Corrigendum to "Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK)" [Kidney International Reports Volume 8, Issue 8, August 2023, Pages 1542-1552].

[This corrects the article DOI: 10.1016/j.ekir.2023.05.026.].

Estimating risk of prolonged mechanical ventilation after liver transplantation in children: PROVE-ALT score.

BACKGROUND: Children at high risk for prolonged mechanical ventilation (PMV) after liver transplantation (LT) need to be identified early to optimize pulmonary support, allocate resources, and improve surgical outcomes. We aimed to develop and validate a metric that can estimate risk for Prolonged Ventilation After LT (PROVE-ALT). METHODS: We identified preoperative risk factors for PMV by univariable analysis in a retrospective cohort of pediatric LT recipients between 2011 and 2017 (n = 205; derivation cohort). We created the PROVE-ALT score by mapping multivariable logistic regression coefficients as integers, with cutoff values using the Youden Index. We validated the score by C-statistic in a retrospectively collected separate cohort of pediatric LT recipients between 2018 and 2021 (n = 133, validation cohort). RESULTS: Among total 338 patients, 21% (n = 72) were infants; 49% (n = 167) had cirrhosis; 8% (n = 27) required continuous renal replacement therapy (CRRT); and 32% (n = 111) required management in hospital (MIH) before LT. Incidence of PMV post-LT was 20% (n = 69) and 3% (n = 12) required tracheostomy. Independent risk factors (OR [95% CI]) for PMV were cirrhosis (3.8 [1-14], p = .04); age <1-year (8.2 [2-30], p = .001); need for preoperative CRRT (6.3 [1.2-32], p = .02); and MIH before LT (12.4 [2.1-71], p = .004). PROVE-ALT score ≥8 [Range = 0-21] accurately predicted PMV in the validation cohort with 73% sensitivity and 80% specificity (AUC: 0.81; 95% CI: 0.71-0.91). CONCLUSION: PROVE-ALT can predict PMV after pediatric LT with a high degree of sensitivity and specificity. Once externally validated in other centers, PROVE-ALT will empower clinicians to plan patient-specific ventilation strategies, provide parental anticipatory guidance, and optimize hospital resources.

Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK).

Introduction: Continuous renal replacement therapy (CRRT) is used for the symptomatic management of acute kidney injury (AKI) and fluid overload (FO). Contemporary reports on pediatric CRRT are small and single center in design. Large international studies evaluating CRRT practice and outcomes are lacking. Herein, we describe the design of a multinational collaborative. Methods: The Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK) is an international collaborative of pediatric specialists whose mission is to improve short- and long-term outcomes of children treated with CRRT. The aims of this multicenter retrospective study are to describe the epidemiology, liberation patterns, association of fluid balance and timing of CRRT initiation, and CRRT prescription with outcomes. Results: We included children (n = 996, 0-25 years) admitted to an intensive care unit (ICU) and treated with CRRT for AKI or FO at 32 centers (in 7 countries) from 2018 to 2021. Demographics and clinical characteristics before CRRT initiation, during the first 7 days of both CRRT, and liberation were collected. Outcomes include the following: (i) major adverse kidney events at 90 days (mortality, dialysis dependence, and persistent kidney dysfunction), and (ii) functional outcomes (functional stats scale). Conclusion: The retrospective WE-ROCK study represents the largest international registry of children receiving CRRT for AKI or FO. It will serve as a broad and invaluable resource for the field of pediatric critical care nephrology that will improve our understanding of practice heterogeneity and the association of CRRT with clinical and patient-centered outcomes. This will generate preliminary data for future interventional trials in this area.

Elevated bile acids are associated with left ventricular structural changes in biliary atresia.

BACKGROUND: In children with biliary atresia (BA), pathologic structural changes within the heart, which define cirrhotic cardiomyopathy, are associated with adverse perioperative outcomes. Despite their clinical relevance, little is known about the pathogenesis and triggers of pathologic remodeling. Bile acid excess causes cardiomyopathy in experimental cirrhosis, but its role in BA is poorly understood. METHODS: Echocardiographic parameters of left ventricular (LV) geometry [LV mass (LVM), LVM indexed to height, left atrial volume indexed to BSA (LAVI), and LV internal diameter (LVID)] were correlated with circulating serum bile acid concentrations in 40 children (52% female) with BA listed for transplantation. A receiver-operating characteristic curve was generated to determine optimal threshold values of bile acids to detect pathologic changes in LV geometry using Youden index. Paraffin-embedded human heart tissue was separately analyzed by immunohistochemistry for the presence of bile acid-sensing Takeda G-protein-coupled membrane receptor type 5. RESULTS: In the cohort, 52% (21/40) of children had abnormal LV geometry; the optimal bile acid concentration to detect this abnormality with 70% sensitivity and 64% specificity was 152 µmol/L (C-statistics=0.68). Children with bile acid concentrations >152 µmol/L had ∼8-fold increased odds of detecting abnormalities in LVM, LVM index, left atrial volume index, and LV internal diameter. Serum bile acids positively correlated with LVM, LVM index, and LV internal diameter. Separately, Takeda G-protein-coupled membrane receptor type 5 protein was detected in myocardial vasculature and cardiomyocytes on immunohistochemistry. CONCLUSION: This association highlights the unique role of bile acids as one of the targetable potential triggers for myocardial structural changes in BA.

The use of tracheostomy to support critically ill children receiving orthotopic liver transplantation: a single-center experience.

BACKGROUND: Children with end-stage liver disease and multi-organ failure, previously considered as poor surgical candidates, can now benefit from liver transplantation (LT). They often need prolonged mechanical ventilation (MV) post-LT and may need tracheostomy to advance care. Data on tracheostomy after pediatric LT are lacking. METHOD: Retrospective chart review of children who required tracheostomy in the peri-LT period in a large, freestanding quaternary children's hospital from 2014 to 2019. RESULTS: Out of 205 total orthotopic LTs performed in 200 children, 18 (9%) required tracheostomy in the peri-transplant period: 4 (2%) pre-LT and 14 (7%) post-LT. Among those 14 needing tracheostomy post-LT, median age was 9 months [IQR = 7, 14] at LT and 10 months [9, 17] at tracheostomy. Nine (64%) were infants and 12 (85%) were cirrhotic at the time of LT. Seven (50%) were intubated before LT. Median MV days prior to LT was 23 [7, 36]. Eight (57%) patients received perioperative continuous renal replacement therapy (CRRT). The median MV days from LT to tracheostomy was 46 [33, 56]; total MV days from initial intubation to tracheostomy was 57 [37, 66]. Four (28%) children died, of which 3 (21%) died within 1 year of transplant. Total ICU and hospital length of stay were 92 days [I72, 126] and 177 days [115, 212] respectively. Among survivors, 3/10 (30%) required MV at home and 8/10 (80%) were successfully decannulated at 400 median days [283, 584]. CONCLUSION: Tracheostomy though rare after LT remains a feasible option to support and rehabilitate critically ill children who need prolonged MV in the peri-LT period.

Population Pharmacokinetics of Vancomycin in Pediatric Extracorporeal Membrane Oxygenation.

OBJECTIVES: Describe the pharmacokinetics of vancomycin in pediatric patients undergoing extracorporeal membrane oxygenation and provide dosing recommendations to attain an area under the curve for 24 hours greater than 400 in this population. DESIGN: Retrospective, population pharmacokinetic analysis. SETTING: PICU of a large tertiary care children's hospital. INTERVENTIONS: Population pharmacokinetic analysis and simulation were performed with NONMEM v7.3 (Icon, PLC, Dublin, Ireland). PATIENTS: Patients less than 19 years old who received IV vancomycin and had serum vancomycin concentration monitoring while undergoing extracorporeal membrane oxygenation from January 1, 2011, to June 30, 2017. MEASUREMENTS AND MAIN RESULTS: A total of 93 patients met study criteria (male 51%, median age 0.64 yr [interquartile range 0.07-6.7 yr]). Mean estimated creatinine clearance was 65 ± 47 mL/min/1.73 m. Patients received 1,116 vancomycin doses (14.6 ± 1.9 mg/kg/dose) and had 433 vancomycin serum concentrations (13.6 ± 6.9 mg/L) at 13.2 ± 10.7 hours after a dose. A two-compartment pharmacokinetic model with allometrically scaled weight on clearance (0.75) and volumes of distribution (1) was developed. Serum creatinine, postmenstrual age were significant covariates for clearance, patient age for central volume of distribution, and albumin for peripheral volume of distribution. Simulation identified a doses of 25-30 mg/kg/dose every 12-24 hours as having the highest percentage of patients with an area under the curve for 24 hours greater than 400 with the highest percentage trough concentrations in the less than 15 mg/L range. CONCLUSIONS: A vancomycin dose of 25-30 mg/kg/dose every 12-24 hours with serum concentration monitoring is a reasonable empiric dosing strategy to obtain an area under the curve for 24 hours greater than 400 in pediatric extracorporeal membrane oxygenation patients.

Vancomycin-associated acute kidney injury in pediatric cardiac intensive care patients.

OBJECTIVE: Acute kidney injury (AKI) is a significant source of morbidity among critically ill pediatric patients, including those that have undergone cardiac surgery. Vancomycin may contribute to AKI in pediatric patients admitted to a cardiac intensive care unit. DESIGN AND SETTING: Patients admitted to the cardiac intensive care unit at Texas Children's Hospital and received vancomycin over a 4-year period were included in a case-control study. Patients were excluded if they underwent renal replacement therapy during vancomycin therapy. Patient demographic and disease state variables, vancomycin therapy variables, and use of other nephrotoxic medications were collected. The overall incidence of AKI was calculated based on doubling of serum creatinine during or within 72 hours of vancomycin therapy (vancomycin-associated AKI [vAKI]). Patients who developed vAKI were matched with three patients who did not develop vAKI, and conditional logistic regression was used to determine independent risk factors for vAKI. RESULTS: A total of 418 patients met study criteria (males 57.8%) and infants (31 days to 2 years) were the most populous age group (48.6%). Vancomycin-associated AKI occurred in 30 patients (7.2%), which resulted in a total of 120 patients (30 cases; 90 controls). No significant differences were noted in vancomycin dosing between groups. Vancomycin-associated AKI patients were less likely to have undergone cardiac surgery (P < .05), more likely to have undergone extracorporeal membrane oxygenation (P < .05), and had greater exposure to nephrotoxic medications (P < .05). A conditional logistic regression model identified extracorporeal membrane oxygenation as associated with vAKI (odds ratio 14.4, 95% confidence interval 1.02-203, P = .048) and patients with prior cardiovascular surgery (odds ratio 0.10, 95% confidence interval 0.02-0.51, P < .01) or an elevated baseline serum creatinine (odds ratio 0.009, 95% confidence interval 0.0002-0.29, P < .01) as less likely to develop vAKI. CONCLUSIONS: Vancomycin-associated AKI occurs infrequently in the pediatric cardiac intensive care population and is strongly associated with patient critical illness.

Fluid overload is associated with impaired oxygenation and morbidity in critically ill children.

RATIONALE: Fluid overload is common in the critically ill and is thought to contribute to oxygenation failure and mortality. Since increasing disease severity often requires more fluid for resuscitation, it is unclear whether fluid overload is a causative factor in morbidity or is simply an indicator of disease severity. OBJECTIVE: Investigate the association between fluid overload and oxygenation while controlling for severity of illness by daily Pediatric Logistic Organ Dysfunction scores. DESIGN AND SETTING: Retrospective chart review, tertiary children's hospital. PATIENTS AND METHODS: The oxygenation index, fluid overload percent, and daily Pediatric Logistic Organ Dysfunction scores were obtained in a retrospective chart review of 80 patients (mean age 58.7 ± 73.0 months) with respiratory failure. Univariate and multivariate approaches were used to assess the independent relation between fluid overload percent and duration of stay and ventilation. INTERVENTIONS: None. MAIN RESULTS: Higher peak fluid overload percent predicted higher peak oxygenation index, independent of age, gender, and Pediatric Logistic Organ Dysfunction (p = .009). Fluid overload percent ≥15% on any given day was also independently associated with that day's oxygenation index, controlled for age, gender, and Pediatric Logistic Organ Dysfunction (p < .05). Peak fluid overload percent and severe fluid overload percent (≥15%) were both independently associated with longer duration of ventilation (p = .004, p = .01), and pediatric intensive care unit (p = .008, p = .01) and hospital length of stay (p = .02, p = .04), controlled for age, gender, Pediatric Logistic Organ Dysfunction, and in the case of ventilation, respiratory admission. CONCLUSION: This is the first study to report that positive fluid balance adversely affected the pediatric intensive care unit course in children who did not receive renal replacement therapy. While timely administration of fluids is lifesaving, positive fluid balance after hemodynamic stabilization may impact organ function and negatively influence important outcomes in critically ill patients.

Urinary interleukin-18 is an acute kidney injury biomarker in critically ill children.

BACKGROUND: Urinary interleukin-18 (uIL-18) is an earlier acute kidney injury (AKI) biomarker than serum creatinine (SCr) in specific populations. In the present study, the relationship between uIL-18 and AKI was determined in a heterogeneous group of critically ill children. METHODS: We studied critically ill children to determine whether uIL-18 was an early predictor of AKI. SCr was determined daily for up to 14 days from mechanical ventilation initiation and up to four serial urine specimens were collected for the uIL-18 measurement. AKI was graded by paediatric modified risk, injury, failure, loss, end-stage kidney disease (pRIFLE) criteria. Day 0 was defined as the day of attaining pRIFLE AKI. RESULTS: One hundred thirty-seven children aged 6.5 +/- 6.4 years (53% male) were studied. The peak levels of IL-18 correlated with the severity of AKI by pRIFLE classification (P < 0.05). In non-septic AKI patients, uIL-18 rose to a level higher than control levels 2 days prior to a significant rise in SCr. Urinary IL-18 concentration from the first urine specimen was associated with AKI development within 48 h (odds ratio = 3.5, P < 0.05) independent of the paediatric risk of mortality (PRISM II) score. Urinary IL-18 concentration > or = 100 pg/ml had a specificity and negative predictive value of 81 and 83% to predict AKI development within 24 h. Urinary IL-18 > or = 200 pg/ml collected within 24 h of Day 0 had a specificity and positive predictive value of 93 and 88% respectively to predict the AKI duration > or = 48 h. Urinary IL-18 was associated with mortality (odds ratio = 1.29, P < 0.05), independent of the PRISM II score. CONCLUSIONS: Urinary IL-18 rises prior to SCr in non-septic critically ill children, predicts severity of AKI and is an independent predictor of mortality.

Urine neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in critically ill children: a prospective cohort study.

INTRODUCTION: Serum creatinine is a late marker of acute kidney injury (AKI). Urine neutrophil gelatinase-associated lipocalin (uNGAL) is an early marker of AKI, where the timing of kidney injury is known. It is unknown whether uNGAL predicts AKI in the general critical care setting. We assessed the ability of uNGAL to predict AKI development and severity in critically ill children. METHODS: This was a prospective cohort study of critically ill children. Children aged between 1 month and 21 years who were mechanically ventilated and had a bladder catheter inserted were eligible. Patients with end-stage renal disease or who had just undergone kidney transplantation were excluded. Patients were enrolled within 24 to 48 hours of initiation of mechanical ventilation. Clinical data and serum creatinine were collected daily for up to 14 days from enrollment, and urine was collected once daily for up to 4 days for uNGAL measurement. AKI was graded using pRIFLE (pediatric modified Risk, Injury, Failure, Loss, End Stage Kidney Disease) criteria. Day 0 was defined as the day on which the AKI initially occurred, and pRIFLEmax was defined as the worst pRIFLE AKI grade recorded during the study period. The chi2 test was used to compare associations between categorical variables. Mann-Whitney and Kruskal-Wallis tests were used to compare continuous variables between groups. Diagnostic characteristics were evaluated by calculating sensitivity and specificity, and constructing receiver operating characteristic curves. RESULTS: A total of 140 patients (54% boys, mean +/- standard deviation Pediatric Risk of Mortality II score 15.0 +/- 8.0, 23% sepsis) were included. Mean and peak uNGAL concentrations increased with worsening pRIFLEmax status (P < 0.05). uNGAL concentrations rose (at least sixfold higher than in controls) in AKI, 2 days before and after a 50% or greater rise in serum creatinine, without change in control uNGAL. The parameter uNGAL was a good diagnostic marker for AKI development (area under the receiver operating characteristic curve [AUC] 0.78, 95% confidence interval [CI] 0.62 to 0.95) and persistent AKI for 48 hours or longer (AUC 0.79, 95% CI 0.61 to 0.98), but not for AKI severity, when it was recorded after a rise in serum creatinine had occurred (AUC 0.63, 95% CI 0.44 to 0.82). CONCLUSION: We found uNGAL to be a useful early AKI marker that predicted development of severe AKI in a heterogeneous group of patients with unknown timing of kidney injury.