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BackgroundAcute kidney injury (AKI) and obesity are independent risk factors for chronic kidney disease (CKD). This study aimed to determine if obesity modifies risk for CKD outcomes after AKI.MethodsThis prospective multisite cohort study followed adult survivors after hospitalization, with or without AKI. The primary outcome was a combined CKD event of incident CKD, progression of CKD and kidney failure, examined using time-to-event Cox proportional hazards models, adjusted for diabetes status, age, pre-existing CKD, cardiovascular disease status and intensive care unit admission, and stratified by study center. Body mass index (BMI) was added as an interaction term to examine effect modification by body size.ResultsThe cohort included 769 participants with AKI and 769 matched controls. After median follow-up of 4.3 years, among AKI survivors, the rate of the combined CKD outcome was 84.7 per1000-person-years with BMI ≥30 kg/m2, 56.4 per 1000-person-years with BMI 25-29.9 kg/m2, and 72.6 per 1000-person-years with BMI 20-24.9 kg/m2. AKI was associated with a higher risk of combined CKD outcomes; adjusted-HR 2.43 (95%CI 1.87-3.16), with no evidence that this was modified by BMI (p for interaction = 0.3). After adjustment for competing risk of death, AKI remained associated with a higher risk of the combined CKD outcome (subdistribution-HR 2.27, 95%CI 1.76-2.92) and similarly, there was no detectable effect of BMI modifying this risk.ConclusionsIn this post-hospitalization cohort, we found no evidence for obesity modifying the association between AKI and development or progression of CKD.

BackgroundThe inclusion of race in equations to estimate the glomerular filtration rate (GFR) has become controversial. Alternative equations that can be used to achieve similar accuracy without the use of race are needed.MethodsIn a large national study involving adults with chronic kidney disease, we conducted cross-sectional analyses of baseline data from 1248 participants for whom data, including the following, had been collected: race as reported by the participant, genetic ancestry markers, and the serum creatinine, serum cystatin C, and 24-hour urinary creatinine levels.ResultsUsing current formulations of GFR estimating equations, we found that in participants who identified as Black, a model that omitted race resulted in more underestimation of the GFR (median difference between measured and estimated GFR, 3.99 ml per minute per 1.73 m2 of body-surface area; 95% confidence interval [CI], 2.17 to 5.62) and lower accuracy (percent of estimated GFR within 10% of measured GFR [P10], 31%; 95% CI, 24 to 39) than models that included race (median difference, 1.11 ml per minute per 1.73 m2; 95% CI, -0.29 to 2.54; P10, 42%; 95% CI, 34 to 50). The incorporation of genetic ancestry data instead of race resulted in similar estimates of the GFR (median difference, 1.33 ml per minute per 1.73 m2; 95% CI, -0.12 to 2.33; P10, 42%; 95% CI, 34 to 50). The inclusion of non-GFR determinants of the serum creatinine level (e.g., body-composition metrics and urinary excretion of creatinine) that differed according to race reported by the participants and genetic ancestry did not eliminate the misclassification introduced by removing race (or ancestry) from serum creatinine-based GFR estimating equations. In contrast, the incorporation of race or ancestry was not necessary to achieve similarly statistically unbiased (median difference, 0.33 ml per minute per 1.73 m2; 95% CI, -1.43 to 1.92) and accurate (P10, 41%; 95% CI, 34 to 49) estimates in Black participants when GFR was estimated with the use of cystatin C.ConclusionsThe use of the serum creatinine level to estimate the GFR without race (or genetic ancestry) introduced systematic misclassification that could not be eliminated even when numerous non-GFR determinants of the serum creatinine level were accounted for. The estimation of GFR with the use of cystatin C generated similar results while eliminating the negative consequences of the current race-based approaches. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

Treatment options for patients with venous thromboembolism (VTE) include warfarin and direct oral anticoagulants (DOACs). Although DOACs are easier to administer than warfarin and do not require routine laboratory monitoring, few studies have directly assessed whether patients are more satisfied with DOACs. We surveyed adults from two large integrated health systems taking DOACs or warfarin for incident VTE occurring between January 1, 2015 and June 30, 2018. Treatment satisfaction was assessed using the validated Anti-Clot Treatment Scale (ACTS), divided into the ACTS Burdens and ACTS Benefits scores; higher scores indicate greater satisfaction. Mean treatment satisfaction was compared using multivariable linear regression, adjusting for patient demographic and clinical characteristics. The effect size of the difference in means was calculated using a Cohen's d (0.20 is considered a small effect and ≥ 0.80 is considered large). We surveyed 2217 patients, 969 taking DOACs and 1248 taking warfarin at the time of survey. Thirty-one point five percent of the cohort was aged ≥ 75 years and 43.1% were women. DOAC users were on average more satisfied with anticoagulant treatment, with higher adjusted mean ACTS Burdens (50.18 v. 48.01, p

BackgroundPatients with chronic kidney disease (CKD) face risks of not only end-stage kidney disease (ESKD), cardiovascular disease (CVD) and death, but also decline in kidney function, quality of life (QOL) and mental and physical well-being. This study describes the multidimensional trajectories of CKD using clinical events, kidney function and patient-reported outcome measures (PROMs). We hypothesized that more advanced CKD stages would associate with more rapid decline in each outcome.MethodsAmong 3939 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study, we evaluated multidimensional disease trajectories by G- and A-stages of enrollment estimated glomerular filtration rate (eGFR) and albuminuria, respectively. These trajectories included clinical events (ESKD, CVD, heart failure and death), eGFR decline and PROMs [kidney disease QOL (KDQOL) burden, effects and symptoms questionnaires, as well as the 12-item short form mental and physical component summaries]. We also evaluated a group-based multitrajectory model to group participants on the basis of longitudinal PROMs and compared group assignments by enrollment G- and A-stage.ResultsThe mean participant age was 58 years, 45% were women, mean baseline eGFR was 44 mL/min/1.73 m2 and median urine albumin:creatinine ratio was 52 mg/g. The incidence of all clinical events was greater and eGFR decline was faster with more advanced G- and A-stages. While baseline KDQOL and physical component measures were lower with more advanced G- and A-stage of CKD, changes in PROMs were inconsistently related to the baseline CKD stage. Groups formed on PROM trajectories were fairly distinct from existing CKD staging (observed agreement 60.6%) and were associated with the risk of ESKD, CVD, heart failure and death.ConclusionsMore advanced baseline CKD stage was associated with a higher risk of clinical events and faster eGFR decline, and was only weakly related to changes in patient-reported metrics over time.

Rationale & objectiveThe clearance of protein-bound solutes by the proximal tubules is an innate kidney mechanism for removing putative uremic toxins that could exert cardiovascular toxicity in humans. However, potential associations between impaired kidney clearances of secretory solutes and cardiovascular events among patients with chronic kidney disease (CKD) remains uncertain.Study designA multicenter, prospective, cohort study.Setting & participantsWe evaluated 3,407 participants from the Chronic Renal Insufficiency Cohort (CRIC) study.ExposuresBaseline kidney clearances of 8 secretory solutes. We measured concentrations of secretory solutes in plasma and paired 24-hour urine specimens using liquid chromatography-tandem mass spectrometry (LC-MS/MS).OutcomesIncident heart failure, myocardial infarction, and stroke events.Analytical approachWe used Cox regression to evaluate associations of baseline secretory solute clearances with incident study outcomes adjusting for estimated GFR (eGFR) and other confounders.ResultsParticipants had a mean age of 56 years; 45% were women; 41% were Black; and the median estimated glomerular filtration rate (eGFR) was 43 mL/min/1.73 m2. Lower 24-hour kidney clearance of secretory solutes were associated with incident heart failure and myocardial infarction but not incident stroke over long-term follow-up after controlling for demographics and traditional risk factors. However, these associations were attenuated and not statistically significant after adjustment for eGFR.LimitationsExclusion of patients with severely reduced eGFR at baseline; measurement variability in secretory solutes clearances.ConclusionsIn a national cohort study of CKD, no clinically or statistically relevant associations were observed between the kidney clearances of endogenous secretory solutes and incident heart failure, myocardial infarction, or stroke after adjustment for eGFR. These findings suggest that tubular secretory clearance provides little additional information about the development of cardiovascular disease events beyond glomerular measures of GFR and albuminuria among patients with mild-to-moderate CKD.

BackgroundThere has recently been considerable interest in better understanding how blood pressure should be managed after an episode of hospitalized AKI, but there are scant data regarding the associations between blood pressure measured after AKI and subsequent adverse outcomes. We hypothesized that among AKI survivors, higher blood pressure measured three months after hospital discharge would be associated with worse outcomes. We also hypothesized these associations between blood pressure and outcomes would be similar among those who survived non-AKI hospitalizations.MethodsWe quantified how systolic blood pressure (SBP) observed three months after hospital discharge was associated with risks of subsequent hospitalized AKI, loss of kidney function, mortality, and heart failure events among 769 patients in the prospective ASSESS-AKI cohort study who had hospitalized AKI. We repeated this analysis among the 769 matched non-AKI ASSESS-AKI enrollees. We then formally tested for AKI interaction in the full cohort of 1538 patients to determine if these associations differed among those who did and did not experience AKI during the index hospitalization.ResultsAmong 769 patients with AKI, 42 % had subsequent AKI, 13 % had loss of kidney function, 27 % died, and 18 % had heart failure events. SBP 3 months post-hospitalization did not have a stepwise association with the risk of subsequent AKI, loss of kidney function, mortality, or heart failure events. Among the 769 without AKI, there was also no stepwise association with these risks. In formal interaction testing using the full cohort of 1538 patients, hospitalized AKI did not modify the association between post-discharge SBP and subsequent risks of adverse clinical outcomes.ConclusionsContrary to our first hypothesis, we did not observe that higher stepwise blood pressure measured three months after hospital discharge with AKI was associated with worse outcomes. Our data were consistent with our second hypothesis that the association between blood pressure measured three months after hospital discharge and outcomes among AKI survivors is similar to that observed among those who survived non-AKI hospitalizations.

INTRODUCTIONAcute kidney injury and chronic kidney disease (CKD) are common in hospitalized patients. To inform clinical decision making, more accurate information regarding risk of long-term progression to kidney failure is required.METHODSWe enrolled 1538 hospitalized patients in a multicenter, prospective cohort study. Monocyte chemoattractant protein 1 (MCP-1/CCL2), uromodulin (UMOD), and YKL-40 (CHI3L1) were measured in urine samples collected during outpatient follow-up at 3 months. We followed patients for a median of 4.3 years and assessed the relationship between biomarker levels and changes in estimated glomerular filtration rate (eGFR) over time and the development of a composite kidney outcome (CKD incidence, CKD progression, or end-stage renal disease). We paired these clinical studies with investigations in mouse models of renal atrophy and renal repair to further understand the molecular basis of these markers in kidney disease progression.RESULTSHigher MCP-1 and YKL-40 levels were associated with greater eGFR decline and increased incidence of the composite renal outcome, whereas higher UMOD levels were associated with smaller eGFR declines and decreased incidence of the composite kidney outcome. A multimarker score increased prognostic accuracy and reclassification compared with traditional clinical variables alone. The mouse model of renal atrophy showed greater Ccl2 and Chi3l1 mRNA expression in infiltrating macrophages and neutrophils, respectively, and evidence of progressive renal fibrosis compared with the repair model. The repair model showed greater Umod expression in the loop of Henle and correspondingly less fibrosis.CONCLUSIONSBiomarker levels at 3 months after hospitalization identify patients at risk for kidney disease progression.FUNDINGNIH.

AimsTo determine the extent of shared decision-making (SDM), during selection of oral anticoagulant (OAC) and rhythm control treatments, in patients with newly diagnosed atrial fibrillation (AF).Methods and resultsWe evaluated survey data from 1006 patients with new-onset AF enrolled at 56 US sites participating in the SATELLITE substudy of the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT II). Patients completed surveys at enrolment and at 6-month follow-up. Patients were asked about who made their AF treatment decisions. Shared decision-making was classified as one that the patient felt was an autonomous decision or a shared decision with their healthcare provider (HCP). Approximately half of patients reported that their OAC treatment decisions were made entirely by their HCP. Compared with those reporting no SDM, patients reporting SDM for OAC were more often female (47.2% vs. 38.4%), while patients reporting SDM for rhythm control were more often male (62.2% vs. 57.6%). The most important factors cited by patients during decision-making for OAC were reducing stroke and bleeding risk, and their HCP's recommendations. After adjustment, patients with self-reported understanding of OAC, and rhythm control options, had higher odds of having participated in SDM [odds ratio (OR) 2.54, confidence interval (CI): 1.75-3.68 and OR 2.36, CI: 1.50-3.71, both P ≤ 0.001, respectively].ConclusionShared decision-making is not widely implemented in contemporary AF practice. Patient understanding about available therapeutic options is associated with a more than a two-fold higher likelihood of SDM, and may be a potential target for future interventions.

Rationale & objectiveStudies using a single measurement of fibroblast growth factor 23 (FGF-23) suggest that elevated FGF-23 levels are associated with increased risk for requirement for kidney replacement therapy (KRT) in patients with chronic kidney disease. However, the data do not account for changes in FGF-23 levels as kidney disease progresses.Study designCase-cohort study.Setting & participantsTo evaluate the association between serial FGF-23 levels and risk for requiring KRT, our primary analysis included 1,597 individuals in the Chronic Renal Insufficiency Cohort Study who had up to 5 annual measurements of carboxy-terminal FGF-23. There were 1,135 randomly selected individuals, of whom 266 initiated KRT, and 462 individuals who initiated KRT outside the random subcohort.ExposureSerial FGF-23 measurements and FGF-23 trajectory group membership.OutcomesIncident KRT.Analytical approachTo handle time-dependent confounding, our primary analysis of time-updated FGF-23 levels used time-varying inverse probability weighting in a discrete time failure model. To compare our results with prior data, we used baseline and time-updated FGF-23 values in weighted Cox regression models. To examine the association of FGF-23 trajectory subgroups with risk for incident KRT, we used weighted Cox models with FGF-23 trajectory groups derived from group-based trajectory modeling as the exposure.ResultsIn our primary analysis, the HR for the KRT outcome per 1 SD increase in the mean of natural log-transformed (ln)FGF-23 in the past was 1.94 (95% CI, 1.51-2.49). In weighted Cox models using baseline and time-updated values, elevated FGF-23 level was associated with increased risk for incident KRT (HRs per 1 SD ln[FGF-23] of 1.18 [95% CI, 1.02-1.37] for baseline and 1.66 [95% CI, 1.49-1.86] for time-updated). Membership in the slowly and rapidly increasing FGF-23 trajectory groups was associated with ∼3- and ∼21-fold higher risk for incident KRT compared to membership in the stable FGF-23 trajectory group.LimitationsResidual confounding and lack of intact FGF-23 values.ConclusionsIncreasing FGF-23 levels are independently associated with increased risk for incident KRT.

Rationale & objectivesFew studies have investigated racial disparities in survival among dialysis patients in a manner that considers risk factors and mortality during the phase of kidney disease before maintenance dialysis. Our objective was to explore racial variations in survival among dialysis patients and relate them to racial differences in comorbid conditions and rates of death in the setting of kidney disease not yet requiring dialysis therapy.Study designRetrospective cohort study.Settings & participants3,288 black and white participants in the Chronic Renal Insufficiency Cohort (CRIC), none of whom were receiving dialysis at enrollment.ExposureRace.OutcomeMortality.Analytic approachCox proportional hazards regression was used to examine the association between race and mortality starting at: (1) time of dialysis initiation and (2) entry into the CRIC.ResultsDuring 7.1 years of median follow-up, 678 CRIC participants started dialysis. Starting from the time of dialysis initiation, blacks had lower risk for death (unadjusted HR, 0.67; 95% CI, 0.51-0.87) compared with whites. Starting from baseline CRIC enrollment, the strength of the association between some risk factors and dialysis was notably stronger for whites than blacks. For example, the HR for dialysis onset in the presence (vs absence) of heart failure at CRIC enrollment was 1.30 (95% CI, 1.01-1.68) for blacks versus 2.78 (95% CI, 1.90-4.50) for whites, suggesting differential severity of these risk factors by race. When we included deaths occurring both before and after dialysis, risk for death was higher among blacks (vs whites) starting from CRIC enrollment (HR, 1.41; 95% CI, 1.22-1.64), but this finding was attenuated in adjusted models (HR, 1.08; 95% CI, 0.91-1.28).LimitationsResidual confounding.ConclusionsThe apparent survival advantage among blacks over whites treated with dialysis may be attributed to selected transition of a subset of whites with more severe comorbid conditions onto dialysis.

BACKGROUND:Few studies describe both inpatient and outpatient treatment and outcomes of patients with acute venous thromboembolism in the United States. METHODS:A multi-institutional cohort of patients diagnosed with confirmed pulmonary embolism or deep venous thrombosis during the years 2004 through 2010 was established from 4 large, US-based integrated health care delivery systems. Computerized databases were accessed and medical records reviewed to collect information on patient demographics, clinical risk factors, initial antithrombotic treatment, and vital status. Multivariable Cox regression models were used to estimate the risk of death at 90 days. RESULTS:The cohort comprised 5497 adults with acute venous thromboembolism. Pulmonary embolism was predominantly managed in the hospital setting (95.0%), while 54.5% of patients with lower extremity thrombosis were treated as outpatients. Anticoagulant treatment differed according to thromboembolism type: 2688 patients (92.8%) with pulmonary embolism and 1625 patients (86.9%) with lower extremity thrombosis were discharged on anticoagulants, compared with 286 patients (80.1%) with upper extremity thrombosis and 69 (54.8%) patients with other thrombosis. While 4.5% of patients died during the index episode, 15.4% died within 90 days. Pulmonary embolism was associated with a higher 90-day death risk than lower extremity thrombosis (adjusted hazard ratio 1.23; 95% confidence interval, 1.04-1.47), as was not being discharged on anticoagulants (adjusted hazard ratio 5.56; 95% confidence interval, 4.76-6.67). CONCLUSIONS:In this multicenter, community-based study of patients with acute venous thromboembolism, anticoagulant treatment and outcomes varied by thromboembolism type. Although case fatality during the acute episode was relatively low, 15.4% of people with thromboembolism died within 90 days of the index diagnosis.

Background We tested associations of cardiac biomarkers of myocardial stretch, injury, inflammation, and fibrosis with the risk of incident atrial fibrillation (AF) in a prospective study of chronic kidney disease patients. Methods and Results The study sample was 3053 participants with chronic kidney disease in the multicenter CRIC (Chronic Renal Insufficiency Cohort) study who were not identified as having AF at baseline. Cardiac biomarkers, measured at baseline, were NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity troponin T, galectin-3, growth differentiation factor-15, and soluble ST-2. Incident AF ("AF event") was defined as a hospitalization for AF. During a median follow-up of 8 years, 279 (9%) participants developed a new AF event. In adjusted models, higher baseline log-transformed NT-proBNP (N-terminal pro-B-type natriuretic peptide) was associated with incident AF (adjusted hazard ratio [HR] per SD higher concentration: 2.11; 95% CI, 1.75, 2.55), as was log-high-sensitivity troponin T (HR 1.42; 95% CI, 1.20, 1.68). These associations showed a dose-response relationship in categorical analyses. Although log-soluble ST-2 was associated with AF risk in continuous models (HR per SD higher concentration 1.35; 95% CI, 1.16, 1.58), this association was not consistent in categorical analyses. Log-galectin-3 (HR 1.05; 95% CI, 0.91, 1.22) and log-growth differentiation factor-15 (HR 1.16; 95% CI, 0.96, 1.40) were not significantly associated with incident AF. Conclusions We found strong associations between higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity troponin T concentrations, and the risk of incident AF in a large cohort of participants with chronic kidney disease. Increased atrial myocardial stretch and myocardial cell injury may be implicated in the high burden of AF in patients with chronic kidney disease.

RATIONALE & OBJECTIVE:Coronary artery calcification (CAC) is prevalent among patients with chronic kidney disease (CKD) and increases risks for cardiovascular disease events and mortality. We hypothesized that a novel serum measure of calcification propensity is associated with CAC among patients with CKD stages 2 to 4. STUDY DESIGN:Prospective cohort study. SETTING & PARTICIPANTS:Participants from the Chronic Renal Insufficiency Cohort (CRIC) Study with baseline (n=1,274) and follow-up (n=780) CAC measurements. PREDICTORS:Calcification propensity, quantified as transformation time (T50) from primary to secondary calciprotein particles, with lower T50 corresponding to higher calcification propensity. Covariates included age, sex, race/ethnicity, clinical site, estimated glomerular filtration rate, proteinuria, diabetes, systolic blood pressure, number of antihypertensive medications, current smoking, history of cardiovascular disease, total cholesterol level, and use of statin medications. OUTCOMES:CAC prevalence, severity, incidence, and progression. ANALYTICAL APPROACH:Multivariable-adjusted generalized linear models. RESULTS:At baseline, 824 (65%) participants had prevalent CAC. After multivariable adjustment, T50 was not associated with CAC prevalence but was significantly associated with greater CAC severity among participants with prevalent CAC: 1-SD lower T50 was associated with 21% (95% CI, 6%-38%) greater CAC severity. Among 780 participants followed up an average of 3 years later, 65 (20%) without baseline CAC developed incident CAC, while 89 (19%) with baseline CAC had progression, defined as annual increase≥100 Agatston units. After multivariable adjustment, T50 was not associated with incident CAC but was significantly associated with CAC progression: 1-SD lower T50 was associated with 28% (95% CI, 7%-53%) higher risk for CAC progression. LIMITATIONS:Potential selection bias in follow-up analyses; inability to distinguish intimal from medial calcification. CONCLUSIONS:Among patients with CKD stages 2 to 4, higher serum calcification propensity is associated with more severe CAC and CAC progression.

Background Patient satisfaction with therapy is an important metric of care quality and has been associated with greater medication persistence. We evaluated the association of patient satisfaction with warfarin therapy to other metrics of anticoagulation care quality and clinical outcomes among patients with atrial fibrillation ( AF ). Methods and Results Using data from the ORBIT - AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registry, patients were identified with AF who were taking warfarin and had completed an Anti-Clot Treatment Scale ( ACTS ) questionnaire, a validated metric of patient-reported burden and benefit of oral anticoagulation. Multivariate regressions were used to determine association of ACTS burden and benefit scores with time in therapeutic international normalized ratio range ( TTR ; both ≥75% and ≥60%), warfarin discontinuation, and clinical outcomes (death, stroke, major bleed, and all-cause hospitalization). Among 1514 patients with AF on warfarin therapy (75±10 years; 42% women; CHA 2 DS 2- VAS c 3.9±1.7), those most burdened with warfarin therapy were younger and more likely to be women, have paroxysmal AF , and to be treated with antiarrhythmic drugs. After adjustment for covariates, ACTS burden scores were independent of TTR ( TTR ≥75%: odds ratio, 1.01 [95% CI , 0.99-1.03]; TTR ≥60%: odds ratio, 1.01 [95% CI , 0.98-1.05]), warfarin discontinuation (odds ratio, 0.99; 95% CI , 0.97-1.01), or clinical outcomes. ACTS benefit scores were also not associated with TTR , warfarin discontinuation, or clinical outcomes. Conclusions In a large registry of patients with AF taking warfarin, ACTS scores provided independent information beyond other traditional metrics of oral anticoagulation care quality and identified patient groups at high risk for dissatisfaction with warfarin therapy.

RATIONALE & OBJECTIVE:Traditional risk estimates for atherosclerotic vascular disease (ASVD) and death may not perform optimally in the setting of chronic kidney disease (CKD). We sought to determine whether the addition of measures of inflammation and kidney function to traditional estimation tools improves prediction of these events in a diverse cohort of patients with CKD. STUDY DESIGN:Observational cohort study. SETTING & PARTICIPANTS:2,399 Chronic Renal Insufficiency Cohort (CRIC) Study participants without a history of cardiovascular disease at study entry. PREDICTORS:Baseline plasma levels of biomarkers of inflammation (interleukin 1β [IL-1β], IL-1 receptor antagonist, IL-6, tumor necrosis factor α [TNF-α], transforming growth factor β, high-sensitivity C-reactive protein, fibrinogen, and serum albumin), measures of kidney function (estimated glomerular filtration rate [eGFR] and albuminuria), and the Pooled Cohort Equation probability (PCEP) estimate. OUTCOMES:Composite of ASVD events (incident myocardial infarction, peripheral arterial disease, and stroke) and death. ANALYTICAL APPROACH:Cox proportional hazard models adjusted for PCEP estimates, albuminuria, and eGFR. RESULTS:During a median follow-up of 7.3 years, 86, 61, 48, and 323 participants experienced myocardial infarction, peripheral arterial disease, stroke, or death, respectively. The 1-decile greater levels of IL-6 (adjusted HR [aHR], 1.12; 95% CI, 1.08-1.16; P

Rationale & objectiveAcute kidney injury (AKI) has numerous sequelae. Repeated episodes of AKI may be an important determinant of adverse outcomes, including chronic kidney disease and death. In a population-based cohort study, we sought to determine the incidence of and predictors for recurrent AKI.Study designRetrospective cohort study.Setting & participants38,659 hospitalized members of Kaiser Permanente Northern California who experienced an episode of AKI from 2006 to 2013.PredictorsDemographic, clinical, and laboratory data, including baseline kidney function, proteinuria, hemoglobin level, comorbid conditions, and severity of AKI.OutcomesIncidence and predictors of recurrent AKI.Analytical approachMultivariable Cox proportional hazard regression.Results11,048 (28.6%) experienced a second hospitalization complicated by AKI during follow-up (11.2 episodes/100 person-years), with the second episode of AKI occurring a median of 0.6 (interquartile range, 0.2-1.9) years after the first hospitalization. In multivariable analyses, older age, black race, and Hispanic ethnicity were associated with recurrent AKI, along with lower estimated glomerular filtration rate, proteinuria, and anemia. Concomitant conditions, including heart failure, acute coronary syndrome, diabetes, and chronic liver disease, were also multivariable predictors of recurrent AKI. Those who had higher acuity of illness during the initial hospitalization were more likely to have recurrent AKI, but greater AKI severity of the index episode was not independently associated with increased risk for recurrent AKI. In multivariable analysis of matched patients, recurrent AKI was associated with an increased rate of death (HR, 1.66; 95% CI, 1.57-1.77).LimitationsAnalyses were based on clinically available data, rather than protocol-driven timed measurements of kidney function.ConclusionsRecurrent AKI is a common occurrence after a hospitalization complicated by AKI. Based on routinely available patient characteristics, our findings could facilitate identification of the subgroup of patients with AKI who may benefit from more intensive follow-up to potentially avoid recurrent AKI episodes.

BACKGROUND:Advanced chronic kidney disease is associated with elevated risk for cognitive impairment. However, it is not known whether and how cognitive impairment is associated with planning and preparation for end-stage renal disease. STUDY DESIGN:Retrospective observational study. SETTING & PARTICIPANTS:630 adults participating in the CRIC (Chronic Renal Insufficiency Cohort) Study who had cognitive assessments in late-stage CKD, defined as estimated glome-rular filtration rate ≤ 20mL/min/1.73m2, and subsequently initiated maintenance dialysis therapy. PREDICTOR:Predialysis cognitive impairment, defined as a score on the Modified Mini-Mental State Examination lower than previously derived age-based threshold scores. Covariates included age, race/ethnicity, educational attainment, comorbid conditions, and health literacy. OUTCOMES:Peritoneal dialysis (PD) as first dialysis modality, preemptive permanent access placement, venous catheter avoidance at dialysis therapy initiation, and preemptive wait-listing for a kidney transplant. MEASUREMENTS:Multivariable-adjusted logistic regression. RESULTS:Predialysis cognitive impairment was present in 117 (19%) participants. PD was the first dialysis modality among 16% of participants (n=100), 75% had preemptive access placed (n=473), 45% avoided using a venous catheter at dialysis therapy initiation (n=279), and 20% were preemptively wait-listed (n=126). Predialysis cognitive impairment was independently associated with 78% lower odds of PD as the first dialysis modality (adjusted OR [aOR], 0.22; 95% CI, 0.06-0.74; P=0.02) and 42% lower odds of venous catheter avoidance at dialysis therapy initiation (aOR, 0.58; 95% CI, 0.34-0.98; P=0.04). Predialysis cognitive impairment was not independently associated with preemptive permanent access placement or wait-listing. LIMITATIONS:Potential unmeasured confounders; single measure of cognitive function. CONCLUSIONS:Predialysis cognitive impairment is associated with a lower likelihood of PD as a first dialysis modality and of venous catheter avoidance at dialysis therapy initiation. Future studies may consider addressing cognitive function when testing strategies to improve patient transitions to dialysis therapy.

Background Chronic kidney disease ( CKD ) is a common comorbidity in patients with atrial fibrillation. The presence of CKD complicates drug selection for stroke prevention and rhythm control. Methods and Results Patients enrolled in ORBIT AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) with baseline renal function and follow-up data were included (N=9019). CKD was defined as an estimated creatinine clearance

Rationale & objectiveAbnormal cardiac structure and function are common in chronic kidney disease (CKD) and end-stage renal disease (ESRD) and linked with mortality and heart failure. We examined changes in echocardiographic measures during the transition from CKD to ESRD and their associations with post-ESRD mortality.Study designProspective study.Setting & participantsWe studied 417 participants with CKD in the Chronic Renal Insufficiency Cohort (CRIC) who had research echocardiograms during CKD and ESRD.PredictorWe measured change in left ventricular mass index, left ventricular ejection fraction (LVEF), diastolic relaxation (normal, mildly abnormal, and moderately/severely abnormal), left ventricular end-systolic (LVESV), end-diastolic (LVEDV) volume, and left atrial volume from CKD to ESRD.OutcomesAll-cause mortality after dialysis therapy initiation.Analytical approachCox proportional hazard models were used to test the association of change in each echocardiographic measure with postdialysis mortality.ResultsOver a mean of 2.9 years between pre- and postdialysis echocardiograms, there was worsening of mean LVEF (52.5% to 48.6%; P

Background Current American College of Cardiology/American Heart Association guidelines suggest that for patients with atrial fibrillation who are at low risk for stroke (CHA2DS2VASc=1) (or women with CHA2DS2VASc=2) a variety of treatment strategies may be considered. However, in clinical practice, patterns of treatment in these "low-risk" patients are not well described. The objective of this analysis is to define thromboembolic event rates and to describe treatment patterns in patients with low-risk CHA2DS2VASc scores. Methods and Results We compared characteristics, treatment strategies, and outcomes among patients with a CHA2DS2VASc=0, CHA2DS2VASc=1, females with a CHA2DS2VASc=2, and CHA2DS2VASc ≥2 in ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) I & II. Compared with CHA2DS2VASc ≥2 patients (84.2%), those with a CHA2DS2VASc=0 (60.3%), 1 (69.9%), and females with a CHA2DS2VASc score=2 (72.4%) were significantly less often treated with oral anticoagulation ( P

Background Current American College of Cardiology/American Heart Association guidelines suggest that for patients with atrial fibrillation who are at low risk for stroke (CHA2DS2VASc=1) (or women with CHA2DS2VASc=2) a variety of treatment strategies may be considered. However, in clinical practice, patterns of treatment in these "low-risk" patients are not well described. The objective of this analysis is to define thromboembolic event rates and to describe treatment patterns in patients with low-risk CHA2DS2VASc scores. Methods and Results We compared characteristics, treatment strategies, and outcomes among patients with a CHA2DS2VASc=0, CHA2DS2VASc=1, females with a CHA2DS2VASc=2, and CHA2DS2VASc ≥2 in ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) I & II. Compared with CHA2DS2VASc ≥2 patients (84.2%), those with a CHA2DS2VASc=0 (60.3%), 1 (69.9%), and females with a CHA2DS2VASc score=2 (72.4%) were significantly less often treated with oral anticoagulation ( P

BackgroundThe high mortality and cardiovascular disease (CVD) burden in patients with end-stage renal disease (ESRD) is well-documented. Recent literature suggests that acute kidney injury is also associated with CVD. It is unknown whether patients with incident ESRD due to dialysis-requiring acute kidney injury (AKI-D) are at higher short-term risk for death and CVD events, compared with incident ESRD patients without preceding AKI-D. Few studies have examined the impact of recovery from AKI-D on subsequent CVD risk.MethodsIn this retrospective cohort study, we evaluated adult members of Kaiser Permanente Northern California who initiated dialysis from January 2009 to September 2015. Preceding AKI-D and subsequent outcomes of death and CVD events (acute coronary syndrome, heart failure, ischemic stroke or transient ischemic attack) were identified from electronic health records. We performed multivariable Cox regression models adjusting for demographics, comorbidities, medication use, and laboratory results.ResultsCompared to incident ESRD patients who experienced AKI-D (n = 1865), patients with ESRD not due to AKI-D (n = 3772) had significantly lower adjusted rates of death (adjusted hazard ratio [aHR] 0.56, 95% CI: 0.47-0.67) and heart failure hospitalization (aHR 0.45, 0.30-0.70). Compared to AKI-D patients who did not recover and progressed to ESRD, AKI-D patients who recovered (n = 1347) had a 30% lower adjusted relative rate of death (aHR 0.70, 0.55-0.88).ConclusionsPatients who transition to ESRD via AKI-D are a high-risk subgroup that may benefit from aggressive monitoring and medical management, particularly for heart failure. Recovery from AKI-D is independently associated with lower short-term mortality.

Patients with chronic kidney diseases (CKDs) are at risk for further loss of kidney function and death, which occur despite reasonable blood pressure treatment. To determine whether arterial stiffness influences CKD progression and death, independent of blood pressure, we conducted a prospective cohort study of CKD patients enrolled in the CRIC study (Chronic Renal Insufficiency Cohort). Using carotid-femoral pulse wave velocity (PWV), we examined the relationship between PWV and end-stage kidney disease (ESRD), ESRD or halving of estimated glomerular filtration rate, or death from any cause. The 2795 participants we enrolled had a mean age of 60 years, 56.4% were men, 47.3% had diabetes mellitus, and the average estimated glomerular filtration rate at entry was 44.4 mL/min per 1.73 m2 During follow-up, there were 504 ESRD events, 628 ESRD or halving of estimated glomerular filtration rate events, and 394 deaths. Patients with the highest tertile of PWV (>10.3 m/s) were at higher risk for ESRD (hazard ratio [95% confidence interval], 1.37 [1.05-1.80]), ESRD or 50% decline in estimated glomerular filtration rate (hazard ratio [95% confidence interval], 1.25 [0.98-1.58]), or death (hazard ratio [95% confidence interval], 1.72 [1.24-2.38]). PWV is a significant predictor of CKD progression and death in people with impaired kidney function. Incorporation of PWV measurements may help define better the risks for these important health outcomes in patients with CKDs. Interventions that reduce aortic stiffness deserve study in people with CKD.

BackgroundFew studies have investigated the changes in weight that may occur over time among adults with the progression of chronic kidney disease (CKD). Whether such weight changes are independently associated with death after the onset of end-stage renal disease has also not been rigorously examined.Study designProspective cohort study.Setting & participantsWe studied 3,933 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study, a longitudinal cohort of patients with CKD. We also performed similar analyses among 1,067 participants of the African American Study of Kidney Disease and Hypertension (AASK).PredictorsEstimated glomerular filtration rate (eGFR) and weight change during CKD.OutcomeWeight and all-cause mortality after dialysis therapy initiation.ResultsDuring a median follow-up of 5.7 years in CRIC, weight change was not linear. Weight was stable until cystatin C-based eGFR (eGFRcys) decreased to 5% annualized weight loss after eGFR decreased to

Mineralocorticoid receptor antagonist (MRA) therapy may be beneficial to patients with atrial fibrillation (AF), but little is known about their use in patients with AF and subsequent outcomes. In order to better understand MRA use and subsequent outcomes, we performed a retrospective cohort study of the contemporary ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registry. AF progression and cardiovascular outcomes were compared using propensity-matched Cox proportional hazards modeling according to MRA use at baseline and new MRA use at follow-up versus patients with no MRA use. Among 7012 patients with nonpermanent AF, 320 patients were taking MRA at enrollment, and 416 patients initiated MRA use during follow-up. The mean patient age was 72.5 years, 56.3% were men, and 70.4% had paroxysmal AF. Among all patients taking MRAs, 434 (59.0%) had heart failure, 655 (89.0%) had hypertension, and 380 (51.6%) had both. After adjustment, new MRA use was not associated with reduced AF progression (hazard ratio, 1.18; 95% confidence interval, 0.88-1.58; P=0.27) but showed a trend towards lower risk of stroke, transient ischemic attack, or systemic embolism (hazard ratio, 0.17; 95% confidence interval, 0.02-1.23; P=0.08). Results were similar for a comparison of new MRA users and baseline MRA users compared with nonusers. In community-based outpatients with AF, the majority of MRA use was for heart failure and hypertension. MRA use also trended towards lower adjusted stroke risk. Future studies should test the hypothesis that MRA use may decrease the risk of stroke in patients with AF.

Anxiety and depression are associated with worse outcomes in several cardiovascular conditions, but it is unclear whether they affect outcomes in atrial fibrillation (AF). In a large diverse population of adults with AF, we evaluated the association of diagnosed anxiety and/or depression with stroke and bleeding outcomes. The Cardiovascular Research Network WAVE (Community-Based Control and Persistence of Warfarin Therapy and Associated Rates and Predictors of Adverse Clinical Events in Atrial Fibrillation and Venous Thromboembolism) Study included adults with AF newly starting warfarin between 2004 and 2007 within 5 health delivery systems in the United States. Diagnosed anxiety and depression and other patient characteristics were identified from electronic health records. We identified stroke and bleeding outcomes from hospitalization databases using validated International Classification of Diseases, Ninth Revision (ICD-9), codes. We used multivariable Cox regression to assess the relation between anxiety and/or depression with outcomes after adjustment for stroke and bleeding risk factors. In 25 570 adults with AF initiating warfarin, 490 had an ischemic stroke or intracranial hemorrhage (1.52 events per 100 person-years). In multivariable analyses, diagnosed anxiety was associated with a higher adjusted rate of combined ischemic stroke and intracranial hemorrhage (hazard ratio, 1.52; 95% confidence interval, 1.01-2.28). Results were not materially changed after additional adjustment for patient-level percentage of time in therapeutic anticoagulation range on warfarin (hazard ratio, 1.56; 95% confidence interval, 1.03-2.36). In contrast, neither isolated depression nor combined depression and anxiety were significantly associated with outcomes. Diagnosed anxiety was independently associated with increased risk of combined ischemic stroke and intracranial hemorrhage in adults with AF initiating warfarin that was not explained by differences in risk factors or achieved anticoagulation quality.

Renal recovery after dialysis-requiring acute kidney injury (AKI-D) is an important clinical and patient-centered outcome. Here we examined whether the pre-admission proteinuria level independently influences risk for non-recovery after AKI-D in a community-based population. All adult members of Kaiser Permanente Northern California who experienced AKI-D between January 1, 2009 and September 30, 2015 were included. Pre-admission proteinuria levels were determined by dipstick up to four years before the AKI-D hospitalization and the outcome was renal recovery (survival and dialysis-independence four weeks and more) at 90 days after initiation of renal replacement therapy. We used multivariable logistic regression to adjust for baseline estimated glomerular filtration rate (eGFR), age, sex, ethnicity, short-term predicted risk of death, comorbidities, and medication use. Among 5,347 adults with AKI-D, the mean age was 66 years, 59% were men, and 50% were white. Compared with negative/trace proteinuria, the adjusted odds ratios for non-recovery (continued dialysis-dependence or death) were 1.47 (95% confidence interval 1.19-1.82) for 1+ proteinuria and 1.92 (1.54-2.38) for 2+ or more proteinuria. Among survivors, the crude probability of recovery ranged from 83% for negative/trace proteinuria with baseline eGFR over 60 mL/min/1.73m2 to 25% for 2+ or more proteinuria with eGFR 15-29 mL/min/1.73m2. Thus, the pre-AKI-D level of proteinuria is a graded, independent risk factor for non-recovery and helps to improve short-term risk stratification for patients with AKI-D.

BACKGROUND AND AIMS:Coronary artery calcification (CAC) is common among patients with chronic kidney disease (CKD) and predicts the risk for cardiovascular disease (CVD). We examined the associations of novel risk factors with CAC progression among patients with CKD. METHODS:Among 1123 CKD patients in the Chronic Renal Insufficiency Cohort (CRIC) Study, CAC was measured in Agatston units at baseline and a follow-up visit using electron beam computed tomography or multidetector computed tomography. RESULTS:Over an average 3.3-year follow-up, 109 (25.1%) participants without CAC at baseline had incident CAC and 124 (18.0%) participants with CAC at baseline had CAC progression, defined as an annual increase of ≥100 Agatston units. After adjustment for established atherosclerotic risk factors, several novel risk factors were associated with changes in CAC over follow-up. Changes in square root transformed CAC score associated with 1 SD greater level of risk factors were -0.20 (95% confidence interval, -0.31 to -0.10; p < 0.001) for estimated glomerular filtration rate, 0.14 (0.02-0.25; p = 0.02) for 24-h urine albumin, 0.25 (0.15-0.34; p < 0.001) for cystatin C, -0.17 (-0.27 to -0.07; p < 0.001) for serum calcium, 0.14 (0.03-0.24; p = 0.009) for serum phosphate, 0.24 (0.14-0.33; p < 0.001) for fibroblast growth factor-23, 0.13 (0.04-0.23; p = 0.007) for total parathyroid hormone, 0.17 (0.07-0.27; p < 0.001) for interleukin-6, and 0.12 (0.02-0.22; p = 0.02) for tumor necrosis factor-α. CONCLUSIONS:Reduced kidney function, calcium and phosphate metabolism disorders, and inflammation, independent of established CVD risk factors, may progress CAC among CKD patients.

ObjectiveTo investigate the effect of LPA gene variants and renal function on lipoprotein(a) [Lp(a)] levels in people with chronic kidney disease and determine the association between elevated Lp(a) and myocardial infarction and death in this setting.Approach and resultsThe CRIC Study (Chronic Renal Insufficiency Cohort) is an ongoing prospective study of 3939 participants with chronic kidney disease. In 3635 CRIC participants with genotype data, carriers of the rs10455872 or rs6930542 variants had a higher median Lp(a) level (mg/dL) compared with noncarriers (73 versus 23; P61.3. There were 315 myocardial infarctions and 822 deaths during a median follow-up of 7.5 years. The second quartile had the lowest event rate. After adjusting for potential confounders and using a Cox proportional hazards model, the highest quartile of Lp(a) was associated with increased risk of myocardial infarction (hazard ratio, 1.49; 95% confidence interval, 1.05-2.11), death (hazard ratio, 1.28; 95% confidence interval, 1.05-1.57), and the composite outcome (hazard ratio, 1.29; 95% confidence interval, 1.07-1.56) compared with the second quartile of Lp(a).ConclusionsAmong adults with chronic kidney disease, elevated Lp(a) is independently associated with myocardial infarction and death. Future studies exploring pharmacological Lp(a) reduction in this population are warranted.

BackgroundOral anticoagulation (OAC) therapy is associated with increased periprocedural risks after cardiac implantable electronic device (CIED) implantation. Patterns of anticoagulation management involving non-vitamin K antagonist oral anticoagulants (NOACs) have not been characterized.HypothesisAnticoagulation strategies and outcomes differ by anticoagulant type in patients undergoing CIED implantation.MethodsUsing the nationwide Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we assessed how atrial fibrillation (AF) patients undergoing CIED implantation were cared for and their subsequent outcomes. Outcomes were compared by oral anticoagulant therapy (none, warfarin, or NOAC) as well as by anticoagulation interruption status.ResultsAmong 9129 AF patients, 416 (5%) underwent CIED implantation during a median follow-up of 30 months (interquartile range, 24-36). Of these, 60 (14%) had implantation on a NOAC. Relative to warfarin therapy, those on a NOAC were younger (70.5 years [range, 65-77.5 years] vs 77 years [range, 70-82 years]), had less valvular heart disease (15.0% vs 31.3%), higher creatinine clearance (67.3 [range, 59.7-99.0] vs 65.8 [range, 50.0-91.6]), were more likely to have persistent AF (26.7% vs 22.9%), and use concomitant aspirin (51.7% vs 35.2%). OAC therapy was commonly interrupted for CIED in 64% (n = 183 of 284) of warfarin patients and 65% (n = 39 of 60) of NOAC patients. Many interrupted patients received intravenous bridging anticoagulation: 33/183 (18%) interrupted warfarin and 4/39 (10%) interrupted NOAC patients. Thirty-day periprocedure bleeding and stroke adverse events were infrequent.ConclusionsManagement of anticoagulation among AF patients undergoing CIED implantation is highly variable, with OAC being interrupted in more than half of both warfarin- and NOAC-treated patients. Bleeding and stroke events were infrequent in both warfarin and NOAC-treated patients.

BackgroundPeople with advanced chronic kidney disease are at risk for the development of end-stage renal disease (ESRD), but also many other adverse outcomes, including cardiovascular disease (CVD) events and death. Determination of risk factors that explain the variability in prognosis and timing of these adverse outcomes can aid patient counseling and medical decision making.Study designProspective research cohort.Setting & participants1,798 participants with estimated glomerular filtration rates (eGFRs)

BackgroundChronic kidney disease (CKD) is associated with increased risk of cardiovascular disease (CVD) and it is especially common among Blacks. Left ventricular hypertrophy (LVH) is an important subclinical marker of CVD, but there are limited data on racial variation in left ventricular structure and function among persons with CKD.MethodsIn a cross-sectional analysis of the Chronic Renal Insufficiency Cohort Study, we compared the prevalence of different types of left ventricular remodeling (concentric hypertrophy, eccentric hypertrophy, and concentric remodeling) by race/ethnicity. We used multinomial logistic regression to test whether race/ethnicity associated with different types of left ventricular remodeling independently of potential confounding factors.ResultsWe identified 1,164 non-Hispanic Black and 1,155 non-Hispanic White participants who completed Year 1 visits with echocardiograms that had sufficient data to categorize left ventricular geometry type. Compared to non-Hispanic Whites, non-Hispanic Blacks had higher mean left ventricular mass index (54.7 ± 14.6 vs. 47.4 ± 12.2 g/m2.7; P < 0.0001) and prevalence of concentric LVH (45.8% vs. 24.9%). In addition to higher systolic blood pressure and treatment with >3 antihypertensive medications, Black race/ethnicity was independently associated with higher odds of concentric LVH compared to White race/ethnicity (odds ratio: 2.73; 95% confidence interval: 2.02, 3.69).ConclusionIn a large, diverse cohort with CKD, we found significant differences in left ventricular mass and hypertrophic morphology between non-Hispanic Blacks and Whites. Future studies will evaluate whether higher prevalence of LVH contribute to racial/ethnic disparities in cardiovascular outcomes among CKD patients.

We recently reported a linear association between higher systolic blood pressure (SBP) and risk of mortality in hemodialysis patients when SBP is measured outside of the dialysis unit (out-of-dialysis-unit-SBP), despite there being a U-shaped association between SBP measured at the dialysis unit (dialysis-unit-SBP) with risk of mortality. Here, we explored the relationship between SBP with cardiovascular events, which has important treatment implications but has not been well elucidated. Among 383 hemodialysis participants enrolled in the prospective CRIC study (Chronic Renal Insufficiency Cohort), multivariable splines and Cox models were used to study the association between SBP and adjudicated cardiovascular events (heart failure, myocardial infarction, ischemic stroke, and peripheral artery disease), controlling for differences in demographics, cardiovascular disease risk factors, and dialysis parameters. Dialysis-unit-SBP and out-of-dialysis-unit-SBP were modestly correlated (r=0.34; P2-fold increased risk of cardiovascular events compared with those with out-of-dialysis-unit-SBP ≤112 mm Hg (3rd SBP quartile: adjusted hazard ratio, 2.08 [95% confidence interval, 1.12-3.87] and fourth SBP quartile: adjusted hazard ratio, 2.76 [95% confidence interval, 1.42-5.33]). In conclusion, among hemodialysis patients, although there is a U-shaped (paradoxical) association of dialysis-unit-SBP and risk of cardiovascular disease, there is a linear association of out-of-dialysis-unit-SBP with risk of cardiovascular disease. Out-of-dialysis-unit blood pressure provides key information and may be an important therapeutic target.

The association of dialysis initiation with changes in cognitive function among patients with advanced chronic kidney disease is poorly described. To better define this, we enrolled participants with advanced chronic kidney disease from the Chronic Renal Insufficiency Cohort in a prospective study of cognitive function. Eligible participants had a glomerular filtration rate of 20 ml/min/1.73m2 or less, or dialysis initiation within the past two years. We evaluated cognitive function by a validated telephone battery at regular intervals over two years and analyzed test scores as z scores. Of 212 participants, 123 did not transition to dialysis during follow-up, 37 transitioned to dialysis after baseline, and 52 transitioned to dialysis prior to baseline. In adjusted analyses, the transition to dialysis was associated with a significant loss of executive function, but no significant changes in global cognition or memory. The estimated net difference in cognitive z scores at two years for participants who transitioned to dialysis during follow-up compared to participants who did not transition to dialysis was -0.01 (95% confidence interval -0.13, 0.11) for global cognition, -0.24 (-0.51, 0.03) for memory, and -0.33 (-0.60, -0.07) for executive function. Thus, among adults with advanced chronic kidney disease, dialysis initiation was associated with loss of executive function with no change in other aspects of cognition. Larger studies are needed to evaluate cognition during dialysis initiation.

Higher diet-dependent nonvolatile acid load is associated with faster chronic kidney disease (CKD) progression, but most studies have used estimated acid load or measured only components of the gold standard, net acid excretion (NAE). Here we measured NAE as the sum of urine ammonium and titratable acidity in 24-hour urines from a random subset of 980 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study. In multivariable models accounting for demographics, comorbidity and kidney function, higher NAE was significantly associated with lower serum bicarbonate (0.17 mEq/l lower serum bicarbonate per 10 mEq/day higher NAE), consistent with a larger acid load. Over a median of 6 years of follow-up, higher NAE was independently associated with a significantly lower risk of the composite of end-stage renal disease or halving of estimated glomerular filtration rate among diabetics (hazard ratio 0.88 per 10 mEq/day higher NAE), but not those without diabetes (hazard ratio 1.04 per 10 mEq/day higher NAE). For comparison, we estimated the nonvolatile acid load as net endogenous acid production using self-reported food frequency questionnaires from 2848 patients and dietary urine biomarkers from 3385 patients. Higher net endogenous acid production based on biomarkers (urea nitrogen and potassium) was modestly associated with faster CKD progression consistent with prior reports, but only among those without diabetes. Results from the food frequency questionnaires were not associated with CKD progression in any group. Thus, disparate results obtained from analyses of nonvolatile acid load directly measured as NAE and estimated from diet suggest a novel hypothesis that the risk of CKD progression related to low NAE or acid load may be due to diet-independent changes in acid production in diabetes.

Blood pressure is a modifiable risk for cardiovascular disease (CVD). Among hemodialysis patients, there is a U-shaped association between blood pressure and risk of death. However, few studies have examined the association between blood pressure and CVD in patients with stage 4 and 5 chronic kidney disease. Here we studied 1795 Chronic Renal Insufficiency Cohort (CRIC) Study participants with estimated glomerular filtration rate 90 mm Hg versus 68 mm Hg versus 68 mm Hg versus

BackgroundHip fractures are among the most serious bone fractures in the elderly, producing significant morbidity and mortality. Several observational studies have found that mild hyponatremia can adversely affect bone, with fractures occurring as a potential complication. We examined if there is an independent association between prolonged chronic hyponatremia (>90 days duration) and risk of hip fracture in the elderly.MethodsWe performed a retrospective cohort study in adults >60 years of age from a prepaid health maintenance organization who had two or more measurements of plasma sodium between 2005 and 2012. The incidence of hip fractures was assessed in a very restrictive population: subjects with prolonged chronic hyponatremia, defined as plasma sodium values 90 days. Multivariable Cox regression was performed to determine the hazard ratio (HR) for hip fracture risk associated with prolonged chronic hyponatremia after adjustment for the propensity to have hyponatremia, fracture risk factors and relevant baseline characteristics.ResultsAmong 31 527 eligible patients, only 228 (0.9%) had prolonged chronic hyponatremia. Mean plasma sodium was 132 ± 5 mmol/L in hyponatremic patients and 139 ± 3 mmol/L in normonatremic patients (P < 0.001). The absolute risk for hip fracture was 7/282 in patients with prolonged chronic hyponatremia and 411/313 299 in normonatremic patients. Hyponatremic patients had a substantially elevated rate of hip fracture [adjusted HR 4.52 (95% CI 2.14-9.6)], which was even higher in those with moderate hyponatremia (

BackgroundIt is not clear whether the pattern of kidney function decline in patients with chronic kidney disease (CKD) may relate to outcomes after reaching end-stage renal disease (ESRD). We hypothesize that an abrupt decline in kidney function prior to ESRD predicts early death after initiating maintenance hemodialysis therapy.Study designProspective cohort study.Setting & participantsThe Chronic Renal Insufficiency Cohort (CRIC) Study enrolled men and women with mild to moderate CKD. For this study, we studied 661 individuals who developed chronic kidney failure that required hemodialysis therapy initiation.PredictorsThe primary predictor was the presence of an abrupt decline in kidney function prior to ESRD. We incorporated annual estimated glomerular filtration rates (eGFRs) into a mixed-effects model to estimate patient-specific eGFRs at 3 months prior to initiation of hemodialysis therapy. Abrupt decline was defined as having an extrapolated eGFR≥30mL/min/1.73m(2) at that time point.OutcomesAll-cause mortality within 1 year after initiating hemodialysis therapy.MeasurementsMultivariable Cox proportional hazards.ResultsAmong 661 patients with CKD initiating hemodialysis therapy, 56 (8.5%) had an abrupt predialysis decline in kidney function and 69 died within 1 year after initiating hemodialysis therapy. After adjustment for demographics, cardiovascular disease, diabetes, and cancer, abrupt decline in kidney function was associated with a 3-fold higher risk for death within the first year of ESRD (adjusted HR, 3.09; 95% CI, 1.65-5.76).LimitationsRelatively small number of outcomes; infrequent (yearly) eGFR determinations; lack of more granular clinical data.ConclusionsAbrupt decline in kidney function prior to ESRD occurred in a significant minority of incident hemodialysis patients and predicted early death in ESRD.

BackgroundSerum β-trace protein (BTP) and β2-microglobulin (B2M) are independently associated with end-stage renal disease (ESRD) and mortality in the general population and high-risk groups with diabetes or advanced chronic kidney disease (CKD). Less is known about their associations with outcomes and predictive ability in adults with moderate CKD.Study designProspective cohort study.Setting & participants3,613 adults from the CRIC (Chronic Renal Insufficiency Cohort) Study (45% women; mean age, 57.9 years; 41.0% non-Hispanic black; 51.9% with diabetes).PredictorsBTP and B2M levels with a reciprocal transformation to reflect their associations with filtration, creatinine-based estimated glomerular filtration rate (eGFRcr), measured GFR, and a 4-marker composite score combining BTP, B2M, creatinine, and cystatin C levels. Predictors were standardized as z scores for comparisons across filtration markers.OutcomesESRD, all-cause mortality, and new-onset cardiovascular disease.ResultsDuring a 6-year median follow-up, 755 (21%) participants developed ESRD, 653 died, and 292 developed new-onset cardiovascular disease. BTP, B2M, and the 4-marker composite score were independent predictors of ESRD and all-cause mortality, and B2M and the 4-marker composite score of cardiovascular events, after multivariable adjustment. These associations were stronger than those observed for eGFRcr (P vs eGFRcr≤0.02). The 4-marker composite score led to improvements in C statistic and 2.5-year risk reclassification beyond eGFRcr for all outcomes.LimitationsFiltration markers measured at one time point; measured GFR available in subset of cohort.ConclusionsBTP and B2M levels may contribute additional risk information beyond eGFRcr, and the use of multiple markers may improve risk prediction beyond this well-established marker of kidney function among persons with moderate CKD.

BackgroundCognitive impairment is common among patients with chronic kidney disease (CKD); however, its prognostic significance is unclear. We assessed the independent association between cognitive impairment and CKD progression in adults with mild to moderate CKD.Study designProspective cohort.Setting & participantsAdults with CKD participating in the CRIC (Chronic Renal Insufficiency Cohort) Study. Mean age of the sample was 57.7±11.0 years and mean estimated glomerular filtration rate (eGFR) was 45.0±16.9mL/min/1.73m(2).PredictorCognitive function was assessed with the Modified Mini-Mental State Examination at study entry. A subset of participants 55 years and older underwent 5 additional cognitive tests assessing different domains. Cognitive impairment was defined as a score > 1 SD below the mean score on each test. Covariates included demographics, kidney function, comorbid conditions, and medications.OutcomesIncident end-stage renal disease (ESRD) and incident ESRD or 50% decline in baseline eGFR.ResultsIn 3,883 CRIC participants, 524 (13.5%) had cognitive impairment at baseline. During a median 6.1 years of follow-up, 813 developed ESRD and 1,062 developed ESRD or a ≥50% reduction in eGFR. There was no significant association between cognitive impairment and risk for ESRD (HR, 1.07; 95% CI, 0.87-1.30) or the composite of ESRD or 50% reduction in eGFR (HR, 1.06; 95% CI, 0.89-1.27). Similarly, there was no association between cognitive impairment and the joint outcome of death, ESRD, or 50% reduction in eGFR (HR, 1.06; 95% CI, 0.91-1.23). Among CRIC participants who underwent additional cognitive testing, we found no consistent association between impairment in specific cognitive domains and risk for CKD progression in adjusted analyses.LimitationsUnmeasured potential confounders, single measure of cognition for younger participants.ConclusionsAmong adults with CKD, cognitive impairment is not associated with excess risk for CKD progression after accounting for traditional risk factors.

The clinical implications of ankle-brachial index (ABI) cutpoints are not well defined in patients with chronic kidney disease (CKD) despite increased prevalence of high ABI attributed to arterial stiffness. We examined the relationship of ABI with cardiovascular disease (CVD) and all-cause mortality among CKD patients. Three thousand six hundred twenty-seven participants without clinical peripheral artery disease (PAD) at baseline from the Chronic Renal Insufficiency Cohort Study were included. ABI was obtained per standard protocol and CVD events were confirmed by medical record adjudication. A U-shaped association of ABI with PAD, myocardial infarction (MI), composite CVD, and all-cause mortality was observed. Individuals with an ABI between 1.0 and

BackgroundThe clinical effects of age occur over an age continuum, yet age as a primary predictor is often analyzed using arbitrary age cut-points.ObjectiveTo assess whether transformation of a continuous variable such as age using a spline function can uncover nonlinear associations between age and cardiovascular outcomes.DesignObservational retrospective cohort study in 1015 Kaiser Permanente Northern California patients with end-stage renal disease after index coronary revascularization. Age, the primary predictor, was modeled by 5 different techniques: 1) dichotomized at 65 years or older; 2) at 80 years or older (as a sensitivity analysis); 3) categorized as younger than 55 years (reference), 55 to 64, 65 to 74, and 75 years or older; 4) linear (every 5 years) variable; and 5) nonlinear by transformation into a cubic spline. Age categories were changed in a sensitivity analysis.Main outcome measuresPrimary and secondary outcomes were all-cause mortality and repeat revascularization, respectively.ResultsGraphical assessment demonstrated that age dichotomized at either 65 years and older or 80 years and older led to loss of information. Categorized age underestimated or overestimated risk at the extremes of age. A sensitivity analysis demonstrated that an arbitrary change in the age category led to a different conclusion. Age modeled linearly adequately represented mortality risk but was suboptimal with repeat revascularization. Only the cubic spline demonstrated the nonlinear association between age and repeat revascularization.ConclusionEmploying the continuous variable age as a case study, we have demonstrated that the use of flexible transformations, such as spline functions, can unearth clinically meaningful associations that would not have been possible otherwise. Future research should determine whether incorporation of these methods can improve decision making at a population level.

BackgroundPatients with sinus node dysfunction (SND) have increased risk of atrial tachyarrhythmias, including atrial fibrillation (AF). To date, treatment patterns and outcomes of patients with SND and AF have not been well described.HypothesisPatients with SND and AF have higher risk of adverse cardiovascular outcomes.MethodsSinus node dysfunction was defined clinically, based on treating physician. Treatment patterns were described and logistic regression analysis performed to assess outcomes.ResultsOverall, 1710 (17.7%) out of 9631 patients had SND at enrollment. Patients with SND and AF had increased comorbid medical illnesses, more severe symptoms (European Heart Rhythm Association class IV: 17.5% vs 13.9%; P = 0.0007), and poorer quality of life (median 12-month Atrial Fibrillation Effect on Quality of Life score: 79.6 vs 85.2; P = 0.0008). There were no differences in AF management strategy between patients with SND and those without (rate control, 69.7% vs 67.7%; rhythm control, 30.0% vs 32.0%; P = 0.11). After adjustment, patients with SND were more likely than those without SND to progress from paroxysmal AF at baseline to persistent or permanent AF at any follow-up, or persistent AF at baseline to permanent AF at any follow-up (odds ratio: 1.23, 95% confidence interval: 1.01-1.49, P = 0.035). However, there was no association between SND and major risk-adjusted outcomes.ConclusionsSinus node dysfunction is present in 1 of 6 patients with AF and is associated with increased comorbidities and higher symptom burden. However, SND is not associated with an increase in major risk-adjusted outcomes.

BackgroundDiagnosed diabetes mellitus (DM) is a consistently documented risk factor for ischemic stroke in patients with atrial fibrillation (AF).ObjectivesThe purpose of this study was to assess the association between duration of diabetes and elevated hemoglobin A1c (HbA1c) with risk of stroke among diabetic patients with AF.MethodsWe assessed this association in the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) California community-based cohort of AF patients (study years 1996 to 2003) where all events were clinician adjudicated. We used Cox proportional hazards regression to estimate the rate of ischemic stroke in diabetic patients according to time-varying measures of estimated duration of diabetes (≥3 years compared with

IntroductionRoutine testing for thrombophilia following venous thromboembolism (VTE) is controversial. The use of large datasets to study the clinical impact of thrombophilia testing on patterns of care and patient outcomes may enable more efficient analysis of this practice in a wide range of settings. We set out to examine how accurately algorithms using International Classification of Diseases 9th Revision (ICD-9) codes and/or pharmacy data reflect laboratory-confirmed thrombophilia diagnoses.Materials and methodsA random sample of adult Kaiser Permanente Colorado patients diagnosed with unprovoked VTE between 1/2004 and 12/2010 underwent medical record abstraction of thrombophilia test results. Algorithms using "ICD-9" (positive if a thrombophilia ICD-9 code was present), "Extended anticoagulation (AC)" (positive if AC therapy duration was >6 months), and "ICD-9 & Extended AC" (positive for both) criteria to identify possible thrombophilia cases were tested. Using positive thrombophilia laboratory results as the gold standard, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value of each algorithm were calculated, along with 95% confidence intervals (CIs).ResultsIn our cohort of 636 patients, sensitivities were low (

BackgroundCardiometabolic disease is a major cause of morbidity and mortality in persons with chronic kidney disease (CKD). Fractalkine (CX3CL1) is a potential mediator of both atherosclerosis and metabolic disease. Studies of the relationship of CX3CL1 with risk of cardiovascular disease (CVD) events and metabolic traits are lacking, particularly in the high-risk setting of CKD.Study designCross-sectional and longitudinal observational analysis.Setting & participantsAdults with CKD from 7 US sites participating in the Chronic Renal Insufficiency Cohort (CRIC) Study.PredictorQuartiles of plasma CX3CL1 levels at baseline.OutcomesBaseline estimated glomerular filtration rate from a creatinine and cystatin C-based equation, prevalent and incident CVD, diabetes, metabolic syndrome and its criteria, homeostatic model assessment of insulin resistance, hemoglobin A1c level, myocardial infarction, all-cause mortality, and the composite outcome of myocardial infarction/all-cause mortality.ResultsAmong 3,687 participants, baseline CX3CL1 levels were associated positively with several CVD risk factors and metabolic traits, lower estimated glomerular filtration rate, and higher levels of inflammatory cytokines, as well as prevalent CVD (OR, 1.09; 95% CI, 1.01-1.19; P=0.03). Higher CX3CL1 level also was associated with prevalent diabetes (OR, 1.26; 95% CI, 1.16-1.38; P

BackgroundChronic kidney disease is a risk factor for heart failure (HF). Patients with chronic kidney disease without diagnosed HF have an increased burden of symptoms characteristic of HF. It is not known whether these symptoms are associated with occurrence of new onset HF.Methods and resultsWe studied the association of a modified Kansas City Cardiomyopathy Questionnaire with newly identified cases of hospitalized HF among 3093 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study who did not report HF at baseline. The annually updated Kansas City Cardiomyopathy Questionnaire score was categorized into quartiles (Q1-4) with the lower scores representing the worse symptoms. Multivariable-adjusted repeated measure logistic regression models were adjusted for demographic characteristics, clinical risk factors for HF, N-terminal probrain natriuretic peptide level and left ventricular hypertrophy, left ventricular systolic and diastolic dysfunction. Over a mean (±SD) follow-up period of 4.3±1.6 years, there were 211 new cases of HF hospitalizations. The risk of HF hospitalization increased with increasing symptom quartiles; 2.62, 1.85, 1.14, and 0.74 events per 100 person-years, respectively. The median number of annual Kansas City Cardiomyopathy Questionnaire assessments per participant was 5 (interquartile range, 3-6). The annually updated Kansas City Cardiomyopathy Questionnaire score was independently associated with higher risk of incident HF hospitalization in multivariable-adjusted models (odds ratio, 3.30 [1.66-6.52]; P=0.001 for Q1 compared with Q4).ConclusionsSymptoms characteristic of HF are common in patients with chronic kidney disease and are associated with higher short-term risk for new hospitalization for HF, independent of level of kidney function, and other known HF risk factors.

BackgroundAlthough digoxin has long been used to treat atrial fibrillation (AF) and heart failure (HF), its safety remains controversial.ObjectivesThis study sought to describe digoxin use over time in patients with AF who were stratified by the presence or absence of HF, to characterize the predictors of digoxin use and initiation, and to correlate digoxin use with outcomes.MethodsLongitudinal patterns of digoxin use and its association with a variety of outcomes were assessed in a prospective outpatient registry conducted at 174 U.S. sites with enrollment from June 2010 to August 2011.ResultsAmong 9,619 patients with AF and serial follow-up every 6 months for up to 3 years, 2,267 (23.6%) received digoxin at study enrollment, 681 (7.1%) were initiated on digoxin during follow-up, and 6,671 (69.4%) were never prescribed digoxin. After adjusting for other medications, heart rate was 72.9 beats/min among digoxin users and 71.5 beats/min among nonusers (p < 0.0001). Prevalent digoxin use at registry enrollment was not associated with subsequent onset of symptoms, hospitalization, or mortality (in patients with HF, adjusted hazard ratio [HR] for death: 1.04; without HF, HR: 1.22). Incident digoxin use during follow-up was not associated with subsequent death in patients with HF (propensity adjusted HR: 1.05), but was associated with subsequent death in those without HF (propensity adjusted HR: 1.99).ConclusionsAfter adjustment for detailed clinical factors, digoxin use in registry patients with AF had a neutral association with outcomes under most circumstances. Because of the multiple conflicting observational reports about digoxin's safety and possible concerns in specific clinical situations, a large pragmatic trial of digoxin therapy in AF is needed.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P

BackgroundDigoxin remains commonly used for rate control in atrial fibrillation, but limited data exist supporting this practice and some studies have shown an association with adverse outcomes. We examined the independent association between digoxin and risks of death and hospitalization in adults with incident atrial fibrillation and no heart failure.Methods and resultsWe performed a retrospective cohort study of 14,787 age, sex, and high-dimensional propensity score-matched adults with incident atrial fibrillation and no previous heart failure or digoxin use in the AnTicoagulation and Risk factors In Atrial fibrillation-Cardiovascular Research Network (ATRIA-CVRN) study within Kaiser Permanente Northern and Southern California. We examined the independent association between newly initiated digoxin and the risks of death and hospitalization using extended Cox regression. During a median 1.17 (interquartile range, 0.49-1.97) years of follow-up among matched patients with atrial fibrillation, incident digoxin use was associated with higher rates of death (8.3 versus 4.9 per 100 person-years; P