approximately unbiased adjustment for unmeasured confounding on binary outcomes when a valid IV is available.

Associations of Anxiety during the COVID-19 Pandemic with Patient Characteristics and Behaviors in CKD Patients: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

Background: Chronic kidney disease (CKD) is associated with anxiety and depression. Although the coronavirus disease 2019 (COVID-19) pandemic has increased stressors on patients with CKD, assessments of anxiety and its predictors and consequences on behaviors, specifically virus mitigation behaviors, are lacking. Methods: From June to October 2020, we administered a survey to 1873 patients in the Chronic Renal Insufficiency Cohort (CRIC) Study, asking participants about anxiety related to the COVID-19 pandemic. We examined associations between anxiety and participant demographics, clinical indexes, and health literacy and whether anxiety was associated with health-related behaviors and COVID-19 mitigation behaviors. Results: The mean age of the study population was 70 years (SD=9.6 years), 47% were women, 39% were Black non-Hispanic, 14% were Hispanic, and 38% had a history of cardiovascular disease. In adjusted analyses, younger age, being a woman, Hispanic ethnicity, cardiovascular disease, household income <$20,000, and marginal or inadequate health literacy predicted higher anxiety. Higher global COVID-19-related anxiety scores were associated with higher odds of reporting always wearing a mask in public (OR=1.3 [95% CI, 1.14 to 1.48], P<0.001) and of eating less healthy foods (OR=1.29 [95% CI, 1.13 to 1.46], P<0.001), reduced physical activity (OR=1.32 [95% CI, 1.2 to 1.45], P<0.001), and weight gain (OR=1.23 [95% CI, 1.11 to 1.38], P=0.001). Conclusions: Higher anxiety levels related to the COVID-19 pandemic were associated not only with higher self-reported adherence to mask wearing but also with higher weight gain and less adherence to healthy lifestyle behaviors. Interventions are needed to support continuation of healthy lifestyle behaviors in patients with CKD experiencing increased anxiety related to the pandemic.

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.

Excessive daytime sleepiness is associated with poor medication adherence in adults with heart failure.

BACKGROUND: A relationship between excessive daytime sleepiness (EDS) and poor treatment adherence has been suspected but not confirmed. We hypothesized that medication adherence would be poorer in adults with heart failure (HF) and EDS and that cognitive status would be the mechanism of effect. METHODS AND RESULTS: A sample of 280 adults with chronic HF were enrolled into a prospective cohort comparison study. We identified a cohort with EDS and a control group without EDS and further divided both groups into those with and without mild cognitive decline. Data on medication adherence were obtained at baseline and 3 and 6 months by using the Basel Assessment of Adherence Scale. Regression analysis was used to clarify the contribution of EDS and cognition to medication adherence and to assess relationships over 6 months after adjusting for age, enrollment site, gender, race, functional class, depression, and premorbid intellect. At baseline, 62% of subjects were nonadherent to their medication regime. Nonadherence was significantly more common in those with EDS, regardless of cognitive status (P = .035). The odds of nonadherence increased by 11% for each unit increase in EDS (adjusted odds ratio 1.11; 95% confidence interval 1.05-1.19; P = .001). In longitudinal models, there was a 10% increase in the odds of nonadherence for each unit increase in EDS (P = .008). The only cognition measure significantly associated with medication adherence was attention (P = .047). CONCLUSIONS: Adults with HF and EDS are more likely to have problems adhering to their medication regimen than those without EDS, regardless of their cognitive status. Identifying and correcting factors that interfere with sleep may improve medication adherence.

Atrial Fibrillation and Longitudinal Change in Cognitive Function in CKD.

BACKGROUND: Studies in the general population suggest that atrial fibrillation (AF) is an independent risk factor for decline in cognitive function, but this relationship has not been examined in adults with chronic kidney disease (CKD). We investigated the association between incident AF and changes in cognitive function over time in this population. METHODS AND RESULTS: We studied a subgroup of 3254 adults participating in the Chronic Renal Insufficiency Cohort Study. Incident AF was ascertained by 12-lead electrocardiogram (ECG) obtained at a study visit and/or identification of a hospitalization with AF during follow-up. Cognitive function was assessed biennially using the Modified Mini-Mental State Exam. Linear mixed effects regression was used to evaluate the association between incident AF and longitudinal change in cognitive function. Compared with individuals without incident AF (n = 3158), those with incident AF (n = 96) were older, had a higher prevalence of cardiovascular disease and hypertension, and lower estimated glomerular filtration rate. After median follow-up of 6.8 years, we observed no significant multivariable association between incident AF and change in cognitive function test score. CONCLUSION: In this cohort of adults with CKD, incident AF was not associated with a decline in cognitive function.

Neighborhood Food Outlet Access and Dietary Intake among Adults with Chronic Kidney Disease: Results from the Chronic Renal Insufficiency Cohort Study.

BACKGROUND: Healthy diet is essential in the management of chronic kidney disease (CKD) and preventing related comorbidities. Food outlet access has been studied in the general population; however, the influence of the local food environment on dietary intake among people with CKD has not been evaluated. OBJECTIVES: This study examined the associations of food outlet density and type of outlets with dietary intake in a multicenter cohort of racially and ethnically diverse patients with CKD. METHODS: The Chronic Renal Insufficiency Cohort Study is a multicenter prospective study of patients with CKD that used a validated food frequency questionnaire to capture dietary intake at the baseline visit. This is a cross-sectional analysis of 2,484 participants recruited in 2003-2006 from seven Chronic Renal Insufficiency Cohort Study centers. Food outlet data were used to construct a count of the number of fast-food restaurants, convenience stores, and grocery stores per 10,000 population for each geocoded census block group. Multivariable linear and logistic regression models were used to evaluate the associations between measures of food outlet availability and dietary factors. RESULTS: The proportion of participants living in zero-, low-, and high-food outlet density areas differed by gender, race or ethnicity, and income level. Among male subjects, living in areas with zero or the highest number of outlets was associated with having the highest caloric intakes in multivariable models. Male subjects living in areas with zero outlets consumed the highest levels of sodium and phosphorous. Female subjects living in areas with zero outlets had the lowest average intake of calories, sodium, and phosphorous. Among low-income female subjects, close proximity to more outlets was associated with higher calorie consumption. Among all participants, access to fast-food restaurants was not associated with an unhealthy diet score, and access to grocery stores was not associated with a healthy diet score. CONCLUSIONS: Average caloric and nutrient intakes differed by outlet availability; however, there were no strong associations with type of food outlet. This should be considered when developing food-focused public health policies.

Health-Related Quality of Life, Depressive Symptoms, and Kidney Transplant Access in Advanced CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Among individuals with chronic kidney disease (CKD), poor self-reported health is associated with adverse outcomes including hospitalization and death. We sought to examine the association between health-related quality-of-life (HRQoL) and depressive symptoms in advanced CKD and subsequent access to the kidney transplant waiting list. STUDY DESIGN: Prospective cohort study. SETTING & POPULATION: 1,676 Chronic Renal Insufficiency Cohort (CRIC) study participants with estimated glomerular filtration rates ≤ 30 mL/min/1.73 m2 at study entry or during follow-up. EXPOSURES: HRQoL ascertained by 5 scales of the Kidney Disease Quality of Life-36 Survey (Physical Component Summary [PCS], Mental Component Summary, Symptoms, Burdens, and Effects), with higher scores indicating better HRQoL, and depressive symptoms ascertained using the Beck Depression Inventory. OUTCOMES: Time to kidney transplant wait-listing and time to pre-emptive wait-listing. ANALYTIC APPROACH: Time-to-event analysis using Cox proportional hazards regression. RESULTS: During a median follow-up of 5.1 years, 652 (39%) participants were wait-listed, of whom 304 were preemptively wait-listed. Adjusted for demographics, comorbid conditions, estimated glomerular filtration rate slope, and cognitive function, participants with the highest scores on the Burden and Effects scales, respectively, had lower rates of wait-listing than those with the lowest scores on the Burden (wait-listing adjusted hazard ratio [aHR], 0.70; 95% CI, 0.57-0.85; P < 0.001) and Effects scales (wait-listing aHR, 0.74; 95% CI, 0.59-0.92; P = 0.007). Participants with fewer depressive symptoms (ie, Beck Depression Inventory score < 14) had lower wait-listing rates than those with more depressive symptoms (aHR, 0.81; 95% CI, 0.66-0.99; P = 0.04). Participants with lower Burden and Effects scale scores and those with higher Symptoms and PCS scores had higher pre-emptive wait-listing rates (aHR in highest tertile of PCS relative to lowest tertile, 1.58; 95% CI, 1.12-2.23; P = 0.01). LIMITATIONS: Unmeasured confounders. CONCLUSIONS: Self-reported health in late-stage CKD may influence the timing of kidney transplantation.

Patient Experience with Primary Care Physician and Risk for Hospitalization in Hispanics with CKD.

BACKGROUND AND OBJECTIVES: In the general population, the quality of the patient experience with their primary care physician may influence health outcomes but this has not been evaluated in CKD. This is relevant for the growing Hispanic CKD population, which potentially faces challenges to the quality of the patient experience related to language or cultural factors. We evaluated the association between the patient experience with their primary care physician and outcomes in Hispanics with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This prospective observational study included 252 English- and Spanish-speaking Hispanics with entry eGFR of 20-70 ml/min per 1.73 m2, enrolled in the Hispanic Chronic Renal Insufficiency Cohort study between 2005 and 2008. Patient experience with their primary care physician was assessed by the Ambulatory Care Experiences Survey subscales: communication quality, whole-person orientation, health promotion, interpersonal treatment, and trust. Poisson and proportional hazards models were used to assess the association between the patient experience and outcomes, which included hospitalization, ESKD, and all-cause death. RESULTS: Participants had a mean age of 56 years, 38% were women, 80% were primary Spanish speakers, and had a mean eGFR of 38 ml/min per 1.73 m2. Over 4.8 years (median) follow-up, there were 619 hospitalizations, 103 ESKD events, and 56 deaths. As compared with higher subscale scores, lower scores on four of the five subscales were associated with a higher adjusted rate ratio (RR) for all-cause hospitalization (communication quality: RR, 1.54; 95% confidence interval [95% CI], 1.25 to 1.90; health promotion: RR, 1.31; 95% CI, 1.05 to 1.62; interpersonal treatment: RR, 1.50; 95% CI, 1.22 to 1.85; and trust: RR, 1.57; 95% CI, 1.27 to 1.93). There was no significant association of subscales with incident ESKD or all-cause death. CONCLUSIONS: Lower perceived quality of the patient experience with their primary care physician was associated with a higher risk of hospitalization.