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Background Continuous kidney replacement therapy (CKRT) is a mainstay of therapy for management of severe acute kidney injury (AKI) in critically ill pediatric patients. There is limited data on the risk of chronic kidney disease (CKD) after discharge in this population. Methods This is a single-center, retrospective cohort study of all pediatric patients ages 0-17 years who received CKRT from 2013 to 2017. The study excluded patients with pre-existing CKD, those who died prior to discharge, and those who had insufficient follow-up data. Patients were followed after hospital discharge and electronic health record data was collected and analyzed to assess for incidence of and risk factors for kidney sequelae. Results A total of 42 patients were followed at a median time of 27 months (IQR 17.2, 39.8). Of these, 26.2% had evidence of CKD and 19% were at risk for CKD. Lower eGFR at hospital discharge was associated with increased odds of kidney sequelae (aOR 0.985; 95% CI 0.972, 0.996). Ages 0- < 1 and 12-17 were not significantly different (aOR 0.235, 95% CI 0.024, 1.718) and had the highest incidence of kidney sequelae (50% and 77%, respectively). Ages 1-5 and 6-11 had a decreased odds of kidney sequelae compared to the 12-17 year age group (aOR 0.098; 95% CI 0.009, 0.703 and aOR 0.035; 95% CI 0.001, 0.39, respectively). Only 54.8% of patients (n = 23) were seen in the nephrology clinic after discharge. Conclusions Patients who receive CKRT for AKI have a significant risk of CKD, while follow-up with a pediatric nephrologist in these high-risk patients is sub-optimal. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information, Author(s): Jeanne Frisby-Zedan [sup.1] [sup.2] , Matthew F. Barhight [sup.1] [sup.2] , Mahima Keswani [sup.1] [sup.2] , Jennifer Arzu [sup.2] , Delphine Nelson [sup.1] [sup.2] Author Affiliations: (1) grid.413808.6, 0000 [...]

Background Serum chloride derangements are associated with poor clinical outcomes, including acute kidney injury (AKI) and mortality. We sought to determine the association between persistent hyperchloremia and renal recovery in critically ill children with AKI. Methods We performed a retrospective cohort study of all patients with day 2 AKI admitted to a large academic pediatric intensive care unit from January 2014 to December 2015. After applying exclusion criteria, 348 patients were categorized as (1) hyperchloremia on both day 2 and day 7 (PersistentCl), (2) hyperchloremia on day 2 with normochloremia on day 7 (RecoveredCl), (3) normochloremia on day 2 with hyperchloremia on day 7 (DelayedCl), and (4) no hyperchloremia on day 2 nor day 7 (NormalCl). Hyperchloremia was defined as [greater than or equal to] 110 mEq/L. The primary outcome was renal recovery on day 7, defined as the absence of AKI criteria. Secondary outcomes included discharge renal recovery, mortality, duration of mechanical ventilation, and hospital length of stay. Results Day 7 renal recovery rates for PersistentCl, RecoveredCl, DelayedCl, and NormalCl were 37%, 66%, 71%, and 52% respectively. PersistentCl had lower odds of day 7 renal recovery (aOR = 0.29; 95% CI, 0.14 to 0.60; p = 0.0009), lower odds of discharge renal recovery (aOR = 0.22; 95% CI, 0.11 to 0.48; p = 0.0001), and higher odds of mortality (aOR = 3.50; 95% CI, 1.11 to 11.10; p = 0.03) when compared with RecoveredCl after adjusting for confounders. Conclusions Persistent hyperchloremia is independently associated with impaired renal recovery as well as higher mortality. Prospective studies are indicated to determine if serum chloride represents a modifiable risk factor for poor outcomes., Author(s): Matthew F. Barhight [sup.1] , John T. Brinton [sup.2] , Danielle E. Soranno [sup.3] [sup.4] , Sarah Faubel [sup.4] , Peter M. Mourani [sup.5] , Katja M. Gist [sup.6] [...]

Purpose To determine if there is an association between mortality and admission chloride levels and/or increases in the chloride level in critically ill children. Methods We performed a retrospective cohort study of all patients admitted to the paediatric intensive care unit (PICU) from January 2014 to December 2015. Patients were excluded for the following reasons: (1) age 18 years, (2) admission to the cardiac intensive care unit, (3) no laboratory values upon admission to the PICU, (4) history of end-stage renal disease, (5) a disorder of chloride transport, and (6) admission for diabetic ketoacidosis. The patients were stratified on the basis of admission chloride levels (hypochloraemia, < 96 mEq/L; normochloraemia, 96-109 mEq/L; and hyperchloraemia, [greater than or equal to] 110 mEq/L) and dichotomised on the basis of an increase in chloride in the first day (< 5 mEq/L, [greater than or equal to] 5 mEq/L). Our primary outcome was in-hospital mortality. Results A total of 1935 patients [55% female, median age 6.3 years IQR (1.9-13.4)] were included. The overall mortality was 4% (n = 71) and day 2 AKI occurred in 17% (n = 333. Hypochloraemia, hyperchloraemia, and an increase in serum chloride [greater than or equal to] 5 mEq/L occurred in 2%, 21%, and 12%, respectively. After adjusting for confounders, increase in chloride [greater than or equal to] 5 mEq/L was associated with a 2.3 (95% CI 1.03-5.21) greater odds of mortality. Conclusions An increase in serum chloride level in the first day of admission is common and an independent risk factor for mortality in critically ill children. Further studies are warranted to identify how chloride disturbances contribute to mortality risk in critically ill children., Author(s): Matthew F. Barhight [sup.1], John Brinton [sup.5], Timothy Stidham [sup.6], Danielle E. Soranno [sup.3] [sup.7], Sarah Faubel [sup.7], Benjamin R. Griffin [sup.7], Jens Goebel [sup.3], Peter M. Mourani [sup.2], [...]

Background The optimal fluid management in critically ill children is currently under investigation with several studies suggesting that hyperchloremia, chloride load, and the use of chloride-rich fluids contribute to worse outcomes. Methods This is a single-center retrospective cohort study of Pediatric Intensive Care Unit patients from 2008 to 2016 requiring continuous renal replacement therapy (CRRT). Patients were excluded if they had end-stage renal disease, a disorder of chloride transport, or concurrent provision of extracorporeal membrane oxygenation therapy. Results Patients (n = 66) were dichotomized into two groups (peak chloride (Cl) [greater than or equal to] 110 mmol/L vs. peak Cl < 110 mmol/L prior to CRRT initiation). Hyperchloremia was present in 39 (59%) children. Baseline characteristics were similar between groups. Fluid overload at CRRT initiation was more common in patients with hyperchloremia (11.5% IQR 3.8-22.4) compared to those without (5.5% IQR 0.9-13.9) (p = 0.04). Mortality was significantly higher in patients with hyperchloremia (n = 26, 67%) compared to those without (n = 8, 29%) (p = 0.006). Patients with hyperchloremia had 10.9 times greater odds of death compared to those without hyperchloremia, after adjusting for percent fluid overload, PRISM III score, time to initiation of CRRT, height, and weight (95% CI 2.4 to 49.5, p = 0.002). Conclusions Hyperchloremia is common among critically ill children prior to CRRT initiation. In this population, hyperchloremia is independently associated with mortality. Further studies are needed to determine the impact of hyperchloremia on all critically ill children and the impact of chloride load on outcomes., Author(s): Matthew F. Barhight [sup.1] [sup.2] , Jennifer Lusk [sup.1] , John Brinton [sup.3] , Timothy Stidham [sup.1] [sup.2] , Danielle E. Soranno [sup.2] [sup.4] [sup.5] , Sarah Faubel [sup.4] [...]

Morphine dependence is characterized by somatic and motivational signs of withdrawal that likely contribute to the maintenance of addictive behavior. The nucleus accumbens (NAc) receives extensive dopaminergic input and is an important substrate for mediating these aversive states. In the NAc, the function of the transcription factor cAMP response element binding protein (CREB) and AMPA glutamate receptor subunit, type 1 (GluR1) can be regulated by dopamine (DA) D1 receptor-mediated phosphorylation (P-CREB, P-GluR1). However, the roles of D1 receptors, CREB, and GluR1 in morphine dependence are not well understood. Here, we show that somatic signs of naloxone-precipitated withdrawal were associated with increased P-CREB, but not P-GluR1, in the NAc of morphine-dependent rats. The D1 receptor agonist chloro-APB hydrobromide (SKF 82958) was rewarding in morphine-dependent rats and blocked naloxone-induced place aversions and somatic signs of withdrawal. Surprisingly, SKF82958 increased P-GluR1, but not P-CREB, in the NAc, and naloxone reduced SKF82958-mediated P-GluR1 induction specifically inmorphine-dependent rats. Together, these results confirm that aversive treatments can increase CREB function in the NAc. Furthermore, they suggest a dependence-associated shift in the molecular mechanisms that regulate the consequences of D1 receptor stimulation, favoring activation of GluR1 rather than CREB. These data raise the possibility that the rewarding effects of SKF 82958 in morphine-dependent rats involve increased P-GluR1 in the NAc, although the involvement of other brain regions cannot be ruled out. Regardless, these findings suggest for the first time that D1 agonists might be useful for the treatment of withdrawal symptoms that contribute to the maintenance of opiate addiction in humans. [ABSTRACT FROM AUTHOR]

Morphine dependence is characterized by somatic and motivational signs of withdrawal that likely contribute to the maintenance of addictive behavior. The nucleus accumbens (NAc) receives extensive dopaminergic input and is an important substrate for mediating these aversive states. In the NAc, the function of the transcription factor cAMP response element binding protein (CREB) and AMPA glutamate receptor subunit, type 1 (GluR1) can be regulated by dopamine (DA) D1 receptor-mediated phosphorylation (P-CREB, P-GluR1). However, the roles of D1 receptors, CREB, and GluR1 in morphine dependence are not well understood. Here, we show that somatic signs of naloxone-precipitated withdrawal were associated with increased P-CREB, but not P-GluR1, in the NAc of morphine-dependent rats. The D1 receptor agonist chloro-APB hydrobromide (SKF 82958) was rewarding in morphine-dependent rats and blocked naloxone-induced place aversions and somatic signs of withdrawal. Surprisingly, SKF 82958 increased P-GluR1, but not P-CREB, in the NAc, and naloxone reduced SKF 82958-mediated P-GluR1 induction specifically in morphine-dependent rats. Together, these results confirm that aversive treatments can increase CREB function in the NAc. Furthermore, they suggest a dependence-associated shift in the molecular mechanisms that regulate the consequences of D1 receptor stimulation, favoring activation of GluR1 rather than CREB. These data raise the possibility that the rewarding effects of SKF 82958 in morphine-dependent rats involve increased P-GluR1 in the NAc, although the involvement of other brain regions cannot be ruled out. Regardless, these findings suggest for the first time that D1 agonists might be useful for the treatment of withdrawal symptoms that contribute to the maintenance of opiate addiction in humans.