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RATIONALE - Intensive care unit (ICU) delirium is highly prevalent and a potentially avoidable hospital complication. The current cost of ICU delirium is unknown.
OBJECTIVES - To specify the association between the daily occurrence of delirium in the ICU with costs of ICU care accounting for time-varying illness severity and death.
RESEARCH DESIGN - We performed a prospective cohort study within medical and surgical ICUs in a large academic medical center.
SUBJECTS - We analyzed critically ill patients (N=479) with respiratory failure and/or shock.
MEASURES - Covariates included baseline factors (age, insurance, cognitive impairment, comorbidities, Acute Physiology and Chronic Health Evaluation II Score) and time-varying factors (sequential organ failure assessment score, mechanical ventilation, and severe sepsis). The primary analysis used a novel 3-stage regression method: first, estimation of the cumulative cost of delirium over 30 ICU days and then costs separated into those attributable to increased resource utilization among survivors and those that were avoided on the account of delirium's association with early mortality in the ICU.
RESULTS - The patient-level 30-day cumulative cost of ICU delirium attributable to increased resource utilization was $17,838 (95% confidence interval, $11,132-$23,497). A combination of professional, dialysis, and bed costs accounted for the largest percentage of the incremental costs associated with ICU delirium. The 30-day cumulative incremental costs of ICU delirium that were avoided due to delirium-associated early mortality was $4654 (95% confidence interval, $2056-7869).
CONCLUSIONS - Delirium is associated with substantial costs after accounting for time-varying illness severity and could be 20% higher (∼$22,500) if not for its association with early ICU mortality.
BACKGROUND AND OBJECTIVES - HDL particles obtained from patients on chronic hemodialysis exhibit lower cholesterol efflux capacity and are enriched in inflammatory proteins compared with those in healthy individuals. Observed alterations in HDL proteins could be due to effects of CKD, but also may be influenced by the hemodialysis procedure, which stimulates proinflammatory and prothrombotic pathways.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - We compared HDL-associated proteins in 143 participants who initiated hemodialysis within the previous year with those of 110 participants with advanced CKD from the Hemodialysis Fistula Maturation Study. We quantified concentrations of 38 HDL-associated proteins relative to total HDL protein using targeted mass spectrometry assays that included a stable isotope-labeled internal standard. We used linear regression to compare the relative abundances of HDL-associated proteins after adjustment and required a false discovery rate value ≤10% to control for multiple testing. We further assessed the association between hemodialysis initiation and cholesterol efflux capacity in a subset of 80 participants.
RESULTS - After adjustment for demographics, comorbidities, and other clinical characteristics, eight HDL-associated proteins met the prespecified false discovery threshold for association. Recent hemodialysis initiation was associated with higher HDL-associated concentrations of serum amyloid A1, A2, and A4; hemoglobin-; haptoglobin-related protein; cholesterylester transfer protein; phospholipid transfer protein; and apo E. The trend for participants recently initiating hemodialysis for lower cholesterol efflux capacity compared with individuals with advanced CKD did not reach statistical significance.
CONCLUSIONS - Compared with advanced CKD, hemodialysis initiation within the previous year is associated with higher concentrations of eight HDL proteins related to inflammation and lipid metabolism. Identified associations differ from those recently observed for nondialysis-requiring CKD. Hemodialysis initiation may further impair cholesterol efflux capacity. Further work is needed to clarify the clinical significance of the identified proteins with respect to cardiovascular risk.
PODCAST - This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_07_25_CJASNPodcast_18_8_W.mp3.
Copyright © 2018 by the American Society of Nephrology.
Maintenance hemodialysis (MHD) patients display significant nutritional abnormalities. Insulin is an anabolic hormone with direct effects on skeletal muscle (SM). We examined the anabolic actions of insulin, whole-body (WB), and SM protein turnover in 33 MHD patients and 17 participants without kidney disease using hyperinsulinemic-euglycemic-euaminoacidemic (dual) clamp. Gluteal muscle biopsies were obtained before and after the dual clamp. At baseline, WB protein synthesis and breakdown rates were similar in MHD patients. During dual clamp, controls had a higher increase in WB protein synthesis and a higher suppression of WB protein breakdown compared with MHD patients, resulting in statistically significantly more positive WB protein net balance [2.02 (interquartile range [IQR]: 1.79 and 2.36) vs. 1.68 (IQR: 1.46 and 1.91) mg·kg fat-free mass·min for controls vs. for MHD patients, respectively, P < 0.001]. At baseline, SM protein synthesis and breakdown rates were higher in MHD patients versus controls, but SM net protein balance was similar between groups. During dual clamp, SM protein synthesis increased statistically significantly more in controls compared with MHD patients ( P = 0.03), whereas SM protein breakdown decreased comparably between groups. SM net protein balance was statistically significantly more positive in controls compared with MHD patients [67.3 (IQR: 46.4 and 97.1) vs. 15.4 (IQR: -83.7 and 64.7) μg·100 ml·min for controls and MHD patients, respectively, P = 0.03]. Human SM biopsy showed a positive correlation between glucose and leucine disposal rates, phosphorylated AKT to AKT ratio, and muscle mitochondrial markers in controls but not in MHD patients. Diminished response to anabolic actions of insulin in the stimulated setting could lead to muscle wasting in MHD patients.
BACKGROUND AND AIMS - Angiotensin receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACEI) reduce cardiovascular events in the general population. Maintenance hemodialysis (MHD) patients are at high cardiovascular risk but few studies have directly addressed the comparative efficacy of these drugs. MHD disrupts the normally atheroprotective actions of high density lipoprotein (HDL), therefore, we compared ACEI or ARB treatment on HDL functions in MHD.
METHODS AND RESULTS - HDL was isolated at the starting point (pre) and 3-6 months later (post) in 30 MHD randomly assigned to placebo, ramipril or valsartan. Outcomes included cholesterol efflux, inflammatory cytokine response, effects on Toll-like receptors (TLR), superoxide production, methylarginine and serum amyloid A (SAA) levels. HDL from ARB- or ACEI-treated subjects was more effective in maintaining efflux than HDL of placebo. HDL from ARB- or ACEI-treated subjects but not placebo lessened cellular superoxide production. In contrast, neither ARB nor ACEI improved HDL anti-inflammatory effect. Indeed, HDL of ACEI-treated subjects potentiated the cytokine responses in association with activation of TLR but did not alter the HDL content of methylarginines or SAA.
CONCLUSION - Both ACEI and ARB stabilized HDL cholesterol acceptor function and sustained cellular anti-oxidative effects but not anti-inflammatory effects, and ACEI-treatment instead amplified the HDL inflammatory response. The findings reveal possible utility of antagonizing angiotensin actions in MDH and suggest a possible mechanism for superiority of ARB vs ACEI in the setting of advanced kidney disease.
Copyright © 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.
Background - Vadadustat, an inhibitor of hypoxia-inducible factor prolyl-4-hydroxylase domain dioxygenases, is an oral investigational agent in development for the treatment of anemia secondary to chronic kidney disease.
Methods - In this open-label Phase 2 trial, vadadustat was evaluated in 94 subjects receiving hemodialysis, previously maintained on epoetin alfa. Subjects were sequentially assigned to one of three vadadustat dose cohorts by starting dose: 300 mg once daily (QD), 450 mg QD or 450 mg thrice weekly (TIW). The primary endpoint was mean hemoglobin (Hb) change from pre-baseline average to midtrial (Weeks 7-8) and end-of-trial (Weeks 15-16) and was analyzed using available data (no imputation).
Results - Overall, 80, 73 and 68% of subjects in the 300 mg QD, 450 mg QD, and 450 mg TIW dose cohorts respectively, completed the study. For all dose cohorts no statistically significant mean change in Hb from pre-baseline average was observed, and mean Hb concentrations-analyzed using available data-remained stable at mid- and end-of-trial. There was one subject with an Hb excursion >13 g/dL. Overall, 83% of subjects experienced an adverse event (AE); the proportion of subjects who experienced at least one AE was similar among the three dose cohorts. The most frequently reported AEs were nausea (11.7%), diarrhea (10.6%) and vomiting (9.6%). No deaths occurred during the study. No serious AEs were attributed to vadadustat.
Conclusions - Vadadustat maintained mean Hb concentrations in subjects on hemodialysis previously receiving epoetin. These data support further investigation of vadadustat to assess its long-term safety and efficacy in subjects on hemodialysis.
OBJECTIVE - We aimed to clarify the impact of extracorporeal membrane oxygenation (ECMO) as a platform to drive hemodialysis (HD) for ammonia clearance on outcomes of neonates with severe hyperammonemia.
STUDY DESIGN - All neonates treated for hyperammonemia at a single children's hospital between 1992 and 2016 were identified. Patient characteristics and outcomes were compared between those receiving medical management or ECMO/HD.
RESULT - Twenty-five neonates were treated for hyperammonemia, of which 13 (52%) received ECMO/HD. Peak ammonia levels among neonates treated with ECMO/HD were significantly higher than those medically managed (1041 [IQR 902-1581] μmol/L versus 212 [IQR 110-410] μmol/L; p = 0.009). Serum ammonia levels in the ECMO/HD cohort declined to the median of medically managed within 4.5 (IQR 2.9-7.0) hours and normalized within 7.3 (IQR 3.6-13.5) hours. All neonates survived ECMO/HD, and nine (69.2%) survived to discharge.
CONCLUSION - ECMO/HD is an effective adjunct to rapidly clear severe hyperammonemia in newborns, reducing potential neurodevelopmental morbidity.
BACKGROUND - Systemic inflammation and muscle wasting are highly prevalent and coexist in patients on maintenance hemodialysis (MHD). We aimed to determine the effects of systemic inflammation on skeletal muscle protein metabolism in MHD patients.
METHODS - Whole body and skeletal muscle protein turnover were assessed by stable isotope kinetic studies. We incorporated expressions of E1, E214K, E3αI, E3αII, MuRF-1, and atrogin-1 in skeletal muscle tissue from integrin β1 gene KO CKD mice models.
RESULTS - Among 129 patients with mean (± SD) age 47 ± 12 years, 74% were African American, 73% were male, and 22% had diabetes mellitus. Median high-sensitivity C-reactive protein (hs-CRP) concentration was 13 (interquartile range 0.8, 33) mg/l. There were statistically significant associations between hs-CRP and forearm skeletal muscle protein synthesis, degradation, and net forearm skeletal muscle protein balance (P < 0.001 for all). The associations remained statistically significant after adjustment for clinical and demographic confounders, as well as in sensitivity analysis, excluding patients with diabetes mellitus. In attempting to identify potential mechanisms involved in this correlation, we show increased expressions of E1, E214K, E3αI, E3αII, MuRF-1, and atrogin-1 in skeletal muscle tissue obtained from an animal model of chronic kidney disease.
CONCLUSION - These data suggest that systemic inflammation is a strong and independent determinant of skeletal muscle protein homeostasis in MHD patients, providing rationale for further studies using anticytokine therapies in patients with underlying systemic inflammation.
FUNDING - This study was in part supported by NIH grants R01 DK45604 and 1K24 DK62849, the Clinical Translational Science Award UL1-TR000445 from the National Center for Advancing Translational Sciences, the Veterans Administration Merit Award I01 CX000414, the SatelliteHealth Normon Coplon Extramural Grant Program, and the FDA grant 000943.
BACKGROUND AND OBJECTIVES - Prognostic uncertainty is one barrier that impedes providers in engaging patients with CKD in shared decision making and advance care planning. The surprise question has been shown to identify patients at increased risk of dying.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - In our prospective observational study, 488 patients ≥60 years of age with CKD stage 4 or 5 were enrolled. Binary surprise question (, "Would you be surprised if this patient died in the next 12 months?") responses were recorded, and dialysis planning preferences, presence of advance care planning documentation, and care preceding death were abstracted.
RESULTS - The median patient age was 71 (65-77) years old. Providers responded no and yes to the surprise question for 171 (35%) and 317 (65%) patients, respectively. Median follow-up was 1.9 (1.5-2.1) years, during which 18% of patients died (33% of surprise question no, 10% of surprise question yes; <0.001). In patients with a known RRT preference (58%), 13% of surprise question no participants had a preference for conservative management (versus 2% of yes counterparts; <0.001). A medical order (, physician order for life-sustaining treatment) was documented in 13% of surprise question no patients versus 5% of yes patients (=0.004). Among surprise question no decedents, 41% died at home or hospice, 38% used hospice services, and 54% were hospitalized in the month before death. In surprise question yes decedents, 39% died at home or hospice (=0.90 versus no), 26% used hospice services (=0.50 versus no), and 67% were hospitalized in the month before death (=0.40 versus surprise question no).
CONCLUSIONS - Nephrologists' prognostic perceptions were associated with modest changes in care, highlighting a critical gap in conservative management discussions, advance care planning, and end of life care among older adults with CKD stages 4 and 5 and high-risk clinical characteristics.
PODCAST - This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_09_18_CJASNPodcast_17_11.mp3.
Copyright © 2017 by the American Society of Nephrology.
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 (=0.34; <0.001). We noted a U-shaped association of dialysis-unit-SBP and risk of cardiovascular events, with the nadir risk between 140 and 170 mm Hg. In contrast, there was a linear stepwise association between out-of-dialysis-unit-SBP with risk of cardiovascular events. Participants with out-of-dialysis-unit-SBP ≥128 mm Hg (top 2 quartiles) had >2-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.
© 2017 American Heart Association, Inc.
A classic response to systemic hypoxia is the increase in red blood cell production. This response is controlled by the prolyl hydroxylase domain/hypoxia-inducible factor (HIF) pathway, which regulates a broad spectrum of cellular functions. The discovery of this pathway as a key regulator of erythropoiesis has led to the development of small molecules that stimulate the production of endogenous erythropoietin and enhance iron metabolism. This review provides a concise overview of the cellular and molecular mechanisms that govern HIF-induced erythropoietic responses and provides an update on clinical experience with compounds that target HIF-prolyl hydroxylases for anemia therapy.
© 2017 International Society for Hemodialysis.