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Rationale & Objective: Acute kidney injury (AKI) is common among hospitalized children and is associated with increased hospital length of stay and costs. However, there are limited data on postdischarge health care utilization after AKI hospitalization. Our objectives were to evaluate health care utilization and physician follow-up patterns after dialysis-treated AKI in a pediatric population., Study Design: Retrospective cohort study, using provincial health administrative databases., Setting & Participants: All children (0-18 years) hospitalized between 1996 and 2017 in Ontario, Canada. Excluded individuals comprised non-Ontario residents; those with metabolic disorders or poisoning; and those who received dialysis or kidney transplant before admission, a kidney transplant by 104 days after discharge, or were receiving dialysis 76-104 days from dialysis start date., Exposure: Episodes of dialysis-treated AKI, identified using validated health administrative codes. AKI survivors were matched to 4 hospitalized controls without dialysis-treated AKI by age, sex, and admission year., Outcome: Our primary outcome was postdischarge hospitalizations, emergency department visits, and outpatient physician visits. Secondary outcomes included outpatient visits by physician type and composite health care costs., Analytical Approach: Proportions with≥1 event and rates (per 1,000 person-years). Total and median composite health care costs. Adjusted rate ratios using negative binomial regression models., Results: We included 1,688 pediatric dialysis-treated AKI survivors and 6,752 matched controls. Dialysis-treated AKI survivors had higher rehospitalization and emergency department visit rates during the analyzed follow-up periods (0-1, 0-5, and 0-10 years postdischarge, and throughout follow-up), and higher outpatient visit rates in the 0-1-year follow-up period. The overall adjusted rate ratio for rehospitalization was 1.46 (95% CI, 1.25-1.69; P<0.0001) and for outpatient visits was 1.16 (95% CI, 1.09-1.23; P=0.01). Dialysis-treated AKI survivors also had higher health care costs. Nephrologist follow-up was infrequent among dialysis-treated AKI survivors (18.6% by 1 year postdischarge)., Limitations: Potential miscoding of study exposures or outcomes. Residual uncontrolled confounding. Data for health care costs and emergency department visits was unavailable before 2006 and 2001, respectively., Conclusions: Dialysis-treated AKI survivors had greater postdischarge health care utilization and costs versus hospitalized controls. Strategies are needed to improve follow-up care for children after dialysis-treated AKI to prevent long-term complications., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Patients receiving intermittent hemodialysis have variable times of recovery to feeling better after dialysis. QT prolongation, a precursor to clinical and subclinical cardiovascular events, may contribute to delayed recovery time. We hypothesized that abnormal electrocardiographic parameters indicating perturbations in ventricular action are associated with longer recovery times thus impacting a patient-centered quality of life., Methods: Among 242 incident in-center hemodialysis participants from the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study, corrected QT interval (QTc), QRST angle and heart rate variance were measured on non-dialysis days using a standard 5-min electrocardiograph recording. Left ventricular hypertrophy (LVH) was defined using the Cornell voltage product. Recovery time was ascertained during a phone interview with a standardized validated questionnaire. Associations between QTc, QRST angle, heart rate variance, and LVH and natural log-transformed recovery time were examined using linear regression adjusted for participant characteristics and electrolytes., Results: Mean age was 55 (standard deviation 13) years, 55% were male, 72% were African American. Longer QTc interval was associated with increased recovery time (per 10 ms increase in QTc, recovery time increased by 6.2%; 95% confidence interval: 0.0-10.5). QRST angle, heart rate, heart rate variability and LVH were not significantly associated with recovery time., Conclusion: Longer QTc intervals are associated with longer recovery time independent of serum electrolytes. This supports a relationship between a patient's underlying arrhythmic status and time to recovery after hemodialysis. Future studies will determine if maneuvers to reduce QTc improves recovery time and quality of life of patients on hemodialysis., (© 2022. The Author(s).)

Study Objectives: Patients with end-stage kidney disease commonly experience sleep disturbances. Sleep disturbance has been inconsistently associated with mortality risk in patients on hemodialysis, but the burden of symptoms from sleep disturbances has emerged as a marker that may shed light on these discrepancies and guide treatment decisions. This study examines whether functional outcomes of sleep are associated with increased risk of intermediary cardiovascular outcomes or mortality among adults initiating hemodialysis., Methods: In 228 participants enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease study, the Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10), which assesses functional outcomes of daytime sleepiness, was administered within 6 months of enrollment. Intermediary cardiovascular outcomes included QT correction (ms), heart rate variance (ms 2 ), left ventricular mass index (g/m 2 ), and left ventricular hypertrophy. The association of FOSQ-10 score with all-cause mortality was examined using proportional hazards regression., Results: Mean age was 55 years, and median body mass index was 28 kg/m 2 (interquartile range, 24, 33), with 70% of patients being African Americans. Median FOSQ-10 score was 19.7 (interquartile range, 17.1, 20.0). A 10% lower FOSQ-10 score was associated with increased mortality risk (hazard ratio, 1.09; 95% confidence interval, 1.01-1.18). Lower FOSQ-10 scores were associated with longer QT correction duration and lower heart rate variance but not left ventricular mass index or left ventricular mass index., Conclusions: In adults initiating dialysis, sleep-related functional impairment is common and is associated with intermediary cardiovascular disease measures and increased mortality risk. Future studies should assess the impact of screening for sleep disturbances in patients with end-stage kidney disease to identify individuals at increased risk for cardiovascular complications and death., Citation: Fitzpatrick J, Kerns ES, Kim ED, et al. Functional outcomes of sleep predict cardiovascular intermediary outcomes and all-cause mortality in patients on incident hemodialysis. J Clin Sleep Med . 2021;17(8):1707-1715., (© 2021 American Academy of Sleep Medicine.)

Background: AKI is common during pediatric hospitalizations and associated with adverse short-term outcomes. However, long-term outcomes among survivors of pediatric AKI who received dialysis remain uncertain., Methods: To determine the long-term risk of kidney failure (defined as receipt of chronic dialysis or kidney transplant) or death over a 22-year period for pediatric survivors of dialysis-treated AKI, we used province-wide health administrative databases to perform a retrospective cohort study of all neonates and children (aged 0-18 years) hospitalized in Ontario, Canada, from April 1, 1996, to March 31, 2017, who survived a dialysis-treated AKI episode. Each AKI survivor was matched to four hospitalized pediatric comparators without dialysis-treated AKI, on the basis of age, sex, and admission year. We reported the incidence of each outcome and performed Cox proportional hazards regression analyses, adjusting for relevant covariates., Results: We identified 1688 pediatric dialysis-treated AKI survivors (median age 5 years) and 6752 matched comparators. Among AKI survivors, 53.7% underwent mechanical ventilation and 33.6% had cardiac surgery. During a median 9.6-year follow-up, AKI survivors were at significantly increased risk of a composite outcome of kidney failure or death versus comparators. Death occurred in 113 (6.7%) AKI survivors, 44 (2.6%) developed kidney failure, 174 (12.1%) developed hypertension, 213 (13.1%) developed CKD, and 237 (14.0%) had subsequent AKI. AKI survivors had significantly higher risks of developing CKD and hypertension versus comparators. Risks were greatest in the first year after discharge and gradually decreased over time., Conclusions: Survivors of pediatric dialysis-treated AKI are at higher long-term risks of kidney failure, death, CKD, and hypertension, compared with a matched hospitalized cohort., (Copyright © 2021 by the American Society of Nephrology.)

Rationale & Objective: Characteristics of the transformation of primary to secondary calciprotein particles (CPPs) in serum, including the size of secondary CPP (CPP2) aggregates and the time of transformation (T 50 ), may be markers for arterial calcification in patients undergoing hemodialysis (HD). We examined the associations of CPP2 aggregate size and T 50 with arterial calcification in incident HD patients., Study Design: Prospective cohort study., Setting & Participants: Incident HD patients (n=402with available CPP2 measures and n=388with available T 50 measures) from the Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease (PACE) Study PREDICTORS: Serum CPP2 size and T 50 at baseline., Outcomes: Primary outcomes were baseline coronary artery and thoracic aorta calcifications. Exploratory outcomes included baseline arterial stiffness, measured by pulse wave velocity (PWV) and ankle brachial index, and longitudinally, repeat measures of PWV and all-cause mortality., Analytical Approach: Tobit regression, multiple linear regression, Poisson regression, linear mixed-effects regression, and Cox proportional hazards regression., Results: Mean age was 55±13 years, 41% were women, 71% were Black, and 57% had diabetes mellitus. Baseline CPP2 size and T 50 were correlated with baseline fetuin A level (r=-0.59 for CPP2 and 0.44 for T 50 ; P<0.001 for both), but neither was associated with baseline measures of arterial calcification or arterial stiffness. Baseline CPP2 size and T 50 were not associated with repeat measures of PWV. During a median follow-up of 3.5 (IQR, 1.7-6.2) years, larger CPP2 was associated with higher risk for mortality (HR, 1.17 [95% CI, 1.05-1.31] per 100nm larger CPP2 size) after adjusting for demographics and comorbid conditions, but there was no association between baseline T 50 and risk for mortality., Limitations: Possible imprecision in assays, small sample size, limited generalizability to incident HD populations with different racial composition, and residual confounding., Conclusions: In incident HD patients, neither CPP2 size nor T 50 was associated with prevalent arterial calcification and stiffness. Larger CPP2 was associated with risk for mortality, but this finding needs to be confirmed in future studies., (Copyright © 2020 National Kidney Foundation, Inc. All rights reserved.)

Background: Frailty, originally characterized in community-dwelling older adults, is increasingly being studied and implemented for adult patients with end-stage kidney disease (ESKD) of all ages (>18 years). Frailty prevalence and manifestation are unclear in younger adults (18-64 years) with ESKD; differences likely exist based on whether the patients are treated with hemodialysis (HD) or kidney transplantation (KT)., Methods: We leveraged 3 cohorts: 378 adults initiating HD (2008-2012), 4,304 adult KT candidates (2009-2019), and 1,396 KT recipients (2008-2019). The frailty phenotype was measured within 6 months of dialysis initiation, at KT evaluation, and KT admission. Prevalence of frailty and its components was estimated by age (≥65 vs. <65 years). A Wald test for interactions was used to test whether risk factors for frailty differed by age., Results: In all 3 cohorts, frailty prevalence was higher among older than younger adults (HD: 71.4 vs. 47.3%; candidates: 25.4 vs. 18.8%; recipients: 20.8 vs. 14.3%). In all cohorts, older patients were more likely to have slowness and weakness but less likely to report exhaustion. Among candidates, older age (odds ratio [OR] = 1.79, 95% CI: 1.47-2.17), non-Hispanic black race (OR = 1.30, 95% CI: 1.08-1.57), and dialysis type (HD vs. no dialysis: OR = 2.06, 95% CI: 1.61-2.64; peritoneal dialysis vs. no dialysis: OR = 1.78, 95% CI: 1.28-2.48) were associated with frailty prevalence, but sex and Hispanic ethnicity were not. These associations did not differ by age (pinteractions > 0.1). Similar results were observed for recipients and HD patients., Conclusions: Although frailty prevalence increases with age, younger patients have a high burden. Clinicians caring for this vulnerable population should recognize that younger patients may experience frailty and screen all age groups., (© 2020 S. Karger AG, Basel.)

Background In patients with end-stage kidney disease, sudden cardiac death is more frequent after a long interdialytic interval, within 6 hours after the end of a hemodialysis session. We hypothesized that the occurrence of paroxysmal arrhythmias is associated with changes in heart rate and heart rate variability in different phases of hemodialysis. Methods and Results We conducted a prospective ancillary study of the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease cohort. Continuous ECG monitoring was performed using an ECG patch, and short-term heart rate variability was measured for 3 minutes every hour (by root mean square of the successive normal-to-normal intervals, spectral analysis, Poincaré plot, and entropy), up to 300 hours. Out of enrolled participants (n=28; age 54±13 years; 57% men; 96% black; 33% with a history of cardiovascular disease; left ventricular ejection fraction 70±9%), arrhythmias were detected in 13 (46%). Nonsustained ventricular tachycardia occurred more frequently during/posthemodialysis than pre-/between hemodialysis (63% versus 37%, P =0.015). In adjusted for cardiovascular disease time-series analysis, nonsustained ventricular tachycardia was preceded by a sudden heart rate increase (by 11.2 [95% CI 10.1-12.3] beats per minute; P <0.0001). During every-other-day dialysis, root mean square of the successive normal-to-normal intervals had a significant circadian pattern (Mesor 10.6 [ 95% CI 0.9-11.2] ms; amplitude 1.5 [95% CI 1.0-3.1] ms; peak at 02:01 [95% CI 20:22-03:16] am; P <0.0001), which was replaced by a steady worsening on the second day without dialysis (root mean square of the successive normal-to-normal intervals -1.41 [95% CI -1.67 to -1.15] ms/24 h; P <0.0001). Conclusions Sudden increase in heart rate during/posthemodialysis is associated with nonsustained ventricular tachycardia. Every-other-day hemodialysis preserves circadian rhythm, but a second day without dialysis is characterized by parasympathetic withdrawal.

Background: Prolonged QT interval in hemodialysis patients may be associated with sudden cardiac death, however, few studies examined the longitudinal associations of modifiable factors such as serum and dialysate concentrations of calcium, potassium, and magnesium with corrected QT (QTc) prolongation in incident hemodialysis patients., Methods: In 330 in-center hemodialysis participants from the PACE study who were followed up for one year, we examined the associations of predialysis serum electrolytes (total calcium [Ca], corrected Ca [cCa], ionized Ca [iCa], potassium [K], magnesium [Mg]), dialysate (dCa and dK), and serum-to-dialysate gradient measures with QTc interval and prolongation (≥460 ms in women and ≥ 450 ms in men)., Results: At the first study visit, 47% had QTc prolongation. Lower iCa and K were associated with longer QTc interval independent of potential confounders (QTc difference = 8.55[95% CI: 2.13, 14.97] ms for iCa; QTc difference = 9.89[1.58, 18.20] ms for K). Lower iCa was also associated with a higher risk of QTc prolongation. At 1 year of follow-up, 31% had persistent QTc prolongation. In longitudinal analyses, the associations of iCa and K with QTc interval remained significant, and lower K was associated with a higher risk of QTc prolongation while the association of iCa with QTc prolongation was borderline statistically significant. Serum Mg, dCa or dK, and respective gradients were not associated with QTc interval or prolongation., Conclusion: Prolonged QTc is very common in incident hemodialysis participants and persists over follow-up. Ionized Ca and K are consistently inversely associated with QTc prolongation, which suggests closer monitoring for a low calcium or potassium level to mitigate risk.

Background: Frail obese community-dwelling older adults are at increased mortality risk. Among hemodialysis (HD) patients, frailty is common and associated with increased mortality risk; however, in dialysis, obesity is associated with decreased mortality risk. Whether the frail-obese phenotype is associated with increased mortality risk among HD patients remains unclear., Methods: This study included 370 incident HD patients enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study. We measured frailty using the Fried phenotype, general obesity [body mass index (BMI) ≥30 kg/m2] and abdominal obesity [waist:hip ratio (WHR) ≥median WHR] and estimated their associations with mortality., Results: The mean age was 55 years, with 42% female, 73% African American, 57% diabetic and 52% frail. Frail HD patients had higher mean BMI (frail = 30.3 kg/m2, non-frail = 28.3 kg/m2; P = 0.02) and similar WHR (P = 0.8). Twenty-two percent were frail with general obesity and 27% were frail with abdominal obesity. Frailty was associated with 1.66-fold increased mortality risk [95% confidence interval (CI) 1.03-2.67]. BMI was associated with a decreased mortality risk [25.0-29.9 kg/m2 hazard ratio (HR) 0.53 (95% CI 0.31-0.93); ≥30 kg/m2 HR 0.34 (95% CI 0.19-0.62)]. Frailty was associated with elevated mortality risk among HD patients with general [HR 3.77 (95% CI 1.10-12.92)] and abdominal obesity [HR 2.38 (95% CI 1.17-4.82)]. Frailty was not associated with mortality among HD patients without general or abdominal obesity., Conclusions: In adults initiating HD, frailty was associated with elevated mortality risk, even among the obese. Frail-obese HD patients may be a high-risk, often-overlooked population, as obesity is assumed to be protective. Measurement of frailty and obesity may facilitate risk stratification.

Background: Recent population-based studies identified plasma sphingolipids as independent predictors of increased cardiovascular disease (CVD) morbidity and mortality. Understanding the impact of sphingolipids on CVD outcomes in patients on dialysis, who suffer from higher risk of these conditions, is important for risk assessment and treatment., Objective: To measure plasma sphingolipid levels and determine their associations with CVD in adults initiating maintenance hemodialysis., Methods: To evaluate associations of plasma sphingolipids with intermediate cardiovascular outcomes (hypertension, left ventricular hypertrophy, and decreased ejection fraction), cardiovascular mortality, and all-cause mortality in patients with end-stage renal disease, we measured plasma levels of ceramides, glucosylceramides, and lactosylceramides from the family of sphingolipids in 368 incident hemodialysis patients enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease study., Results: Glucosylceramide C16GC (per 1 log μM increase) was associated with higher odds of having uncontrolled hypertension (odds ratio [OR]: 1.34; 95% confidential interval [CI]: 1.01-1.76), left ventricular hypertrophy (OR: 1.53; 95% CI: 1.11-2.13), and reduced ejection fraction (OR: 1.05; 95% CI: 1.00-1.11) in fully adjusted models. During a median 2.5 years of follow-up, there were 78 deaths from all causes, of which 33 were from CVD. Mortality was higher among those in the highest tertile of C16GC for all causes (HR: 1.81; 95% CI: 1.02-3.22) and CVD (HR: 2.63, 95% CI: 1.08-6.55)., Conclusions: These results suggest that abnormal glycosphingolipid metabolism might contribute to increased CVD risk in end-stage renal disease., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Arteriovenous (AV) access dysfunction is a common complication in hemodialysis patients. Markers of vascular calcification are associated with cardiovascular outcomes and mortality in this population, but their association with vascular access outcomes is unknown. In this study, we aimed to evaluate the association between selected vascular calcification makers and vascular access complications in a cohort of hemodialysis patients., Method: Fetuin-A, osteopontin (OPN), osteoprotegerin (OPG), and bone morphogenetic protein-7 (BMP-7) were measured in blood samples from 219 dialysis patients in the Choice for Healthy Outcomes in Caring for end-stage renal disease study; these patients were using a permanent vascular access. Participants were followed for up to 1 year or until the occurrence of a vascular access intervention or replacement. Associations with AV fistula (AVF) and AV graft (AVG) intervention-free survival were assessed in models adjusted for demographic characteristics, comorbidities, and inflammation., Results: A total of 24 out 103 participants with an AVF and 43 out of 116 participants with an AVG had an intervention during follow-up. Lower fetuin-A, higher OPN, and higher BMP-7 were associated with a higher risk of AVF intervention (adjusted hazard ratios [aHR] for highest versus lowest tertile = 0.30 [95% CI 0.10-0.94]) for fetuin-A, 3.84 (95% CI 1.16-12.74) for OPN, and 3.49 (95% CI 1.16-10.52) for BMP-7. OPG was not significantly associated with the risk of AVF intervention. The associations of OPN and BMP-7 with AVF intervention appeared stronger among participants without diabetes (aHR 8.06; 95% CI 1.11-58.57 for OPN and aHR 2.55; 95% CI 1.08-6.08 for BMP-7, respectively) than among their counterparts with diabetes (p interaction = 0.06). None of the markers studied were significantly associated with AVG interventions., Conclusion: Lower fetuin-A and higher OPN and BMP-7 are associated with complications in AVF but not in AVG, suggesting a role for calcification in the pathogenesis AVF failure., (© 2018 S. Karger AG, Basel.)

Background: Childhood chronic kidney disease (CKD) and dialysis are associated with increased long-term cardiovascular risk. We examined subclinical alterations in myocardial mechanics longitudinally in children with CKD, during dialysis, and following renal transplantation., Methods: Forty-eight children with CKD (stage III or higher) who received kidney transplants from 2008 to 2014 were included in a retrospective study and compared to 192 age- and sex-matched healthy children. Measurements of cardiac systolic and diastolic function were performed, and global longitudinal strain (GLS) and circumferential strain (GCS) were measured by speckle-tracking echocardiography at CKD, during dialysis, and 1 year following kidney transplantation. Mixed-effects modeling examined changes in GLS and GCS over different disease stages., Results: Children with CKD had a mean age of 10 ± 5 years and 67% were male. Eighteen children received preemptive transplantation. Children with CKD had increased left ventricular mass, lower GLS, and impaired diastolic function (lower E/A ratio and E' velocities) than healthy children. Changes in left ventricular diastolic parameters persisted during dialysis and after renal transplantation. Dialysis was associated with reduced GLS compared to CKD (β = 1.6, 95% confidence interval 0.2-3.0); however, this was not significant after adjustment for systolic blood pressure and CKD duration. Post-transplantation GLS levels were similar to those at CKD assessment. GCS was unchanged during dialysis but significantly improved following transplantation., Conclusions: There are differences in diastolic parameters in childhood CKD that persist during dialysis and after transplantation. Systolic parameters are preserved, with significant improvement in systolic myocardial deformation following transplantation. The impact of persistent diastolic changes on long-term outcomes requires further investigation.

The single leading cause of mortality on hemodialysis is sudden cardiac death. Whether measures of electrophysiologic substrate independently associate with mortality is unknown. We examined measures of electrophysiologic substrate in a prospective cohort of 571 patients on incident hemodialysis enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease Study. A total of 358 participants completed both baseline 5-minute and 12-lead electrocardiogram recordings on a nondialysis day. Measures of electrophysiologic substrate included ventricular late potentials by the signal-averaged electrocardiogram and spatial mean QRS-T angle measured on the averaged beat recorded within a median of 106 days (interquartile range, 78-151 days) from dialysis initiation. The cohort was 59% men, and 73% were black, with a mean±SD age of 55±13 years. Transthoracic echocardiography revealed a mean±SD ejection fraction of 65.5%±12.0% and a mean±SD left ventricular mass index of 66.6±22.3 g/m 2.7 During 864.6 person-years of follow-up, 77 patients died; 35 died from cardiovascular causes, of which 15 were sudden cardiac deaths. By Cox regression analysis, QRS-T angle ≥75° significantly associated with increased risk of cardiovascular mortality (hazard ratio, 2.99; 95% confidence interval, 1.31 to 6.82) and sudden cardiac death (hazard ratio, 4.52; 95% confidence interval, 1.17 to 17.40) after multivariable adjustment for demographic, cardiovascular, and dialysis factors. Abnormal signal-averaged electrocardiogram measures did not associate with mortality. In conclusion, spatial QRS-T angle but not abnormal signal-averaged electrocardiogram significantly associates with cardiovascular mortality and sudden cardiac death independent of traditional risk factors in patients starting hemodialysis., (Copyright © 2016 by the American Society of Nephrology.)

Patients with end stage renal disease (ESRD) on hemodialysis experience a high incidence of cardiovascular mortality, and sudden cardiac death (SCD) accounts for approximately 25% of all deaths in this patient population. Despite this high risk of SCD, many non-invasive SCD risk stratification tools that are frequently applied to other patient populations (such as those with prior myocardial infarction and reduced left ventricular systolic function) may be less useful markers of increased SCD risk in ESRD. Improved SCD risk stratification tools for use specifically in patients on hemodialysis are therefore necessary to optimally target use of primary prevention interventions aimed at decreasing SCD incidence. Electrocardiography is an effective, non-invasive SCD risk stratification tool in hemodialysis patients. This article reviews data supporting the association between various ECG parameters (QT interval, spatial QRS-T angle, signal averaged ECG, heart rate variability, and T-wave alternans) and mortality/SCD in the dialysis population. Despite the association between abnormal ECG parameters and SCD, it remains unclear if these abnormal parameters (such as prolonged QT interval) are mechanistically related to SCD and/or ventricular arrhythmias, or if they are simply markers for more severe cardiac disease, such as left ventricular hypertrophy, that may independently predispose to SCD. Current obstacles that impair widespread implementation of ECG risk stratification in the hemodialysis population are also discussed., (Copyright © 2016. Published by Elsevier Inc.)

Background and Objectives: Patients of all ages undergoing hemodialysis (HD) have a high prevalence of cognitive impairment and worse cognitive function than healthy controls, and those with dementia are at high risk of death. Frailty has been associated with poor cognitive function in older adults without kidney disease. We hypothesized that frailty might also be associated with poor cognitive function in adults of all ages undergoing HD., Design, Setting, Participants, & Measurements: At HD initiation, 324 adults enrolled (November 2008 to July 2012) in a longitudinal cohort study (Predictors of Arrhythmic and Cardiovascular Risk in ESRD) were classified into three groups (frail, intermediately frail, and nonfrail) based on the Fried frailty phenotype. Global cognitive function (3MS) and speed/attention (Trail Making Tests A and B [TMTA and TMTB, respectively]) were assessed at cohort entry and 1-year follow-up. Associations between frailty and cognitive function (at cohort entry and 1-year follow-up) were evaluated in adjusted (for sex, age, race, body mass index, education, depression and comorbidity at baseline) linear (3MS, TMTA) and Tobit (TMTB) regression models., Results: At cohort entry, the mean age was 54.8 years (SD 13.3), 56.5% were men, and 72.8% were black. The prevalence of frailty and intermediate frailty were 34.0% and 37.7%, respectively. The mean 3MS was 89.8 (SD 7.6), TMTA was 55.4 (SD 29), and TMTB was 161 (SD 83). Frailty was independently associated with lower cognitive function at cohort entry for all three measures (3MS: -2.4 points; 95% confidence interval [95% CI], -4.2 to -0.5; P=0.01; TMTA: 12.1 seconds; 95% CI, 4.7 to 19.4; P<0.001; and TMTB: 33.2 seconds; 95% CI, 9.9 to 56.4; P=0.01; all tests for trend, P<0.001) and with worse 3MS at 1-year follow-up (-2.8 points; 95% CI, -5.4 to -0.2; P=0.03)., Conclusions: In adult incident HD patients, frailty is associated with worse cognitive function, particularly global cognitive function (3MS)., (Copyright © 2015 by the American Society of Nephrology.)

Sudden cardiac death (SCD) accounts for a quarter of all deaths in end-stage renal disease (ESRD) patients. While causative mechanisms of SCD in this high risk population remain poorly defined, interaction of the vulnerable myocardium with dialysis-related arrhythmic triggers is thought to play a major role. Recent evidence suggests that dialysis-induced derangement of calcium concentrations contributes to the increased risk of all-cause and cardiovascular mortality, vascular calcification, and SCD. Current KDIGO guidelines recommend avoiding high dialysate calcium concentrations as a precaution against adverse outcomes of increased calcium burden and vascular calcification. Conversely, low calcium concentration is also implicated in the development of SCD via increased QT dispersion and prolonged QT interval. Consequently, the optimal dialysate calcium concentration in dialysis patients remains debated and further studies are needed to establish the best strategy for managing calcium in dialysis patients., (© 2015 Wiley Periodicals, Inc.)

Background and Objectives: Numerous substances accumulate in the body in uremia but those contributing to cardiovascular morbidity and mortality in dialysis patients are still undefined. We examined the association of baseline free levels of four organic solutes that are secreted in the native kidney - p-cresol sulfate, indoxyl sulfate, hippurate and phenylacetylglutamine - with outcomes in hemodialysis patients., Design, Setting, Participants and Measurements: We measured these solutes in stored specimens from 394 participants of a US national prospective cohort study of incident dialysis patients. We examined the relation of each solute and a combined solute index to cardiovascular mortality and morbidity (first cardiovascular event) using Cox proportional hazards regression adjusted for demographics, comorbidities, clinical factors and laboratory tests including Kt/VUREA., Results: Mean age of the patients was 57 years, 65% were white and 55% were male. In fully adjusted models, a higher p-cresol sulfate level was associated with a greater risk (HR per SD increase; 95% CI) of cardiovascular mortality (1.62; 1.17-2.25; p=0.004) and first cardiovascular event (1.60; 1.23-2.08; p<0.001). A higher phenylacetylglutamine level was associated with a greater risk of first cardiovascular event (1.37; 1.18-1.58; p<0.001). Patients in the highest quintile of the combined solute index had a 96% greater risk of cardiovascular mortality (1.96; 1.05-3.68; p=0.04) and 62% greater risk of first cardiovascular event (1.62; 1.12-2.35; p=0.01) compared with patients in the lowest quintile. Results were robust in sensitivity analyses., Conclusions: Free levels of uremic solutes that are secreted by the native kidney are associated with a higher risk of cardiovascular morbidity and mortality in incident hemodialysis patients.

Background: There is uncertainty regarding treatment of hypertension in hemodialysis patients due to the observed J-shaped association between blood pressure (BP) and death. We hypothesized that this association reflects confounding by cardiovascular disease (CVD) and that stratification by CVD biomarkers, cardiac troponin I (cTnI) and N-terminal fragment of prohormone brain natriuretic peptide (NT-proBNP), might change this association., Study Design: National prospective cohort study., Setting & Participants: 446 incident hemodialysis patients., Predictor: Predialysis systolic BP., Outcomes: Mortality (all-cause and CVD) and first CVD event assessed using Cox regression adjusted for demographics, comorbid conditions, and clinical factors., Measurements: Participants with cTnI level ≥0.1 ng/mL or NT-proBNP level ≥9,252 pg/mL were classified as the high-biomarker group; remaining participants were included in the low-biomarker group., Results: Participants in the high-biomarker group (n=138 [31%]) were older (61 vs. 57 years) and had a higher prevalence of CVD (67% vs. 23%), but similar baseline BPs (152 vs. 153 mm Hg). There were 323 deaths (143 from CVD) and 271 CVD events. The high-biomarker group had a higher risk of mortality than the low-biomarker group (HR, 1.75; 95% CI, 1.37-2.24). The association between BP and outcomes differed between the 2 biomarker groups (P for interaction=0.01, 0.2, and 0.07 for all-cause mortality, CVD mortality, and first CVD event, respectively). In the low-biomarker group, BP was associated with greater risk of outcomes: HR per 10 mm Hg higher BP was 1.07 (95% CI, 1.01-1.14), 1.10 (95% CI, 0.96-1.25), and 1.04 (95% CI, 0.96-1.13) for all-cause mortality, CVD mortality, and first CVD event, respectively. Importantly, lower BP was not associated with increased risk of outcomes in stratified models, including for those in high biomarker group., Limitations: BP measurements not standardized., Conclusions: The observed J-shaped association between BP and outcomes in hemodialysis patients is due to confounding by subclinical CVD. A stratification approach based on cTnI and NT-proBNP levels has the potential to inform BP treatment in hemodialysis patients., (Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: To explore whether disparities in age and sex in access to kidney transplantation (KT) originate at the time of prereferral discussions about KT., Design: Cross-sectional survey., Setting: Outpatient dialysis centers in Maryland (n = 26)., Participants: Individuals who had recently initiated hemodialysis treatment (N = 416)., Measurements: Participants reported whether medical professionals (nephrologist, primary medical doctor, dialysis staff) and social group members (significant other, family member, friend) discussed KT with them and, when applicable, rated the tone of discussions. Relative risks were estimated using modified Poisson regression., Results: Participants aged 65 and older were much less likely than those who were younger to have had discussions with medical professionals (44.5% vs 74.8%, P < .001) or social group members (47.3% vs 63.1%, P = .005). Irrespective of sex and independent of race, health-related factors, and dialysis-related characteristics, older adults were more likely not to have had discussions with medical professionals (relative risk (RR) = 1.13, 95% confidence interval (CI) = 1.03-1.24, for each 5-year increase in age through 65; RR = 1.28, 95% CI = 1.14-1.42, for each 5-year increase in age beyond 65). Irrespective of age, women were more likely (RR = 1.45, 95% CI = 1.12-1.89) not to have had discussions with medical professionals. For each 5-year increase in age, men (RR = 1.04, 95% CI = 0.99-1.10) and women (RR = 1.17, 95% CI = 1.10-1.24) were more likely not to have discussions with social group members. Of those who had discussions with medical professionals or social group members, older participants described these discussions as less encouraging (all P < .01)., Conclusion: Older adults and women undergoing hemodialysis are less likely than younger adults and men to have discussions about KT as a treatment option, supporting a need for better clinical guidelines and education for these individuals, their social network, and their providers., (© 2014, Copyright the Authors Journal compilation © 2014, The American Geriatrics Society.)

Objective: Assays for serum total glycated proteins (fructosamine) and the more specific glycated albumin may be useful indicators of hyperglycemia in dialysis patients, either as substitutes or adjuncts to standard markers such as hemoglobin A1c, as they are not affected by erythrocyte turnover. However, their relationship with long-term outcomes in dialysis patients is not well described., Research Design and Methods: We measured fructosamine and glycated albumin in baseline samples from 503 incident hemodialysis participants of a national prospective cohort study, with enrollment from 1995-1998 and median follow-up of 3.5 years. Outcomes were all-cause and cardiovascular disease (CVD) mortality and morbidity (first CVD event and first sepsis hospitalization) analyzed using Cox regression adjusted for demographic and clinical characteristics, and comorbidities., Results: Mean age was 58 years, 64% were white, 54% were male, and 57% had diabetes. There were 354 deaths (159 from CVD), 302 CVD events, and 118 sepsis hospitalizations over follow-up. Both fructosamine and glycated albumin were associated with all-cause mortality; adjusted HR per doubling of the biomarker was 1.96 (95% CI 1.38-2.79) for fructosamine and 1.40 (1.09-1.80) for glycated albumin. Both markers were also associated with CVD mortality [fructosamine 2.13 (1.28-3.54); glycated albumin 1.55 (1.09-2.21)]. Higher values of both markers were associated with trends toward a higher risk of hospitalization with sepsis [fructosamine 1.75 (1.01-3.02); glycated albumin 1.39 (0.94-2.06)]., Conclusions: Serum fructosamine and glycated albumin are risk factors for mortality and morbidity in hemodialysis patients.

Background and Objectives: Residual kidney function in dialysis patients is associated with better survival, but there are no simple methods for its assessment. β-Trace protein is a novel endogenous filtration marker of kidney function that is not removed during hemodialysis and may serve as a marker for residual kidney function similar to serum creatinine in patients not on dialysis. The objective of this study was to determine the association of serum β-trace protein with mortality in incident hemodialysis patients., Design, Setting, Participants, & Measurements: Serum β-trace protein was measured in baseline samples from 503 participants of a national prospective cohort study of incident dialysis patients with enrollment during 1995-1998 and follow-up until 2004. Outcomes were all-cause and cardiovascular disease mortality analyzed using Cox regression adjusted for demographic, clinical, and treatment factors., Results: Serum β-trace protein levels were higher in individuals with no urine output compared with individuals with urine output (9.0±3.5 versus 7.6±3.1 mg/L; P<0.001). There were 321 deaths (159 deaths from cardiovascular disease) during follow-up (median=3.3 years). Higher β-trace protein levels were associated with higher risk of mortality. The adjusted hazard ratio and 95% confidence interval for all-cause mortality per doubling of serum β-trace protein was 1.36 (1.09-1.69). The adjusted hazard ratios (95% confidence intervals) for all-cause mortality in the middle and highest tertiles compared with the lowest tertile were 0.95 (0.69-1.32) and 1.72 (1.25-2.37). Similar results were noted for cardiovascular disease mortality., Conclusions: The serum level of β-trace protein is an independent predictor of death and cardiovascular disease mortality in incident hemodialysis patients.

Background: African Americans have increased susceptibility to nondiabetic nephropathy relative to European Americans., Study Design: Follow-up of a pooled genome-wide association study (GWAS) in African American dialysis patients with nondiabetic nephropathy; novel gene-gene interaction analyses., Setting & Participants: Wake Forest sample: 962 African American nondiabetic nephropathy cases, 931 non-nephropathy controls. Replication sample: 668 Family Investigation of Nephropathy and Diabetes (FIND) African American nondiabetic nephropathy cases, 804 non-nephropathy controls., Predictors: Individual genotyping of top 1,420 pooled GWAS-associated single-nucleotide polymorphisms (SNPs) and 54 SNPs in 6 nephropathy susceptibility genes., Outcomes: APOL1 genetic association and additional candidate susceptibility loci interacting with or independently from APOL1., Results: The strongest GWAS associations included 2 noncoding APOL1 SNPs, rs2239785 (OR, 0.33; dominant; P = 5.9 × 10(-24)) and rs136148 (OR, 0.54; additive; P = 1.1 × 10(-7)) with replication in FIND (P = 5.0 × 10(-21) and 1.9 × 10(-05), respectively). rs2239785 remained associated significantly after controlling for the APOL1 G1 and G2 coding variants. Additional top hits included a CFH SNP (OR from meta-analysis in the 3,367 African American cases and controls, 0.81; additive; P = 6.8 × 10(-4)). The 1,420 SNPs were tested for interaction with APOL1 G1 and G2 variants. Several interactive SNPs were detected; the most significant was rs16854341 in the podocin gene (NPHS2; P = 0.0001)., Limitations: Nonpooled GWASs have not been performed in African American patients with nondiabetic nephropathy., Conclusions: This follow-up of a pooled GWAS provides additional and independent evidence that APOL1 variants contribute to nondiabetic nephropathy in African Americans and identified additional associated and interactive nondiabetic nephropathy susceptibility genes., (Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: The success of percutaneous interventions on stenotic hemodialysis prosthetic grafts and autogenous fistulas is assessed by comparing vessel diameter before and after treatment. These changes do not correlate with gold standard access blood flow (ABF) measurements obtained during hemodialysis. The AngioFlow (AngioDynamics, Inc, Queensbury, New York) calculates real-time blood flow through access circuits and may provide more physiologically relevant data in the interventional suite. This study compares angiographic vessel diameter and access circuit flow rates obtained with the AngioFlow Meter before and after percutaneous interventions on stenotic hemodialysis prosthetic grafts and autogenous fistulas ABF measurements obtained during hemodialysis., Materials and Methods: Angiographic images and AngioFlow measurements for 76 procedures in 35 patients undergoing hemodialysis with arteriovenous grafts or fistulas were analyzed retrospectively. Correlations between ABF, fistulography, and AngioFlow measurements before and after treatment were computed. Regression analyses of AngioFlow measurements and measurements after ABF were performed to account for confounding factors. Time to failure of treatment was modeled in first-time patients stratified by AngioFlow values obtained after treatment. Only patients with ABF measurements obtained within 5 weeks of intervention were included., Results: Correlations between initial ABF and fistulography measurement (ρ = 0.781), initial ABF and AngioFlow (ρ = 0.675), and final AngioFlow and ABF measurement (ρ = 0.798) were statistically significant. The correlation between final ABF and AngioFlow was significantly stronger than final ABF and fistulography (difference = 0.418, 95% bootstrap confidence interval [CI] [0.054, 0.914]). AngioFlow values and access survival after treatment did not show significant correlation., Conclusions: AngioFlow measurements performed after treatment correlate more strongly with hemodialysis ABF values than fistulography measures. Further studies are needed to determine the target AngioFlow value obtained after treatment that is associated with the greatest survival benefit for access circuits., (Copyright © 2011. Published by Elsevier Inc.)

Background and Objectives: Stroke remains a leading cause of morbidity and mortality for patients on dialysis; however, its risk factors in this population and measures to prevent it are not well understood., Design, Setting, Participants, & Measurements: We investigated whether inflammation was associated with cerebrovascular events in a national US cohort of 1041 incident dialysis patients enrolled from October 1995 to June 1998 and followed until January 31, 2004. Incident cerebrovascular events were defined as nonfatal (hospitalized stroke, carotid endarterectomy) and fatal (stroke death) events after dialysis initiation. With Cox proportional hazards regression analysis accounting for the competing risk of nonstroke death, we assessed the independent event risk associated with baseline levels of multiple inflammatory markers (high-sensitivity C-reactive protein [hsCRP], interleukin-6 (IL-6), matrix metalloproteinase-3 [MMP-3], and P-selectin) and hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) use, which may have pleiotropic inflammatory effects., Results: 165 patients experienced a cerebrovascular event during 3548 person-years of follow-up; overall incidence rate was 4.9/100 person-years. None of the inflammatory markers were associated with cerebrovascular event risk (adjusted hazard ratios [HRs] per log unit [95% confidence interval]: hsCRP, 0.97 [0.85 to 1.11]; IL-6, 1.04 [0.85 to 1.26]; MMP-3, 1.02 [0.70 to 1.48]; P-selectin, 0.98 [0.57 to 1.68]). Statin use was also not associated with significant risk of events in unadjusted (HR 1.07 [0.69 to 1.68]) or propensity-score adjusted analyses (HR 0.98 [0.61 to 1.56])., Conclusions: In conclusion, neither inflammatory markers nor statin use was associated with risk of cerebrovascular events. Further studies are needed to understand the pathophysiology and prevention of stroke in patients on dialysis.

Background: Residual kidney function (RKF) is associated with improved survival in peritoneal dialysis patients, but its role in hemodialysis patients is less well known. Urine output may provide an estimate of RKF. The aim of our study is to determine the association of urine output with mortality, quality of life (QOL), and inflammation in incident hemodialysis patients., Study Design: Nationally representative prospective cohort study., Setting & Participants: 734 incident hemodialysis participants treated in 81 clinics; enrollment, 1995-1998; follow-up until December 2004., Predictor: Urine output, defined as producing at least 250 mL (1 cup) of urine daily, ascertained using questionnaires at baseline and year 1., Outcomes & Measurements: Primary outcomes were all-cause and cardiovascular mortality, analyzed using Cox regression adjusted for demographic, clinical, and treatment characteristics. Secondary outcomes were QOL, inflammation (C-reactive protein and interleukin 6 levels), and erythropoietin (EPO) requirements., Results: 617 of 734 (84%) participants reported urine output at baseline, and 163 of 579 (28%), at year 1. Baseline urine output was not associated with survival. Urine output at year 1, indicating preserved RKF, was independently associated with lower all-cause mortality (HR, 0.70; 95% CI, 0.52-0.93; P = 0.02) and a trend toward lower cardiovascular mortality (HR, 0.69; 95% CI, 0.45-1.05; P = 0.09). Participants with urine output at baseline reported better QOL and had lower C-reactive protein (P = 0.02) and interleukin 6 (P = 0.03) levels. Importantly, EPO dose was 12,000 U/wk lower in those with urine output at year 1 compared with those without (P = 0.001)., Limitations: Urine volume was measured in only a subset of patients (42%), but agreed with self-report (P < 0.001)., Conclusions: RKF in hemodialysis patients is associated with better survival and QOL, lower inflammation, and significantly less EPO use. RKF should be monitored routinely in hemodialysis patients. The development of methods to assess and preserve RKF is important and may improve dialysis care., (Copyright (c) 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

There have been no studies in pediatric dialysis patients to evaluate the impact of higher estimated glomerular filtration rate (eGFR) at dialysis initiation on clinical outcomes. Baseline clinical and demographic information was collected for children aged 1-18 years undergoing incident dialysis from 1995-2002 within the United States Renal Data System. Baseline eGFRs calculated by the Schwartz formula were categorized as high (>15 ml/min/1.73 m(2)) or low (< or = 15 ml/min/1.73 m(2)). We determined predictors of eGFR at baseline, and associations between baseline eGFR and subsequent hospitalization for hypertension (HTN) or pulmonary edema (PE) in a longitudinal nonconcurrent pediatric end-stage renal disease (ESRD) cohort. Twenty percent of children had a high eGFR at initiation. Black children were less likely to initiate dialysis with a high eGFR [adjusted odds ratio (adjOR) 0.71, p < 0.001]. Girls were less likely to have a high eGFR at baseline (adjOR 0.71, p < 0.001). Children who received predialysis erythropoietin therapy were more likely to start dialysis with a high eGFR (adjOR 6.67, p < 0.001). Children with higher baseline eGFR were found to have a 21% decreased risk of hospitalization [adjusted hazard ratio (HR) 0.79, 95% confidence interval (CI) 0.65-0.96, p = 0.02]. It is not known whether this clinical benefit will result in decreased mortality and complication rates from cardiovascular disease.

Background and Objectives: Peripheral vascular disease (PVD) is prevalent among dialysis patients, and many dialysis patients undergo PVD-related procedures. We aimed to examine the risk factors for and prognosis after such procedures in the dialysis setting., Design, Setting, Participants, & Measurements: In a national prospective cohort study of 1041 incident dialysis patients, we examined the factors that are associated with PVD procedures (lower extremity amputations and bypasses) after the start of dialysis. Adjusted risk for PVD procedures of various factors was estimated using multivariable Cox proportional hazards models. Incidence rates of subsequent cardiovascular events, infectious hospitalizations, PVD- and cardiovascular disease-related mortality, and all-cause mortality were compared for those with and without a PVD procedure., Results: Overall, 217 (21%) patients underwent a PVD procedure after the start of dialysis. For those without diabetes, only PVD history (relative hazard [RH] 2.9; 95% confidence interval [CI] 1.3 to 6.6) and increased fibrinogen (RH 1.2; 95% CI 1.0 to 1.5) predicted PVD procedures. For those with diabetes, increased serum phosphate (RH 1.2; 95% CI 1.1 to 1.4), along with decreased albumin, increased C-reactive protein and fibrinogen, and lower SBP, was associated with risk for PVD procedures. Of those who had a procedure compared with those who did not, 68 versus 30% experienced a subsequent cardiovascular event, 85 versus 66% an infectious hospitalization, 11 versus 2% a PVD-related death, and 81 versus 59% all-cause death (mean follow-up 3.0 yr)., Conclusions: Prognosis after PVD procedures is poor, and providers should be aware that risk factors for PVD procedures may differ by diabetes status.

Background: Stroke is the third most common cause of cardiovascular disease death in patients on dialysis therapy; however, characteristics of cerebrovascular disease, including clinical subtypes and subsequent consequences, have not been well described., Study Design: Prospective national cohort study, the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) Study., Settings & Participants: 1,041 incident dialysis patients treated in 81 clinics enrolled from October 1995 to July 1998, followed up until December 31, 2004., Predictor: Time from dialysis therapy initiation., Outcomes & Measurements: Cerebrovascular disease events were defined as nonfatal (hospitalized stroke and carotid endarterectomy) and fatal (stroke death) events after dialysis therapy initiation. Stroke subtypes were classified by using standardized criteria from the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) system. The incidence of cerebrovascular event subtypes was analyzed by using time-to-event analyses accounting for competing risk of death. Clinical outcomes after stroke were abstracted from medical records., Results: 165 participants experienced a cerebrovascular event with an overall incidence of 4.9 events/100 person-years. Ischemic stroke was the most common (76% of all 200 events), with cardioembolism subtype accounting for 28% of the 95 abstracted ischemic events. Median time from onset of symptoms to first stroke evaluation was 8.5 hours (25th and 75th percentiles, 1 and 42), with only 56% of patients successfully escaping death, nursing home, or skilled nursing facility., Limitations: Relatively small sample size limits power to determine risk factors., Conclusions: Cerebrovascular disease is common in dialysis patients, is identified late, and carries a significant risk of morbidity and mortality. Stroke etiologic subtypes on dialysis therapy are multifactorial, suggesting risk factors may change the longer one has end-stage renal disease. Additional studies are needed to address the poor prognosis through prevention, early identification, and treatment.

Background: Increasing evidence supports a role for cell-mediated immunity in the pathogenesis of cardiovascular disease. Single-nucleotide polymorphisms (SNPs) in JAK3, STAT4, and STAT6 of the Janus kinase-signal transducer and activator of transcription (Jak-Stat) signal transduction pathway were examined for association with time to new cardiovascular events in incident dialysis patients from the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease Study., Study Design: Prospective cohort study., Setting & Participants: 764 white (n = 518) and black (n = 246) participants from 79 dialysis centers., Predictor: SNPs in JAK3, STAT4, and STAT6 selected using a pairwise approach to identify a maximally informative set of tag SNPs for populations of European and African descent., Outcomes & Measurements: Cox proportional hazards models were used to estimate unadjusted and multivariable-adjusted hazard ratios (HRs) for incident cardiovascular disease events after dialysis therapy initiation associated with each race-specific SNP., Results: 2 European tag SNPs (rs3212780 and rs3213409) in JAK3 were associated with new cardiovascular disease events in white patients with unadjusted HRs of 1.92 (P < 0.001) and 1.82 (P = 0.07), respectively. One dual-tag SNP (rs3212752) in JAK3 was associated with new cardiovascular events in white patients with an unadjusted HR of 2.09 (P < 0.001) and in black patients with an HR of 2.07 (P = 0.007). SNP rs3213409 codes for a valine to isoleucine change at amino acid 722, a potentially functional mutation. SNPs in STAT4 and STAT6 were not associated with cardiovascular events after the initiation of dialysis therapy., Limitations: This study does not provide direct evidence for the mechanism of increased risk. Replication in independent cohorts is necessary., Conclusions: Genetic polymorphisms in the Jak-Stat signaling pathway are associated with an increased risk of new cardiovascular events in incident dialysis patients.

Background: There has been controversy about the utility of new third-generation parathyroid hormone (PTH) assays measuring only 1-84 PTH, with few large studies comparing second- and third-generation PTH measurements in patients with ESRD., Methods: We measured 1-84 PTH ('biointact' or 'whole' PTH) and total PTH ('intact' PTH) in a national cohort of 515 incident dialysis patients from banked frozen EDTA plasma (median follow-up, 35 months) and examined the accuracy of estimating 1-84 PTH from total PTH and the associations of these levels with patient characteristics and mortality., Results: The 1-84 PTH and total PTH levels were closely correlated. Higher 1-84 PTH was associated with African-American race and higher serum phosphate and lower calcium levels. The percentage of total PTH represented by 1-84 PTH was, on average, 53%, but with a wide range (25-89%). Calculating 1-84 PTH from total PTH using a proposed standard conversion factor (54%) led to misclassification of 8% of the population compared with measured 1-84 PTH. In a multivariate Cox proportional hazards model for all-cause mortality, a 1-84 PTH value >160 pg/ml was associated with increased risk of mortality (HR = 1.62, 95% CI, 1.03-2.54) compared to a level of 80-160 pg/ml. Elevated total PTH, 7-84 PTH and the 1-84 PTH/7-84 PTH ratio were not significantly associated with mortality., Conclusions: The 1-84 PTH and total PTH are highly correlated. Elevated 1-84 PTH was significantly associated with increased mortality, whereas total PTH did not reach statistical significance. Thus, although in other respect they are similar, there may be utility in measuring 1-84 PTH for its associations with mortality.

Background: Atherosclerotic cardiovascular disease (ASCVD) is increasing in incidence in persons with human immunodeficiency virus (HIV). It is not known whether the morbidity and mortality rate of ASCVD is similarly increasing among patients with HIV end-stage renal disease (ESRD), who are living longer since the initiation of newer therapeutic regimens in 1997., Methods: We conducted a population-based study of 8,312 HIV ESRD patients enrolled in the US Renal Data System from 1987 to 2001. We determined the incidence of fatal and nonfatal ASCVD events stratified by date of dialysis therapy initiation., Results: There were 3,112 HIV ESRD patients (77.9% men; mean age, 39.6 +/- 9.6 years) who initiated dialysis therapy before 1997 and 2,371 patients (71.5% men; mean age, 41.3 +/- 9.7 years) who initiated dialysis therapy after 1997. Cumulative incidences of ASCVD for those initiating dialysis therapy before 1997 compared with after 1997 were 10.6% versus 13.5% at 12 months, 18.8% versus 27.6% at 24 months, 26.2% versus 42.4% at 36 months, and 33.7% versus 65.9% at 48 months (P < 0.0001 by log rank). Those who initiated dialysis therapy after 1997 had a greater risk for developing ASCVD (adjusted hazard ratio, 1.57; 95% confidence interval, 1.29 to 1.92) than those who initiated dialysis therapy before 1997 after adjusting for demographics and ASCVD risk factors., Conclusion: There is an increased risk for ASCVD in patients with HIV who initiated dialysis therapy after 1997. This may reflect the long-term complications of multidrug regimens, as well as improved survival from these regimens leading to prolonged exposure to ASCVD risk factors.

White individuals who are on dialysis experience much higher overall and cardiovascular mortality rates than black individuals despite a more favorable risk factor profile, but the incidence of nonfatal cardiovascular disease (CVD) to this racial disparity has not been well studied. A longitudinal study of 16,103 people who had ESRD and were enrolled in the United Renal Data System from 1993 to 1996 was conducted. The incidence of new and recurrent atherosclerotic CVD (ASCVD) events was determined using Medicare claims for hospitalizations and mortality among blacks and whites, stratified by ASCVD at baseline. ASCVD was defined as coronary heart disease, peripheral vascular disease, and cerebrovascular disease. Incidence of new ASCVD in people without ASCVD at baseline was 146.9 per 1000 person-years in whites and 118.7 per 1000 person-years in blacks. Incidence of recurrent ASCVD was 404.1 per 1000 person-years in whites and 317.5 per 1000 person-years in blacks. Whites were 1.35 (95% confidence interval, 1.18 to 1.55) times more likely to develop incident ASCVD compared with blacks and 1.25 (95% confidence interval, 1.14 to 1.36) times more likely to develop recurrent disease after adjusting for traditional CVD and dialysis-related risk factors. Excess risk for recurrent ASCVD in whites compared with blacks was consistently present no matter the duration of dialysis: Hazard ratio 1.42 for 0 to 6 mo and 1.40 for 6 to 12 mo. Whites who are treated with dialysis have a higher incidence of ASCVD than blacks who are on dialysis, both new and recurrent. Although differences in survival before the initiation of dialysis may contribute to the observed difference in ASCVD risk, it is not explained by baseline traditional and dialysis-related ASCVD risk factors.

BackgroundA better understanding of the pathophysiology involving coronary artery calcification (CAC) in patients on hemodialysis (HD) will help to develop new therapies. We sought to identify the differences in metabolomics profiles between patients on HD with and without CAC.MethodsIn this case-control study, nested within a cohort of 568 incident patients on HD, the cases were patients without diabetes with a CAC score >100 (n=51), and controls were patients without diabetes with a CAC score of zero (n=48). We measured 452 serum metabolites in each participant. Metabolites and pathway scores were compared using Mann-Whitney U tests, partial least squares-discriminant analyses, and pathway enrichment analyses.ResultsCompared with controls, cases were older (64±13 versus 42±12 years) and were less likely to be Black (51% versus 94%). We identified three metabolites in bile-acid synthesis (chenodeoxycholic, deoxycholic, and glycolithocholic acids) and one pathway (arginine/proline metabolism). After adjusting for demographics, higher levels of chenodeoxycholic, deoxycholic, and glycolithocholic acids were associated with higher odds of having CAC; comparing the third with the first tertile of each bile acid, the OR was 6.34 (95% CI, 1.12 to 36.06), 6.73 (95% CI, 1.20 to 37.82), and 8.53 (95% CI, 1.50 to 48.49), respectively. These associations were no longer significant after further adjustment for coronary artery disease and medication use. Per 1 unit higher in the first principal component score, arginine/proline metabolism was associated with CAC after adjusting for demographics (OR, 1.83; 95% CI, 1.06 to 3.15), and the association remained significant with additional adjustments for statin use (OR, 1.84; 95% CI, 1.04 to 3.27).ConclusionsAmong patients on HD without diabetes mellitus, chenodeoxycholic, deoxycholic, and glycolithocholic acids may be potential biomarkers for CAC, and arginine/proline metabolism is a plausible mechanism to study for CAC. These findings need to be confirmed in future studies.

BACKGROUND:Mortality in end-stage renal disease (ESRD) occurs predominantly from cardiovascular disease (CVD) and sudden cardiac death (SCD). Obstructive sleep apnea (OSA) is characterized by periodic airflow limitation associated with sleep arousal and oxygen desaturation and is prevalent in patients with ESRD. Whether OSA increases the risk for SCD, cardiovascular and all-cause mortality among hemodialysis patients remains unknown. METHODS:In a prospective cohort of 558 incident hemodialysis patients, we examined the association of OSA with all-cause mortality, cardiovascular mortality, and SCD using Cox proportional hazards models controlling for traditional CVD risk factors. RESULTS:Sixty-six incident hemodialysis patients (12%) had OSA. Mean age (56 years) and percentage of males (56%) were identical in OSA and no-OSA groups. Fewer African Americans had OSA than non-African Americans (9 vs. 18%, respectively). Participants with OSA had higher body-mass index, Charlson comorbidity score, and left ventricular mass index and greater prevalence of diabetes and coronary artery disease. During 1,080 person-years of follow-up, 104 deaths occurred, 29% of which were cardiovascular. OSA was associated with a higher risk of all-cause mortality (HR 1.90 [95% CI 1.04-3.46]) and cardiovascular mortality (HR 3.62 [95% CI 1.36-9.66]) after adjusting for demographics and body-mass index. OSA was associated with a higher risk of SCD after adjusting for demographics (HR 3.28 [95% CI 1.12-9.57]) and multiple cardiovascular risk factors. CONCLUSIONS:Incident hemodialysis patients with OSA are at increased risk of all-cause and cardiovascular mortality and SCD. Future studies should assess the impact of screening for OSA and OSA-targeted interventions on mortality in ESRD.

BackgroundThe risk of cardiovascular mortality is high among adults with end-stage renal disease (ESRD) undergoing hemodialysis. Waist-to-hip ratio (WHR), a metric of abdominal adiposity, is a predictor of cardiovascular disease (CVD) and mortality in the general population; however, no studies have examined the association with CVD mortality, particularly sudden cardiac death (SCD), in incident hemodialysis.MethodsAmong 379 participants incident (< 6 months) to hemodialysis enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in ESRD study, we evaluated associations between WHR and risk of CVD mortality, SCD, and non-CVD mortality in Cox proportional hazards regression models.ResultsAt study enrollment, mean age was 55 years with 41% females, 73% African Americans, and 57% diabetics. Mean body mass index was 29.3 kg/m2, and mean WHR was 0.95. During a median follow-up time of 2.5 years, there were 35 CVD deaths, 15 SCDs, and 48 non-CVD deaths. Every 0.1 increase in WHR was associated with higher risk (hazard ratio [95% CI]) of CVD mortality (1.75 [1.06-2.86]) and SCD (2.45 [1.20-5.02]), but not non-CVD mortality (0.93 [0.59-1.45]), independently of demographics, body mass index, comorbidities, inflammation, and traditional CVD risk factors.ConclusionsWHR is significantly associated with CVD mortality including SCD, independently of other CVD risk factors in incident hemodialysis. This simple, easily obtained bedside metric may be useful in dialysis patients for CVD risk stratification.

BackgroundSudden cardiac death (SCD) is the most common etiology of death in hemodialysis patients but not much is known about its risk factors. The goal of our study was to determine the association and risk prediction of SCD by serum N-terminal prohormone of brain natriuretic peptide (NTproBNP) troponin I (cTnI) in hemodialysis patients.MethodsWe measured NTproBNP and cTnI in 503 hemodialysis patients of a national prospective cohort study. We determined their association with SCD using Cox regression, adjusting for demographics, co-morbidities, and clinical factors and risk prediction using C-statistic and Net Reclassification Improvement (NRI).ResultsPatients' mean age was 58 years and 54 % were male. During follow-up (median 3.5 years), there were 75 outpatient SCD events. In unadjusted and fully-adjusted models, NTproBNP had a significant association with the risk of SCD. Analyzed as a continuous variable, the risk of SCD increased 27 % with each 2-fold increase in NTproBNP (HR, 1.27 per doubling; 95 % CI, 1.13-1.43; p 7,350 pg/mL) compared with the lowest tertile (

BackgroundAbnormalities in mineral homeostasis are ubiquitous in patients on dialysis, and influenced by race. In this study, we determine the race-specific relationship between mineral parameters and mortality in patients initiating hemodialysis.MethodsWe measured the levels of fibroblast growth factor 23 (FGF23) and 25-hydroxyvitamin D (25 D) in 184 African American and 327 non-African American hemodialysis patients who enrolled between 1995 and 1998 in the Choices for Healthy Outcomes in Caring for ESRD Study. Serum calcium, phosphorus, parathyroid hormone (PTH) and total alkaline phosphatase levels were averaged from clinical measurements during the first 4.5 months of dialysis. We evaluated the associated prospective risk of mortality using multivariable Cox proportional hazards models stratified by race.ResultsPTH and total alkaline phosphatase levels were higher, whereas calcium, phosphorus, FGF23 and 25 D levels were lower in African Americans compared to those of non-African Americans. Higher serum phosphorus and FGF23 levels were associated with greater mortality risk overall; however, phosphorus was only associated with risk among African Americans (HR 5.38, 95% CI 2.14-13.55 for quartile 4 vs. 1), but not among non-African Americans (p-interaction = 0.04). FGF23 was associated with mortality in both groups, but more strongly in African Americans (HR 3.91, 95% CI 1.74-8.82 for quartiles 4 vs. 1; p-interaction = 0.09). Serum calcium, PTH, and 25 D levels were not consistently associated with mortality. The lowest and highest quartiles of total alkaline phosphatase were associated with higher mortality risk, but this did not differ by race (p-interaction = 0.97).ConclusionsAberrant phosphorus homeostasis, reflected by higher phosphorus and FGF23, may be a risk factor for mortality in patients initiating hemodialysis, particularly among African Americans.